Cephalosporin intermediates
This is a division of application Ser. No. 07/409,290, filed Sep. 19, 1989, now U.S. Pat. No. 5,049,558, issued Sep. 17, 1991, which is a continuation of application Ser. No. 06/738,646 filed May 28, 1985 now abandoned. 
    
    
     This invention relates to cephalosporin derivatives which have antibacterial activity. 
     According to the invention there is provided a cephalosporin derivative of the formula I: 
     
         [Formula I--given hereafter] 
    
     in which X is sulphur, oxygen, methylene or sulphinyl (R or S configuration); 
     R1 is 2-aminothiazol-4-yl or 2-aminooxazol-4-yl each optionally substituted in the 5-position by fluorine, chlorine or bromine, or R1 is 5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl, 3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl, 2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2-amino- 3,4-thiadiazol-5-yl or 5-amino-l-methyl-1,2,4-triazol-3-yl; 
     R50 is chloromethylene or a radical of the formula ═N.O.R2, wherein R2 is hydrogen, (1-6C)alkyl, (3-8C)cyclo-alkyl, (1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl, optionally substituted by carboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl, (2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, (1-4C)alkylcarbamoyl(1-4C)alkyl, di(1-4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)haloalkylcarbamoyl(1-4C)alkyl, triphenylmethyl, (1-3C)haloalkyl, (2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (1-4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl, (1-4C)alkane-sulphonyl(1-4C)alkyl, (2-6C)aminoalkyl, (1-4C)alkyl-amino(1-6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl, (1-5C)cyanoalkyl, 3-amino-3-carboxypropyl, 2-(amidinothio)ethyl, 2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl, or 2-oxotetrahydrofuran-3-yl, 
     or --R2 is the formula --(CH 2 ) n  --R6 in which n is 1 to 4 and R6 is piperidino, pyrrolidino, morpholino, piperazino or N-methylpiperazino, each value of R6 being optionally substituted by (1-4C)alkyl, phenyl or benzyl, 
     or --R2 is of the formula --(CH 2 ) m  --W--R7 in which m is 0 to 3, W is sulphur or a direct bond, and R7 is phenyl or pyridinio(1-4C)alkylene or R7 is pyridyl, imidazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1-(1-4C)alkyltetrazolyl, thiazolyl, isothiazolyl or isoxazolyl in which the link with W is via a carbon or uncharged nitrogen, each value of R7 being optionally substituted, where possible, by one or two groups selected from (1-4C)alkyl, amino, hydroxy, carboxy, carbamoyl, nitro, (2-5C)alkoxycarbonyl, cyano or sulpho, 
     or --R2 is of the formula --(CH 2 ) n  --CO--R8 in which n is 1 to 4 and R8 is (1-4C)alkyl, phenyl or benzyl, 
     or --R2 is of the formula --COR9 or --(CH 2 ) n  --OCO--R9 in which n is 1-4 and R9is hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, phenyl or benzyl, 
     or --R2 is of the formula --G--CH 2  --R10 in which G is carbonyl or a direct bond and R10 is phthalimido, 
     or --R2 is of the formula --NR11R12R13 in which R11, R12 and R13 are (1-4C)alkyl, or R11 is (1-4C)-alkyl and R12 and R13 are joined to form a (3-6C)carbocyclic ring, or R11, R12 and R13 are joined to form a 1-azonia-4-azabicyclo[2,2,2]octane or 1-azonia-3,5,7-triazatricyclo[3,3,1,1 3 ,7 ]decane, 
     or --R2 is of the formula II 
     
         [Formula II] 
    
     in which p is I or 2 and R14 and R15 are hydrogen or (1-4C)alkyl, 
     or --R2 is of the formula --P(O)R16R17 in which R16 is hydroxy, (1-4C)alkoxy, (2-8C)dialkylamino, phenoxy, phenylamino or one of the values given above for R6, and R17 is (1-4C)alkyl, (1-4C)alkoxy (2-8C)-dialkylamino, phenoxy, phenylamino, piperidino, pyrrolidino, morpholino, piperazino or N-methylpiperazino, 
     or --R2 is of the formula --CH 2  P(O)R18R19 in which R18 and R19 are hydroxy or (1-4C)alkoxy, 
     or --R2 is of the formula --CH(SR20)COOR21 in which R20 is (1-4C)alkyl and R21 is hydrogen or (1-6C)alkyl, 
     or --R2 is of the formula III: 
     
         [Formula III] 
    
     in which m is 0-3, R22 is hydrogen, (1-3C)alkyl or methylthio, R23 is hydrogen, (1-3C)alkyl, (C3-C7)cycloalkyl, cyano, carboxy, (2-5C)carboxyalkyl or methanesulphonylamino, or phenyl optionally substituted by amino or hydroxy, or R22 and R23 are joined to form, together with the carbon to which they are attached, a (3-7C) carbocyclic ring, and R24 is hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino, phenylamino or of the formula R6 given above or of the formula NHOR25 in which R26 is hydrogen, (1-4C)alkyl, phenyl or benzyl, provided that when R2 contains phenyl, and unless otherwise stated, the phenyl is optionally substituted by 1 or 2 groups selected from halogen, hydroxy, amino, carboxy, nitro, carbamoyl, cyano and aminomethyl; 
     R3 is hydrogen or methoxy; 
     R4 is hydrogen, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carboxy (1-4)alkyl, amino (1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl, benzyl or pyridyl(1-4C)alkyl; 
     R5 is an aromatic heterocyclic ring system which is linked via carbon and is one of the formula IV to LI inclusive each of these ring systems being optionally substituted where possible, on a carbon atom or atoms, by one, two or three substituents selected from halogen, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbonyl, (2-6C)- alkoxycarbonyl(1-4C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, cyano, (2-4C)cyanoalkyl, amino, (1-6C)alkylamino, (2 8C)dialkylamino, benzylamino (optionally substituted in the benzene ring thereof by nitro), thenylamino, allylamino, (1-6C)aminoalkylamino, (1-6C)alkoxy(1-6C)alkylamino, (1-6C)hydroxyalkylamino, hydroxy, mercapto, carbamoyl, (2-6C)alkylcarbamoyl, (3-10C)dialkylcarbamoyl, phenylthio and heteroarylthio wherein heteroaryl is a 5- or 6-membered ring containing 1, 2 or 3 hetero atoms selected from oxygen, nitrogen and sulphur; 
     and in which Y is oxygen, sulphur or NR27; 
     Z is nitrogen or CH; 
     one of A, B, D and E is +NR27 and the remainder are nitrogen; 
     and ring systems of Formula IV, XVI or XVII, which are optionally fused, on a carbon-carbon bond, with a 5- to 7-membered saturated carbocyclic ring; 
     R27 is nitrogen-linked and is (1-6C)alkyl, (1-6C)alkyl(2-6C)alkenyl, (2-6C)alkenyl, (2-8C)alkoxyalkyl, carboxy(1-6C)alkyl, [(1-6C)alkoxy]carbonyl(1-6C)alkyl, carbamoyl(1-6C)alkyl, carboxyamino-carbonyl(1-6C)alkyl, [(1-6C)alkoxy]carbonylamino-carbonyl(1-6C)alkyl, [(2-8C)alkanoyl]methyl, benzoylmethyl, (1-6C)hydroxyalkyl, (1-6C)alkylamino, or phenyl(1-6C)alkyl or phenyl, each optionally substituted by 1 or 2 groups selected from halogen, hydroxy, amino, carboxy, nitro, carbamoyl, cyano, trifluoromethyl, and aminomethyl; 
     R26 is hydrogen, (1-6C)alkyl, phenyl or benzyl; 
     R28 is cyano(3-6C)cycloalkenyl, or phenyl optionally substituted by 1 or 2 groups selected from halogen, nitro, amino, (1-4C)alkanoyl, (1-4C)alkanoylamino, halo(1-4C)alkyl, hydroxy, carboxy, (2-6C)alkoxycarbonyl, carbamoyl, mono- or di(1-4C)alkylcarbamoyl, cyano, mesyl, vinyl, and sulpho; or R28 is (2-6C)alkenyl, optionally substituted by halogen, cyano, carbamoyl, mono- or di(1-4C alkyl)carbamoyl, piperidinocarbonyl or morpholinocarbonyl, cyano(1-4C)alkyl, 2-ureidoethyl, 2-thioureidoethyl, 2-(thioacetyl-amino)ethyl, sulphamoyl, 2-amino-2-carboxyethyl, acetylaminomethyl, phthalimidomethyl, 4,5-dihydroimidazo1-2-ylmethyl, 3,4,5,6-tetrahydro-pyrimidin-2-ylmethyl, 2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl, 2-hydroxyiminopropyl (syn or anti) or 2-[(1-4C)alkoxyimino]propyl (syn or anti), 
     or --R28 is of the formula --(CH 2 ) 2  --NR29R30R31 in which R29, R30 and R31 are (1-4C)alkyl, or --R28 is of the formula --(CH 2 ) q  --R32 in which q is 0-2 and --R32 is pyridine, pyridazine, pyrimidine, pyrazine, 1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 2-[(1-4C)alkyl]-1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 1-[(1-4C)alkyl]tetrazole, furan, thiophene, pyrrole, 1-[(1-4C)alkyl]pyrrole, oxazole, thiazole, imidazole, 1-[(1-4C)alkyl]imidazole, isoxazole, isothiazole, pyrazole, 1,2,3-thiadiazole, 1-[(1-4C)alkyl]pyrazole, benzfuran, benzthiophene, indole, oxindole, 1-[(1-4C)alkyl]indole, benzoxazole, benzthiazole, benzimidazole, 1-[(1-4C)alkyl]benzimidazole, 3,4-dihydro-4-oxo-2H-benzo[e]oxazine each of these ring systems being linked to (CH 2 ) q  through carbon and each ring system being optionally substituted by halogen, amino, (1-6C)alkyl, (1-4C)-haloalkyl, (3-6C)cycloalkyl, (2-6C)alkenyl, carboxy, (2-6C)alkoxycarbonyl, (1-6C)alkoxy, cyano, (2-6C)cyanoalkenyl, carbamoyl, mono- or di (1-4C)alkylcarbamoyl, (1-4C)alkanoylamino, guanidino, hydroxy, nitro, amino; and for those ring systems which contain nitrogen, the N-oxides thereof where chemically possible; 
     or, when R4 is hydrogen then R5 is also a radical of the formula LI: 
     
         [Formula LI] 
    
     in which R28 is 2-guanidino-thiazol-4-ylmethyl, hydroxybenzoyl-methyl, 2-thenyl, 2-imidazolylmethyl or cinnamyl, optionally substituted by halogen, (1-6C)alkyl, hydroxy, (1-4C)alkoxy, carboxy, (2-6C)alkoxycarbonyl, nitro or carbamoyl, 
     and when R4 is other than hydrogen then R5 is also a radical of the formula LII in which ring J is pyridine, pyrimidine, oxazole, thiazole, isoxazole, isothiazole or imidazole to each of which is optionally fused, when possible, a benzene, cyclopentane or cyclohexane ring; 
     R33 is hydrogen, amino, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)alkenyl, (2-8C)alkoxyalkyl, --(CH 2 ) t  --COOR35, --(CH 2 ) t  --CONH 2 , --(CH 2 ) t  --NHCO--R36 or --(CH 2 ) t  S(O) s  --R36 in which t is 1-6, R35 is hydrogen or (1-6C)alkyl, s is 0, 1 or 2, and R36 is (1-6C)alkyl or (1-6C)alkoxy, 
     or R33 is (3-8C)alkanoylmethyl, benzoylmethyl, (1-6C)primaryhydroxyalkyl, (1-6C)primaryaminoalkyl, (1-4C)alkylamino(1-6C)alkyl, di(1-4C)alkylamino(1-6C)alkyl, carbamoyl(1-4C)alkyl, mono- or di(1-4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-6C)alkoxy, (1-4C)alkoxy(2-4C) alkoxy(1-4C)alkyl, (1-6C)alkylamino, phenyl(1-6C)alkyl or phenyl(1-6C)alkoxy or of the formula (CH 2 ) 2  N═CR37NR38R39 or (CH 2 ) n  C(NR37)NR38R39 or a tautomer thereof in which R37, R38 and R39 are hydrogen or (1-4C)alkyl; 
     R34 is hydrogen or one or two substituents selected from halogen, amino, nitro, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbcnyl, (1-6C)alkoxy, cyano, carbamoyl, (1-6C)haloalkyl, (1-6C)azidoalkyl, (1-6C)aminoalkyl, (2-4C)aminoalkylthio(1-4C)alkyl, (2-6C)alkanoylamino, (2-4C)alkanoylamino(1-4C)alkyl, (2-6C)alkanoyloxy(1-4C)alkyl, benzyl, benzyloxy and heteroarylthio, 
     wherein, when R33 contains phenyl, the phenyl is optionally substituted by halogen, nitro, (1-6C)alkyl, hydroxy, (1-4C)alkoxy, carboxy, (2-6C)alkoxycarbonyl, carbamoyl, sulphamoyl, sulpho, mono- or di(1-4C)alkylcarbamoyl, or mono- or di-(1-4C)alkylsulphamoyl, and wherein when R34 is heteroarylthio, the heteroaryl ring is a 5- or 6-membered ring containing 1,2 or 3 hetero atoms selected from oxygen, nitrogen and sulphur; 
     and the salts formed with acids and bases which afford pharmaceutically acceptable anions and cations respectively. 
     It is to be understood that in the above formula I and throughout this specification, the illustrated stereochemistry of the ceph-3-em nucleus, and its optional modifications at the 1-position, is the absolute configuration. It is also to be understood that, since R5 contains a quaternary nitrogen, the compounds of the formula I will normally exist in zwitter-ionic form, involving the quaternary nitrogen and the carboxy group. When the compound of the formula I contains further acidic or basic substituents, it is to be understood that the possibility of a double zwitter-ionic form of the compound will arise. Alternatively, exogenous anions or cations may be included, to form pharmaceutically-acceptable base-addition or acid-addition salts, as defined above. 
     A particular value for R2 is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl, cyclopentenyl, cyclohexenyl, propargyl, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, triphenylmethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methylthioethyl, 2-methanesulphinylethyl, 2-methanesulphonylethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 2-dimethylaminoethyl, cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, ureidomethyl, 3-amino-3-carboxypropyl, 2-(amidino)ethyl, 2-(N-aminoamidino)ethyl, tetrahydropyran-2-yl, thietan-3-yl or 2-oxo-tetrahydrofuran-3-yl, 
     or, when R2 is of the formula --(CH 2 ) n  --R6 in which n is 1 to 4 and R6 is piperidino, pyrrolidino, morpholino, piperazino or N-methylpiperazino, a particular value of R2 is when each value of R6 is optionally substituted by methyl, phenyl or benzyl, 
     or, when R2 is of the formula --(CH 2 ) m  --W--R7 in which m is 0 to 3, W is sulphur or a direct bond, particular values for R2 are when R7 is phenyl, pyridiniomethylene, 2-pyridinioethylene or R7 is pyridyl, imidazolyl, 1,3,4-thiadiazolyl, tetrazolyl, 1-methyltetrazolyl, thiazolyl, isothiazolyl or isoxazolyl in which the link with W is via a carbon or uncharged nitrogen, each value of R7 being optionally substituted, where possible, by one or two groups selected from methyl, amino, hydroxy, carboxy, carbamoyl, nitro, methoxycarbonyl, ethoxycarbonyl, cyano or sulpho, 
     or, when R2 is of the formula --(CH 2 ) n  --CO--R8 in which n is 1 to 4, a particular value for R2 is when R8 is methyl, ethyl, phenyl or benzyl, 
     or, when R2 is of the formula --COR9 or --(CH 2 ) n  --OCO--R9 in which n is 1-4, a particular value for R2 is when R9 is hydrogen, methyl, chloromethyl, bromomethyl, 2-chloroethyl, 2-bromoethyl, phenyl or benzyl, 
     or, when R2 is of the formula --G--CH 2  --R10, a particular value for R2 is when G is carbonyl or a direct bond and RIO is phthalimido, 
     or, when R2 is of the formula --NR11R12R13, a particular value for R2 is when R11, R12 and R13 are methyl or ethyl, or R11 is methyl or ethyl and R12 and R13 are joined to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, or R11, R12 and R13 are joined to form a 1-azonia-4-azabicyclo[2,2,2]octane or 1-azonia-3,5,7-triazatricyclo[3,3,1,1 3 ,7 ]decane, 
     or, when R2 is of the formula II: 
     
         [Formula II] 
    
     in which p is 1 or 2, a particular value for R2 is when and R14 and R15 are hydrogen or methyl, 
     or when R2 is of the formula --P(O)R16R17, a particular value for R2 is when R16 is hydroxy, methoxy, ethoxy, dimethylamino, diethylamino, phenoxy, phenylamino, or one of the particular values given above for R6, and R17 is methyl, ethyl, methoxy, ethoxy, dimethylamino, diethylamino, phenoxy, phenylamino, piperidino, pyrrolidino, morpholino, piperazino or N-methylpiperazino, 
     or, when R2 is of the formula --CH 2  P(O)R18R19, a particular value for R2 is when R18 and R19 are hydroxy, methoxy or ethoxy, 
     or, when R2 is of the formula --CH(SR20)COOR21, a particular value for R2 is when R20 is methyl or ethyl and R21 is hydrogen, methyl, ethyl or isopropyl, 
     or, when R2 is of the formula III: 
     
         [Formula III] 
    
     in which m is 0-3, a particular value for R2, when m=0, is when R22 is hydrogen, methyl or methylthio, R23 is hydrogen, methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyano, carboxy, carboxymethyl, 2-carboxyethyl or methanesulphonylamino, or phenyl optionally substituted by amino or hydroxy, or R23 and R24 are joined to form, together with the carbon to which they are attached, a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane ring and R25 is hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino, phenylamino or one of the particular values for R6 given above or of the formula NHOR25 in which R25 is hydrogen, methyl, ethyl, phenyl or benzyl, 
     provided that when R2 contains phenyl, and unless otherwise stated above, the phenyl is optionally substituted by 1 or 2 groups selected from fluorine, chlorine, bromine, hydroxy, amino, carboxy, nitro, carbamoyl, cyano and aminomethyl. 
     A particular value for R3 is hydrogen or methoxy. 
     A particular value for R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxymethyl, 2-methoxyethyl, carboxymethyl, (R) and (S)-1-carboxyethyl, 2-aminoethyl, 2-cyanoethyl, 2-formamidoethyl, allyl, furfuryl, benzyl or 4-pyridylmethyl. 
     A particular value for an optional substituent on one of the ring systems of the formula IV to LI inclusive is one, two or three substituents selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy, ethoxy, methylthio, ethylthio, cyano, cyanomethyl, 2-cyanoethyl, amino, methylamino, ethylamino, isopropylamino, dimethylamino, benzylamino, (optionally substituted in the benzene ring by nitro), allylamino, 2-aminoethyl-amino, 2-methoxyethylamino, 2-hydroxyethylamino, hydroxy, mercapto, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, phenylthio and heteroarylthio in which the heteroaryl ring is a furan, thiophene, imidazole, thiazole, pyrazole, thiadiazole, pyridine, pyrimidine, pyrazine or pyridazine. 
     A particular value for R27 is methyl, ethyl, n-propyl, isopropyl, allyl, methoxymethyl, 2-methoxyethyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, carbamoylmethyl, 2-carbamoylethyl, carboxyaminocarbonylmethyl, 2-(carboxyaminocarbonyl)ethyl, methoxycarbonylaminocarbonylmethyl, 2-(methoxycarbonylaminocarbonyl)ethyl, acetylmethyl, propionylmethyl, benzoylmethyl, hydroxymethyl, 2-hydroxyethyl, methylamino, ethylamino, benzyl or 2-phenethyl, or phenyl optionally substituted by 1 or 2 groups selected from fluorine, chlorine, bromine, hydroxy, amino, carboxy, nitro, carbamoyl, cyano, trifluoromethyl and aminomethyl. 
     A particular value for R26 is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl or benzyl. 
     A particular value for R28 is 3-cyanocyclopent-2-enyl or phenyl optionally substituted by 1 or 2 groups selected from fluorine, chlorine, bromine, nitro, amino, acetyl, acetamido, trifluoromethyl, hydroxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyano, mesyl and sulpho, 
     or vinyl, 2,4-pentadienyl, 3-chloroallyl (cis and trans), 3-cyanoallyl, cyanomethyl, 3-cyanopropyl, 2-ureidoethyl, 2-thioureidoethyl, 2-(thioacetylamino)ethyl, sulphamoyl, 2-amino-2-carboxyethyl, acetylaminomethyl, phthalimidomethyl, 4,5-dihydroimidazol-2-ylmethyl, 3,4,5,6-tetrahydropyrimidin-2-ylmethyl, 2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl, 2-hydroxyiminopropyl (syn or anti), 2-(mathoxyimino)propyl (syn or anti) or 2-(ethoxyimino)propyl (syn or anti), 
     or of the formula --(CH 2 ) 2  --NR29R30R31 in which R29, R30 and R31 are methyl or ethyl, 
     or of the formula --(CH 2 ) q  --R32 in which q is 0-2 and R32 is pyridine, pyridazine, pyrimidine, pyrazine, 1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 2-(methyl or ethyl)-1,2,5,6-dihydro-5,6-dioxo-1,2,4-triazine, 1-(methyl or ethyl)tetrazole, furan, thiophene, pyrrole, 1-(methyl or ethyl)pyrrole, oxazole, thiazole, imidazole, 1-(methyl or ethyl)imidazole, isoxazole, isothiazole, pyrazole, 1-(methyl or ethyl) pyrazole, 1,2,3-thiadiazole, benzfuran, benzthiophene, indole, 1-(methyl or ethyl)indole, benzoxazole, benzthiazole, benzimidazole, 3,4-dihydro-4-oxo-2H-benzo[eloxazine, 1-(methyl or ethyl)benzimidazole, each of these ring systems being linked to (CH 2 ) q  through carbon and each ring system being optionally substituted by fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropylmethyl, formamido, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxy, ethoxy, cyano, 3-cyanoallyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, hydroxy, guanidino, nitro, amino and for those ring systems which contain nitrogen, the N-oxides thereof where chemically possible; 
     or, when R4 is hydrogen --R28 is 2-guanidinothiazol-4-ylmethyl, 3-hydroxybenzoylmethyl, 2-thenyl, 2-imidazolylmethyl or cinnamyl, optionally substituted by fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl or carbamoyl; 
     and when R4 is other than hydrogen, a further particular value for R5 is of the formula LI: 
     
         [Formula LII] 
    
     in which ring J is pyridine, pyrimidine, oxazole, thiazole, isoxazole, isothiazole or imidazole to each of which is optionally fused, when possible, a benzene, cyclopentane or cyclohexane ring. 
     A particular value for R33 is hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, allyl, 3-chloroallyl (cis or trans) methoxymethyl, --(CH 2 ) t  --COOR35, (CH 2 ) t  --CONH 2 , (CH 2 ) t  --NH--CO--R36 or --(CH 2 ) t  S(O) s  --R36 in which t is 1-6, R35 is hydrogen, methyl or ethyl, s is 0, 1 or 2 and R36 is methyl, ethyl, methoxy or ethoxy, 
     or acetylmethyl,propionylmethyl, benzoylmethyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, carbamoylmethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, 2-methoxymethyl, methoxy, ethoxy, 2-methoxyethoxymethyl, methylamino, ethylamino, benzyl, 2-phenethyl, 2-(3,4-dihydro-4-oxo-H-benzo[e]- oxazin-2-yl)ethyl, benzyloxy or 2-phenylethoxy or of the formula (CH 2 ) 2  --N═CR37NR38R39 or (CH 2 ) 2  C(N37)NR38R39 in which R37, R33 and R39 are hydrogen or methyl, wherein when R33 contains phenyl the phenyl is optionally subtituted by fluorine, chlorine, bromine, methyl, ethyl, hydroxy, methoxy, ethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, sulpho, carbamoyl, methylcarbamoyl or dimethylcarbamoyl. 
     A particular value for R34 is hydrogen or one or two substituents selected from fluorine, chlorine, bromine, amino, nitro, methyl, ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxy, ethoxy, cyano, carbamoyl, chloromethyl, 2-chloroethyl, azidomethyl, aminomethyl, 2-aminoethyl, 2-aminoethylthiomethyl, acetylamino, propionylamino, acetylaminomethyl, acetoxymethyl, benzyl, benzyloxy, 2-thenylamino or heteroarylthio and in which when R34 is heteroarylthio the heteroaryl ring is furan, thiophene, pyrrole, imidazole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, thiadiazole, pyridine, 
     A particular acid which affords a pharmaceutically-acceptable anion is, for example, hydrochloric, hydrobromic, phosphoric, sulphuric, citric or maleic acid. 
     A particular base which affords a pharmaceutically acceptable cation is, for example, a base containing an alkali metal, (e.g. sodium or potassium) or an alkaline earth metal (e.g. calcium or magnesium), or a primary, secondary or tertiary organic amine (e.g. triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine or N,N&#39;-dibenzylethylenediamine), or other amine which has been used to form salts with cephalosporins. 
     The following are preferred features of the cephalosporin derivative of the invention. When any one of these features is taken, either singly or in combination, with the other general or particular features of the cephalosporin derivative of the invention listed above, there are obtained preferred sub-groups of compounds. 
     1. X is sulphur. 
     2. R1 is 2-aminothiazol-4-yl or 5-amino-1,2,4-thiadiazol-3-yl. 
     3. R50 is chloromethylene. 
     4. R50 is ═N.OR2 in which R2 is (1-6C)alkyl, (3-6)alkenyl optionally substituted by carboxy, (3-6C)alkynyl, (3-8C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (1-4C)haloalkyl, (1-5C)cyanoalkyl, (2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (2-6C)aminoalkyl or benzyl. 
     5. R2 is methyl, ethyl, i-propyl, allyl, propargyl, cyclopentyl, cyclopropylmethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, cyanomethyl, 2-cyanoethyl, 2-hydroxyethyl, 2-ethoxyethyl or benzyl. 
     6. R2 is of the formula III. 
     7. In formula III, m is 0. 
     8. In formula III, R24 is hydroxy or (1-4C)alkoxy. 
     9. In formula III, R22 and R23 are both hydrogen or (1-3C)alkyl, or R22 and R23 are joined to form, together with the carbon to which they are attached, a (3-7C) carbocyclic ring. 
     10. In formula III, R22 and R23 are both hydrogen or methyl, or R22 and R23 are joined to form, together with the carbon to which they are attached, a cyclobutane or cyclopentane ring. 
     11. R5 is of the formula XVI, XXVIII, XLII, XLIII, XLVI, XLVII or LI, each of these ring systems being optionally substituted, where possible, on a carbon atom or atoms, by one or two substituents selected from halogen, (1-6C)alkyl, carboxy, (2-6C)alkoxycarbonyl(1-4C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, amino, (1-6C)alkylamino, (2-8C)dialkylamino, benzylamino, optionally substituted in the benzene ring thereof by nitro, allylamino, (1-6C)aminoalkylamino, (1-6C)- alkoxy(1-6C)alkylamino, (1-6C)hydroxyalkylamino and hydroxy. 
     12. In formulae XVI, XXVIII, XLII, XLIII, XLVI and XLVII, the ring substituents are selected from chlorine, fluorine, methyl, ethyl, n-propyl, isopropyl, carboxy, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxy, ethoxy, methylthio, amino, isopropylamino, dimethylamino, p-nitrobenzylamino, allyamino, 2-aminoethylamino, 2-methoxyethylamino, 2-hydroxyethylamino and hydroxy. 
     13. In formulae XVI, XXVIII and XLVII, R27 is (1-6C)alkyl, allyl or phenyl optionally substituted by nitro or trifluoromethyl. 
     14. In formulae XLII and LI, R28 is phenyl optionally substituted by 1 or 2 groups selected from halogen, nitro, amino, (1-4C)alkanoyl, (1-4C)alkanoylamino, (1-4C)haloalkyl, hydroxy, (2-6C)alkoxycarbonyl, carbamoyl, mono- or di(1-4C)alkylcarbamoyl, cyano, mesyl and vinyl. 
     15. In formulae XLII and LI, the substituents in R28, when R28 is phenyl, are selected from chlorine, fluorine, nitro, amino, acetyl, acetamido, trifloromethyl, hydroxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, cyano, mesyl and vinyl. 
     16. In formulae XLII and LI, R28 is (2-6C)alkenyl, optionally substituted by halogen or cyano, cyano(1-4C)alkyl, phthalimidomethyl or 2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl. 
     17. In formulae XLII and LI, R28 is vinyl, 2,4-pentadienyl, 3-cyanopropyl, 3-chloroallyl, 3-cyanoallyl, phthalimidomethyl or 2-(1,2,3,6-tetrahydro-2,6-dioxopurin-7-yl)ethyl. 
     18. In formulae XLII and LI, R28 is of the formula (CH 2 ) q  --R32, wherein q is 0 or 1 and R32 is pyridine, pyridine-N-oxide, pyridazine, pyrazine, pyrazine-N-oxide, pyrimidine, furan, thiophene, thiazole, imidazole, 1,2,3-thiadiazole, oxazole, oxindole, benzimidazole or 3,4-dihydro-4-oxo-2H-benzo[e]-oxazine, optionally substituted by halogen, amino, (1-6C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl, (2-6C)alkoxycarbonyl, cyano, (2-6C)cyanoalkenyl, carbamoyl, mono- or di(1-4C)alkylcarbamoyl, (1-4C)alkanoylamino, guanidino, hydroxy, nitro or amino. 
     19. The substituent in R32 is chlorine, fluorine, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, methoxycarbonyl, ethoxycarbonyl, cyano, 3-cyanoallyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, formamido, guanidino, hydroxy, nitro or amino. 
     20. In formula LII, R33 is (1-6C)alkyl and R34 is hydrogen. 
     21. R33 is methyl or ethyl. 
     22. R4 is hydrogen, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carboxy(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanoylamino(1-4C)alkyl, allyl, furfuryl, benzyl or pyridyl (1-4C)alkyl. 
     23. R4 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, carboxymethyl, 2-aminoethyl, 2-cyanoethyl, 2-formamidoethyl, allyl, furfuryl, benzyl or 4-pyridylmethyl. 
     24. R5 is of the formula XVI, XXVIII, XLII, XLIII, XLVI, LI or LII. 
     25. R5 is of the formula XVI wherein the ring is substituted by (1-6C)alkyl and/or amino. 
     26. R5 is of the formula XXVIII wherein Y is sulphur, Z is CH and R27 is (1-6C)alkyl, particularly methyl. 
     27. R5 is of the formula XLII wherein R29 is (2-6C)alkenyl, optionally substituted by cyano or halogen, particularly chlorine, or R28 is (CH 2 ) q  R32 in which q is 1 and R32 is 1,2,3-thiadiazole, thiophen or thiazole optionally substituted by guanidino or cyano. 
     28. R5 is of the formula XLIII wherein Y is sulphur. 
     29. R5 is of the formula XLVI wherein the optional bond is a double bond. 
     30. R5 of the formula LI wherein R28 is (CH 2 ) q  R32 in which q is 1 and R32 is thiophen. 
     31. R5 is of the formula LII wherein ring J is pyridine, R33 is amino, (1-6C)alkyl, (1-6C)primary-aminoalkyl, or benzyl optionally substituted by nitro, and R34 is hydrogen or (1-6c)alkyl. 
     Particular compounds of the invention are described in the Examples, and of these, the group consisting compounds of Examples 37, 55, 60, 64, 66, 71, 81, 87, 88, 95, 96, 104, 110, 111, 149, 150, 151, 153, 177, 178, 184, 185, 188, 195, 202, 209, 213, 215, 218, 219, 225, 226, 232, 244, 249, 251, 255, and 261 is preferred. A more preferred group consists of the compounds of Examples 37, 55, 60, 64, 66, 71, 88, 96, 104, 110, 149, 150, 153, 178, 184, 213, 219, 225, 244, 249, 255, and 261. Within this group, the compounds of Examples 60, 66, 104, 110, 184, 188, 219, 225, 255 and 261 are particularly preferred, and of these the compounds of Examples 110, 184, 219 and 225 are especially preferred. 
     The cephalosporin derivatives of the formula I may be manufactured by methods known in themselves for the manufacture of chemically analogous compounds. The for following processes, R1, R2, R3, R4, R5, R50 and X having the meanings stated above, unless indicated otherwise, and therefore provided as further features of the invention. 
     The process of the invention is characterised by 
     (a) reaction of a compound of the formula LIII 
     
         [Formula LIII] 
    
      with a compound of the formula R5-R40 in which R40 is a displaceable radical [e.g. fluorine, chlorine, bromine, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkanesulphinyl or (1-6C)alkanesulphonyl]. 
     (b) reaction of a compound of the formula LIV: 
     
         [Formula LIV] 
    
      with an acid of the formula LV: 
     
         [Formula LV] 
    
      or an activated derivative thereof. 
     (c) deprotection, to form carboxy, of the corresponding compound which carries a protecting group in place of the acidic hydrogen atom of the carboxy 
     (d) deprotection, to form a primary or secondary amino, of the corresponding compound which carries a protecting group in place of the amino hydrogen. 
     (e) for those compounds in which X is sulphinyl, oxidation of the corresponding compound in which X is sulphur. 
     (f) reaction of a compound of the formula LVI 
     
         [Formula LVI] 
    
      with a compound of the formula R2--O--NH 2 . 
     (g) for those compounds in which R2 is other than hydrogen, reaction of a compound of the formula I in which R2 is hydrogen with a compound of the formula R41-R40 in which R40 is a displaceable radical and R41 is one of the values given above for R2, other than hydrogen. 
     (h) for those compounds which contain an aminophenyl group, the reduction of the corresponding nitrophenyl compound. 
     (i) the reaction of a compound of the formula LVIII, wherein R40 is a displaceable radical, with a compound of the formula R4R5NH. 
     When the process of the invention manufacture the compound of the formula I in the form of the zwitterion, and a salt is required, the compound of the formula I in the zwitterionic form is reacted with an acid which affords a pharmaceutically-acceptable anion, or with a base which affords a pharmaceutically-acceptable cation. 
     The starting material of the formula LIII may be prepared by acylation of the appropriate 7-amino-3-azidomethylcephalosporin derivative with an acid of the formula LV, or an activated derivative thereof, followed by reduction of the 3-azidomethyl group to the 3-aminomethyl group. During this process it may be necessary to protect amino and carboxy groups. There is thus obtained the compound of the formula LIII in which R4 is hydrogen. This procedure is illustrated in Examples 1-4, 5-6, 7-14 and 15-16. When R4 is other than hydrogen, the compound in which R4 is hydrogen is then alkylated or benzylated. 
     The starting material of the formula LIV may be prepared by reaction of the compound of the formula LVII: 
     
         [Formula LVII] 
    
     with a compound of the formula R5-R40 in which R40 is a displaceable radical. During this reaction it may be necessary to protect the 7-amino and/or 3-carboxy group. 
     The starting material of the formula LIV in particularly valuable and is regarded as a further feature of the invention. 
     The starting materials of the formulae LV, LVI, LVII and LVIII are prepared by conventional methods known in the chemical literature for analogous compounds. 
     As noted above the cephalosporin derivatives of the invention have antibacterial properties. Thus they are useful antibacterial agents, many of them having a broad spectrum of activity in vitro against standard laboratory microorganisms, both Gram-negative and Gram- positive, which are used to screen for activity against pathogenic bacteria. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system. 
     The antibacterial properties of the compounds of the invention may also be demonstrated in conventional mouse protection tests, and the preferred compounds of this invention have MIC 50  values of less than 2 μg./ml. against both Pseudomonas aeruginosa and Staphyllococcus aureus. 
     Cephalosporin derivatives have generally been found to be relatively non-toxic to warm-blooded animals, and this generalisation holds true for the compounds of the present invention. A number of compounds were administered to mice at doses in excess of those required to afford protection against bacterial infections, and no overt toxic symptoms or side effects attributable to the administered compounds were noted. 
     According to a further feature of the invention there is provided a pharmaceutical composition which comprises a cephalosporin derivative of the invention in association with a pharmaceutically-acceptable diluent or carrier. 
     The pharmaceutical composition of the invention may, for example, be in a form suitable for oral, rectal or parenteral administration, for which purposes it may be formulated by means known to the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions. 
     In addition to the cephalosporin derivative of the formula I the pharmaceutical composition of the invention may also contain, or be co-administered with, one or more known drugs selected from other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), inhibitors of beta-lactamase (for example clavulanic acid), renal tubular blocking agents (e.g. probenicid) and inhibitors of metabolising enzymes (for example inhibitors of peptidases, for example Z-2-acylamino-3-substituted propenoates). 
     A preferred pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable containing between 1 and 10% w/w of the cephalosporin derivative, or one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg. and 1 g. of the cephalosporin derivative. 
     The pharmaceutical composition of the invention will normally be administered to man in order to combat infections caused by bacteria, in the same general manner as that employed for cephalothin, cefoxitin, cephradine and other known clinically used cephalosporin derivatives, due allowance being made in terms of dose levels for the potency of the cephalosporin derivative of the present invention relative to the known clinically used cephalosporins. Thus each patient will receive a daily intravenous, subcutaneous or intramuscular dose of 0.5 to 50 g., and preferably 0.5 to 10 g., of the cephalosporin derivative, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose will be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose. Thus a preferred daily oral dose is 0.5 to 10 g. of the cephalosporin derivative, the composition being administered 1 to 4 times per day. 
     The invention is illustrated, but not limited, by the following Examples. The n.m.r. spectra are quoted in delta relative to tetramethylsilane (delta=0) as internal standard, (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad). The n.m.r. are measured at a field strength of 90 or 400 MHz. The n.m.r. solvents are as follows: 
     
         Solvent A:-d.sub.6 DMSO+CD.sub.3 COOD 
    
     
         Solvent B:-d.sub.6 DMSO+CD.sub.3 COOD+TFA 
    
     
         Solvent C:-CDCl.sub.3 +CD.sub.3 COOD 
    
     The temperatures are in degrees Centigrade. The following contractions are used: 
     
         ______________________________________                                    
TFA         =     trifluoroacetic acid                                    
THF         =     tetrahydrofuran                                         
HOAc        =     acetic acid                                             
EtOAc       =     ethyl acetate                                           
MeOH        =     methanol                                                
DMF         =     dimethylformamide                                       
DMSO        =     dimethylsulphoxide                                      
ether       =     diethyl ether                                           
HPLC        =     high pressure liquid                                    
                  chromatography                                          
Et.sub.3 N  =     triethylamine                                           
Lawesson&#39;s reagent                                                        
            =     2,4-dithioxo-P.sup.5,P.sup.5 -                          
                  1,3,2,4-dithia-                                         
                  phosphatane.                                            
MCBPA       =     m-chloroperbenzoic                                      
                  acid.                                                   
DCCI        =     N,N&#39;dicyclohexyl-                                       
                  carbodi-imide.                                          
CAZAMCA     =                                                             
 ##STR3##                                                                 
BOC         =     tert-butyoxycarbonyl.                                   
______________________________________                                    
 
    
    
    
     EXAMPLES 1-4 
     To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (0.4 mmole) in DMF (11 ml.) and water (3 ml.) at 0° was added sodium bicarbonate (4.8 mmole) dissolved in the minimum volume of water followed by the appropriate 4-chloroheterocycle (0.4 mmole). After 1 hour the mixture was treated with HOAC (4.8 mmole) and evaporated to dryness under reduced pressure. The residue was dissolved in water and purified by HPLC on an octadecylsilane column using MeOH/water/HOAC 40:60:1 v/v/v eluant. Using this general method the following compounds were thus obtained 
     
         ______________________________________                                    
 ##STR4##                                                                 
Example                                                                   
       R                  Yield %  Footnotes                              
______________________________________                                    
        ##STR5##          39       1, 2                                   
2                                                                         
        ##STR6##          31       3, 4                                   
3                                                                         
        ##STR7##          33       5, 6                                   
4                                                                         
        ##STR8##          31       5, 7                                   
______________________________________                                    
Footnotes                                                                 
1. The starting material was prepared by                                  
reaction of 1-phenyl-4-pyridone with                                      
toluene- - p-sulphonylchloride in refluxing toluene to                    
give 4-chloro-1-phenyl toluene- -p-sulphonate.                            
2. n.m.r. in solvent A: 1.5(s, 6H); 3.35                                  
(d, 1H); 3.68(d, 1H); 4.3(d, 1H); 4.6(d, 1H); 5.12                        
(d, 1H); 5.75(d, 1H); 6.68(s, 1H); 7.1(d, 1H); 7.6(m,                     
6H); 8.4(d, 1H); 8.5(d, 1H).                                              
3. The starting material was prepared as                                  
follows. A mixture of 2,6-dicarboxy-4-pyrone (1.84 g.)                    
and 4-fluoroaniline (1.9 ml.) was heated at 180° under             
argon until evolution of gas ceased. The cooled                           
mixture was purified by chromatography on silica gel,                     
eluting with CH.sub.2 Cl.sub.2 /MeOH 100-90:0-10 v/v to give, after       
sublimation (150°/0.01 mmHg) 1-(4-fluorophenyl)-4-                 
pyridone(1.24 g.). n.m.r. in CDCl.sub.3 : 6.45(d, 2H); 7.3                
(m, 4H); 7.54(d, 2H). Reaction of this compound with                      
toluene- -p-sulphonylchloride in refluxing toluene gave                   
4-chloro-1-(4-fluorophenyl)pyridinium                                     
toluene- -p-sulphonate.                                                   
4. n.m.r. in solvent A: 1.4(s, 6H); 3.35                                  
(d, 1H); 3.65(d, 1H); 4.25(d, 1H); 4.46(d, 1H); 5.1                       
(d, 1H); 5.8(d, 1H); 6.7(s, 1H); 6.9-7.8(complex, 6H);                    
8.3(d, 1H); 8.5(d, 1H).                                                   
5. The starting material was prepared by the                              
method described in Footnote 3, using the appropriate                     
substituted aniline.                                                      
6. n.m.r. in solvent A: 1.4(s, 6H); 3.36                                  
(d, 1H); 3.64(d, 1H); 4.27(d, 1H); 4.48(d, 1H); 5.1                       
(d, 1H); 5.8(d, 1H); 6.7(s, 1H); 6.9-7.7(m, 6H); 8.35                     
(d, 1H); 8.5(d, 1H).                                                      
7. n.m.r. in solvent A: 1.45(s, 6H); 3.4                                  
(d, 1H), 3.68(d, 1H); 4.3(d, 1H); 4.5(d, 1H); 5.12                        
(d, 1H); 5.85(d, 1H); 6.75(s, 1H); 6.9-7.9(m, 5H); 8.2                    
(d, 1H); 8.4(d, 1H).                                                      
 
    
     The cephalosporin starting material may be obtained as follows: 
     To a stirred mixture of DMF (5.80 ml.) in anhydrous methylene chloride (415 ml.) at -10° was added dropwise oxalyl chloride (6.15 ml.). Stirring was continued at -10° for 30 minutes to give a gelatinous white precipitate of (chloromethylene)dimethylammonium chloride. To this stirred suspension was added powdered 2-((Z)-1-t-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (40.0 g.) followed by N-methylmorpholine (8.8 ml.). Stirring was continued for 30 minutes between -5° and -15°. 
     In another flask a suspension of 7-amino-3-azidomethylceph-3-em-4-carboxylic acid (17.85 g.) in anhydrous methylene chloride (150 ml.)was stirred for 1 hour with N,O-bis(trimethylsilyl)acetamide (34.5 ml.) to give a clear orange solution. This was transferred by syringe to the above acid chloride solution which was stirred at -10° during the addition. The reaction mixture was then allowed to warm to room temperature and stirred for a further 90 minutes. The mixture was then poured into water (500 ml.) and extracted with EtoAc (3×500 ml.). The combined EtOAc extracts were washed with water, dried (Na 2  SO 4 ) and the solvent was evaporated under reduced pressure to yield a buff foam. The crude product was dissolved in methylene chloride and applied to a column of Kieselgel 60 (125 g.). Elution with methylene chloride/MeOH/HOAc 96:2:2 v/v/v gave 3-azidomethyl-7-[2-(2-tritylaminothiazol-4-yl)-2-((Z)-1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]ceph- 3-em-4-carboxylic acid (46.4 g.) as a white foam n.m.r. in solvent A: 1.30 (s, 9H); 1.35 (s,6H), 3.37 (d, 1H), 3.65 (d, 1H), 3.90 (d,1H), 4.35 (d,1H), 5.1 (d,1H); 5.7 (d,1H); 6.66 (s,1H), 7.25 (s,15H). 
     An aqueous slurry of Raney nickel (10.2 g.) was added in one portion to a stirred solution of the azide (20.0 g.) in a mixture of MEOH (60 ml.) and TFA (60 ml.) at room temperature. A vigorous effervescence was observed. Stirring was continued for 1 hour and the Raney nickel was removed by filtration through diatomaceous earth. The filter pad was washed well with MEOH and the washings were combined with the filtrate. The solvents were evaporated under reduced pressure to give a pale green solid residue which was then stirred for 2 hours with a mixture of TFA (60 ml.) and water (15 ml.). This mixture was evaporated to dryness and the residue was stirred vigorously with water (400 ml.) for 30 minutes. The resulting solution was filtered through diatomaceous earth to remove the undissolved triphenylmethanol and the filtrate was applied to a column of Diaion HP 20 resin (1 l.). The column was eluted with water (500 ml.) to remove inorganic material and then with aqueous MEOH 1:1  v/v. The fractions which were shown by HPLC to contain the product were evaporated under reduced pressure to yield 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (4.2 g.) as a pale yellow foam having the following n.m.r. in solvent A: 1.4 (s,6H); 3.1-3.8 (complex, 4H); 4.95 (d,1H); 5.7(d,1H); 6.72 (s,1H). 
     EXAMPLES 5-6 
     The general process described in Examples 1-4 was repeated, and the following compounds were obtained. 
     
         __________________________________________________________________________
 ##STR9##                                                                 
Example No.                                                               
          R           Yield %                                             
                           Footnotes                                      
__________________________________________________________________________
5         C.sub.2 H.sub.5                                                 
                      64   1, 2, 3                                        
           ##STR10##  55   4, 5                                           
__________________________________________________________________________
Footnotes                                                                 
1. The starting material may be prepared as follows. Reaction of (        
.sub.-- Z)-2-                                                             
ethoxyimino-2-(2-trityl-aminothiazol-4-yl)acetic acid and 7-amino-3-      
azidomethyl-ceph-3-em-4-carboxylic acid (previously treated with N,O-     
bistrimethylsilylacetamide in the presence of chloromethyleneammonium     
chloride and N-methylmorpholine) in CH.sub.2 Cl.sub.2 /DMF gave after     
purification by chromatography on silica gel 3-azidomethyl-7-[( .sub.--   
Z)-2-                                                                     
ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic 
acid; n.m.r. in CDCl.sub. 3 : 1.29(t, 3H); 3.3(d, 1H); 3.54(d, 1H);       
3.87(d,                                                                   
1H), 4.3(q, 2H); 4.38(d, 1H); 4.97(d, 1H); 5.73(q, 1H); 6.72(s, 1H);      
7.26                                                                      
(m, 15H).                                                                 
This 3-azidomethyl compound in TFA acid was reduced with Raney nickel to  
give, after purification by chromatography on a Diaion CHP20P             
column, 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-( .sub.-- Z)-2-ethoxyimin
o)-                                                                       
acetamido]ceph-3-em-4-carboxylic acid; n.m.r. in solvent A:               
1.2(t, 3H); 3.26(d, 1H); 3.48(br s, 2H); 3.68(d, 1H); 4.08(q, 2H);        
4.97(d, 1H),                                                              
5.66(d, 1H); 6.69(s, 1H).                                                 
2. The quaternised starting material was 3-chloro-1-methylpyridazinium    
iodide.                                                                   
3. n.m.r. in solvent A: 1.2(t, 3H); 3.31(d, 1H); 3.61(d, 1H); 4.12(q,     
2H);                                                                      
4.23(s, 3H); 4.48(d, 1H); 4.99(d, 1H); 5.65(d, 1H); 6.69(d, 1H); 7.6      
(m, 1H); 7.9(dd, 1H); 8.88(d, 1H).                                        
4. n.m.r. in solvent A: 1.9(m, 2H); 2.45(m, 4H); 3.44(d, 1H); 3.66(d,     
1H);                                                                      
4.1(d, 1H); 4.28(s, 3H); 4.57(d, 1H); 5.1(d, 1H); 5.82(d, 1H); 6.83       
(s, 1H); 7.63(br, 1H); 7.92(br, 1H); 8.9(d, 1H).                          
5. The starting material was prepared from 2-[( .sub.-- Z)-               
1-(t-butoxycarbonyl)cyclobut-1-yloxyimino]-2-(2-tritylaminothiazol-4-yl)  
acetic acid by the general method described in Footnote 1. to give        
3-azido-                                                                  
methyl-7-(( .sub.-- Z)-2-[ 1- .sub.- t-butoxycarbonyl)cyclobut-1-         
yloxyimino]-2-[2-tritylaminothiazol-4-yl]acetamido)ceph-3-em-4-           
carboxylic acid, having the following n.m.r. in solvent A: 1.38(s, 9H);   
1.78(m, 1H); 1.89(m, 1H); 2.35(m, 4H); 3.45(d, 1H); 3.63(d, 1H); 3.9(d,   
1H); 4.38(d, 1H); 5.13(d, 1H); 5.76(d, 1H); 6.68(s, 1H); 7.18-7.37(m,     
15H).                                                                     
 
    
     The above 3-azidomethylcephalosporin derivative was reduced by the general method described in Footnote 1 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylic acid, which was partially purified by chromatography on Diaion CHP20 resin before use without further characterisation. 
     EXAMPLES 7-14 
     The general process described in Examples 1-4 was repeated using the appropriate heterocyclic starting material. The reactions were carried out in DMF in the presence of triethylamine or DMF/water mixtures in the presence of NaHCO 3  at a temperature in the range ambient to 90° for 1-20 hours. The product was purified on an octadecylsilane column and the following compounds were thus prepared. 
     
         __________________________________________________________________________
 ##STR11##                                                                
Example                                                                   
      R.sup.1  R.sup.2    Yield %                                         
                               Footnotes                                  
__________________________________________________________________________
 7.   C(CH.sub.3).sub.2 COOH                                              
                ##STR12## 17   1, 2, 3                                    
 8.   C(CH.sub.3).sub.2 COOH                                              
                ##STR13##  7   4, 2, 5                                    
 9.   C(CH.sub.3).sub.2 COOH                                              
                ##STR14## 16   6, 7, 8                                    
10.   C(CH.sub.3).sub.2 COOH                                              
                ##STR15## 26   9, 2, 10                                   
__________________________________________________________________________
Example                                                                   
      R.sup.1  R          Yield %                                         
                               Footnotes                                  
__________________________________________________________________________
11    CH.sub.3                                                            
                ##STR16## 33   11, 12, 13                                 
12    CH.sub.3                                                            
                ##STR17## 36   14, 15                                     
13    C(CH.sub.3).sub.2 COOH                                              
                ##STR18## 22   16, 17, 18                                 
14    C(CH.sub.3).sub.2 COOH                                              
                ##STR19## 20   19, 17, 20                                 
__________________________________________________________________________
Footnotes                                                                 
1. The starting material was prepared by reaction of 3-chloropyridazine   
with trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 18 hours 
to give                                                                   
3-chloro-1-methylpyridazinium tetrafluoroborate.                          
2. HPLC eluant MeOH/water/HOAc 20:79:1 v/v/v.                             
3. n.m.r. in solvent B: 1.53(s, 3H); 1.52(s, 3H); 3.56(m, 2H); 4.26(s,    
3H); 4.1(d,                                                               
1H); 4.6(d, 1H); 5.17(d, 1H); 5.88(d, 1H); 6.94(s, 1H); 7.7(d, 1H);       
7.98(dd,                                                                  
1H); 8.95(d, 1H).                                                         
4. The starting material was prepared by reaction of 3-fluoropyrazine     
with                                                                      
trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 4 hours       
under reflux to give 1-methyl-3-fluoropyrazinium tetrafluoroborate.       
5. n.m.r. in solvent B: 1.53(s, 3H); 1.54(s, 3H); 3.55(m, 2H); 4.21(s,    
3H);                                                                      
4.2(d, 1H); 4.7(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 8.0         
(d, 1H); 8.19(s, 1H); 8.6(d, 1H).                                         
6. The starting material was obtained as follows. Reaction of 3,6-        
dichloropyridazine with trimethyloxonium tetrafluoroborate gave           
3,6-dichloro-1-methylpyridazinium tetrafluoroborate. To this compound     
(2.0 mmole) in acetonitrile was added NaHCO.sub.3 (2.0 mmole), a few      
drops of triethylamine and 2-acetamido-1-mercaptoethane (2.4 mmole).      
After 1 hour at ambient temperature the mixture was filtered,             
the filtrate evaporated and ether and CH.sub.2 Cl.sub.2 added. The        
product                                                                   
crystallised to give 3-chloro-1-methyl-6-(2-acetamidoethylthio)pyridaziniu
tetrafluoroborate.                                                        
7. HPLC eluant MeOH/water/HOAc 23:76:1 v/v/v.                             
8. n.m.r. in solvent B: 1.53(s, 1H); 1.54(s, 1H); 3.6(br s, 2H); 3.99(s,  
3H);                                                                      
4.6(d, 1H); 4.8(d, 1H); 5.17(d, 1H); 5.9(d, 1H); 6.95(s, 1H); 8.16(dd,    
2H).                                                                      
9. The starting material was obtained by reaction of 4-methoxypyridazine  
with trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 8 hours  
at                                                                        
ambient temperature to give 4-methoxy-1-methylpyridazinium                
tetrafluoroborate.                                                        
10. n.m.r in solvent B: 1.53(br s, 6H); 4.1(s, 3H); 4.39(m, 2H); 5.19(d,  
1H);                                                                      
5.85(d, 1H); 7.0(s, 1H); 7.37(dd, 1H); 8.55(d, 1H); 8.9(d, 1H).           
11. The 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-methoxyim
ino)                                                                      
acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate used as starting   
material may be prepared as follows: To a solution of cefotaxime (5.24    
g.)                                                                       
in phosphate buffer (pH 6.4, 440 ml.) was added sodium azide (2.86 g.)    
and                                                                       
sodium iodide (1.65 g.) and the mixture was immersed in a 70° bath 
with                                                                      
stirring for 4.5 hours. The solvent was evaporated to the point of        
precipita-                                                                
tion and then the pH adjusted to 2.5 with 2N aqueous HCl. The resulting   
precipitate was collected, washed with water, acetone and ether and       
dried                                                                     
over P.sub.2 O.sub.5 to give 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((
 .sub.-- Z)-                                                              
methoxyimino)acetamido]ceph-3-em-4-carboxylic acid in quantative yield,   
having the following n.m.r. in solvent A: 3.4(d, 1H); 3.7(d, 1H);         
3.86(s,                                                                   
3H); 3.95(d, 1H); 4.4(d, 1H); 5.15(d, 1H); 5.78(d, 1H); 6.75(s, 1H).      
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at       
0° was                                                             
added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- 
)-                                                                        
methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/     
TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was        
diluted                                                                   
with MeOH and filtered through paper. The filtrate was evaporated, the    
residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v              
as eluant and the product dried over P.sub.2 O.sub.5 to give              
3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-                 
methoxyimino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate       
(yield 45%) having the following n.m.r. in solvent A: 3.5-4.2(m, 4H);     
3.9(s, 3H); 5.15(d, 1H); 5.85(d, 1H); 6.75(s, 1H).                        
12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v.                            
13. n.m.r. in solvent B: 3.46(d, 1H), 3.72(d, 1H); 3.97(s, 3H); 4.25(s,   
3H);                                                                      
4.11(d, 1H); 4.63(d, 1H); 5.13(d, 1H); 5.73(d, 1H); 6.97(s, 1H); 7.57     
(d, 1H); 7.98(dd, 1H); 8.93(d, 1H).                                       
14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v.                            
15. n.m.r. in solvent B: 3.43(d, 1H); 3.69(d, 1H); 3.97(s, 3H); 4.19(s,   
3H);                                                                      
4.23(d, 1H); 4.66(d, 1H); 5.12(d, 1H); 5.69(d, 1H); 7.0(s, 1H); 7.98      
(d, 1H); 8.2(s, 1H); 8.6(d, 1H).                                          
16. The starting material was prepared by reaction of 3,6-difluoropyridazi
ne                                                                        
and trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 for 15 hours  
at ambient                                                                
temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate.  
This compound in acetonitrile was treated with a solution of ammonia in   
chloroform in the presence of 1 equivalent of NaHCO.sub.3 for 0.5 hours   
at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium     
tetrafluoroborate.                                                        
17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                            
18. n.m.r. in solvent B: 1.53(s, 6H); 3.5(m, 2H); 3.7(s, 3H); 3.95(d,     
1H); 4.5(d,                                                               
1H); 5.15(d, 1H); 5.8(d, 1H); 7.0(s, 1H); 7.3(s, 2H).                     
19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluor
o-                                                                        
pyrazine and trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 at   
ambient                                                                   
temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium        
tetrafluoroborate.                                                        
20. n.m.r. in solvent B: 1.53(s, 6H); 2.38(s, 3H); 2.53(s, 3H); 3.5(m,    
2H); 4.1(s,                                                               
3H); 4.2(d, 1H); 4.85(d, 1H); 5.1(d, 1H); 5.85(d, 1H); 7.05(s, 1H);       
7.9(s, 1H).                                                               
 
    
     EXAMPLES 15-16 
     The general process described in Examples 7-14 was repeated using the appropriate 3-aminomethylcephalosporin derivative and the appropriate chloroheterocycle and the following compounds were obtained. 
     
         __________________________________________________________________________
 ##STR20##                                                                
Example R               Yield %                                           
                               Footnotes                                  
__________________________________________________________________________
15                                                                        
         ##STR21##      35     1                                          
16      CH.sub.2 CH.sub.2 Br                                              
                        11     2                                          
__________________________________________________________________________
Footnotes                                                                 
1. n.m.r. in solvent A: 2.68(s, 3H); 3.6(m, 4H); 4.0-4.8(m, 4H); 4.25(s,  
3H);                                                                      
5.15(d, 1H); 5.81(d, 1H); 7.0(s, 1H); 7.61(d, 1H); 7.99(dd, 1H); 8.97(d,  
1H).                                                                      
2. n.m.r. in solvent A: 3.6-3.9(m, 4H); 4.0-4.6(m, 4H); 4.26(s, 3H);      
5.14(d, 1H);                                                              
5.82(d, 1H); 6.97(s, 1H); 7.65(d, 1H); 8.02(dd, 1H); 9.0(d,               
__________________________________________________________________________
1H).                                                                      
 
    
     The starting materials for use in the above process may be obtained as follows: 
     Reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate (UK patent application 2017702A) with 2-mercapto-5-methyl-1,3,4-thiadiazole and hydrolysis of the ester gave 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(5-methyl-1,3,4-thiadiazol-2-ylthio)ethoxyimino]acetic acid; n.m.r. in solvent C: 2.7 (s,3H); 3.65 (t,2H); 4.51 (t,2H); 6.65 (s,1H); 7.34 (s,15H). 
     Triethylamine (1.0 mmole.) and phosphorus pentachloride (1.0 mmole) were added to a solution of 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-(S-methyl-1,3,4-thiadiazol-2-ylthio)ethoxyimino]acetic acid (1.0 mmole) in CH 2  Cl 2  (2.5 ml.) under argon at 0° and the mixture stirred for 1.5 hours. The solvent was evaporated and the residue dissolved in CH 2  Cl 2 . To this solution was added a solution of 7-amino-3-azidomethylceph-3-em-4-carboxylic acid (1.0 mmole.) in CH 2  Cl 2  (2.5 ml.) under argon [this solution having been previously treated at 0° with N,O-bistrimethylsilylacetamide (2.0 mmole.) and allowed to warm to ambient temperature over 2 hours]. After 1.5 hours the mixture was diluted with CH 2  Cl 2  and the organic layer washed with water, brine and dried (MgSO 4 ). Evaportion of the solvent and purification of the residue by chromatography on silica gel gave the product. Using this general process the following compounds were prepared. 
     
         __________________________________________________________________________
 ##STR22##                                                                
R                         Footnotes                                       
__________________________________________________________________________
 ##STR23##                1                                               
CH.sub.2 CH.sub.2 Br      2, 3                                            
__________________________________________________________________________
Footnotes                                                                 
1. n.m.r. in solvent A: 2.68(s, 3H); 3.64(m, 4H); 3.92(d, 1H); 4.46(d,    
1H);                                                                      
4.48(m, 2H); 5.2(d, 1H); 5.8(d, 1H); 6.92(s, 1H); 7.37(s, 15H).           
2. The starting material was 2-(2-tritylamino-thiazol-4-yl)-2-(( .sub.--  
Z)-2-                                                                     
bromoethoxyimino)acetic acid (UK patent application 2017702A).            
3. n.m.r. in solvent A: 3.5-3.9(m, 4H); 4.2-4.5(m, 4H); 5.16(d, 1H);      
5.76(d, 1H);                                                              
6.8(s, 1H); 7.34(s, 15H).                                                 
 
    
     The 3-azidomethylcephalosporin derivative was dissolved in formic acid and treated with an excess of wet Raney nickel for 50 minutes. The mixture was filtered through diatomaceous earth and the pad rinsed with MeOH/water 1:1 v/v. The filtrate was evaporated and the residue dissolved in TFA/water 9:1 v/v (5 ml.) at ambient temperature. After 1.5 hours the solvent was evaporated and the residue purified by chromatography on Diaion HP 20 resin, eluting with increasing proportions of MeOH in water. There were thus obtained the following compounds. 
     
         ______________________________________                                    
 ##STR24##                                                                
R                       Footnotes                                         
______________________________________                                    
 ##STR25##              1                                                 
CH.sub.2 BH.sub.2 Br    2                                                 
______________________________________                                    
Footnotes                                                                 
1. n.m.r. in solvent A: 2.67(s, 3H); 3.62                                 
(m, 6H); 4.47(t, 2H); 5.15(d, 1H); 5.86(d, 1H); 7.0                       
(s, 1H).                                                                  
2. n.m.r. in solvent A: 3.65-3.9(m, 6H); 4.42                             
(t, 2H); 5.17(d, 1H); 5.88(d, 1H); 6.97(s, 1H).                           
 
    
     EXAMPLE 17 
     To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (400 mg.) and 4-chloro-1,7-dimethyl-1,8-naphthyridinium tetrafluoroborate (190 mg.) in DMF (2 ml.) was added triethylamine (285 ul.) at ambient temperature. After 1 hour the solvent was evaporated and the residue purified by HPLC on an octadecylsilane column using MeOH/aqueous ammonium carbonate (2 g./l) 30:70 v/v as eluant to give the following compound ##STR26## in 10% yield, n.m.r. in solvent B: 1.5 (s,6H); 2.73 (s,3H); 3.6 (s,2H); 4.1 (s,3H); 4.65 (s,2H), 5.2 (d,1H); 6.9 (d,1H), 7.0 (s,1H); 7.0 (d,1H); 7.7 (d,1H); 8.8 (dd,1H). 
     The starting material may be obtained as follows. 3-Carboxy-4-hydroxy-7-methyl-1,8-naphthyridine was heated at 300° in a tube equipped with a cold finger to give 4-hydroxy-7-methyl-1,8-naphthyridine. Reaction of this compound with phosphorous oxychloride at 100° for 30 minutes gave 4-chloro-7-methyl-1,8-naphthyridine. Reaction of this compound with trimethyloxonium tetrafluoroborate in CH 2  Cl 2  at ambient temperature for 3 hours gave, after evaporation of solvent and washing of the residue with ether, 4-chloro-1,7-dimethyl-1,8-naphthyridinium tetrafluoroborate which was used without further purification. 
     EXAMPLES 18-24 
     The following compounds were prepared by reaction of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid with the appropriate quaternary heterocycle in the manner described in Example 1. 
     
         ______________________________________                                    
 ##STR27##                                                                
Exam-                        Yield   Foot-                                
ple   R                      (%)     notes                                
______________________________________                                    
       ##STR28##             22      1                                    
       ##STR29##             27      2, 3                                 
20.                                                                       
       ##STR30##             40      4, 5                                 
       ##STR31##             14      6, 7                                 
       ##STR32##             13      8, 9                                 
       ##STR33##             14      10, 11                               
       ##STR34##             16      12, 13                               
______________________________________                                    
Footnotes                                                                 
1. N.m.r. in solvent A: 1.42(s, 6H), 2.52(s, 3H), 2.7(s, 3H), 3.68(dd,    
2H), 4.42(d, 1H), 4.8(d, 1H) 5.12(d, 1H), 5.9(d, 1H), 7.0(s, 1H),         
7.82(m, 1H), 8.1(d, 1H).                                                  
2. N.m.r. in solvent A: 1.42(s, 6H), 3.32(d, 1H), 3.61(d, 1H),            
4.22(d, 1H), 4.61(d, 1H), 5.05(d, 1H), 5.76(d, 1H), 6.72(s,               
1H) 7.02(d, 1H), 7.78(d, 1H), 8.1(d, 1H), 8.7(d, 1H).                     
3. The staring material may be prepared as follows: Lawesson&#39;s            
reagent (5.26 g.) was added to a boiling solution of                      
8H-thiazolo[3,2-a]pyrimidin-7-one (4.0 g.) in CH.sub.3 CN                 
(200 ml.) and the mixture was heated under reflux with stirring           
for 1.5 h. On cooling silica gel (70-230 mesh, 15 g.) was added           
and the mixture was evaporated to dryness. The residue was                
applied to a column of silica gel (300 g.) and eluted with                
MeOH/CH.sub.2 Cl.sub.2  (5-10%) to give 8H-thiazolo[3,2-a]-               
pyrimidin-7-thione (2.7 g.). Trimethyloxonium tetrafluoroborate           
(2.0 g.) was added to a stirred suspension of 8H-thiazolo[3,2-a]-         
pyrimidin-7-thione (1.5 g.) in dry CH.sub.3 CN (50 ml.). After            
stirring for 2 h, the solution was concentrated to about 20 ml.,          
and with vigorous stirring anhydrous ether (100 ml.) was added            
to precipitate 7-methylthiothiazolo[3,2-a]pyrimidinium                    
tetrafluoroborate (1.3 g.), having nmr in d.sub.6 DMSO: 2.78(s, 3H),      
8.04(d, 1H), 8.22(d, 1H), 8.55(d, 1H), 9.24(d, 1H).                       
4. N.m.r. in solvent A: 1.42(s, 6H), 3.5(d, 2H) 3.68(m, 2H), 4.18(d,      
1H), 4.6(m, 3H), 5.1(d, 1H), 5.82(d, 1H), 6.62(d, 1H), 6.72(s, 1H),       
8.12(d, 1H).                                                              
5. Starting from 2,3-dihydro-8H-thiazolo[3,2-a]pyrimidin-7-one,           
2,3-dihydro-7-methylthiothiazolo[3,2-a]pyrimidinium                       
tetrafluoroborate was prepared in the same way as described in            
footnote 3.                                                               
6. N.m.r. in solvent A: 1.42(s, 6H), 3.58(dd, 2H), 4.25(d, 1H),           
4.75(d, 1H), 5.1(d, 1H), 5.82(d, 1H), 6.75(s, 1H), 7.39(s, 1H),           
7.6(d, 1H), 9.21(s, 1H).                                                  
7. Starting from 5-methoxycarbonyl-8H-thiazolo[3,2-a]-                    
pyrimidin-7-one, 5-methoxycarbonyl-7-methylthiothiazolo[3,2-a]-           
pyrimidinium tetraborate was prepared in the same way as                  
described in footnote 3. Upon reaction with the amino-                    
methylcephalosporin, as described in Example 1, this material             
underwent hydrolysis of the methyl ester in addition to                   
displacement of the methylthio group.                                     
8. N.m.r. in solvent A: 1.12(t, 3H), 1.42(s, 6H), 2.7(s, 2H),             
3.3(d, 1H), 3.58(d, 1H), 4.2(d, 1H), 4.6(d, 1H), 5.09(d, 1H),             
5.68(d, 1H), 6.66(s, 1H), 8.0(d, 1H), 8.1(s, 1H), 9.18(d, 1H).            
9. The starting material may be prepared as follows:                      
2-Amino-5-ethoxycarbonylmethylthiazole (3.72 g.), ethyl                   
propiolate (1.96 g.) and 25% aqueous tetramethylammonium                  
hydroxide (0.15 ml.) in absolute EtOH (50 ml). were heated under          
reflux for 16 h. The solution was concentrated and the residue            
purified by column chromatography (silica gel; 10%                        
MeOH/CH.sub.2 Cl.sub.2) to give 3-ethoxycarbonylmethyl-8H-                
thiazolo[3,2-a]pyrimidin-7-one (1.6 g.), as a solid having                
nmr in d.sub.6 DMSO: 1.2(t, 3H), 4.1(m, 4H), 6.15(d, 1H),                 
7.15(s, 1H), 8.18(d, 1H). This material was converted to                  
3-ethoxycarbonylmethyl-7-methylthiothiazolo[3,2-a]pyrimidinium            
tetrafluoroborate in the same way as described in footnote 3.             
10. N.m.r. in solvent A: 1.4(s, 6H), 3.35(d, 1H), 3.65(d, 1H),            
4.32(d, 1H), 4.65(d, 1H), 5.05(d, 1H), 5.78(d, 1H), 6.75(s, 1H),          
7.12(d, 1H), 7.7(m, 2H), 8.25(m 1H), 9.23(d, 1H).                         
11. 1H-Benzo[4,5]thiazolo[3,2-a]pyrimidin-2-one was converted to          
2-methylthiobenzo[4,5]thiazolo[3,2-a]pyrimidinium tetra-                  
fluoroborate in the same was as described in footnote 3.                  
12. N.m.r. in solvent A: 1.4(s, 6H), 2.75(s, 3H) 3.35(d, 1H), 3.61(d,     
1H), 4.28(d, 1H) 4.68(d, 1H), 5.04(d, 1H). 5.78(d, 1H), 6.72(s, 1H),      
7.03(d, 1H), 8.98(d, 1H).                                                 
13. 8H-2-Methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-one was               
converted to 2-methyl-7-methylthio-1,3,4-thiadiazolo[3,2-a]-              
pyrimidinium tetrafluoroborate in the same way as described in            
footnote 3.                                                               
 
    
     EXAMPLES 25-28 
     To a stirred suspension of 3-aminomethyl-7-[2-(2 aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4 carboxylic acid (200 mg.-0,4 mmole) and triethylamine (120 μl. - 0.8 mmole) in DMF(2 ml.) at 25° C. was added to the appropriate N-alkylated-4-methylthio pyrimidinium salt (0.6 mmole). 
     After 30 minutes, the solution was evaporated to dryness under reduced pressure and the residue purified by preparative HPLC (octadecyl silane column). 
     Using this general process and the appropriate quaternised heterocycle the following compounds were obtained. 
     
         __________________________________________________________________________
 ##STR35##                                                                
Examples                                                                  
       R               Yield (%)                                          
                             Footnotes                                    
__________________________________________________________________________
        ##STR36##      67    1    2                                       
        ##STR37##      25    3    4                                       
        ##STR38##      24    5    6                                       
        ##STR39##      25    7    8                                       
__________________________________________________________________________
Footnotes                                                                 
1. N.m.r. in solvent B: 1.54(s, 6H), 3.60 (m, 2H), 4.3(d, 1H), 4.8(d,     
1H), 5.2(br, 1H),                                                         
5.3(s, 2H), 5.9(br, 1H), 7.0(d, 1H), 7.1(s, 1H), 7.5(s, 1H), 8.3(s, 1H),  
9.0(s, 1H).                                                               
2. The pyrimidinium salt may be prepared as follows: A suspension of      
4-methylthio-                                                             
pyrimidine (350 mg. 2.8 mmole) and alkyl halide (2.8 mmole) was heated at 
80° C.                                                             
for 1 hour. The residue was triturated with EtOAc and the resulting solid 
filtered                                                                  
off. N.m.r. in solvent B: 2.52(s, 3H), 5.6(s, 2H), 7.5(s, 1H), 8.1(d,     
1H), 9.0(d, 1H),                                                          
9.62(s, 1H).                                                              
3. N.m.r. in solvent B: 1.54(s, 6H), 3.6(m, 2H), 4.3(d, 1H), 4.8(d, 1H),  
5.0(d, 2H);                                                               
5.2(d, 1H), 5.9(d, 1H), 6.8(s, 1H), 7.05(m, 3H), 7.45(m, 5H), 8.3(d, 1H), 
8.95(s, 1H).                                                              
4. The starting material may be prepared in the same way as described in  
footnote                                                                  
2. N.m.r in solvent B: 2.74(s, 3H), 5.36(d, 2H), 6.8(m, 2H), 7.4(m, 5H),  
8.12(d, 1H),                                                              
8.93(d, 1H), 9.6(s, 1H).                                                  
5. N.m.r. in solvent B: 1.54(s, 6H), 3.56(m, 2H), 4.3(d, 1H), 4.8(d, 1H), 
5.2(d, 1H),                                                               
5.6(s, 2H), 5.9(d, 1H) 7.0(m, 2H), 7.05(s, 1H), 7.24(s, 1H), 7.46(d, 1H), 
8.2(d, 1H),                                                               
9.0(s, 1H).                                                               
6. The starting material may be prepared in the same was as described in  
footnote 2.                                                               
N.m.r. in solvent B: 2.74(s, 3H), 5.87(s, 2H), 6.9-7.8(m, 3H), 8.06(d,    
1H),                                                                      
8.95(d, 1H), 9.6(s, 1H).                                                  
7. N.m.r. in solvent B: 1.54(s, 6H), 3.6(m, 2H), 4.4(d, 1H), 4.8(d, 1H),  
5.2(d, 1H),                                                               
5.8(s, 2H), 5.95(d, 1H), 7.04(d, 1H), 7.15(s, 1H), 7.7(s, 2H), 8.3(d,     
1H), 9.0(s, 1H).                                                          
8. The starting material may be prepared in the same way as described in  
footnote                                                                  
2. N.m.r. in solvent B: 2.74(s, 3H), 6.12(s, 2H), 7.7(s, 2H), 8.3(d,      
1H),                                                                      
9.1(d, 1H), 9.7(s, 1H).                                                   
 
    
     EXAMPLE 29 ##STR40## 
     To a stirred suspension of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (205 mg.-0.5 mmole) and triethylamine (70 μl. 0.5 mmole) in DMF (2 ml.) at 25° C. was added the quaternised pyrimidine described in Example 28, footnote 8 (185 mg. 0.5 mmole). After 30 min the solution was evaporated to dryness and the residue was purified by preparative HPLC (octecycl silane column). Yield 33%. N.m.r. in solvent B: 3.6 (m, 2H), 4.0 (s, 3H), 4.3 (d, 1H), 4.8 (d, 1H), 5.15 (m, 1H), 5.85 (br, 3H), 7.05 (m, 2H), 7.7 (s, 2H), 8.3 (d, 2H), 9.0 (s, 1H). 
     EXAMPLE 30 ##STR41## 
     To a stirred suspension of 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (160 mg. 0.31 mmole) and triethylamine (85 μl - 0.62 mmole) in DMF (2 mi.) at 25° C. was added the N-alkylated-4-methylthiopyrimidine (140 mg. 0.62 mmole). 
     To a stirred suspension of 3-ethylaminomethyl-7-[92-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (160 mg. 0.31 mmole) and triethylamine (85 μl - 0.62 mmole) in DMF (2 ml.) at 25° C. was added the N-alkylated-4-methylthiopyrimidine (140 mg. 0.62 mmole). After 2 hr. at 45° C., the solution was evaporated to dryness and the residue was purified by preparative HPLC. 
     N.m.r. in solvent B: 1.16 (m, 3H), 1.54 (s, 6H), 3.6 (m, 4H), 4,6-5.3 (m, 5H), 5.9 (d, 1H), 7.05 (s, 1H), 7.2 (m, 1H), 8.3 (d, 1H), 8,8 (s, 1H). 
     The starting material may be prepared as follows: 
     A suspension of 4-methylthiopyrimidine (504 mg. 4 mmoles) and 2-chloroacetamide (375 mg. 4 mmoles) was heated at 90° C. for 3 hr. The reaction mixture was triturated with EtOAc, and the resulting solid was filtered off. 
     N.m.r. in solvent B: 2.52 (s, 3H), 5.2 (s, 2H), 8.1 (d, 1H), 8.8 (d, 1H), 9.3 (s, 1H). 
     EXAMPLES 31-32 
     The process described in Example 29 was repeated, using 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-2-chloroethoxyimino)acetamido]ceph-3-em-4-carboxylic acid as starting material, to give the following compounds: 
     
         ______________________________________                                    
 ##STR42##                                                                
Example                                                                   
       R                 Yield (%) Footnotes                              
______________________________________                                    
        ##STR43##        12        1, 2, 3                                
        ##STR44##        31        1, 2, 4                                
______________________________________                                    
Footnotes                                                                 
1. To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-           
((Z)-2-chloroethoxyimino)acetamido]ceph-3-em-4-carboyxlic acid.           
(2 g. 4.3 mmoles) in MeOH (120 ml.) was added triethylamine               
(0.6 ml. 4.3 mmoles) and sodium cyanoborohydride (0.14 g.                 
2.2 mmoles). After addition of acetaldehyde (0.15 ml. 2.2                 
mmoles) the mixture was stirred at room temperature for 1 hour.           
After evaporation the residue was purified on HP20 resin. N.m.r.          
in solvent B: 1.21(s, 3H), 2.8-3.1(m, 2H), 3.2-4.2(m, 6H),                
4.2-4.6(m, 2H), 5.4(d, 1H), 5.8(d, 1H), 7.1(s, 1H).                       
2. The above 3-ethylaminomethyl cephalosporin was reacted with            
the appropriate quaternised heterocycle in the same way as                
described in Example 30.                                                  
3. N.m.r. in solvent B: 1.2(br, 3H), 3.5(br, 4H), 3.85(s, 3H),            
4.0(br, 2H), 4.5(m, 4H), 5.3(d, 1H), 5.9(d, 1H), 7.05(s, 1H), 7.4(d,      
1H), 7.8(d, 1H).                                                          
4. N.m.r. in solvent B: 1.2(br, 3H), 3.0-4.0(m, 6H), 4.2-5.3(m, 7H),      
5.85(d, 1H), 7.04(s, 1H), 7.2(d, 1H), 8.3(d, 1H) 8.7(s, 1H).              
 
    
     EXAMPLES 33-34 
     The process described in Example 25 was repeated, using the appropriate methylthio heterocycle, to give the following compounds. 
     
         ______________________________________                                    
 ##STR45##                                                                
Example R              Yield (%)   Footnotes                              
______________________________________                                    
         ##STR46##     42%         1, 2                                   
         ##STR47##     14%         3, 4                                   
______________________________________                                    
1. N.m.r. in solvent B: 1.55(s, 6H), 3.6(m, 2H), 4.02(s, 3H),             
4.7(d, 1H), 5.1(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.05(s, 1H),              
7.9(m, 1H), 9.1(m, 3H).                                                   
2. The starting material may be obtained as follows: 4-Methylthio-        
pyrido[2,3-d]pyrimidine (700 mg. 4 mmoles) was reacted with               
trimethyloxonium tetrafluoroborate (582 mg. 4 mmoles) in                  
CH.sub.2 Cl.sub.2 (20 ml.) at ambient temperature for 1 hr. After         
filtration the solvent was evaporated to give a solid which was           
used without further purification.                                        
3. N.m.r. in solvent B: 1.55(s, 6H), 3.65(br, 2H), 4.37(s, 3H), 4.6(d,    
1H), 5.0(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 8.0(m, 1H),          
8.8(s, 1H), 9.45(m, 2H).                                                  
4. The solid obtained in footnote 2 was used after trituration            
in MeOH.                                                                  
 
    
     EXAMPLE 35 ##STR48## 
     To a stirred suspension of 3-aminomethyl-7-[2-(2 aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (200 mg.-0.4 mmole) and triethylamine (120 μl. - 0.8 mmole) in DMF (2 ml.) at 25° C. was added the N-alkylated-4-methylthio heterocycle (0.6 mmole). After 30 min., the solution was evaporated to dryness under reduced pressure and the residue purified by preparative HPLC (octadecyl silane column). 
     N.m.r. in solvent B: 1.54 (s, 6H), 3.6 (m, 2H), 4.35 (d, 1H), 4.8 (d, 1H), 5.2 (d, 1H), 5.8 (s, 2H), 5.9 (d, 1H), 7.0 (m, 4H), 7.9 (d, 2H), 8.1 (d, 1H), 8.7 (s, 1H). 
     The methylthio heterocycle used as starting material may be prepared in the same way as described in Example 25, footnote 2. 
     N.m.r. in solvent B: 2.75 (s, 3H), 6.14 (s, 2H), 7.0 (d, 2H), 8.0 (d, 2H), 8.2 (d, 1H), 8.8 (d, 1H), 9.4 (s, 1H). 
     EXAMPLES 36-37 
     The process described in Example 30 was repeated, using the appropriate methylthio heterocycle as starting material, to give the following compounds: 
     
         ______________________________________                                    
 ##STR49##                                                                
Exam-                                                                     
ple   R                  Yield (%) Footnotes                              
______________________________________                                    
       ##STR50##         46%       1, 2                                   
       ##STR51##         46%       3, 4                                   
______________________________________                                    
Footnotes:                                                                
N.m.r. solvent B: 1.52(s, 9H), 3.51(s, 2H), 4.0(s, 5H), 4.95(d, 1H),      
5.2(m, 2H), 5.9(d, 1H), 7.0(s, 1H), 7.9(m, 1H), 8.7(d, 1H), 9.1(m, 2H).   
2. The starting material was described in Example 33, footnote 2.         
3. N.m.r in solvent B: 1.13(m, 3H), 1.53(s, 6H), 3.2-3.9(m, 4H),          
4.6(d, 1H), 4.8-5.3(m, 2H), 5.6(s, 2H), 5.85(d, 1H), 6.9-7.6(m,           
5H), 8.4(d, 1H), 9.0(s, 1H).                                              
4. Starting material described in Example 27, Footnote 6.                 
 
    
     EXAMPLE 38 ##STR52## 
     The general process described in Example 27 was repeated, using the appropriate 4-methylsulphinyl pyridinium salt. 
     N.m.r. in solvent B: 1.54 (s, 6H), 2.5 (br, 2H), 2.8 (br, 2H), 3.55 (m, 2H), 4.35 (br, 2H), 5.2 (d, 1H), 5.7 (m, 1H), 5.9 (d, 1H), 7.0 (m, 4H), 8.2 (m, 2H). 
     The pyridinium salt was used as starting material may be obtained by condensation of the known 4-methylthiopyridine and 3-bromo-1-cyanocyclopentene in MeOH at 20° C. for 12 hr. 
     N.m.r. in solvent B: 2,3-3.0 (m, 7H), 5.8 (br, 1H), 6.7 (s, 1H), 7.6 (d, 2H), 8.5 (d, 2H). 
     This product, as its tetrafluoroborate salt, was oxidised with MCPBA in CH 2  Cl 2  /TFA at 20° C. for 3 hr. After evaporation of the solvents the solid was triturated with ether and used without further purification. 
     EXAMPLES 39-53 
     A solution of NaHCO 3  (0.6 mM) in water (750 ml.) was added to a solution of 7-acyl-3-aminomethyl- cephalosporin derivative (0.2 mM) in DMF (2 ml.), followed after a few minutes by the appropriate quaternised heterocyclic starting material (0.22 mM). The mixture was stirred at room temperature during 3hrs. The mixture was evaporated to dryness and the residue purified by HPLC on an octadecylsilane column. 
     Using this general process the following compounds were prepared. 
     
         __________________________________________________________________________
 ##STR53##                                                                
                                   Yield                                  
Example                                                                   
     R.sub.1    R.sub.2            (%) Footnotes                          
__________________________________________________________________________
39.  CH.sub.2 CHCHCO.sub.2 H                                              
                 ##STR54##         36  1, 2                               
40.  CH.sub.2 CH.sub.2 SOCH.sub.3                                         
                 ##STR55##         32  3, 4                               
41.  CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                  
                 ##STR56##         59  5, 6                               
42.  CH.sub.2 CH.sub.2 SOCH.sub.3                                         
                 ##STR57##         32  7, 8                               
43.  CH.sub.2 CN                                                          
                 ##STR58##         37  9, 10                              
44.  CH.sub.2 CN                                                          
                 ##STR59##         49  11, 12                             
45.  CH.sub.2 CH.sub.2 F                                                  
                 ##STR60##         40  13, 14                             
      ##STR61##                                                           
                 ##STR62##         37  15, 16                             
      ##STR63##                                                           
                 ##STR64##         55  17, 18                             
48.  CH.sub.2 CH.sub.2 F                                                  
                 ##STR65##         21  19, 20                             
49.  CH.sub.2 CF.sub.3                                                    
                 ##STR66##         4   21, 22                             
50.  CH.sub.2 CF.sub.3                                                    
                 ##STR67##         48  23, 24                             
51.  CH.sub.2 CF.sub.3                                                    
                 ##STR68##         31  25, 26                             
      ##STR69##                                                           
                 ##STR70##         30  27, 28                             
53.  CH.sub.2 CH.sub.2 F                                                  
                 ##STR71##         52  29, 30                             
__________________________________________________________________________
1. Reaction time: 1 Hour 40 minutes.                                      
2. N.m.r. in solvent B: 3.35-3.85(m, 2H), 4.3(s, 3H), 4.1-4.5(m, 2H),     
4.8(d, 2H), 5.2(d, 1H),                                                   
5.9(d, 1H), 6.1(d, 1H), 7.05(s, 1H), 6.8-7.2(m, 1H), 7.8-9.1(m, 4H).      
3. The process was carried out using 3-aminomethyl-7-[2-(2-aminothiazol-4-
yl)-2-(Z-methylthio-                                                      
ethoxyimino)acetamido]ceph-3-em-4-carboxylic acid and 3-chloro-1-methyl-py
ridinium iodide,                                                          
during 2 hours. The crude product was not purified after evaporation but  
was oxidised directly as                                                  
follows: A solution of crude 7-[2-(2-aminothiazol-4-yl)-2-(Z-methylthioeth
oxyimino)acetamido]-                                                      
3-(1-methyl-3-pyridazinio)aminomethylceph-3-em-4-carboxylic acid (0.5 mM) 
in TFA (4.0 ml.)                                                          
and CH.sub.2 Cl.sub.2 (6.0 ml.) was cooled to -25° C. with         
vigourous stirring                                                        
m-chloroperbenzoic acid (0.5 mM) was added portion wise during 1 hr. The  
temperature was                                                           
allowed to rise to ambient, the mixture was evaporated to dryness and the 
residue was purified                                                      
by HPLC on an octadecylsilane column.                                     
4. N.m.r. in solvent B: 2.6(s, 3H), 3.2(d, 2H), 3.6(dd, 2H), 4.3(s, 3H),  
4.6(m, 4H), 5.2(d, 1H),                                                   
5.8(d, 1H), 7.1(s, 1H), 7.65(d, 1H), 8.0(dd, 1H) 8.9(d, 1H).              
5. Reaction time: 1 Hour 45 minutes.                                      
6. N.m.r. in solvent B: 2.9(s, 3H), 3.5-3.7(m, 4H), 4.2(s, 3H),           
4.5-4.7(m, 4H), 5.1(d, 1H),                                               
5.57, (d, 1H), 7.05(s, 1H), 7.55(d, 1H), 8.0(dd, 1H), 9.0(d, 1H).         
7. Prepared in two stages, condensation and oxidatin as in footnote 3.    
Reaction time for the                                                     
condensation: 4 hours 30 minutes at 50° C.                         
8. N.m.r. in solvent B: 2.61(s, 3H), 3.2(d, 2H), 3.9(s, 5H), 4.7(m, 4H),  
5.2(d, 1H), 5.9(d, 1H),                                                   
7.05(s, 1H), 7.65(d, 1H), 7.75(d, 1H).                                    
9. Reaction time: 2 hours 30 minutes at 50° C.                     
10. N.m.r. in solvent B: 3.53(m, 2H), 3.7(s, 3H), 4.23(m, 2H), 5.08(s,    
2H), 5.2(d, 1H), 5.77(d, 1H)                                              
7.08(s, 1H), 7.34(s, 2H).                                                 
11. Reaction time: 2 hours.                                               
12. N.m.r. in solvent B: 3.51(m, 2H), 4.52(m, 2H), 5.05(s, 2H), 5.11(d,   
1H), 5.75(s, 2H), 5.8(d, 1H)                                              
7.0(d, 1H), 7.17(s, 1H), 7.78(s, 2H), 8.24(d, 1H), 8.96(s, 1H).           
13. Reaction temperature: 50° C.                                   
14. N.m.r. in solvent B: 3.5(m, 2H), 3.7(s, 3H), 3.8-4.6(m, 5H), 4.9(m,   
1H), 5.15(d, 1H),                                                         
5.78(d, 1H), 6.99(s, 1H), 7.3(s, 2H).                                     
15. Reaction temperature: 50° C.                                   
16. N.m.r. in solvent B: 3.6(m, 2H), 3.72(s, 3H), 4.3(dd, 2H), 5.15(d,    
1H), 5.43(s, 2H),                                                         
5.8(d, 1H), 7.06(s, 1H), 7.33(s, 2H), 7.73(s, 2H).                        
17. Reaction time: 45 minutes at 50° C.                            
18. N.m.r. in solvent B: 3.55(m, 2H), 4.5(dd, 2H), 5.05(d, 1H), 5.45(s,   
2H), 5.8(d, 1H), 7.0(d, 1H),                                              
7.05(s, 1H), 7.65(d, 2H), 7.7(d, 1H), 8.05(d, 1H), 8.80(d, 1H).           
19. Reaction time: 20 hours.                                              
20 N.m.r. in solvent B: 3.5(m, 2H), 4.1-4.8(m, 5H), 4.9(m, 2H), 5.13(d,   
1H), 5.81(d, 1H),                                                         
7.01(d, 1H), 7.02(s, 1H), 7.65(d, 1H), 8.11(d, 1H), 8.74(d, 1H).          
21. Reaction time: 1 hour.                                                
22. N.m.r. in solvent B: 3.42(d, 1H), 3.68(d, 1H), 4.07(s, 3H), 4.57(d,   
1H), 4.95(d, 1H), 4.64(d,                                                 
1H), 4.82(d, 1H), 5.12(d, 1H), 5.77(d, 1H), 7.07(s, 1H), 7.91(s, 2H),     
8.85(s, 1H).                                                              
23. Reaction time: 1 hour.                                                
24. N.m.r. in solvent B: 3.57(d, 1H), 3.65(d, 1H), 3.67(t, 2H), 4.18(d,   
1H), 4.4-4.9(m, 5H),                                                      
5.11(d, 1H), 5.78(d, 1H), 6.61(d, 1H), 7.0(s, 1H), 8.15(d, 1H).           
25. Reaction time: 2 hours 30 minutes at 50° C.                    
26. N.m.r. in solvent B: 3.4(d, 1H), 3.62(d, 1H), 3.68(s, 3H), 3.95(d,    
1H), 4.42(d, 1H),                                                         
4.63(d, 1H), 4.82(d, 1H), 5.11(d, 1H), 5.74(d, 1H), 7.0(s, 1H), 7.3(s,    
2H).                                                                      
27. Reaction time: 2 hours at 50° C.                               
28. N.m.r. in solvent B: 3.25(m, 2H), 3.6(s, 3H), 4.0(dd, 2H), 4.8(d,     
1H), 5.15(s, 2H), 5.5(d, 1H),                                             
6.65(s, 1H), 7.15(d, 1H), 7.4(d, 2H), 8.25(m, 3H).                        
29. Reaction time: 20 hours.                                              
30. N.m.r. in solvent B: 3.55(m, 2H), 4.2-4.9(m, 5H), 4.98(t, 1H),        
5.19(d, 1H), 5.39(s, 2H),                                                 
5.81(d, 1H), 7.02(s, 1H), 7.0-7.3(m, 2H), 7.38(d, 2H), 7.68(d, 2H),       
8.3-8.7(m, 2H).                                                           
 
    
     The cephalosporin starting materials for use in the above process are obtained by the method described above. 
     Using this general process the following compounds were prepared. 
     
         ______________________________________                                    
 ##STR72##                                                                
R                  Footnotes                                              
______________________________________                                    
CH.sub.2 CHCHCO.sub.2 t-Bu                                                
                   1, 2                                                   
CH.sub.2 CH.sub.2 SCH.sub.3                                               
                   3, 4                                                   
CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                       
                   5, 6                                                   
CH.sub.2 CN        7                                                      
CH.sub.2 CH.sub.2 F                                                       
                   8, 9                                                   
 ##STR73##         10, 11, 12, 13                                         
CH.sub.2 CF.sub.2  14, 15, 16, 13                                         
 ##STR74##         17, 18, 15, 13                                         
______________________________________                                    
 Footnotes                                                                
1. The starting material was prepared by reaction of 4-nitrobenzyl        
2-(2-tritylaminothiazol-4-yl)-2-(Z)-hydroxyiminoacetate with t-buyl       
4-bromobut-2-enoate and hydrogenolysis of the resulting ester to          
give 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-3-t-butoxycarbonyl-             
prop-2-enyloxyimino]acetic acid. N.m.r. in solvent C: 1.44(s, 9H),        
4.75(d, 2H), 5.92(m, 1H), 6.56(s, 1H), 6.7-6.9(m, 2H), 7.29(s, 15H).      
2. N.m.r. in solvent C: 3.4(m, 2H), 3.9(d, 1H), 4.45(d, 1H), 4.9(m,       
2H), 5.02(d, 1H), 5.7(m, 1H), 5.95(d, 1H), 6.83(s, 1H), 6.9(d, 1H),       
7.32(s, 15H).                                                             
3. The starting material was prepared by reaction of ethyl                
2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-bromoethoxyimino)acetate           
(UK Patent Application 217702A) with the sodium salt of methyl            
mercaptan and hydrolysis of the resulting ester to give 2-(2-trityl-      
aminothiazol-4-yl)-2-((Z)-2-methylthioethoxyimino)acetic acid. N.m.r.     
in solvent C: 2.1(s, 8H), 2.8(t, 2H) 4.3(t, 2H), 6.6(s, 1H), 7.3(s,       
15H).                                                                     
4. N.m.r. in solvent C: 2.1(s, 3H), 2.9(m, 2H), 3.5(s, 2H),               
3.95-4.6(m, 4H), 5.1(d, 1H), 5.95(d, 1H), 6.8(s, 1H), 7.35(s, 15H).       
5. The starting material was prepared by oxidation of the product in      
Footnote 3 to give 2-(2-tritylaminothiazol-4-yl)-2-((Z)-2-                
methanesulphonylethoxyimino)acetic acid.                                  
N.m.r. in solvent C: 2.9(s, 3H), 3.5(t, 2H),4.5(t, 2H), 6.65(s, 1H),      
7.3(s, 15H).                                                              
6. N.m.r. in solvent C: 3.0(s, 3H, 3.5-3.7(m, 4H), 4.3(m, 2H), 4.7(m,     
2H),                                                                      
5.1(d, 1H), 5.9(d, 1H) 6.8(s, 1H), 7.4(s, 15H).                           
7. N.m.r. in solvent A: 3.4(s, 2H), 3.9(d, 1H), 4.4(d, 1H), 4.8(s, 2H),   
4.9(d, 1H), 5.7(d, 1H), 6.8(s, 1H), 7.2(s, 15H).                          
8. The starting material may be prepared as follows. Reaction of ethyl    
2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-hydroxyethoxyimino]acetate with    
diethylamino sulphur trifluoride and hydrolysis of the resulting ester    
gave 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-fluoroethoxyimino]acetic      
acid.                                                                     
N.m.r. in solvent A: 4.15(m, 1H), 4.38(m, 1H), 4.48(m, 1H), 4.92(m, 1H),  
6.94(s, 1H), 7.4(s, 15H).                                                 
9. N.m.r. in solvent C: 3.4(m, 2H), 4.2-4.6(m, 4H), 4.7(m, 1H), 5.0(m,    
1H), 5.1(d, 1H), 5.9(d, 1H), 6.9(s, 1H), 7.4(s, 15H).                     
10. The starting material was prepared by reaction of 2-bromo             
methylimidazole with N-hydroxy-phthalimide, deprotection to give          
0-(imidazol-2-yl)methylhydroxylamine and condensation with                
2-(2-aminothiazol-4-yl)-glyoxylic acid to give 2-(2-aminothiazol-4-       
yl)-2-[(Z)-(imidazol-2-yl)-methyoxyimino]acetic acid. N.m.r. in           
solvent B: 5.42(s, 2H), 7.17(s, 1H), 7.67(s, 2H).                         
11. A suspension of the product from Footnote 10 (4.4 mM) in DMF          
(40 ul.) at 0° C. was dissolved by the addition of 3M HCl in       
ether                                                                     
(8.8 mM). N-hydroxybenzotriazole (4.4 mM) and t-butyl 7-amino-3-          
azidomethylceph-3-em-4-carboxylate (4.0 mM) were added to the             
solution, followed by dropwise addition of a solution of DCCI             
(4,4 mM) in CH.sub.3 CN (15 ml.) during 20 minutes. The mixture was       
left to stir for 23 hours at 0° C. and 1 hour at room              
temperature.                                                              
The precipitate was filtered, washed with DMF (3 ml.) and the             
residue evaporated to dryness. Trituration at 0° C. with aqueous   
NaHCO.sub.3 (5%) yielded a yellow solid which was treated at room         
temperature with TFA/H.sub.2 O (15:1) during 2 hours. Evaporation to      
dyrness and purification of the residue by chromatography on              
Dianion HP 20 resin gave the required product.                            
12. N.m.r. in solvent B: 3.6(m, 2H), 4.2(dd, 2H), 5.25(d, 1H), 5.5(s,     
2H), 5.9(d, 1H), 7.25(s, 1H) 7.7(s, 2H).                                  
13. This molecule is not tritylated on the                                
14. The starting material was prepared by condensation of                 
0-(2,2,2-trifluoroethyl)hydroxylamine with 2-(2-aminothiazol-4-yl)-       
glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-2,2,2-trifluoro-    
ethoxyimino]acetic acid. N.m.r. in solvent B: 4.73(q, 2H), 6.93(s,        
1H).                                                                      
15. The method of condensation was that described in Footnote 11.         
16. N.m.r. in solvent B: 3.5(d, 1H), 3.75(d, 1H), 3.95(d, 1H),            
4.5(d, 1H), 4.75(d, 1H), 4.95(d, 1H), 5.3(d, 1H), 5.9(d, 1H), 7.2(s,      
1H).                                                                      
17. The starting material was prepared by reaction of                     
0-(1-methylimidazol-2-yl)methylhydroxylamine with 2-(2-amino-             
thiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-            
[(Z)-(1-methylimidazol-2-yl)methoxy-imino]acetic acid.                    
N.m.r. in solvent B: 3.90(s, 3H), 5.51(s, 2H), 7.17(s, 1H),               
7.57(s, 1H), 7.62(s, 1H).                                                 
18. N.m.r. in solvent B: 3.6(m, 2H), 3.9(s, 3H), 4.2(dd, 2H), 5.2(d,      
1H), 5.5(s, 2H), 5.85(d, 1H), 7.05(s, 1H), 7.7(dd, 2H).                   
 
    
     Using the general process of reduction described in Footnote 3 of the description of starting materials for Example 16, the following compounds were prepared: 
     
         ______________________________________                                    
 ##STR75##                                                                
R                  Footnotes                                              
______________________________________                                    
CH.sub.2 CCHCO.sub.2 H                                                    
                   1                                                      
CH.sub.2 CH.sub.2 SCH.sub.3                                               
                   2                                                      
CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                                       
                   3                                                      
CH.sub.2 CN        4                                                      
CH.sub.2 CH.sub.2 F                                                       
                   5                                                      
 ##STR76##         6                                                      
CH.sub.2 CF.sub.3  7                                                      
 ##STR77##         8                                                      
______________________________________                                    
1. N.m.r. in solvent B: 3.66(s, 2H), 3.78(m, 2H) 4.88(m, 2H),             
5.18(d, 1H), 5.88(d, 1H), 6.05(d, 1H), 6.92(d, 1H), 6.94(s, 1H).          
2. N.m.r. in solvent B: 2.1(s, 3H), 2.85(t, 2H), 3.6-3.9(m, 4H),          
4.4(t, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H).                           
3. N.m.r. in solvent B: 2.95(s, 3H), 3.65(m, 6H), 4.6(t, 2H), 5.15(d,     
1H), 5.85(d, 1H), 7.05(s, 1H).                                            
4. N.m.r. in solvent A: 3.66(s, 2H), 3.78(q, 2H), 5.02(s, 2H),            
5.15(d, 1H), 5.84(d, 1H) 6.98(s, 1H).                                     
5. N.m.r. in solvent B: 3.6-4.0(m, 4H), 4.32(m, 1H), 4.4-4.7(m, 2H),      
5.08(m, 1H), 5.24(d, 1H) 5.58(d, 1H), 6.98(s, 1H).                        
6. N.m.r. in solvent B: 3.8(m, 4H), 5.15(d, 1H), 5.43(s, 2H), 5.86(d,     
1H), 7.12, (s, 1H), 7.66(s, 2H).                                          
7. N.m.r. in solvent B: 3.4-4.0(m, 4H), 4.65(d, 1H), 4.85(d, 1H),         
5.17(d, 1H), 5.85(d, 1H), 7.05(s, 1H).                                    
8. N.m.r. in solvent B: 3.6-3.9(m, 4H), 3.9(s, 3H); 5.15(d, 1H),          
5.5(s, 2H), 5.85(d, 1H), 7.05(s, 1H), 7.65(dd, 2H).                       
 
    
     EXAMPLES 54-75 
     The appropriate C3 1  -N-substituted CAZAMCA (1 eq.) and an excess (1.5 eq.) of an appropriate quaternay heterocyclic salt were reacted in a mixture of DMF/H 2  O (2:1) in the presence of NaHCO 3  (4 eq.) at 40° C. for 2.5 hr., and the product was purified by HPLC, using MeOH/H 2  O/HOAc as eluant, to give the following compounds: 
     
         __________________________________________________________________________
 ##STR78##                                                                
                                Yield                                     
Example                                                                   
     R          R.sup.1         (%) Footnotes                             
__________________________________________________________________________
54   PhCH.sub.2                                                           
                 ##STR79##      30  1, 2                                  
55   Et                                                                   
                 ##STR80##      58  3, 4                                  
56.  furfuryl                                                             
                 ##STR81##      40  5, 6                                  
57.  CH.sub.2.CO.sub.2 H                                                  
                 ##STR82##      31  7, 8                                  
58.  (CH.sub.2).sub.2 OH                                                  
                 ##STR83##      14  9, 10                                 
59.  Et                                                                   
                 ##STR84##      33  11                                    
60.  Et                                                                   
                 ##STR85##      11  12                                    
61.  Et                                                                   
                 ##STR86##      47  13                                    
      ##STR87##                                                           
                 ##STR88##      10  14, 15                                
63.  (CH.sub.2).sub.2 OCH.sub.3                                           
                 ##STR89##      36  16, 17                                
64.  Et                                                                   
                 ##STR90##      10  18                                    
65.  i-Pr                                                                 
                 ##STR91##       5  19, 20                                
66.  Et                                                                   
                 ##STR92##      23  21                                    
67.  (CH.sub.2).sub.2 NH.sub.2                                            
                 ##STR93##      30  22, 23                                
68.  (CH.sub.2).sub.2 F                                                   
                 ##STR94##      23  24, 25                                
69.  Et                                                                   
                 ##STR95##      15  26                                    
70.  Me                                                                   
                 ##STR96##      22  27, 28                                
71.  Et                                                                   
                 ##STR97##      14  29                                    
72.  allyl                                                                
                 ##STR98##      13  30, 31                                
73.  Pr                                                                   
                 ##STR99##      18  32                                    
74.  (CH.sub.2).sub.2 CN                                                  
                 ##STR100##     33  33, 34                                
75.  (CH.sub.2).sub.2 NH.CHO                                              
                 ##STR101##     37  35                                    
__________________________________________________________________________
Footnotes                                                                 
1. Eluant proportion 35:65:1. N.m.r. in solvent B: 1.55(m, 6H),           
3.4-3.6(m, 2H), 4.0(s,3H),                                                
4.7-5.0(m, 4H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.2-7.5(m, 7H),       
8.4(d, 2H).                                                               
2. The precursor C3.sup.1 N-benzyl CAZAMCA was obtained by reductive      
amination of                                                              
benzaldehyde with CAZAMCA. Thus, CAZAMCA (1 eq.) was treated with         
benzaldehyde (1.4 eq) and Et.sub.3 N (1.4 eq.) in anhydrous MeOH in the   
presence of 3A                                                            
molecular seives with NaBH.sub.3.CN (1.4 eq.) for 1/2 hr. at room         
temperature. The                                                          
product was purified by HPLC, eluant proportion 30:70:1. N.m.r. in        
solvent B: 1.5(s, 6H),                                                    
3.5-3.7(m, 2H), 3.8-4.0(m, 2H), 4.0-4.3(m, 2H), 5.2(d, 1H), 5.9(d, 1H),   
7.0(s,                                                                    
1H), 7.4-7.6(m, 5H).                                                      
3. Used 2 eq. pyridinium salt. Reaction time 1.5 hr. Eluent proportion    
25:75:1. N.m.r. in                                                        
solvent B: 1.6(s, 6H), 3.2-3.8(m, 4H), 4.0(s, 3H), 4.6-4.8(m, 2H), 5.3(d, 
1H), 6.0(d, 1H),                                                          
7.15(s, 1H), 7.2-7.4(m, 2H), 8.2-8.4(m, 2H).                              
4. The precursor C.sub.3 &#39; N-ethyl CAZAMCA was obtained by reductive      
amination of                                                              
acetaldehyde (1.1 eq.) with CAZAMCA (1.0 eq.) in presence of NaBH.sub.3   
CN (1.0 eq.) and                                                          
Et.sub.3 N (1.0 eq.). The acetaldehyde was added dropwise at room         
temperature in MeOH, and                                                  
the mixture stirred for 1/2 hr. The product was purified by preparative   
HPLC using                                                                
MeOH/H.sub.2 O/HOAc 10:90:1 v/v/v, followed by 15:85:1. N.m.r. in solvent 
B: 1.3 (t, 3H):                                                           
1.6(s, 6H), 2.8-3.2(m, 2H), (m, 2H) 3.7-4.1(m, 4H), 5.3(d, 1H), 6.0(d,    
1H), 7.2(s, 1H).                                                          
5. N.m.r. in solvent B: 1.55(m, 6H), 3.3-3.6(m, 2H), 4.0(s, 3H),          
4.8-5.0(m, 4H), 5.2(d, 1H),                                               
5.95(d, 1H), 6.4-6.6(m, 2H), 7.1(s, 1H) 7.3-7.6(d, 2H), 7.6- 7.7(m, 1H)   
8.3-8.6(d, 2H).                                                           
6. The precursor was obtained by reductive amination of 2-furaldehyde     
with CAZAMCA,                                                             
as in Footnote 2. Reaction time 1.5 hr. Eluant proportion 20:80:1. N.m.r. 
in solvent B:                                                             
1.6(s, 6H), 3.6-3.8(m, 2H), 3.9-4.1(m, 2H), 4.2-4.4(m, 2H), 5.25(d, 1H),  
5.95(d,                                                                   
1H), 6.5-6.8(m, 2H), 7.1(s, 1H), 7.8(d, 1H).                              
7. Eluant proportion 30:70:1. N.m.r. in solvent B: 1.5-1.6(m, 6h),        
3.3-3.6(m, 2H),                                                           
4.0(s, 3H), 4.4-4.6(m, 2H), 4.6-4.8(m, 2H), 5.3(d, 1H), 6.0(d, 1H),       
7.1(s, 1H),                                                               
7.0-7.5(m, 2H), 8.3-8.5(m, 2H).                                           
8. Precursor obtained as in Footnote 4, starting from glyoxylic acid.     
Eluant proportion                                                         
15:85:1. Yield 40% N.m.r. in solvent B; 1.6(m, 6H), 3.6-4.2(m, 6H),       
5.3(d, 1H),                                                               
6.0(d, 1H), 7.1(s, 1H).                                                   
9. Eluant proportion 20:80:1. N.m.r. in solvent B: 1.55(s, 6H),           
3.2-3.6(m, 2H),                                                           
3.5-3.8(m, 4H), 3.35(s, 3H), 4.6-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H),      
7.1(s, 1H),                                                               
7.3(d, 2H), 8.3(d, 2H).                                                   
10. Precursor obtained by reductive amination of glycolaldehyde as in     
Footnote 4. Eluant                                                        
proportion 15:85:1. Yield 43%. N.m.r. in solvent B; 1.6(s, 6H),           
3.0-3.4(m, 2H),                                                           
3.6-4.0(m, 4H), 4.2-4.6(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H).       
11. Reacted at 50° C. for 2 hrs. Eluant proportion 30:70:1. N.m.r. 
in solvent B: 1.2(m,                                                      
3H), 1.5(s, 6H), 3.2-3.8(m, 4H), 4.6-4.8(m, 2H), 5.2(s, 1H), 5.9(s, 1H),  
7.1(s, 1H),                                                               
7.2-8.0(m, 7H).                                                           
12. Reacted at 45° C. for 20 hrs. Eluant proportion 25:75:1. N.m.r 
in solvent B:                                                             
1.0-1.3(m, 3H), 1.55(s, 6H), 3.5-3.8(m, 4H), 3.8(s, 3H), 4.3(d, 1H),      
4.7(d, 1H),                                                               
5.2(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.35(d, 1H), 7.7(d, 1H).             
13. Reacted at room temperature for 3.5 hrs, using N-(Boc-aminoethyl)-4-ch
loropyridinium                                                            
chloride as the quaternary heterocyclic salt. The product was deprotected 
by treating with                                                          
TFA at room temperature for 1 hr. Eluant proportion 35:65:1. N.m.r. in    
solvent B:                                                                
1.0-1.3(m, 3H), 1.6(s, 6H), 3.2-3.8(m, 4H), 4.3-4.8(m, 4H), 5.2(d, 1H)    
5.9(d, 1H),                                                               
7.1(s, 1H), 7.2-7.4(d, 2H), 8.3-8.5(d, 2H).                               
14. Reacted at room temperature for 5 hrs. Eluant proportion 15:85:1.     
N.m.r. in solvent B:                                                      
1.6(s, 6H), 3.2-3.7(m, 2H) 4.0(s, 3H), 4.5-4.9(m, 2H), 5.0-5.4(m, 2H),    
5.2(d, 1H),                                                               
5.9(d, 1H), 7.1(s, 1H), 7.2-7.4(m, 2H), 7.9-8.0(m, 2H), 8.2-8.5(m, 2H),   
8.9-9.0(m, 2H).                                                           
15. The precursor obtained as in Footnote 4 by reductive amination of     
pyridine-4-                                                               
carboxaldehyde. Eluant proportion 20:80:1. Yield 37%. N.m.r. spectrum in  
solvent B:                                                                
1.6(s, 6H), 3.6-3.8(m, 2H), 3.9-4.3(m, 2H), 4.4-5.0(m, 2H), 5.2(d, 1H),   
6.0(d, 1H),                                                               
7.1(s, 1H), 8.0-8.3(m, 2H), 8.8-9.2(m, 2H).                               
16. Reacted at room temperature for 1.5 hrs. Eluant porportion 25:75:1.   
N.m.r. in solvent                                                         
B: 1.55(s, 6H), 3.2(s, 3H), 3.2-4.0(m, 6H), 3.9(s, 3H), 4.6-4.9(m,        
2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.2(d, 2H), 8.2(d, 2H).          
17. The precursor was obtained as in Footnote 4 by reductive amination of 
2-methoxy-                                                                
acetaldehyde, 2 hrs at room temperature. Eluant proportion 20:80:1. Yield 
24%. N.m.r. in                                                            
solvent B: 1.6(s, 6H), 3.3(s, 3H), 3.2-4.0(m, 8H), 5.2(d, 1H), 5.9(d,     
1H), 7.05(s, 1H).                                                         
18. Reacted for 2 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:    
1.2(t, 3H),                                                               
1.55(s, 6H), 2.3(s, 3H), 3.2-3.9(m 4H), 4.7(s, 2H), 4.9(m, 2H),           
5.2-5.5(m, 3H),                                                           
5.9-6.5(m, 2H), 7.0-7.5(m, 5H), 7.55(d, 2H), 8.4(d, 2H).                  
19. Reaction time 8 hrs. at 45° C. Eluant proportion 20:80:1.      
N.m.r. in solvent B:                                                      
1.1-1.4(m, 6H), 1.6(s, 6H), 2.2-2.4(m, 1H), 3.2-3.6(m, 2H), 4.0(s, 3H),   
4.2-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H), 7.3(d, 2H), 8.3(d,    
2H).                                                                      
20. The precursor was obtained as in Footnote 4, by reductive amination   
of acetone                                                                
(4 eq.). Eluant proportion 20:80:1. Yield 50%. N.m.r. in solvent B:       
1.2(d, 6H), 1.6(s, 6H),                                                   
3.2-4.0(m, 5H), 5.2(d, 1H), 5.9(d, 1H), 7.05(d, 1H).                      
21. Reacted at 40-45° C. for 4 hrs. Eluant proportion 25:75:1.     
N.m.r. in solvent B: 1.2(t,                                               
3H), 1.55(s, 6H), 3.5(m, 2H), 3.4-3.8(m, 2H), 3.6(m, 2H), 5.2(d, 1H),     
5.9(d, 1H), 5.9(s, 2H),                                                   
7.05(s, 1H), 7.1-7.3(m, 1H), 8.5(d, 1H), 9.3(s, 1H).                      
22. Reacted at room temperature for 1.5 hrs, using Boc-aminoethyl CAZAMCA 
as                                                                        
starting material. Eluant proportion 35:65:1. The product was deprotected 
by solution in                                                            
TFA at room temperature for 1/2 hr. N.m.r. in solvent B: 155(s, 6H),      
2.6-4.0(m, 6H),                                                           
4.0(s, 3H, 4.6-4.9(m, 2H), 5.3(d, 1H), 6.0(d, 1H), 7.0(s, 1H), 7.2(d,     
1H), 8.2(d, 1H).                                                          
23. The precursor was obtained by reductive amination of                  
2-(Boc-amino)acetaldehyde at                                              
room temperature for 2 hrs. Eluant proportion 35:65:1. Yield 20%. N.m.r.  
in solvent B:                                                             
1.4(s, 9H), 1.55(s, 6H), 2.7-3.4(m, 4H), 3.6-4.2(m, 4H), 5.2(d, 1H),      
5.9(d, 1H),                                                               
7.05(s, 1H). The 2-(Boc-amino)propionaldehyde was obtained by oxidation   
of                                                                        
2-(Boc-amino)ethanol with pyridinium chlorochromate in CH.sub.2 Cl.sub.2  
containing                                                                
sodium acetate, at 0° C. for 2 hrs, and purification by            
chromatography on silica. Yield 68%.                                      
24. Reaction time 2 hrs. at room temperature. Eluant proportion 25:75:1.  
N.m.r. in solvent B:                                                      
1.55(s, 6H), 3.2-3.6(m, 2H), 3.8-4.0(m, 2H), 4.0(s, 3H), 4.2-4.5(m, 1H),  
4.8-5.1(m, 1H),                                                           
4.6-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.05(s, 1H), 7.3(d, 1H), 8.3(d,   
1H).                                                                      
25. The precursor was obtained by reductive alkylation of an excess of    
2-fluoroacetaldehyde in                                                   
CH.sub.2 Cl.sub.2 solution, for 2.5 hrs. at room temperature. Eluant      
proportion 25:75:1. Yield 23%.                                            
N.m.r. in solvent B: 1.55(s, 6H), 3.4-3.6(m, 2H), 3.6-4.1(m, 2H),         
4.4-4.6(m, 1H),                                                           
5.0-5.2(m, 1H), 5.2(d, 1H), 5.9(d, 1H), 7.1(s, 1H).                       
26. Reaction carried out for 3 hrs. at room temperature and 1 hr. at      
40° C. Eluant                                                      
proportion 25:75:1. N.m.r. in solvent B: 1.2(m, 3H), 1.55(s, 6H),         
3.5-3.9(m, 4H),                                                           
3.95(s, 3H), 4.7(s, 2H), 5.25(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.3-7.7(m,  
1H), 8.2(d, 1H),                                                          
8.65(d, 1H).                                                              
27. Reaction carried out at 45° C. for 1 hr. Eluant proportion     
20:80:1.                                                                  
N.m.r. in solvent B: 1.5(s, 6H), 3.1(s, 3H), 3.2(d, 1H), 3.5(d, 1H),      
3.9(s, 3H), 4.5(d, 1H),                                                   
4.65(d, 1H), 5.2(d, 1H), 5.85(d, 1H), 7.05(s, 1H), 7.0-7.2(m, 2H),        
8.2-8.4(m, 2H).                                                           
28. The CAZAMCA starting material was obtained as follows: A solution of  
4-chloro-                                                                 
N-methylbutyramide in CH.sub.2 Cl.sub.2 was treated dropwise with silver  
fluoroborate in                                                           
a mixture of CH.sub.2 Cl.sub.2 and benzene at -20° C., and the     
reaction was allowed                                                      
to warm to room temperature. The silver chloride precipitate was filtered 
off, and the                                                              
product was purified by silica chromatography, eluting with CH.sub.2      
Cl.sub.2 /MeOH, 4:1,                                                      
to yield N-methyliminobutyrolactone fluoroborate, 71%, which was          
converted to free base                                                    
by reaction with 1 eq. of 1,8-diazabicylo[5,4,0]undec-7-ene (DBU) in      
CH.sub.2 Cl.sub.2                                                         
(yield 62% of free base). This product was reacted with                   
7-[2-(2-aminothiazol-4-yl)-2-                                             
[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-iodomethylceph-3-em-4-carb
oxylic                                                                    
acid in acetonitrile at room temperature for 1/2 hr. to give the          
corresponding                                                             
3-[N-(1,2,3,4-tetrahydo-2-furylidene)-N-methylaminomethyl]cephem, which   
was                                                                       
hydrolysed with 4 eq. of sodium bicarbonate in water at room temperature  
for 1/2 hr.,                                                              
and the product purified by preparative HPLC eluting with MeOH/H.sub.2    
O/HOAc, 20:80:1 to                                                        
yield the required starting material, yield 45%.                          
29. Reaction carried out in DMF/H.sub.2 O, 1:1, at 40° C. for 4    
hours. Eluant proportion                                                  
25:75:1. N.m.r. in solvent B: 1.1(m, 3H), 1.55(s, 6H), 2.5(s, 3H),        
3.0-3.7(m, 4H),                                                           
3.8(s, 3H), 4.6(s, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0-7.05(m, 3H), 8.2(d,   
1H).                                                                      
30. Reaction at room temperature for 1.5 hrs. Eluant proportion 25:75:1.  
N.m.r. in                                                                 
solvent B: 1.6(s, 6H), 3.2-3.6(m, 4H), 4.0(s, 3H), 4.0-4.3(m, 1H),        
4.5-4.8(m, 2H),                                                           
5.0-5.2(m, 1H), 5.2(d, 1H), 5.5-6.0(m, 1H), 5.9(d, 1H), 7.1(s, 2H),       
7.2(d, 2H), 8.3(d, 1H).                                                   
31. The precursor CAZAMCA derivative was a mixture of N-allyl and         
N-propyl,                                                                 
obtained by reductive alkylation of acrylaldehyde, as in Footnote 4,      
using 1.2 eq.                                                             
of the aldehyde, and reacting at room temperature for 1 hr. Eluant        
proportion                                                                
20:80:1. This mixture was used to prepare the final product, purification 
of which                                                                  
separated the N-allyl and N-propyl analogues.                             
32. Eluant proportion 25:75:1. N.m.r. in solvent B: 0.9(t, 3H), 1.6(s,    
6H), 3.1-3.8(m, 4H),                                                      
3.9(s, 3H), 4.5-4.8(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.2(d,    
2H), 8.2(d, 2H).                                                          
33. Reacted overnight at room temperature. Eluant proportion 20:80:1.     
N.m.r. in solvent                                                         
B: 1.5(s, 6H), 2.6-3.0(m, 2H), 3.95(d, 1H), 3.25(d, 1H), 3.95(s, 3H),     
4.5-4.8(m, 2H),                                                           
5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H), 7.4(d, 2H), 8.4(d, 2H).               
34. The precursor was obtained as in Footnote 4 by Michael addition of    
acrylonitrile to                                                          
CAZAMCA The product was purified by HPLC, eluant proportion 15:85:1.      
Yield 31%.                                                                
N.m.r. in solvent B: 1.55(s, 6H), 2.8-3.1(m, 2H), 3.2-3.4(m, 2H),         
3.5-3.8(m, 2H), 3.8-4.2(m, 2H), 5.2(d, 1H), 5.9(d, 1H), 7.0(s, 1H).       
35. This compound obtained by reacting the product of Example 67 with     
formic acetic                                                             
anhydride in MeOH at room temperature for 1/2 hr. Eluant proportion       
20:80:1. N.m.r.                                                           
in solvent B: 1.55(s, 6H), 3.2-3.8(m, 6H), 3.9(s, 3H), 3.5-3.8(m, 2H),    
5.2(d, 1H),                                                               
5.9(d, 1H), 7.0(s, 1H), 7.2(d, 2H), 8.0(s, 1H), 8.2(d, 2H).               
 
    
     EXAMPLES 76-87 
     The appropriate 3-acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-(substituted oximino) acetamido]ceph- 3-em-4-carboxylic acid and the appropriate amino-substituted quaternary heterocycle were reacted together at 85° C. at pH 7.0-7.5. The pH was maintained with this range by the addition of dilute HOAc or NaHCO 3  solution as necessary. The product was purified by preparative HPLC, using a mixture of MeOH/H 2  O/HOAc as eluant. 
     The following compounds were prepared: 
     
         __________________________________________________________________________
 ##STR102##                                                               
Example                                                                   
     R.sup.11 R      R.sup.1         Yield                                
                                         Footnotes                        
__________________________________________________________________________
76.  Me       H                                                           
                      ##STR103##     11  1                                
77.  Me       H                                                           
                      ##STR104##     6   2                                
78   C(CH.sub.3).sub.2 COOH                                               
              H                                                           
                      ##STR105##     8   3                                
79   Me       H                                                           
                      ##STR106##     7   4, 5                             
80   Me       Me                                                          
                      ##STR107##     31  6, 7                             
81.  C(CH.sub.3).sub.2 COOH                                               
              H                                                           
                      ##STR108##     6   8                                
82.  C(CH.sub.3).sub.2 COOH                                               
              H                                                           
                      ##STR109##     9   9                                
83.  C(CH.sub.3).sub.2 COOH                                               
              Me                                                          
                      ##STR110##     13  10                               
84.  C(CH.sub.3).sub.2 COOH                                               
              Et                                                          
                      ##STR111##     13  11, 12                           
85.  C(CH.sub.3).sub.2 COOH                                               
              (CH.sub.2).sub.2 NH.sub.2                                   
                      ##STR112##     7   13, 14, 15                       
86.  C(CH.sub.3).sub.2 COOH                                               
              Et                                                          
                      ##STR113##     4   16, 17                           
87.  C(CH.sub.3).sub.2 COOH                                               
              H                                                           
                      ##STR114##     12  18                               
__________________________________________________________________________
Footnotes                                                                 
1. Reaction time 3 hrs. Eluant proportion 15-20: 85-80:1. N.m.r. in       
solvent B: 3.55(s, 2H), 3.95(s, 3H),                                      
4.4(s, 3H), 4.4(s, 2H), 5.2(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.25(d, 1H), 
7.6(d, 1H), 7.85(t, 1H),                                                  
8.6(d, 1H), 8.8(d, 1H), 9.8(s, 1H).                                       
2. Reaction time 2 hrs. Eluant proportions as in Footnote 1. N.m.r. in    
solvent B; 3.55(s, 2H),                                                   
4.0(s, 3H), 4.46(s, 3H), 4.46(s, 2H), 5.15(d, 1H), 5.75(d, 1H), 7.0(s,    
1H), 7.0(d, 1H), 7.45(d, 1H),                                             
7.8-8.05(m, 2H), 9.3(d, 1H), 9.5(d, 1H).                                  
3. Reaction time 2 hrs. Eluant proportion 30-35: 70-65:1. N.m.r. in       
solvent B: 1.55(s, 6H), 3.55(s, 2H),                                      
4.4(s, 3H), 4.4(s, 2H), 5.15(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.15(d,     
1H), 7.55(d, 1H), 7.75(t, 1H),                                            
8.5(d, 1H), 8.7(d, 1H), 9.7(s, 1H).                                       
4. Eluant proportion 20-25: 80-75:1. N.m.r. in solvent B: 3.55(s, 2H),    
3.95(s, 3H), 4.4(s, 2H),                                                  
5.2(d, 1H), 5.5(s, 2H), 5.8(d, 1H), 7.05(s, 1H), 7.3(d, 1H), 7.65(d, 1H), 
7.85(t, 1H), 8.6(d, 1H),                                                  
8.8(d, 1H), 9.8(s, 1H).                                                   
5. The 5-amino-2-carbamoylmethylisoquinolinium chloride used as starting  
material was obtained by                                                  
alkylation of 5-aminoisoquinoline (1 eq.) with 2-chloroacetamide (1 eq.)  
in DMF overnight at 45° C.                                         
The precipitate was washed with DMF, then CH.sub.2 Cl.sub.2, and dried.   
Yield 76%. N.m.r. in solvent B:                                           
5.45(s, 2H), 7.4(dd, 1H), 7.6(d, 1H), 7.75(t, 1H), 8.45(d, 1H), 8.6(d,    
1H), 9.8(s, 1H).                                                          
6. Eluant proportion as in Footnote 4. N.m.r. in solvent B: 2.8(s, 3H),   
3.6(s, 2H), 4.0(s, 3H),                                                   
4.15(s, 2H), 4.45(s, 3H), 5.15(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.6-8.1,  
8.4-8.6 and                                                               
9.6-9.9(3m, 6H).                                                          
7. The 2-methyl-5-methylaminoisoquinolinium iodide used as starting       
material was obtained by                                                  
reacting 5-methylaminoisiquinoline with a large excess of methyl iodide   
at room temperature for 17                                                
hrs. in CH.sub.2 Cl.sub.2. The solvents were evaporated to give the       
required salt. Yield 100%.                                                
N.m.r. in solvent B: 4.0(s, 3H), 4.4(s, 3H), 7.05(d, 1H), 7.55(d, 1H),    
7.85(t, 1H), 8.6(s, 2H),                                                  
9.8(s, 1H).                                                               
8. Reaction time 3 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:   
1.5(s, 6H), 3.55(s, 2H),                                                  
4.45(s, 2H), 5.2(d, 1H), 5.45(s, 2H), 5.85(d, 1H), 7.05(s, 1H),           
7.15-7.4(m, 1H), 7.5-7.9(m, 2H),                                          
8.3-8.9(m, 2H), 9.7-9.9(m, 1H).                                           
9. Eluant proportions 20-25-30:80-75-70:1. N.m.r. in solvent B; 1.5(s,    
6H), 3.6(s, 2H),                                                          
4.5(s, 5H), 5.2(d, 1H), 5.85(d, 1H), 7.0(s, 1H), 6.7-7.1(m, 1H), 7.5(d,   
1H), 7.8-8.1(m, 2H),                                                      
9.3-9.6(m, 2H).                                                           
10. Eluant proportion 20-30:80-70:1. N.m.r. in solvent B: 1.5(s, 6H),     
2.8(s, 3H), 3.55(s, 2H),                                                  
4.4(s, 2H), 4.45(s, 3H), 5.1(d, 1H), 5.8(d, 1H), 7.05(s, 1H), 7.0-7.2,    
7.6-8.2, 8.4-8.6, and                                                     
9.6-10.0 (4 × m, 6H).                                               
11. Eluant proportion 25-30:75-70:1. N.m.r. in solvent B: 0.9(t, 3H),     
1.55(s, 6H), 3.2(q, 2H),                                                  
3.55(s, 2H), 4.4(s, 2H), 4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s,    
1H), 7.0-7.2, 7.6-8.2,                                                    
8.4-8.6 and 9.6-10.0 (4 × m, 6H).                                   
12. The 5-ethylamino-1-methylisoquinolinium iodide was prepared by the    
process described in                                                      
Footnote 7. N.m.r. in solvent B: 1.3(t, 3H), 3.3(q, 2H), 4.4(s, 3H),      
7.1(d, 1H), 7.55(d, 1H),                                                  
7.8(t, 1H), 8.6(d, 1H), 8.65(d, 1h), 9.75(s, 1H).                         
13. The quaternary heterocycle used as starting material was              
5-(2-Boc-aminoethylamino)-2-                                              
methylisoquinolinium methosulphate. Reaction time 2.5 hrs. Eluant         
proportion 30-40: 70-60:1.                                                
N.m.r. in solvent B: 1.3(s, 9H), 1.55(s, 6H), 3.1-3.5(m, 4H), 3.55(s,     
2H), 4.4(s, 2H),                                                          
4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.0-7.2, 7.6-8.2,      
8.4-8.6 and                                                               
9.6-10.0 (4 × m, 6H).                                               
14. The product was deprotected by dissolving in CH.sub.2 Cl.sub.2 /TFA   
(1:2) for 10 minutes at                                                   
room temperature. N.m.r. in solvent B: 1.55(s, 6H), 2.9-3.5(m, 4H),       
3.55(s, 2H), 4.4(s, 2H),                                                  
4.45(s, 3H), 5.05(d, 1H), 5.75(d, 1H), 7.0(s, 1H), 7.0-7.2, 7.6-8.2,      
8.4-8.6 and                                                               
9.6-10.0 (4 × m, 6H).                                               
15. The 5-(2-Boc-aminoethylamino)-2-methylisoquinolinium methosulphate    
starting material was                                                     
prepared as follows: 5-Hydroxyisoquinoline (1 eg.) and ethylene diamine   
(10 eq.), were reacted                                                    
in a Bucherer reaction, in water with sodium hydrogen sulphite (2 eq.) at 
160° C. for 20 hrs.                                                
The product was purified by chromatography on silica, eluting with        
CH.sub.2 Cl.sub.2 /MeOH,                                                  
97-90:3-10. Yield 26%. N.m.r. in d.sub.6 -DMSO: 2.9(t, 2H), 3.2(dt, 2H),  
6.3(t, 1H),                                                               
6.75(dd, 1H), 7.25(d, 1H), 7.45(t, 1H), 8.05(d, 1H), 8.4(d, 1H), 9.15(s,  
1H). The Boc derivative                                                   
was formed by reacting the above product with 0,0.sup.1 -di-tert-butyl    
carbonic anhydride                                                        
(1.5 eq.) in THF for 1 hr. The Boc compound was purified by               
chromatography on silica, eluting                                         
with ether. Yield 66%. N.m.r. in CDCl.sub.3 : 1.45(s, 9H), 3.2-3.7(m,     
4H), 4.8-5.1(m, 1H),                                                      
5.3-5.6(m, 1H), 6.7(dd, 1H), 7.3(d, 1H), 7.45(t, 1H), 7.65(d, 1H),        
8.45(d, 1H), 9.15(s, 1H).                                                 
This Boc product was quaternised with dimethyl sulphate, in CH.sub.2      
Cl.sub.2 at room temperature                                              
or 2 hrs. The solvent was evaporated, and the residue was washed with     
ether. N.m.r. in CDCl.sub.3 ;                                             
1.45(s, 9H), 3.2(m, 2H), 3.55(m, 2H), 3.8(s, 6H), 4.5(s, 3H), 6.7(d, 1H), 
7.3(d, 1H), 7.55(t, 1H),                                                  
8.1(d, 1H), 8.5(d, 1H), 9.5(s, 1H).                                       
16. Eluant proportion as in Footnote 11. N.m.r. in solvent B: 0.95(t,     
3H), 1.55(s, 6H), 3.25(q, 2H),                                            
3.6(s, 2H), 4.4(s, 2H), 4.6(s, 3H), 5.05(d, 1H), 5.8(d, 1H), 7.0(s, 1H),  
7.2-7.5, 7.8-8.2,                                                         
9.2-9.5(3 × m, 6H).                                                 
17. The 5-ethylamino-1-methylquinolinium iodide used as starting material 
obtained by the                                                           
process described in Footnote 7, starting from 5-ethylaminoquinoline, 72  
hrs at room temperature.                                                  
Yield 100%. N.m.r. in solvent B: 1.3(t, 3H), 3.35(q, 2H), 4.5(s, 3H),     
6.85(d, 1H), 7.35(d, 1H),                                                 
7.7-8.1(m, 2H), 9.25(d, 1H), 9.45(d, 1H).                                 
18. Eluant proportion as in Footnote 10. N.m.r. in solvent B: 1.55(s,     
6H), 3.55(s, 2H) 4.3(s, 2H),                                              
4.5(s, 3H), 5.2(d, 1H), 5.85(d, 1H), 7.0(s, 1H), 7.2(d, 1H), 7.6(dd, 1H), 
7.8(dd, 1H), 8.15(d, 1H),                                                 
8.6(d, 1H), 8.85(d, 1H).                                                  
 
    
     EXAMPLES 88-106 
     The appropriate quaternary chloro-hetercycle (1 eq.) was reacted with 3-aminomethyl 7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (1 eq.) in DMF/H 2  O (2:1). The solvents were evaporated and the residue was purified by HPLC, eluting with a mixture of MeOH/H 2  O/HOAc. The following compounds were prepared: 
     
         __________________________________________________________________________
 ##STR115##                                                               
Example                                                                   
       R                   Yield                                          
                               Footnotes                                  
__________________________________________________________________________
        ##STR116##         33  1, 2, 38                                   
        ##STR117##         23  3, 4, 38                                   
90.                                                                       
        ##STR118##         18  5, 6, 38                                   
        ##STR119##         26  7, 8, 38                                   
        ##STR120##         35  9, 10, 38                                  
        ##STR121##         40  11, 12, 38                                 
        ##STR122##         28  13, 14, 38                                 
        ##STR123##         40  15, 16, 38                                 
        ##STR124##         45  17, 18, 38                                 
        ##STR125##         44  19, 20, 38                                 
        ##STR126##         15  21, 22, 38                                 
        ##STR127##         14  23, 24, 38                                 
100.                                                                      
        ##STR128##         21  25, 26, 38                                 
101.                                                                      
        ##STR129##         36  27, 28, 38                                 
102.                                                                      
        ##STR130##         35  29, 30, 38                                 
103.                                                                      
        ##STR131##         37  31, 32, 38                                 
104.                                                                      
        ##STR132##         32  33, 34, 38                                 
105.                                                                      
        ##STR133##         17  35, 36, 38                                 
106.                                                                      
        ##STR134##         21  37, 38                                     
__________________________________________________________________________
Footnotes                                                                 
1. Reaction time 3 hrs. at room temperature. Eluant proportion 20:80:1.   
N.m.r. in                                                                 
solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H), 5.2(d, 1H),  
5.3(s, 2H),                                                               
5.85(d, 1H), 7.05(s, 1H), 6.9-7.2 and 8.2-8.6 (2 × m, 4H).          
2. The starting pyridinium salt was obtained by condensation of           
4-methylthio-                                                             
pyridine and 4-chloromethyl-2-quanidinothiazole hydrochloride in          
EtOH/DMF                                                                  
(5:1) under reflux overnight. The product was purified by silica          
chromatography,                                                           
eluting with CH.sub.2 Cl.sub.2 /MeOH, 100-70:30. Yield 20%. N.m.r. in     
solvent B: 2.65(s, 3H), 5.65(s, 2H), 7.55(s, 1H), 7.85 and 8.9 (2 × 
d, 4H).                                                                   
3. Reaction time 1 hr. at room temperature. Eluant proportion as in       
Footnote 1.                                                               
N.m.r. in solvent B: 1.55(s, 6H), 3.45(d, 1H), 3.75(d, 1H), 4.4(s, 2H),   
5.1(s, 2H),                                                               
5.25(d, 1H), 5.9(d, 1H), 5.3(s, 1H), 7.1(s, 1H), 7.0-7.3(m, 2H),          
8.1-8.5(m, 2H).                                                           
4. The starting pyridinium salt was obtained by the process in Footnote   
2, by                                                                     
alkylating 4-methylsulphonylpyrimidine with 6-chloromethyluracil. Yield   
47%.                                                                      
N.m.r. in solvent B: 2.7(s, 3H), 5.4(s, 3H), 7.9(d, 2H), 8.7(d, 2H).      
5. Reaction time 2.5 hrs. at room temperature. Eluant proportion 30:70:1. 
N.m.r. in                                                                 
solvent B: 1.55(s, 6H), 3.55(s, 2H), 4.4(s, 2H), 5.2(d, 1H), 5.9(d, 1H),  
6.0(s, 2H),                                                               
6.9-7.2(m, 2H), 7.1(s, 1H), 7.95(s, 4H), 8.1-8.5(m, 2H).                  
6. The starting pyridinium salt was obtained by the process of Footnote   
2. Yield 30%.                                                             
N.m.r. in solvent B: 2.65(s, 3H), 6.25(s, 2H), 7.9(s, 4H), 7.9 and 8.7(2  
× d, 4H).                                                           
7. Reaction as Footnote 3. N.m.r. in solvent B: 1.6(s, 6H), 3.6(s, 2H),   
4.4(s, 2H),                                                               
5.3(d, 1H), 5.4(s, 2H), 5.95(s, 1H), 7.1(s, 1H), 7.0-7.3(m, 2H),          
8.2-8.6(m, 2H),                                                           
8.85(s, 1H).                                                              
8. The starting pyridinium salt was obtained by the process of Footnote   
2, carried                                                                
out at room temperature for 40 hrs. Yield 81%. N.m.r. in solvent B:       
2.7(s, 3H),                                                               
5.65(s, 2H), 7.95(d, 2H), 8.8(d, 2H), 8.8(s, 1H).                         
9. Reaction time 2 hrs. Eluant proportion 25:75:1. N.m.r. in solvent B:   
1.55(s, 6H),                                                              
3.25(s, 3H), 3.45(s, 3H), 3.55(s, 2H), 4.35(s, 2H), 4.7(s, 4H), 5.25(d,   
1H), 5.9(d, 1H),                                                          
7.0(s, 1H), 6.8-7.2(m, 2H), 7.8(s, 1H), 7.9-8.3(m, 2H).                   
10. The starting pyridinium salt was obtained by the process of Footnote  
2. Yield                                                                  
46%. N.m.r. in solvent B: 2.7(s, 3H), 3.2(s, 3H), 3.45(s, 3H), 4.85(s,    
4H),                                                                      
7.85(s, 1H), 7.95(d, 2H), 8.5(d, 2H).                                     
11. Reaction time 1.5 hrs. at room temperature, using a 50% excess of     
the                                                                       
pyridinium salt. Eluant proportion 30:70:1. N.m.r. in solvent B: 1.55(s,  
6H),                                                                      
2.55(s, 3H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H), 5.25(d, 1H), 5.9(d,     
1H),                                                                      
5.45(s, 2H), 7.05(s, 1H), 7.55(s, 1H), 6.9-7.2(m, 2H), 8.2-8.6(m, 2H).    
12. The starting pyridinium salt was obtained by the process of Footnote  
2, in EtOH                                                                
as solvent. Yield 19%. Nmr in solvent B: 2.6(s, 3H), 2.7(s, 3H), 5.75(s,  
2H), 7.75(s,                                                              
1H), 7.95(d, 2H), 8.8(d, 2H).                                             
13. Reaction time 1.5 hrs. at room temperature. Eluant proportion         
30:70:1. N.m.r. in                                                        
solvent B: 1.3(t, 3H), 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H),  
4.4(q, 2H),                                                               
5.25(d, 1H), 5.9(d, 1H), 5.6(s, 2H), 7.15(s, 1H), 6.9-7.2(m, 2H), 8.25(s, 
1H), 8.2-                                                                 
8.6(m, 2H).                                                               
14. The starting pyridinium salt was obtained by the process of Footnote  
2. Yield                                                                  
70%. N.m.r. in solvent B: 1.3(t, 3H), 2.65(s, 3H), 4.35(q, 2H), 5.86(s,   
2H), 7.9(d,                                                               
2H), 8.25(s, 1H), 8.8(d, 2H).                                             
15. Reaction time 2 hrs. at room temperature. Eluant proportion as        
Footnote 1.                                                               
N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.35(s, 2H),    
5.2(d, 1H),                                                               
5.5(s, 2H), 5.85(d, 1H), 7.1(s, 1H) 6.9-7.2(m, 2H), 8.05(s, 1H),          
8.1-8.4(m, 2H).                                                           
16. The starting pyridinium salt was obtained by the process of Footnote  
2. Yield                                                                  
18%. N.m.r. in solvent B: 2.75(s, 3H), 5.9(s, 2H), 7.8(d, 2H), 8.25(s,    
1H), 8.85(d,                                                              
2H).                                                                      
17. Reaction time 1/2 hr. at room temperature. Eluant proportion as       
Footnote 5.                                                               
N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1H),    
4.5(d, 1H),                                                               
5.2(d, 1H), 5.6(s, 2H), 5.9(d, 1H), 7.05(s, 1H), 7.0-7.2(m, 2H), 8.4(s,   
1H), 8.2-                                                                 
8.6(m, 2H).                                                               
18. The starting pyridinium salt is obtained by the process of Footnote   
2. Yield 90%.                                                             
N.m.r. in solvent B: 2.7(s, 3H), 5.9(s, 2H), 8.05(d, 2H), 8.45(s, 1H),    
8.8(d, 2H).                                                               
19. Reaction time 2 hrs. at room temperature. Eluant proportion as        
Footnote 2.                                                               
N.m.r. in solvent B; 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1H),    
4.5(d, 1H),                                                               
5.25(d, 1H), 5.9(d, 1H), 5.95(s, 2H), 7.15(s, 1H), 6.9-7.2(d, 2H),        
8.3-8.7(d, 2H), 9.4(s,                                                    
1H).                                                                      
20. The starting pyridinium salt was obtained by the process of Footnote  
2, but for                                                                
48 hrs. at room temperature. Yield 48%. N.m.r. in solvent B: 2.55(s, 3H), 
2.7(s, 3H),                                                               
6.25(s, 2H), 7.95(d, 2H), 8.95(d, 2H), 9.45(s, 1H).                       
21. Reaction time 3.5 hrs. at room temperature. Eluant proportion         
20-30:80-70:1.                                                            
N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H),     
5.25(d, 1H), 5.4(s,                                                       
1H), 5.9(d, 1H), 7.15(s, 1H), 6.9-7.2(m, 2H), 7.35(s, 1H), 8.55(s, 1H),   
8.2-8.6(m,                                                                
2H).                                                                      
22. The starting pyridinium salt was obtained by the process of Footnote  
2. Yield                                                                  
39%. N.m.r. in solvent B: 2.7(s, 3H), 5.7(s, 2H), 7.4(s, 1H), 7.95(d,     
2H), 8.5(s, 1H),                                                          
8.8(d, 2H).                                                               
23. The 3-aminomethyl cephem was alkylated with the corresponding         
2-(Boc-                                                                   
amino)thiazole derivative, at room temperature for 40 minutes. The Boc    
protecting                                                                
group was removed by dissolving the product in TFA/CH.sub.2 Cl.sub.2      
(4:1) at room                                                             
temperature for 50 minutes. Eluant proportion 30-35:70-65:1. N.m.r. in    
solvent B:                                                                
1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H), 5.2(s, 2H), 5.25(d, 1H), 
5.9(d, 1H),                                                               
7.05(s, 1H), 6.9-7.2(m, 2H), 8.0-8.4(m, 2H).                              
24. The starting Boc-amino-chloromethylthiazole was obtained by the       
process of                                                                
Footnote 2. Yield 65%. N.m.r. in solvent B; 1.45(s, 9H), 2.7(s, 3H),      
5.7(s, 2H),                                                               
7.35(s, 1H), 7.9(d, 2H), 8.75(d, 2H).                                     
25. Reaction time 1.25 hrs. at room temperature. Eluant proportion        
30-40:70-60:1.                                                            
N.m.r. in solvent B: 1.5(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.25(d, 1h),     
4.5(d, 1H), 5.15(d,                                                       
1H), 5.85(d, 1H), 6.0(s, 2H), 7.1(s, 1H), 7.0-7.2(m, 2H), 7.5-7.7(m, 2H), 
7.7-7.9(m,                                                                
2H), 8.2-8.6(m, 2H).                                                      
26. The starting pyridinium salt was obtained by the process of Footnote  
2, at room                                                                
temperature overnight followed by 3 hrs. under reflux in EtOH/DMF (3:2).  
The                                                                       
solvent was evaporated, and the product was precipitated with ether.      
Yield 54%.                                                                
N.m.r. in solvent B: 2.7(s, 2H), 6.35(s, 2H), 7.55(m, 2H), 7.75(m, 2H),   
8.0(d, 2H),                                                               
8.9(d, 2H).                                                               
27. Reaction time 40 minutes at room temperature. Eluant proportion as    
Footnote 1.                                                               
N.m.r. in solvent B: 1.55(s, 6H), 2.4(dt, 2H), 3.4(d, 1H), 3.7(d, 1H),    
4.4(m, 4H),                                                               
5.2(d, 1H), 5.5(t, 1H), 5.9(d, 1H), 6.9(d, 1H), 7.1(s, 1H), 7.0-7.2(m,    
2H), 7.15(t,                                                              
1H), 7.55(dt, 1H), 7.9(dd, 1H), 8.2-8.6(m, 2H).                           
28. The starting pyridinium salt was obtained by the process of Footnote  
2, at room                                                                
temperature overnight followed by 24 hrs. under reflux. Yield 20%. N.m.r. 
in sol-                                                                   
vent B: 2.5(dt, 2H), 2.7(s, 3H), 4.7(t, 2H), 5.5(t, 1H), 6.9(d, 1H),      
7.15(t, 1H), 7.55(dt,                                                     
1H), 7.9(dd, 1H), 8.0(d, 2H), 8.9(d, 2H).                                 
29. Reaction time 2 hrs. at room temperature. Eluant proportion           
10-25:90-75:1.                                                            
N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 3.9(s, 3H),     
4.4(s, 2H), 5.2(d,                                                        
1H), 5.85(d, 1H), 5.85(s, 2H), 7.0(s, 1H), 7.7(d, 1H), 7.75(d, 1h),       
7.0-7.4(m, 2H), 8.2-                                                      
8.6(m, 2H).                                                               
30. The starting pyridinium salt was obtained by the process of Footnote  
2, at room                                                                
temperature for 96 hrs. Yield 30%. N.m.r. in solvent B: 2.7(s, 3H),       
3.95(s, 3H),                                                              
6.2(s, 2H), 7.7(d, 1H), 7.75(d, 1H), 7.95(d, 1H), 8.85(d, 1H).            
31. Reaction time 3 hrs. room temperature. Eluant proportion              
10-20:90-80:1. N.m.r.                                                     
in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H), 5.2(d,     
1H), 5.75(s, 2H),                                                         
5.85(d, 1H), 7.05(s, 1H), 7.65(s, 2H), 7.0-7.3(m, 2H), 8.2-8.4(m, 2H).    
32. The starting pyridinium salt was obtained by the process of Footnote  
2. Yield                                                                  
83%. N.m.r. in solvent B: 2.75(s, 3H), 6.15(s, 2H), 7.75(s, 2H), 8.05(d,  
2H), 8.85(d,                                                              
2H).                                                                      
33. Reaction time 1.5 hrs. at room temperature. Eluant proportion as      
Footnote 1.                                                               
N.m.r. in solvent B: 1.5(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.4(s, 2H),      
5.15(d, 1H), 5.55(s,                                                      
2H), 5.85(d, 1H), 7.05(s, 1H), 7.05(dd, 1H), 7.0-7.2(m, 2H), 7.4(d, 1H),  
7.55(d, 1H),                                                              
8.2-8.6(m, 2H).                                                           
34. The starting pyridinium salt was obtained by the process of Footnote  
2, at room                                                                
temperature overnight followed by 4 hrs. under reflux. Yield 46%. N.m.r.  
in sol-                                                                   
vent B: 2.65(s, 3H), 5.9(s, 2H), 7.05(dd, 1H), 7.4(d, 1H), 7.55(d, 1H),   
7.85(d, 2H),                                                              
8.8(d, 2H).                                                               
35. Reaction time 3 hrs. at room temperature. Eluant proportion           
40-50:60-50:1.                                                            
N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 1H), 3.7(d, 1H), 4.3(d, 1H),     
4.5(d, 1H), 5.2(d,                                                        
1H), 5.85(s, 2H), 5.9(d, 1H), 7.05(s, 1H), 7.0-7.3(m, 2H), 7.7(d, 1H),    
8.1(dd, 1H),                                                              
8.5(d, 1H), 8.2-8.6(m, 2H).                                               
36. The starting pyridinium salt was obtained by the process of Footnote  
2, heating                                                                
under reflux for 6 hrs., then overnight at room temperature. Yield 77%.   
N.m.r. in                                                                 
solvent B: 2.7(s, 3H), 6.1(s, 2H), 7.7(d, 1H), 7.95(d, 2H), 8.1(dd, 1H),  
8.5(d, 1H),                                                               
8.85(d, 2H).                                                              
37. This compound obtained by reduction of the product of Example 105     
with                                                                      
titanium trichloride (5 eq.) in MeOH/TFA (99:1) for 1 hr. at room         
temperature.                                                              
Eluant proportion as Footnote 1. N.m.r. in solvent B: 1.55(s, 6H), 3.4(d, 
1H), 3.7(d,                                                               
1H), 4.3(d, 1H), 4.5(d, 1H), 5.2(d, 1H), 5.9(d, 1H), 5.9(s, 2H), 7.1(s,   
1H), 7.0-7.3(m,                                                           
2H), 7.44(d, 1H), 7.85(dd, 1H), 7.9(d, 1H) 8.2-8.6(m, 2H).                
38. The quaternised thiomethyl heterocycle salt was oxidised with MCPBA   
in                                                                        
CH.sub.2 Cl.sub.2 containing a catalytic amount of TFA at 0° C. to 
room temperature for up                                                   
to 4 hours, to give the corresponding sulphinyl compound, often also      
containing sul-                                                           
phone and sulphide, but not further purified.                             
 
    
     EXAMPLE 107 
     An activated ester was prepared from (2-aminothiazol-4-yl)-(2-methoxyimino)acetic acid (1.1 eq.) by reaction with hydroxybenzotriazole (1.1 eq.) and N,N&#39;-dicyclohexylcarbodi-imide (1.1 eq.) in DMF, at room temperature for 2 hrs. To this ester was added a solution of 7-amino-3-[N-ethyl-N-(l-methyl-4-pyridinio)aminomethyl]ceph-3-em-4-carboxylate (1.0 eq.) in DMF and Et3N (2 eq.). The reaction mixture was stirred at room temperature for 2 hrs. and filtered, and the solvents were evaporated. The product, 7-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-(N-ethyl)-[N-(1-methylpyridinio)]aminomethylceph-3-em-4-carboxylate, was purified by preparative HPLC eluting with MeOH/H 2  O/HOAc, 10:90:1. N.m.r. in solvent B: 1.0-1.3 (m, 3H), 3.0-3.8 (m, 4H), 3.9 (s, 3H), 3.95 (s, 3H), 4.5-4.7 (m, 2H), 5.2 (d, 1H), 5.8 (d, 1H), 7.0 (s, 1H), 7.15 (d, 2H), 8.2 (d, 2H). 
     The cephem starting material was obtained as follows: 
     3-Aminomethyl-7-(Boc-amino)ceph-3-em-4-carboxylic acid (1 eq.) was dissolved in MEOH, with Et 3  N (1 eq.) and NaBH 3  CN (1 eq.) at room temperature. Acetaldehyde (1 eq.) was added over 15 minutes at room temperature, the solvent was evaporated, and the product, 7-(Boc-amino)-3-ethylaminomethylceph-3-em-4-carboxylic acid, was purified by preparative HPLC, eluting with MEOH/H 2  O/HOAC, 30:70:1. Yield 59%, contaminated with some disubstituted material. 
     The above product (1 eq.) was treated DMF/H 2  O (3:2) with 4-chloro-1-methylpyridinium iodide (1 eq.) in presence of NAHCO 3  (3 eq.). After 2 hrs. at room temperature, the solvents were evaporated and the product was purified by preparative HPLC, eluting with MeOH/H 2  O/HOAc, 30:70:1. Yield 20%. N.m.r. in d 6  -DMSO: 1.0-1.2 (m, 3H), 1.4 (s, 9H), 2.8-3.8 (m, 4H), 3.9 (s, 3H), 4.2-4.8 (m, 2H), 4.9 (d, 1H), 5.2 (dd, 1H), 7.7 (d, 2H), 8.2 (d, 2H). 
     The above product was deprotected by dissolving in TFA and leaving for 1/2 hr. at room temperature. The TFA was evaporated, the residue triturated with ether to give the required starting material. Yield 84%. N.m.r. in solvent B: 0.9-1.3 (m, 3H), 3.2-3.8 (m, 4H), 3.9 (s, 3H), 4.5-4.8 (m, 2H), 5.2 (s, 2H), 7.15 (d, 2H), 8.25 (d, 2H). 
     EXAMPLES 108-115 
     Method A 
     The appropriate quaternised heterocyclic starting material (0.28mM) dissolved in a mixture of CH 3  CN/H 2  O (1:1; 2 ml) was added to a stirred solution of 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylic acid (0.28 mm) in CH 3  CN/H 2  O (1:1; 3 ml) at room temperature under an atmosphere of argon. Sodium bicarbonate (1.14 mM) was added to the reaction mixture which was stirred for 5 hr. and then poured into water (100 ml). The resulting solution was adjusted to pH 3.5 with acetic acid and then concentrated by rotary evaporation under vacuum at 20° C. The resulting aqueous solution was filtered and then diluted with water (100 ml) before loading on to an HP20SS column (20mm×350mm). The product was eluted from the resin by increasing amounts of CH 3  CN in H 2  O. Fractions containing the required product were combined and concentrated in vacuo and the aqueous residues freeze dried to give lyophilized solids. 
     Method B 
     The appropriate quaternised heterocyclic starting material (0.29 mM) in dimethylformamide (2 ml) was added at room temperature to a stirred solution of the N-ethylaminocephem-carboxylic acid of Method A (0.28 mM) in DMF (3 ml.). Triethylamine (0.56mm) was then added to the mixture and the reaction was allowed to continue for 16 hr. The mixture was then poured into water (100 ml) and the pH adjusted to 3.5 with acetic acid. After filtering, the solution was applied to an HP20SS column (20 mm×350 mm) and the product was eluted with increasing amounts of CH 3  CN in H 2  O. The fractions containing the required product were pooled and concentrated by rotary evaporation at 20° C. to give an aqueous concentrate which was then freeze dried. 
     Using these general processes the following compounds were prepared: 
     
         __________________________________________________________________________
 ##STR135##                                                               
Example                                                                   
     R                     Yield %                                        
                                Method                                    
                                     Footnotes                            
__________________________________________________________________________
108                                                                       
      ##STR136##           14   A    1, 2                                 
109                                                                       
      ##STR137##           31   A    3, 4                                 
110                                                                       
      ##STR138##           42   B    5, 6                                 
111                                                                       
      ##STR139##           44   B    7, 8                                 
112                                                                       
      ##STR140##           37   A    9, 10                                
113                                                                       
      ##STR141##           16   B    11, 12                               
__________________________________________________________________________
 
    
     The same general processes were also utilized with the corresponding aminomethyl intermediate to synthesize the following unalkylated 3-aminomethyl derivatives: 
     
         ______________________________________                                    
                                       Foot-                              
Example                                                                   
       R               Yield %  Method notes                              
______________________________________                                    
114                                                                       
        ##STR142##     19       B      13. 14                             
115                                                                       
        ##STR143##     25       A      15, 16                             
______________________________________                                    
Footnotes                                                                 
1. The starting material was 6-chloro-1-methyl-1,2,4-                     
triazolo[4,3-b]pyridazinium iodide.                                       
2. n.m.r. in solvent A: 9.62(s, 1H); 8.48(d, 1H); 8.15(m, 1H); 6.73(s,    
1H); 5.70(d, 1H); 5.03(d, 1H); 4.6(m, 2H); 4.14(s, 3H); 3.5-3.8(m,        
2H); 3.15-3.5(ABq, 2H); 2.15-2.80(m, 6H); 1.05-1.25(m, 3H).               
3. The starting material was 3-chloro-1-methyl-pyridazinium               
iodide                                                                    
4. n.m.r. in solvent A: 8.95(m, 1H); 8.05(m, 2H); 6.72(s, 1H);            
5.75(d, 1H); 5.08(d, 1H); 4.45-4.80(ABq, 2H); 4.30(s, 1H); 3.56-          
3.75(m, 2H); 3.20-3.55(ABq, 2H); 2.20-2.60(m, 6H); 1.05-1.30(m,           
3H).                                                                      
5. The starting material was 1-methyl-4-methylthiothieno[2,3-             
d]pyrimidine tetrafluoroborate.                                           
6. n.m.r. in solvent A: 8.86(s, 1H); 7.93(d, 1H); 7.80(d, 1H); 6.74(s,    
1H); 5.79(d, 1H); 5.11(d, 1H); 4.74-5.39(ABq, 2H); 4.02(m, 5H);           
3.15-3.59(ABq, 2H); 2.20-2.48(m, 6H); 1.20-1.42(m, 3H).                   
7. The starting material was 2,3-dihydro-7-methylthiothiazolo[2,3-        
a]pyrimidinium tetrafluoroborate.                                         
8. n.m.r. in solvent A: 8.3(m, 1H); 6.90-7.4(m, 1H); 6.74(s, 1H);         
5.75(m, 1H); 5.05(m, 1H); 4.65-5.0(ABq, 2H); 4.50-4.65(m, 2H);            
3.75-3.95(m, 2H); 3.55-3.75(t, 2H); 3.0-3.55(ABq, 2H), 2.20-              
2.5(m, 6H); 1.1(t, 3H).                                                   
9. Prepared using 4-chloro-1-(trans-3-chloroalkyl)pyridinium              
tosylate as starting material (see Example 151, Footnote 38) and          
method A, except that:                                                    
DMF was used instead of CH.sub.3 CN and the reaction was worked           
up by adjusting the pH to 7 with HOAc, concentrating to dryness           
under vacuum at 20° and redissolving in water prior to HP20SS      
chromatography.                                                           
10. n.m.r. in solvent A: 8.22(d, 2H); 7.51(m, 1H); 7.10(m, 1H);           
6.75(s, 1H); 6.73(d, 1H); 6.25(m, 1H); 5.73(d, 1H); 5.07(d, 1H);          
4.81(d, 2H); 4.73, 4.49(ABq, 2H); 3.65(m, 2H); 3.45, 3.13(ABq,            
2H); 2.36(m, 4H); 1.86(m, 2H)); 1.12(t, 3H).                              
11. The starting material was 1-(4-dimethylaminosulphonylbenzyl)-         
4-methanesulphinyl pyridinium tetrafluoroborate, which was                
obtained as follows:                                                      
4-Dimethylsulphamoylbenzyl bromide (0.005M) was mixed with                
4-methylthiopyridine (0.005M) and reacted exothermically, and             
was then left to stand overnight. The product was dissolved in            
CH.sub.2 Cl.sub.2, and after standing for 3 hrs. was added dropwise to    
rapidly stirred ether to precipitate 1-(4-dimethylsulphamoyl-             
benzyl)-4-methylthiopyridinium bromide, which was converted to            
the corresponding tetrafluoroborate salt with silver tetra-               
fluoroborate.                                                             
The pyridinium tetrafluoroborate (1.34 mM) was dissolved in               
CH.sub.2 Cl.sub.2 (15 ml) and treated at 0° with sufficient TFA to 
obtain                                                                    
a solution, then MCPBA (1.34 mM) was added. The mixture was               
stirred at 0° for 15 minutes then at room temperature for 4 hrs.,  
and the product was precipitated by the dropwise addition of ether        
to give 1-(4-dimethylsulphamoyl)benzyl-4-methylsulphinyl-                 
pyridinium tetrafluoroborate, the required starting material.             
12. n.m.r. in solvent A: 8.31(m, 2H); 7.3-7.90(m, 6H); 7.08(m,            
1H); 6.73(s, 1H), 5.76(d, 1H); 5.48(s, 2H); 5.06(d, 1H); 4.35-            
4.85(m, 2H), 3.40-3.80(m, 2H); 3.10-3.44(ABq, 2H); 2.56(s, 6H);           
2.10-2.50(m, 6H); 1.0-1.25(m, 3H).                                        
13. See Footnote 1.                                                       
14. n.m.r. in solvent A: 9.65(s, 1H); 8.35(d, 1H); 7.51(d, 1H);           
6.76(s, 1H); 5.80(d, 1H); 5.08(d, 1H); 4.05-4.50(ABq, 2H); 4.17(s,        
3H); 3.36-3.76(ABq, 2H), 2.20-2.47(m, 6H)                                 
15. See Footnote 5.                                                       
16. n.m.r. in solvent A: 8.85(s, 1H); 7.90(m, 1H); 6.75(s, 1H);           
5.81(d, 1H); 5.08(d, 1H); 4.46-4.95(ABq, 2H); 4.04(s, 3H);                
3.30-3.70(ABq, 2H), 2.17-2.46(m, 6H).                                     
 
    
     The 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylic acid used as starting material was prepared as follows: 
     3-Aminomethyl-7-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxycyclobut-1-yloxyimino)acetamido]ceph-3-em-4-carboxylic acid (10 g; 2.016×10 -2  mole) was stirred in MeOH (1.0 l.) and to this mixture was added triethylamine (2.8 ml; 2.016×10 -2  mole) dropwise, which resulted in a clear solution. Sodium cyanoborohydride (1.266 g; 2.016×10 -2  mole) was added in one portion to the above solution followed by 8g of activated molecular sieves (4A). A solution of acetaldehyde (1.125 ml in 75 ml methanol) was added to the reaction mixture, under an argon atmosphere, over a period of 40 minutes using an infusion pump and the status of the ensuing reaction was monitored by HPLC (Spherisorb 5ODS, 4 mm×30 cm; MeOH/H 2  O/TFA (40:60:0.2 by volume), 2 ml/min flow rate and monitoring by u.v. at 270 nm). Reaction was continued for 1 hr., the mixture was then filtered, and the filtrate was concentrated to dryness on a rotary evaporator under high vacuum. The residue was dissolved in water (100 ml) and loaded onto an HP20 macroreticular resin (3 l.) previously equilibrated with 0.2% TFA in water. The column was washed with 0.2% TFA in water (2 l.) and then water (5 l.) followed by increasing amounts of CH 3  CN in water. Fractions (2 l.) were collected and the desired product eluted with 15% CH 3  CN/H 2  O. Fractions (21-23) containing the required product were pooled, and concentrated on a rotary evaporator under high vacuum to give a clear solution (100 ml) which was freeze dried to yield 3 g lyophilised solid. Further fractions containing less pure amounts of the required product were also combined and concentrated to give a crude sample (2 g) of the N-ethyl derivative. This crude sample was purified by medium pressure chromatography on HP20SS resin (350 mm×50 mm; flow rate 49 ml/min, 250 ml fractions) to give an additional pure sample (1 g) of the required intermediate. 
     n.m.r. in solvent A: 6.75 (s, 1H); 5.75 (d, 1H); 5.05 (d, 1H), 3.25-3.85 (m, 4H=two AB quartets); 2.95 (q, 2H), 2.30-2.50 (m, 6H), 1.15 (t, 3H). 
     EXAMPLES 116-151 
     To a solution of 3-aminomethyl-7-C2-(2-aminothiazol-4-yl)-2-C(Z)-1-carboxy-1-methylethoxyamino)acetamido]ceph-3-em-4-carboxylic acid (0.4 mmole) in DMF (11 ml) and water (3 ml) at 0° was added sodium bicarbonate (4.8 mmole) dissolved in the minimum volume of water followed by the appropriate 4-chloropyridinium toluene-p-sulphonate salt (0.4 mmole). After 1 hour the mixture was treated with HOAC (4.8 mmole) and evaporated to dryness under reduced pressure. The residue was dissolved in water and purified by one of the following methods: 
     (a) HPLD on an octadecylsilane column using MeOH/water/HOAc 40:60:1 by volume as eluant. 
     (b) Medium pressure liquid chromatography on a column of Diaion HP20SS resin (supplied commercially by Mitsubishi Chemical Industries Ltd.) using increasing concentrations of acetonitrile (from 0% to 30% v/v) in water as eluant. 
     In each case the eluant containing the required product was evaporated on a Buchi Rotavapor to remove the organic solvent and the resulting aqueous soution was dried by lyophilisation. Using this general method the following compounds were obtained: 
     
         ______________________________________                                    
 ##STR144##                                                               
Ex-                                                                       
am-                          Yield   Foot-                                
ple  R                       %       notes                                
______________________________________                                    
116                                                                       
      ##STR145##             70       1                                   
117                                                                       
      ##STR146##             37       2                                   
118                                                                       
      ##STR147##             36       3                                   
119                                                                       
      ##STR148##             18       4                                   
120                                                                       
      ##STR149##             36       5                                   
121                                                                       
      ##STR150##             43       6                                   
122                                                                       
      ##STR151##             62       7                                   
123                                                                       
      ##STR152##             52       8                                   
124                                                                       
      ##STR153##             25       9                                   
125                                                                       
      ##STR154##             17      10                                   
126                                                                       
      ##STR155##             20      11                                   
127                                                                       
      ##STR156##             32      12                                   
128                                                                       
      ##STR157##             19      13                                   
129                                                                       
      ##STR158##             13      14                                   
130                                                                       
      ##STR159##             30      15                                   
131                                                                       
      ##STR160##              6      16                                   
132                                                                       
      ##STR161##             35      17                                   
133                                                                       
      ##STR162##             44      18                                   
134                                                                       
      ##STR163##              6      19                                   
135                                                                       
      ##STR164##             22      20                                   
136                                                                       
      ##STR165##             11      21                                   
137                                                                       
      ##STR166##             22      22                                   
138                                                                       
      ##STR167##             47      23, 24                               
139                                                                       
      ##STR168##             23      25, 26                               
140                                                                       
      ##STR169##             30      27                                   
141                                                                       
      ##STR170##             25      28                                   
142                                                                       
      ##STR171##             15      29                                   
143                                                                       
      ##STR172##              9      30                                   
144                                                                       
      ##STR173##             27      31                                   
145                                                                       
      ##STR174##             14      32                                   
146                                                                       
      ##STR175##             17      33                                   
147                                                                       
      ##STR176##             20      34                                   
148                                                                       
      ##STR177##             37      35                                   
149                                                                       
      ##STR178##             18      36                                   
150                                                                       
      ##STR179##              5      37                                   
151                                                                       
      ##STR180##             20      38                                   
______________________________________                                    
Footnotes                                                                 
1. n.m.r. in solvent A: 1.40(s, 6H); 3.43(d, 2H); 3.64(d, 1H); 4.30(d,    
1H); 4.48(d, 1H); 5.15(d, 1H); 5.84(d, 1H); 6.74(s, 1H); 7.06(dd,         
1H); 7.26(dd, 1H); 7.53(d, 1H); 7.66(q, 1H); 7.89(m, 1H); 8.34(dd,        
1H); 8.54(dd, 1H).                                                        
2. n.m.r. in solvent A: 1.46(s, 6H); 3.45(d, 1H); 3.66(d, 1H); 4.35(d,    
1H); 4.51(d, 1H); 5.17(d, 1H); 5.86(d, 1H); 6.74(s, 1H); 7.10(d, 1H);     
7.28(d, 1H); 7.86(d, 2H); 8.12(d, 2H); 8.46(d, 1H); 8.64(d, 1H).          
3. n.m.r. in solvent A: 1.44(s, 6H); 3.45(d, 1H); 3.65(d, 1H); 4.31(d,    
1H); 4.52(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 6.75(s, 1H); 7.13(dd,         
1H); 7.31(dd, 1H); 7.68-7.84(m, 2H); 7.90(dd, 1H); 8.07(dd, 1H);          
8.33(dd, 1H); 8.54(dd, 1H).                                               
4. n.m.r. in solvent A: 1.40(s, 6H); 3.34(d, 1H); 3.57(d, 1H); 4.31(d,    
1H); 4.56(d, 1H); 5.05(d, 1H); 5.72(d, 1H); 6.75(s, 1H); 7.09(dd,         
1H); 7.53(dd, 1H); 8.20(dd, 1H); 8.34(d, 1H); 8.42(dd, 1H); 8.52(d,       
1H); 8.60(dd, 1H).                                                        
5. n.m.r. in solvent A: 1.35(s, 6H); 3.30(d, 1H); 3.57(d, 1H); 4.24(d,    
1H); 4.44(d, 1H); 5.05(d, 1H); 5.70(d, 1H); 6.65(s, 1H); 7.00(d, 1H);     
7.15(d, 1H); 7.80(d, 2H); 8.30(d, 2H); 8.30(d, 1H); 8.48(d, 1H).          
6. A solution of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-           
methylethoxyimino)acetamido]-3-[1-(4-nitrophenyl)-4-pyridinio-            
aminomethyl]ceph-3-em-4-carboxylate (110 mg) in a mixture of              
water (12 ml) and DMF (6 ml) was stirred for 1 hr. with 10%               
palladium on carbon in an atmosphere of hydrogen. The solution            
was filtered through delite, and the filtrate was evaporated to           
dryness. The resulting solid was washed with a mixture of water           
and methanol (3:1 v/v, 3 ml), collected by filtration and dried in        
vacuo to yield 3-[1-(4-aminophenyl)-4-pyridinio]aminomethyl-7-            
[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-           
acetamido]ceph-3-em-4-carboxylate (45 mg) having n.m.r. in                
solvent A: 1.45(s, 6H); 3.35(d, 1H); 3.60(d, 1H); 4.20(d, 1H);            
4.40(d, 1H); 5.10(d, 1H); 5.78(d, 1H); 6.70(s, 1H); 6.80-                 
8.50(complex, 8H).                                                        
7. n.m.r. in solvent A: 1.40(s, 6H); 3.35(d, 1H); 3.65(d, 1H);            
4.27(d, 1H); 4.50(d, 1H); 5.10(d, 1H); 5.78(d, 1H); 6.70(s, 1H);          
7.00-7.30(m, 2H); 7.70-8.10(m, 2H); 8.20-8.60(m, 4H).                     
8. The method described in Footnote 6 was repeated using 7-(2-            
(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-              
acetamido]-3-[1-(3-nitrophenyl)-4-pyridinio]aminomethylceph-              
3-em-4-carboxylate to yield 3-[1-(3-aminophenyl)-4-pyridinio]-            
aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-                
methylethoxyiminoacetamido]ceph-3-em-4-carboxylate having                 
n.m.r. in solvent A: 1.44(s, 6H); 3.45(d, 1H); 3.65(d, 1H); 4.34(d,       
1H); 4.47(d, 1H); 5.15(d, 1H); 5.84(d, 1H); 6.75(s, 1H); 6.90-7.45(m,     
6H); 8.35(d, 1H); 8.54(d, 1H).                                            
9. The toluene-p-sulphonate salt of 7-[2-(2-aminothiazol-4-yl)-2-         
((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(4-tert-               
butoxycarbonylphenyl)-4-pyridinio]aminomethylceph-3-em-4-                 
carboxylate (320 mg) was dissolved with stirring in TFA (4 ml).           
After 15 minutes the solution was evaporated to dryness and the           
residue was purified by HPLC to yield the toluene-p-sulphonate            
salt of 7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methyl-             
ethoxyimino)acetamido]-3-[1-(4-carboxyphenyl-4-pyridinio]amino-           
methylceph-3-em-4-carboxylate (73 mg) having n.m.r. in solvent            
A: 1.43(s, 6H); 2.27(s, 3H); 3.43(d, 1H); 3.64(d, 1H); 4.34(d, 1H);       
4.53(d, 1H); 5.15(d, 1H); 5.82(d, 1H); 6.75(s, 1H); 7.12(d, 3H);          
7.35(d, 1H); 7.50(d, 2H); 7.77(d, 2H); 8.16(d, 2H); 8.47(d, 1H);          
8.65(d, 1H).                                                              
The tert-butyl ester used as starting material in the                     
above process was obtained by the general method using 1-(4-tert-         
butoxycarbonylphenyl)-4-chloropyridinium toluene-p-sulphonate             
as starting material.                                                     
10. Ice cold TFA (5 ml) was added to a stirred mixture of anisole         
(1 ml) and 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methyl-          
ethoxyimino)acetamido]-3-[1-(4-tert-butoxyphenyl)-4-pyridinio]-           
aminomethylceph-3-em-4-carboxylate (200 mg). The reaction                 
mixture was allowed to warm to 10° C. and after 90 mins was        
evaporated to dryness. Purification of the residue by HPLC                
yielded 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methyl-             
ethoxyimino)acetamido]-3-[1-(4-hydroxyphenyl)-4-pyridinio]-               
aminomethylceph-3-em-4-carboxylate having n.m.r. in solvent A:            
1.50(s, 6H); 3.28(d, 1H); 3.60(d, 1H); 4.26(d, 1H); 4.60(d, 1H);          
5.05(d, 1H); 5.74(d, 1H); 6.75(s, 1H); 6.93(d, 2H); 7.45(d, 2H);          
6.9-7.5(m, 3H); 8.30(d, 1H); 8.45(d, 1H).                                 
The tert-butyl ether used as starting material in the above process       
was obtained by the general method using 1-(4-tert-butoxyphenyl)-         
4-chloropyridinium toluene-p-sulphonate as starting material.             
11. n.m.r. in solvent A: 1.40(s, 6H); 3.45(d, 1H); 3.65(d, 1H);           
4.35(d, 1H); 4.50(d, 1H); 5.15(d, 1H); 5.75(d, 1H); 6.75(s, 1H);          
7.10(dd, 1H); 7.30(m, 1H); 7.90(d, 1H); 8.15(m, 1H); 8.60(d, 1H);         
8.80(dd, 1H); 8.95(dd, 1H).                                               
12. n.m.r. in solvent A: 1.40(s, 6H); 3.35(d, 1H); 3.62(d, 1H);           
4.25(d, 1H); 4.46(d, 1H); 5.05(d, 1H); 5.80(d, 1H); 6.75(s, 1H);          
7.04(d, 1H); 7.10(d, 1H); 7.55(dd, 1H); 8.05(d, 1H); 8.35(d, 1H);         
8.52(d, 1H); 8.65(d, 1H); 8.80(d, 1H).                                    
13. n.m.r. in solvent A: 1.40(s, 6H); 3.34(d, 1H); 3.67(d, 1H),           
4.36(d, 1H); 4.57(d, 1H); 5.07(d, 1H); 5.75(d, 1H); 6.74(s, 1H);          
7.12(d, 1H); 7.55(d, 1H); 8.15(d, 1H); 8.60(dd, 1H); 8.82(d, 1H);         
8.95(d, 1H); 9.05(d, 1H).                                                 
14. n.m.r. in solvent A: 1.42(s, 6H); 3.34(d, 1H); 3.56(d, 1H);           
4.37(d, 1H); 4.56(d, 1H); 5.07(d, 1H); 5.74(d, 1H); 6.74(s, 1H);          
7.12(dd, 1H); 7.50(dd, 1H); 7.60(t, 1H); 8.98(d, 2H); 9.14(dd, 1H);       
9.24(dd, 1H).                                                             
15. n.m.r. in solvent A: 1.45(s, 6H); 3.35(d, 1H); 3.58(d, 1H);           
4.35(d, 1H); 4.60(d, 1H); 5.07(d, 1H); 5.74(d, 1H); 6.74(s, 1H);          
7.14(dd, 1H); 7.58(dd, 1H); 8.26(d, 1H); 8.38(d, 1H); 8.76(dd, 1H);       
8.86(dd, 1H).                                                             
16. n.m.r. in solvent A: 1.44(s, 6H); 3.30(d, 1H); 3.56(d, 1H);           
4.30(d, 1H); 4.60(d, 1H); 5.07(d, 1H); 5.72(d, 1H); 6.72(s, 1H);          
7.19(dd, 1H); 7.60(dd, 1H); 7.9-8.6(m, 2H); 8.86(m, 2H);                  
9.37(q, 1H).                                                              
17. n.m.r. in solvent A: 1.45(s, 6H); 3.29(d, 1H); 3.54(d, 1H);           
4.28(d, 1H); 4.56(d, 1H); 5.05(d, 1H); 5.71(d, 1H); 6.70(dd, 1H);         
6.75(s, 1H); 6.88(dd, 1H); 7.06(dd, 1H); 7.58(dd, 1H); 7.76(dd, 1H);      
8.44(dd, 1H); 8.60(dd, 1H).                                               
18. n.m.r. in solvent A: 1.44(s, 6H); 3.44(d, 1H); 3.64(d, 1H);           
4.32(d, 1H); 4.47(d, 1H); 5.16(d, 1H); 5.84(d, 1H); 6.74(s, 1H);          
7.10(dd, 1H); 7.05(dd, 1H); 7.25(dd, 1H); 7.85(dd, 1H); 8.36(dd,          
1H); 8.41(dd, 1H); 8.58(dd, 1H).                                          
19. n.m.r. in solvent A: 1.43(s, 6H); 3.40(d, 1H); 3.60(d, 1H);           
4.30(d, 1H); 4.58(d, 1H); 5.13(d, 1H); 5.81(d, 1H) (d, 1H); 6.74(s,       
1H); 7.00-7.15(m, 2H); 7.20(dd, 1H); 7.46(dd, 1H); 7.54(dd, 1H);          
8.32(dd, 1H); 8.50(dd, 1H).                                               
20. n.m.r. in solvent A: 1.45(s, 6H); 3.46(d, 1H); 3.67(d, 1H);           
4.34(d, 1H); 4.52(d, 1H); 5.17(d, 1H); 5.85(d, 1H); 6.75(s, 1H);          
7.08(dd, 1H); 7.24(dd, 1H); 7.50(dd, 1H); 7.80(dd, 1H); 7.98(dd,          
1H); 8.46(dd, 1H); 8.64(dd, 1H).                                          
21. n.m.r. in solvent A: 1.45(s, 6H); 2.10(s, 3H); 3.30(d, 1H);           
3.55(d, 1H); 4.35(d, 1H); 4.55(d, 1H); 5.05(d, 1H), 5.70(d, 1H);          
6.75(s, 1H); 7.05(d, 2H); 7.15(d, 2H); 7.95(s, 1H); 8.60(dd, 2H);         
8.70(dd, 2H).                                                             
22. n.m.r. in solvent A: 1.43(s, 6H); 3.33(d, 1H); 3.56(d, 1H),           
4.35(d, 1H); 4.56(d, 1H); 5.06(d, 1H); 5.72(d, 1H), 6.75(s, 1H);          
7.08(dd, 1H); 7.51(dd, 1H); 7.74(s, 2H); 8.66(dd, 1H); 8.75(dd, 1H).      
23. Prepared by the general method using 1-(2-benzoxazolyl)-4-            
methylsulphinylpyridinium chloride in place of the 4-chloropy-            
ridinium toluene-p-sulphonate.                                            
The pyridinium salt was prepared as follows.                              
A solution of 2-chlorobenzoxazole (1.38 g) and 4-methylthio-              
pyridine (1.13 g) in anhydrous methylene chloride was kept in the         
dark overnight. The resulting crystalline precipitate of 1-(2-            
benzoxazolyl)-4-methylthiopyridinium chloride (1.86 g) was                
collected by filtration, washed with anhydrous methylene chloride         
and dried in vacuo.                                                       
A solution of 3-chloroperbenzoic acid (127 mg, 85% pure) in               
methylene chloride (3 ml) was added dropwise to a stirred ice             
cold solution of 1-(2-benzoxazolyl)-4-methylthiopyridinium                
chloride (139 mg) in methylene chloride (3 ml) and TFA (0.10              
ml). The solution was allowed to warm to 20° C. After 40           
minutes, toluene (2 ml) was added and the mixture was                     
evaporated to dryness to yield a mixture of 1-(2-benzoxazolyl)-           
4-methylsulphinylpyridinium chloride and 3-chlorobenzoic acid             
which was used directly in the general method.                            
24. n.m.r. in solvent A: 1.45(s, 6H); 3.30(d, 1H); 3.65(d, 1H);           
4.35(d, 1H); 4.62(d, 1H); 5.05(d, 1H); 5.70(d, 1H); 6.74(s, 1H);          
7.00-7.90(m, 6H); 8.75(dd, 1H); 8.85(dd, 1H).                             
25. Prepared by the process described in Footnote 23, using               
2-chlorobenzothiazole as starting material in place of 2-chloro-          
benzoxazole.                                                              
26. n.m.r. in solvent A: 1.40(s, 6H); 3.33(d, 1H); 3.56(d, 1H);           
4.37(d, 1H); 4.64(d, 1H); 5.06(d, 1H); 5.72(d, 1H); 6.74(s, 1H);          
7.15(d, 1H); 7.45-7.70(m, 3H); 8.00(d, 1H); 8.18(d, 1H); 8.80(d,          
1H); 8.86(d, 1H).                                                         
27. n.m.r. in solvent A: 1.45(s, 6H); 3.30(d, 1H); 3.55(d, 1H);           
4.20(d, 1H); 4.45(d, 1H); 5.05(d, 1H); 5.15(d, 1H); 5.25(d, 1H);          
5.70(d, 1H); 6.75(s, 1H); 6.80-7.20(m, 3H); 8.15(d, 1H); 8.30(d, 1H).     
28. n.m.r. in solvent A: 1.45(s. 6H), 3.40(d, 1H); 3.52(d, 1H);           
3.82(s, 3H); 4.28(d, 1H); 4.44(d, 1H); 5.04(d, 1H); 5.75(d, 1H);          
6.75(s, 1H); 7.00-7.22(m, 3H); 7.35-7.62(m, 3H); 8.30(d, 1H);             
8.45(d, 1H).                                                              
29. n.m.r. in solvent A: 1.45(s, 6H); 2.10(s, 3H); 3.30(d, 1H);           
3.65(d, 1H); 4.29(d, 1H); 4.59(d, 1H); 5.07(d, 1H); 5.71(d, 1H);          
6.75(s, 1H); 7.07(d, 1H); 7.57(d, 2H); 7.57(d, 1H); 7.80(d, 2H);          
8.35(d, 1H); 8.50(d, 1H).                                                 
30. n.m.r. in solvent A: 1.35(s, 6H); 1.45(t, 3H); 3.48(d, 1H);           
3.66(d, 1H); 4.30(m, 3H); 4.50(d, 1H); 5.17(d, 1H); 5.85(d, 1H);          
6.75(s, 1H); 7.11(d, 1H); 7.36(d, 1H); 7.82(d, 2H); 9,15(d, 2H);          
9.50(d, 1H); 9.70(d, 1H).                                                 
31. n.m.r. in solvent A: 1.40(s, 6H); 2.80(s, 6H); 3.30(d, 1H);           
3.58(d, 1H); 4.25(d, 1H); 4.50(d, 1H); 5.05(d, 1H); 5.70(d, 1H);          
6.72(s, 1H); 7.00(d, 1H); 7.30(d, 1H); 7.60(m, 4H); 8.30(d, 1H);          
8.45(d, 1H).                                                              
32. n.m.r. in solvent A: 1.45(s, 6H); 3.30(s, 3H); 3.45(d, 1H);           
3.65(d, 1H); 4.35(d, 1H); 4.50(d, 1H); 5.15(d, 1H); 5.85(d, 1H);          
6.75(s, 1H); 7.14(d, 1H); 7.33(d, 1H); 7.94(d, 2H); 8.16(d, 2H);          
8.46(d, 1H); 8.66(d, 1H).                                                 
33. n.m.r. spectrum in solvent A: 1.45(s, 6H), 3.35(d, 1H); 3.60(d,       
1H); 4.35(d, 1H); 4.55(d, 1H); 5.05(d, 1H); 5.70(d, 1H), 6.70(s, 1H);     
7.10(dd, 1H); 7.46(dd, 1H); 8.12(d, 1H); 8.50(d, 1H); 8.80(d, 1H);        
8.94(d, 1H); 8.97(broad, 1H).                                             
34. n.m.r. spectrum in solvent A: 1.45(s, 6H); 2.70(s, 3H); 3.30(d,       
1H); 3.55(d, 1H); 4.30(d, 1H); 4.60(d, 1H); 5.05(d, 1H); 5.70(d, 1H);     
6.75(s, 1H); 7.10(d, 1H); 7.60(d, 1H); 7.80(d, 2H); 8.15(d, 2H);          
8.35(d, 1H), 8.55(d, 1H).                                                 
35. n.m.r. in solvent A: 1.40(s, 6H); 2.08(m, 2H); 2.50(t, 2H);           
3.26(d, 1H); 3.50(d, 1H); 4.15(t, 2H); 4.20(d, 1H); 4.42(d, 1H);          
5.02(d, 1H); 5.69(d, 1H); 6.73(d, 1H); 6.94(d, 1H); 7.35(d, 1H);          
9.10(d, 1H); 8.25(d, 1H).                                                 
36. n.m.r. in solvent A: 1.46(s, 6H); 3.26(d, 1H); 3.50(d, 1H);           
4.20(d, 1H); 4.44(d, 1H); 4.80(d, 2H); 5.05(d, 1H); 5.20(d, 1H);          
5.32(d, 1H); 5.72(d, 1H); 5.90(d t, 1H); 6.3-6.6(m, 2H); 6.74(s,          
1H); 6.94(d, 1H); 7.38(d, 1H); 8.16(d, 1H); 8.25(d, 1H).                  
37. n.m.r. in solvent A: 1.40(s, 6H); 3.40(d, 1H); 3.60(d, 1H);           
4.25(d, 1H); 4.40(d, 1H); 4.90(d, 2H); 5.15(d, 1H); 5.80(d, 1H);          
6.20(m, 1H); 6.65(d, 1H); 6.75(d, 1H); 6.90(d, 1H); 7.10(d, 1H);          
8.05(d, 1H); 8.20(d, 1H).                                                 
38. n.m.r. in solvent A: 1.40(s, 6H); 3.40(d, 1H); 3.60(d, 1H);           
4.25(d, 1H); 4.35(d, 1H); 4.80(d, 2H); 5.15(d, 1H); 5.85(d, 1H);          
6.20(m, 1H); 6.20(m, 1H); 6.70(d, 1H); 6.75(s, 1H); 6.90(d, 1H);          
7.10(d, 1H); 8.10(d, 1H); 8.25(d, 1H).                                    
 
    
     The 1-substituted-4-chloropyridinium toluene-p-sulphonate salts used as starting materials in the above processes may be prepared as follows: 
     A solution of the appropriate 1-substituted-4-pyridone (2.5 mmole) and toluene-p-sulphonyl chloride (3.8 mmole) in DMF (10 ml) was stirred at 100° C. for 10 mins. The reaction mixture was cooled and evaporated to dryness. Trituration of the residue with ether yielded the required 4-chloropyridinium toluene-p-sulphonate salt as a solid which was used without further purification in the preparation of the final product. Using the general process the following compounds were prepared: 
     
         ______________________________________                                    
 ##STR181##                                                               
                          Starting Material                               
R               Footnotes for Example Number                              
______________________________________                                    
3,4-difluorophenyl                                                        
                 1        116                                             
4-cyanophenyl    2        117                                             
2-cyanophenyl    3        118                                             
3,4-dicyanophenyl                                                         
                 3        119                                             
4-nitrophenyl    3        120, 121                                        
3-nitrophenyl    4        122, 123                                        
4-tert-butoxycarbonylphenyl                                               
                 5        124                                             
4-tert-butoxyphenyl                                                       
                 6        125                                             
2-pyridyl        7        126                                             
3-pyridyl        4        127                                             
5-cyano-2-pyridyl                                                         
                 7        128                                             
2-pyrimidinyl    7        129                                             
6-chloro-3-pyridazinyl                                                    
                 7        130                                             
3-pyridazinyl    8        131                                             
2-furyl          9        132                                             
3-furyl         10        133                                             
2-thienyl       11        134                                             
3-thienyl       11        135                                             
4-methyl-2-oxazolyl                                                       
                12        136                                             
2-thiazolyl     13        137                                             
vinyl                     140                                             
4-methoxyphenyl  4        141                                             
4-acetamidophenyl                                                         
                14        142                                             
4-ethoxycarbonylphenyl                                                    
                 5        143                                             
4-dimethylaminocarboxy-                                                   
                15        144                                             
phenyl                                                                    
4-methylsulphonylphenyl                                                   
                16        145                                             
5-trifluoromethyl-2-pyridyl                                               
                 7        146                                             
4-acetoxyphenyl  5        147                                             
3-cyanopropyl   17        148                                             
penta-2,4-dienyl                                                          
                18        149                                             
cis-3-chlorallyl                                                          
                19        150                                             
trans-3-chloroallyl                                                       
                19        151                                             
______________________________________                                    
Footnotes                                                                 
1. The starting material was prepared as follows:                         
A mixture of alpha-pyrone (880 mg.), 3,4-difluoroaniline                  
(1.54 g.) and concentrated hydrochloric acid (0.8 ml.)                    
in water (10 ml.) was stirred under reflux for 2 hours.                   
The reaction mixture was cooled and basified with                         
aqueous ammonia solution. The precipitated product was                    
filtered off, washed with cold ethyl acetate (10 ml.)                     
and dried in vacuo to yield 1-(3,4-difluorophenyl)-4-                     
pyridone (1.10 g.) as a buff solid.                                       
2. The starting material was prepared as follows:                         
Sodium hydride (410 mg. of a 1% dispersion in mineral                     
oil) was placed in an argon atmosphere, washed free of                    
oil with  -n-pentane and suspended in DMF (10 ml.). Solid                 
4-hydroxypyridine (1.00 g.) was added in small portions                   
to the suspension. Stirring was continued for 15                          
minutes after the evolution hydrogen gas had ceased and                   
then a solution of 4-fluorobenzonitrile (1.27 g.) in DMF                  
(3 ml.) was added. The resulting mixture was stirred at                   
110° C. for 30 minutes and then poured whilst still hot            
into cold water (60 ml.). After cooling for 30 minutes                    
in ice the crystalline precipitate of 1-(4-cyanophenyl)-                  
4-pyridone (1.45 g.) was collected by filtration, washed                  
with water, dried in vacuo and recrystallised from                        
EtOAc.                                                                    
3. The pyridone starting material was prepared by                         
the method described in Footnote 2, using the                             
appropriate substituted chlorobenzene in place of                         
4-fluorobenzonitrile.                                                     
4. The starting material was prepared by the                              
method described in Example 2 using the appropriate                       
aniline in place of 4-fluoroaniline.                                      
5. The pyridone starting material was prepared by                         
the method described in Footnote 2, using the                             
appropriate substituted fluorobenzene in place of                         
4-fluorobenzonitrile.                                                     
6. The pyridone starting material was prepared as                         
follows:                                                                  
A mixture of alpha-pyridone (440 mg.), 4-tert-butoxy-                     
aniline (755 mg.) and HOAc (0.262 ml.) was stirred at                     
100° C. for 10 minutes in an argon atmosphere. The                 
cooled reaction mixture was evaporated to dryness, using                  
the azeotropic evaporation of added toluene to remove                     
the last traces of HOAc. The residue was purified by                      
chromatography on a column of Kieselgel 60, eluting with                  
methylene chloride, then 95:5 v/v methylene chloride;                     
methanol, to give 1-(4-tert-butoxyphenyl)-4-pyridone                      
(340 mg.) having n.m.r. in CDC1.sub.3 :                                   
1.40(s, 9H), 6.50(d, 2H), 7.0-7.3(m, 4H), 7.60                            
(d, 2H).                                                                  
7. The pyridone starting material was prepared                            
by the method described in Footnote 2, using the                          
appropriate 2-chloroheterocycle in place of 4-fluoro-                     
benzonitrile.                                                             
8. The pyridone starting material was prepared as                         
follows:                                                                  
A solution of 1-(6-chloro-3-pyridazinyl)-4-pyridone                       
(1.00 g.) and sodium acetate (0.50 g.) in EtOH (50 ml.)                   
and water (3 ml.) containing 10% palladium on carbon                      
(200 mg.) was stirred for 75 minutes in an atmosphere                     
of hydrogen.                                                              
The mixture was filtered through kieselguhr                               
and the filtrate was evaporated to dryness.                               
Recrystallisation of the residue from EtOAc yielded                       
1-(3-pyridazinyl)-4-pyridone, (350 mg.) having n.m.r. in                  
solvent A:                                                                
6.35(d, 2H), 7.95(q, 1H), 8.20(q, 1H), 8.50(d, 2H),                       
9.30(q, 1H).                                                              
9. The pyridone starting material was prepared as                         
follows:                                                                  
Sodium hydride (1.69 g. of a 1% dispersion in mineral                     
oil) was placed in an argon atmosphere, washed free of                    
oil with  -n-pentane and suspended in DMSO (27 ml.).                      
Solid 4-hydroxypyridine (4.12 g.) was added in small                      
portions to the stirred suspension. Stirring was                          
continued for 15 minutes after the evolution of hydrogen                  
gas had ceased. Powdered methyl 5-nitro-2-furoate                         
(6.18 g.) was then added and stirring was continued for                   
48 hours. The reaction mixture was evaporated to                          
dryness and the dark brown residue was extracted with                     
95:5 v/v methylene chloride/MeOH (3 × 100 ml.). The                 
extracts were passed through a column of Kieselgel 60                     
(50 mg.) and the eluent was evaporated to dryness. The                    
residue was dissolved in methylene chloride (100 ml.)                     
and the solution was filtered. Evaporation of the                         
filtrate to a volume of ca 20 ml. deposited pale brown                    
crystals of the methyl ester, 1-(5-methoxycarbonyl-                       
2-furyl)-4-pyridone (3.07 g.), having m.p. 194 - 6° C.             
Chromatography of the mother liquor on Kieselgel 60                       
afforded a further crop (863 mg.) of the same product.                    
The methyl ester (3.95 g.) was stirred in                                 
methanol (78 ml.) in an argon atmosphere, while a                         
solution of potassium hydroxide (4.87 g.) in water                        
(39 ml.) was added. The methyl ester rapidly dissolved.                   
Stirring was continued overnight and the reaction                         
mixture was evaporated to dryness. The residue was                        
dissolved in the minimum volume of water and acidified                    
with N-hydrochloric acid to pH. 1. The resulting                          
precipitate was isolated by centrifugation, washed with                   
water then acetone, and dried in vacuo to yield the                       
acid, 1-(5-carboxy-2-furyl)-4-pyridone (3.74 g.)                          
A mixture of the acid (3.74 g.), copper bronze                            
(1.64 g.) and quinoline (8 ml.) was stirred at 210° C. in          
an argon atmosphere until the evolution of carbon                         
dioxide ceased (ca. 30 minutes). The cooled reaction                      
mixture was dissolved in EtOAc and filtered through                       
kieselguhr. The filtrate was evaporated to dryness and                    
the residue was purified by chromatography on Kieselgel                   
60 (30 g.) eluting initially with methylene chloride to                   
remove quinoline then with 95:5 v/v methylene                             
chloride/MeOH to afford 1-(2-furyl)-4-pyridone (2.20 g.).                 
10. The pyridone starting material was prepared as                        
follows:                                                                  
A mixture of 3-bromofuran (2.50 g.), freshly sublimed                     
4-hydroxypyridine (1.61 g.), copper powder (2.20 g.) and                  
powdered anhydrous potassium carbonate (4.80 g.) in DMF                   
(25 ml.) was stirred at 150° C. for 2 hours in an argon            
atmosphere. The cooled reaction mixture was filtered                      
through kieselguhr and the filtrate was evaporated to                     
dryness. The residue was extracted with warm 95:5 v/v                     
chloroform/MeOH (100 ml.). The resulting solution was                     
applied to a column of Kieselgel 60 (30 g.). Elution                      
with the same solvent gave 1-(3-furyl)-4-pyridone                         
(1.17 g.).                                                                
11. The pyridone starting material was prepared by                        
the method described in footnote 10, using the                            
appropriate bromothiophene in place of 3-bromofuran.                      
12. The pyridone starting material was prepared by                        
the method described in footnote 2, using 4-methyl-2-                     
methylsulphinyloxazole in place of 4-fluorobenzo-                         
nitrile.                                                                  
13. The pyridone starting material was prepared by                        
the method described in footnote 2, using 2-bromo-                        
thiazole in place of 4-fluorobenzonitrile.                                
14. The starting material was prepared as follows:                        
A solution of 1-(4-nitrophenyl)-4-pyridone (500 mg) in                    
EtOH (5 ml) and DMF (5 ml) was stirred at 80° C. for 30            
minutes with 10% palladium on carbon (150 mg) in an                       
atmosphere of hydrogen. The reaction mixture was                          
cooled and filtered through kieselguhr. The filtrate was                  
evaporated to dryness and the solid residue was stirred                   
overnight with a mixture of acetic anhydride (1 ml),                      
pyridine (3 ml) and DMF (3 ml). The reaction mixture was                  
evaporated to dryness to yield 1-(4-acetamidophenyl)-4-                   
pyridone (420 mg.) as a white solid.                                      
15. The pyridone starting material was prepared as                        
follows:                                                                  
A mixture of 1-(4-ethoxycarbonylphenyl)-4-pyridone                        
(1.0 g) and 33% w/v dimethylamine in ethanol was stirred                  
during the dropwise addition of a solution of sodium                      
ethoxide [prepared by the addition of sodium metal                        
(50 mg) to ethanol (2.5 ml)]. Stirring was continued                      
overnight, then the reaction mixture was evaporated to                    
dryness to yield 1-(4-dimethylcarbamoylphenyl)-4-                         
pyridone which was used without purification.                             
16. The pyridone starting material was prepared as                        
follows:                                                                  
Using the method described in Example 2,4-methyl-                         
thioaniline was converted into 1-(4-methylthiophenyl)-4-                  
pyridone. A mixture of the pyridone (1.80 mg), HOAc                       
(14 ml) and 100 volumes aqueous hydrogen peroxide (4.5 ml)                
were stirred at 70° C. for 2 hours. The cooled reaction            
mixture was diluted with water and extracted with ethyl                   
acetate. The ethyl acetate solution was washed with                       
aqueous sodium metabisulphite, dried with sodium                          
sulphate, and evaporated to yield 1-(4-methylsulphonyl-                   
phenyl)-4-pyridone (1.15 g) which was used without                        
further purification.                                                     
17. The pyridone starting material was prepared by                        
the method described in footnote 2, using 4-bromobutyro-                  
nitrile in place of 4-fluorobenzonitrile.                                 
18. The pyridone starting material was prepared as                        
follows:                                                                  
A mixture of 2-chloropenta-2,4-diene (1.49 g), 4-hydroxy-                 
pyridine (1.39 g), powdered anhydrous potassium carbonate                 
(4.14 g) and DMF (10 ml) was stirred for 90 minutes at                    
80° C. in an argon atmosphere. The reaction mixture was            
cooled and the DMF was evaporated. The residue was                        
extracted with 9:1 v.v methylene chloride/methanol                        
(200 ml). The extacts were filtered through a pad of                      
Kieselgel 60 (30 g) and the filtrates were evaporated to                  
dryness to give a brown oil. Chromatography of this                       
oil on Kieselgel 60, eluting initially with methylene                     
chloride, then 19:1 v/v methylene chloride/methanol,                      
afforded 1-(penta-2,4-dienyl)-4-pyridone (1.36 g) as a                    
pale orange oil.                                                          
19. The pyridone starting materials were prepared                         
as follows:                                                               
A solution of 1,3-dichloropropene (cis/trans mixture,                     
1.97 ml) and 4-hydroxypyridine (2.00 g) in acetone (25 ml)                
was stirred with powdered anhydrous potassium carbonate                   
(2.90 g) for 1 hour under reflux. Further portions of                     
1,3-dichloropropene (1.97 ml) and potassium carbonate                     
(2.90 g) were added and the reaction mixture was stirred                  
for a further hour under reflux. The cooled reaction                      
mixture was filtered and the solid residue was washed                     
well with acetone. The combined acetone filtrates were                    
evaporated to dryness. The oily residue was                               
chromatographed on a column of Kieselgel 60 (100 g)                       
eluting with methylene chloride, then 19:1 v/v methylene                  
chloride/methanol, to separate the cis and trans isomers                  
of the product, 2-(3-chlorallyl)-4-pyridone.                              
 
    
     EXAMPLES 152-158 
     To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-1-carboxy-1-methylethoxyamino)acetamido]ceph-3-em-4-carboxylic acid (0.4 mmole) in DMF (11 ml.) and water (3 ml) at 0° was added sodium bicarbonate (4.8 mmole) dissolved in the minimum volume of water, followed by a solution of the appropriate pyridinium salt (0.5 mmole) in DMF (5 ml). After 1 hour the mixture was treated with HOAc (4.8 mmole) and evaporated to dryness under reduced pressure. The residue was dissolved in water and purified by chromatography on Diaion HP20SS resin. 
     Using this general process the following compounds were prepared 
     
         __________________________________________________________________________
 ##STR182##                                                               
Example                                                                   
     R                       Yield %                                      
                                  Footnotes                               
__________________________________________________________________________
152                                                                       
      ##STR183##             10   1                                       
153                                                                       
      ##STR184##             16   2                                       
154                                                                       
      ##STR185##             30   3                                       
155                                                                       
      ##STR186##             24   4                                       
156                                                                       
      ##STR187##             44   5                                       
157                                                                       
      ##STR188##             15   6                                       
158                                                                       
      ##STR189##              8   7                                       
__________________________________________________________________________
1. n.m.r. in solvent A: 1.40(s, 6H); 3.30(d, 1H); 3.50(d, 1H); 4.20(d,    
1H); 4.40(d, 1H);                                                         
4.95(d, 2H); 5.05(d, 1H); 5.70(d, 1H); 6.70(s, 1H); 6.95(d, 1H); 7.25(d,  
1H); 7.65(d,                                                              
2H); 8.10(d, 1H); 8.15(d, 2H); 8.30(d, 1H).                               
2. n.m.r. in solvent A: 1.45(s, 6H); 3.27(d 1H); 3.50(d, 1H); 4.21(d,     
1H); 4.43(d, 1H);                                                         
4.95(d, 2H); 5.04(d, 1H); 5.68(d, 1H); 6.28(m, 1H); 6.74(s, 1H);          
6.90-7.45(m, 3H);                                                         
8.02(d, 1H); 8.20(d, 1H).                                                 
3. n.m.r. in solvent A: 1.40(m, 12H); 3.24(d, 1H); 3.45(m, 5H); 4.20(d,   
1H); 4.48(d,                                                              
1H); 4.90 (broad, 2H); 5.05(d, 1H); 5.70(d, 1H); 6.70(s, 1H); 6.80(m,     
1H); 6.95(m,                                                              
2H); 7.50(dd, 1H); 8.10(d, 1H); 8.28(d, 1H).                              
4. n.m.r. in solvent A: 1.44(s, 6H); 3.55(m 10H); 4.25(d, 1H); 4.40(d,    
1H); 4.90(d,                                                              
2H); 5.15(d, 1H); 5.83(d, 1H); 6.65(m, 2H); 6.75(s, 1H); 6.95(d, 1H);     
7.07(d, 1H);                                                              
8.10(d, 1H); 8.27(d, 1H).                                                 
5. n.m.r. in solvent A: 0.85(t, 3H), 1.35(m, 2H); 1.40(s, 6H); 3.05(m,    
2H); 3.25(d,                                                              
1H); 3.50(d, 1H); 4.20(d, 1H); 4.45(d, 1H); 4.90(d, 1H); 5.05(d, 1H);     
5.70(d, 1H);                                                              
5.85(d, 1H); 6.75(s, 1H); 6.80(m, 1H); 6.95(dd, 1H); 7.40(dd, 1H);        
8.10(d, 1H); 8.20                                                         
(d, 1H).                                                                  
6. n.m.r. in solvent A: 1.40(s, 6H); 3.25(d, 1H); 3.50(d, 1H); 4.20(d,    
1H); 4.50(d, 1H);                                                         
4.95(d, 2H); 5.05,(d, 1H); 5.70(d, 1H); 5.80(d, 1H); 6.75(s, 1H); 6.80(m, 
1H); 7.00                                                                 
(dd, 1H); 7.45(dd, 1H); 8.10(d, 1H); 8.25(d, 1H).                         
7. n.m.r. in solvent A: 1.45(s, 6H); 1.95(s, 3H); 3.40(d, 1H); 3.60(d,    
1H); 4.25(d, 1H);                                                         
4.40(d, 1H); 4.90(s, 2H); 5.15(d, 1H); 5.30(s, 1H); 5.85(d, 1H); 6.75(s,  
1H); 6.95(d,                                                              
1H); 7.10(d, 1H); 8.00(d, 1H); 8.20(d, 1H).                               
 
    
     The pyridinium salts used as starting materials in the above process may be prepared as follows: 
     A solution of 3-chloroperbenzoic acid (1.05 mmole) in anhydrous methylene chloride (2 ml) was added dropwise to a stirred solution at the appropriate 1-substituted-4-methylthiopyridinium salt (0.5 mmole) in methylene chloride (5 ml) and TFA (0.1 ml) at 0°. The reaction mixture was allowed to warm to room temperature over 1 hour and was then evaporated to dryness. The residue was washed with ether to remove 3-chlorobenzoic acid and the insoluble residue, a mixture of the appropriate 4-methylsulphinyl- and 4-methylsulphonylpyridinium salts, was used directly in the above process. 
     Using this general procedure the following compounds were prepared: 
     
         ______________________________________                                    
 ##STR190##                                                               
                                Starting Material                         
R             X      Footnotes  for Example No.                           
______________________________________                                    
4-nitrocinnamyl                                                           
              Cl     1          152                                       
trans-3-cyanoallyl                                                        
              BF.sub.4                                                    
                     2          153                                       
trans-3-(2-piperidino-                                                    
              Br     3          154                                       
carboxy)allyl                                                             
trans-3-(1-morpholino-                                                    
              Br     4          155                                       
carboxy)allyl                                                             
trans-3-(N-propyl-                                                        
              Br     4          156                                       
aminocarboxy)allyl                                                        
trans-3-(amino-                                                           
              Br     4          157                                       
carboxy)allyl                                                             
 .sub.-- E-3-cyano-2-methyl-                                              
              Br     4          158                                       
allyl                                                                     
______________________________________                                    
Footnotes                                                                 
1. The 1-(4-nitrocinnamyl)-4-methylthiopyridinium                         
chloride starting material was prepared as follows. A                     
solution of 4-nitrocinnamyl chloride (181 mg) and                         
4-methylthiopyridine (125 mg) in acetonitrile (1 ml) was                  
kept in the dark for 48 hours. The solvent was                            
evaporated and the residue was triturated with ether to                   
give the required starting material as an off-white                       
solid (170 mg).                                                           
2. The 1-(trans-3-cyanoallyl)-4-methylthio-                               
pyridinium tetrafluoroborate starting material was                        
prepared as follows. A solution of 4-bromocrotono-                        
nitrile (660 mg) and 4-methylthiopyridine (565 mg) in                     
anhydrous methylene chloride (3 ml) was kept in the dark                  
for 48 hours. The resulting black crystalline solid                       
(888 mg) was filtered off and dried in vacuo. This                        
solid was dissolved in a mixture of water (20 ml) and DMF                 
(10 ml). To this stirred solution was added a solution of                 
silver tetrafluoroborate (636 mg) in water (3 ml). After                  
5 minutes the solution was filtered through celite and                    
evaporated to dryness. The resulting gum was dissolved                    
in water (20 ml), refiltered and freeze-dried to yield                    
the starting material as a fluffy orange solid (810 mg).                  
3. The 1-[trans-3(1-piperidinocarboxy)]allyl-4-                           
methylthiopyridinium bromide starting material was                        
prepared as follows. A solution of trans-3-(1-                            
piperidinocarboxy)allyl bromide (440 mg) and 4-methyl-                    
thiopyridine (240 mg) in acetonitrile (5 ml) was kept in                  
the dark for 24 hours. The solvent was evaporated and                     
the residue was washed with ether to afford the required                  
starting material as a gum.                                               
4. The required starting material was prepared,                           
using the procedure in Footnote 3, by reacting 4-methyl-                  
thiopyridine with the appropriate substituted allyl                       
bromide.                                                                  
 
    
     EXAMPLES 159-160 
     Using the general processes described in Example 116, with the appropriate 3-aminomethylcephalosporin and pyridinium salt starting materials the following compounds were prepared. 
     
         ______________________________________                                    
 ##STR191##                                                               
                           Yield                                          
Example                                                                   
       R                   %       Footnotes                              
______________________________________                                    
159                                                                       
        ##STR192##         17      1                                      
160                                                                       
        ##STR193##         15      2                                      
______________________________________                                    
Footnotes                                                                 
1. n.m.r. in solvent A: 2.40(m, 6H); 3.40(d,                              
1H); 3.60(d, 1H); 4.25(d, 1H); 4.38(d, 1H); 4.80(d,                       
1H); 5.15(d, 1H); 5.85(d, 1H); 6.20(m, 1H); 6.70(d,                       
1H); 6.75(s, 1H); 6.90(d, 1H); 7.10(d, 1H); 8.05(d,                       
1H); 8.25(d, 1H).                                                         
2. n.m.r. in solvent A: 1.96(s, 3H); 2.40(m,                              
6H); 3.42(d, 1H); 3.65(d, 1H); 4.27(d, 1H); 4.40(d,                       
1H); 4.95(s, 2H); 5.16(d, 1H); 5.32(s, 1H); 5.85(d,                       
1H); 6.74(s, 1H); 6.97(d, 1H); 7.10(d, 1H); 8.04(d,                       
1H); 8.25(d, 1H).                                                         
 
    
     EXAMPLES 161-171 
     The general process described in Example 1 was repeated using the appropriate heterocyclic starting material. The reactions were carried out in DMF/water mixtures in the presence of NaHCO 3  at the temperature in the range ambient to 75° for 0.4-4 hours. The product was purified on a octadecylsilane column and the following compounds were thus prepared. 
     
         __________________________________________________________________________
 ##STR194##                                                               
                        Yield                                             
Example R               %      Footnotes                                  
__________________________________________________________________________
161     CH.sub.3        7      1, 2, 3                                    
162     NHCH.sub.2 CHCH.sub.2                                             
                        18     4, 5, 6                                    
163     NHCH(CH.sub.3).sub.2                                              
                        22     7, 8, 9                                    
154     N(CH.sub.3).sub.2                                                 
                        25     10, 11, 12                                 
165                                                                       
         ##STR195##     14     13, 14, 15                                 
166                                                                       
         ##STR196##     4.5    16, 17, 18                                 
167     NHCH.sub.2 CH.sub. 2 NH.sub.2                                     
                        12     19, 20, 21, 22                             
168     NHCH.sub.2 CH.sub.2 OH                                            
                        11     23, 24, 25                                 
169     NHCH.sub.2 CH.sub.2 OCH.sub.3                                     
                         6     26, 27, 28                                 
170     SCH.sub.3       32     29, 30, 31                                 
171     SCH.sub.2 CH.sub.2 NHCOCH.sub.3                                   
                        20     32, 33, 34                                 
__________________________________________________________________________
Footnotes                                                                 
1. The starting material was prepared by reaction of 3-chloro-6-methylpyri
dazine with trimethloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2 15     
hours at ambient                                                          
temperature to give 3-chloro-1,6-dimethylpyridazinium tetrafluoroborate.  
2. HPLC eluant MeOH/water/HOAc 15:84:1, v/v/v.                            
3. n.m.r. in solvent B; 1.53(br.s, 6H); 2.62(s, 3H); 3.6(m, 2H); 4.14(s,  
3H); 5.15(d,                                                              
1H); 4.85(d, 1H); 7.05(s, 1H); 7.55(d, 1H); 7.85(d, 1H).                  
4. (a) The starting material was obtained as follows. Reaction of 3,6-    
difluoropyridazine with trimethyloxonium tetrafluoroborate gave 3,6-      
difluoro-1-methylpyridazinium tetrafluoroborate.                          
(b) To this compound (1.5 mmole) in acetonitrile (5 ml) was added a       
solution of allylamine (1.5 mmole) in acetonitrile (3 ml) and             
NaHCO.sub.3. After 2 hours at ambient temperature the mixture was         
filtered, and the filtrate was evaporated to yield an oil, which          
crystallised to give 3-fluoro-1-methyl-6-(allylamino)-pyridazinium        
tetrafluoroborate.                                                        
5. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                             
6. n.m.r. in solvent B: 1.56(br.s, 6H); 3.55(m, 2H); 3.78(s, 3H); 4.0(m,  
2H); 3.95(d, 1H); 4.5(d, 1H); 5.15(m, 3H); 5.83(m, 2H); 7.06(s, 1H);      
7.42(s, 2H).                                                              
7. The starting material was prepared by reaction of 3,6-difluoro-1-methyl
pyridazinium tetrafluoroborate (Footnote 4a) with 2 equivalents of        
isopropylamine in acetonitrile at ambient temperature, to give 3-fluoro-  
1-methyl-6-isopropylamino-pyridazinium tetrafluoroborate.                 
8. HPLC eluant MeOH/water/HOAc 30:69:1 v/v/v.                             
9. n.m.r. in solvent B: 1.21(s, 3H); 1.28(s, 3H); 1.54(br.s, 6H); 3.5(m,  
2H); 3.76(s,                                                              
3H); 3.85(d, 1H); 4.0(m, 1H); 4.45(d, 1H); 5.15(d, 1H); 5.83(d, 1H);      
7.05(s,                                                                   
1H); 7.4(d, 1H); 7.67(d, 1H).                                             
10. The starting material was prepared as follows. To a stirred solution  
of                                                                        
3,6-difluoro-1-methyl-pyridazinium tetrafluoroborate (2.00 mmoles,        
Footnote                                                                  
4a) in acetonitrile under argon at room temperature was added MgO (2.0    
mmoles) followed by a solution of dimethylamine in toluene (4.0 mmoles).  
After 2 hours, the mixture was filtered, and the filtrate was evaporated  
to                                                                        
an oil, which crystallised after trituration with ether, to give          
3-fluoro-1-                                                               
methyl-6-(N,N-dimethylamino)pyridazinium tetrafluoroborate.               
11. HPLC eluant MeOH/water/HOAc 22.5:77.5:1 v/v/v                         
12. n.m.r. in solvent B: 1.53(br.s, 6H); 3.06(s, 6H); 3.45(d, 1H); 3.7(d, 
1H); 3.89                                                                 
(s, 3H); 4.05(d, 1H); 4.5(d, 1H); 5.13(d, 1H); 5.80(d, 1H); 7.05(s, 1H);  
7.32(d,                                                                   
1H); 7.52(d, 1H).                                                         
13. The starting material was prepared by the method described in         
Footnote 7,                                                               
using p-nitrobenzyl-amine, to give 3-fluoro-1-methyl-6-(p-nitrobenzylamino
)-                                                                        
pyridazinium tetrafluoroborate.                                           
14. HPLC eluant MeOH/water/HOAc 35:64:1 v/v/v.                            
15. n.m.r. in solvent B: 1.53(br.s, 6H); 3.5(m, 2H); 3.86(s, 3H); 3.95(d, 
1H);                                                                      
4.45(d, 1H); 5.14(d, 1H); 5.8(d, 1H); 7.05(s, 1H); 7.36(br.s, 2H);        
7.62(d, 2H);                                                              
8.18(d, 2H).                                                              
16. The starting material was prepared by the method described in         
Footnote 4 to                                                             
give 3-fluoro-1-methyl-6-(2-thenylamino)pyridazinium tetrafluoroborate.   
17. HPLC eluant MeOH/aqueous ammonium carbonate (2 g/l) 30:70 v/v.        
18. n.m.r. in solvent B: 1.53(s, 6H); 3.55(m, 2H); 3.93(s, 3H); 3.95(d,   
1H); 4.45(d,                                                              
1H); 4.95(s, 2H); 5.15(d, 1H); 5.8(d, 1H); 7.05(s, 1H); 6.97-7.7(m, 5H).  
19. The starting material was prepared by the method described in         
Footnote 4                                                                
using N-Boc ethylene diamine.                                             
20. HPLC eluant MeOH/aqueous ammonium carbonate (2 g/l), 30:70 v/v.       
21. Cleavage of the Boc protecting group was achieved after the HPLC by   
treatment with TFA for 5 minutes.                                         
22. n.m.r. in solvent B: 1.56(s, 6H); 3.1(m, 2H); 3.85(m, 4H); 3.94(s,    
3H); 4.64(m,                                                              
2H); 5.27(d, 1H); 5.98(d, 1H); 7.06(s, 1H); 8.05(d, 1H); 8.85(d, 1H).     
23. The starting material was prepared by a slow addition of a solution   
of                                                                        
ethanolamine in acetontrile under argon, followed by NaHCO.sub.3. After   
1 hour at ambient temperature the mixture was filtered, and the filtrate  
was                                                                       
evaporated to an oil, which crystallised to give 3-fluoro-6-(2-hydroxyethy
l-                                                                        
amino)-1-methyl pyridazinium tetrafluoroborate.                           
24. HPLC eluant MeOH/water/HOAc 20:79:1 v/v/v.                            
25. n.m.r. in solvent B: 1.53(s, 6H); 3.54(m, 6H); 3.73(s, 3H); 3.95(d,   
1H); 4.4(d,                                                               
1H); 5.1(d, 1H); 5.8(d, 1H); 7.06(s, 1H); 7.35(d, 1H); 7.55(d, 1H).       
26. The starting material, 3-fluoro-6-(2-methoxy-ethylamino)-1-methyl-pyri
dazinium tetrafluorobate was prepared by the method described in Foot-    
note 7 using 2-methoxyethylamine.                                         
27. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                            
28. n.m.r. in solvent B: 1.53(s, 6H); 3.23(s, 3H); 3.5(m, 6H); 3.73(s,    
3H); 3.95(d,                                                              
1H); 4.5(d, 1H); 5.15(d, 1H); 3.85(d, 1H); 7.07(s, 1H); 7.4(d, 1H);       
7.7(d, 1H).                                                               
29. The starting material was obtained by reaction of 3,6-difluoro-1-methy
lpyri-                                                                    
dazinium tetrafluoroborate (Footnote 4a) with sodium thiomethylate in     
acetonitrile for 1 hour at ambient temperature to give 3-fluoro-1-methyl-6
methylthiopyridazinium tetrafluoroborate.                                 
30. The crude condensation product was purified by chromatography on      
Diaion                                                                    
HP20 resin, eluting with increasing proportions of MeOH in water.         
31. n.m.r. in solvent B: 1.54(br.s, 6H); 2.76(s, 3H); 3.56(m, 2H);        
4.07(s, 3H);                                                              
4.02(d, 1H); 4.55(d, 1H); 5.15(d, 1H); 5.85(d, 1H); 7.06(s, 1H); 7.6(d,   
1H); 7.95(d, 1H).                                                         
32. The starting material was prepared by the method described in         
Footnote 7,                                                               
using 2-acetamido-1-mercaptoethane to give 3-fluoro-1-methyl-6-(2-acetamid
o-                                                                        
ethylthio)pyridazinium tetrafluoroborate as a paste.                      
33. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v.                            
34. n.m.r. in solvent B: 1.54(s, 6H); 1.83(s, 3H); 3.2-3.8(m, 6H); 4.0(s, 
3H);                                                                      
4.6(m, 2H); 5.19(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.93(s, 2H).            
 
    
     EXAMPLES 172-178 
     The general process described in Example 1 was repeated using the appropriate 3-aminomethylcephalosporin derivative and the appropriate heterocycle. The following compounds were obtained: 
     
         __________________________________________________________________________
 ##STR197##                                                               
Example                                                                   
No.  R.sup.1  R.sup.2                                                     
                   R.sup.3      Yield                                     
                                    Footnote                              
__________________________________________________________________________
172  CH.sub.3 H    CH.sub.3     30  1, 2, 3                               
173  CH.sub.2 CH.sub.2 Cl                                                 
              H    CH.sub.3     24  1, 4, 5                               
174  C(CH.sub.3).sub.2 CO.sub.2 H                                         
              H                                                           
                    ##STR198##  14  6, 7, 8                               
175  &#34;        H    CH.sub.2 CHCH.sub.2                                    
                                18  9, 10, 11                             
176  &#34;        H                                                           
                    ##STR199##  23  12, 13, 14                            
177                                                                       
      ##STR200##                                                          
              C.sub.2 H.sub.5                                             
                   CH.sub.3     12  1, 15, 16                             
178                                                                       
      ##STR201##                                                          
              H    CH.sub.3     32  1, 17, 18                             
__________________________________________________________________________
Footnotes                                                                 
1. The starting material was 6-amino-3-fluoro-1-methylpyridazinium        
tetrafluoroborate                                                         
see Example 13, Footnote 16.                                              
2. HPLC eluant MeOH/water/HOAc, 15:84:1 v/v/v.                            
3. n.m.r. in solvent B: 3.25-3.8(m, 2H); 3.7(s, 3H); 4.0(s, 3H); 3.8(d,   
1H); 4.5(d, 1H);                                                          
5.12(d, 1H); 5.76(d, 1H); 7.05(s, 1H); 7.25(s, 2H).                       
4. HPLC eluant MeOH/water/HOAc, 20:79:1, v/v/v.                           
5. n.m.r. in solvent B: 3.55(m, 2H); 3.7(s, 3H); 3.9-4.4(m, 6H); 5.15(d,  
1H); 5.76(d, 1H);                                                         
7.05(s, 1H); 7.3(s, 2H).                                                  
6. The starting material may be prepared as follows: 3,6-difluoropyridazin
e was mixed                                                               
with a solution of ammonia (10 equivalents) in ethanol, and heated in a   
sealed tube                                                               
for 3 hours at 80-85° C. The solvent was evaporated and            
6-amino-3-fluoropyri-                                                     
dazine was extracted from the residue with EtOAc in a Soxhlet apparatus   
for 3.5 hours.                                                            
This compound in EtOH was further treated with p-nitrobenzyl bromide for  
2.5 hours                                                                 
at 40° C. The solvent was evaporated and the residue was washed    
twice with anhydrous                                                      
ether, to give 6-amino-3-fluoro-1-(4-nitrobenzyl)pyridazinium bromide.    
7. HPLC eluant MeOH/water/HOAc, 35:64:1, v/v/v.                           
8. n.m.r. in solvent B: 1.57(br.s., 6H); 3.5(m, 2H); 4.0(d, 1H); 4.45(d,  
1H); 5.15(d, 1H);                                                         
5.45(br.s, 2H); 5.87(d, 1H); 7.1(s, 1H); 7.47(s, 2H); 7.65(d, 2H);        
8.35(d, 2H).                                                              
9. The starting material may be prepared as follows: 6-amino-3-fluoropyrid
azine (2.5                                                                
mmoles; Footnote 6), and 2 ml of allyl bromide in the minimum of          
nitromethane were                                                         
heated to 60° C. for 3 hours. Evaporation of the solvent, washing  
of the residue                                                            
with ether and drying under vacuum over P.sub.2 O.sub.5  gave             
1-allyl-6-amino-3-                                                        
fluoropyridazinium bromide.                                               
10. HPLC eluant MeOH/water/HOAc, 30:69:1, v/v/v.                          
11. n.m.r. in solvent B: 1.6(br.s, 6H); 3.57(m, 2H); 3.8-4.9(m, 4H);      
5.1-5.45(m, 3H);                                                          
5.85(m, 2H); 7.17(s, 2H); 7.4(s, 2H).                                     
12. The starting material was prepared as follows: 6-amino-3-fluoropyridaz
ine (1.15                                                                 
mmoles; Footnote 6) and alpha&#39;-chloro-alpha,alpha,alpha-trifluoro-m-xylene
 in the                                                                   
minimum of DMF were heated to 60° C. for 4 hours. Evaporation of   
the solvent                                                               
and trituration of the residue with anhydrous either gave                 
6-amino-3-fluoro-1-(3-                                                    
trifluoromethylbenzyl)-pyridazinium chloride.                             
13. HPLC eluant MeOH/water/HOAC, 45:54:1, v/v/v.                          
14. n.m.r. in solvent B: 1.54(s, 6H); 3.5(m, 2H); 4.03(d, 1H); 4.45(d,    
1H); 5.11(d, 1H);                                                         
5.43(d, 1H); 5.9(d, 1H); 7.1(s, 1H); 7.45(s, 2H); 7.62-7.95(m, 4H).       
15. HPLC eluant MeOH/water/HOAc, 25-30:74-69:1 v/v/v.                     
16. n.m.r. in solvent B: 1.07(t, 3H); 1.9-3.0(m, 6H); 3.46(m, 4H);        
4.25(d, 1H); 4.6(d,                                                       
1H); 5.2(d, 1H); 5.86(d, 1H); 6.98(s, 1H); 7.4(d, 1H); 7.76(d, 2H).       
17. HPLC eluant MeOH/water/HOAc, 25-30:74-69:1 v/v/v.                     
18. n.m.r. in solvent B: 1.72(m, 4H); 2.15(m, 4H); 3.55(m, 2H); 3.7(s,    
3H); 4.05(d, 1H);                                                         
4.55(d, 1H); 5.15(d, 1H); 5.83(d, 1H); 7.06(s, 1H); 7.3(s, 2H).           
 
    
     EXAMPLES 179-180 
     The process described in Example 1 was repeated, using the appropriate heterocycle as starting material, to give the following compounds: 
     
         ______________________________________                                    
 ##STR202##                                                               
Example                                                                   
No.     R                 Yield %  Footnotes                              
______________________________________                                    
179                                                                       
         ##STR203##       15       1, 2, 3, 4                             
180                                                                       
         ##STR204##        9       5, 6, 7, 8                             
______________________________________                                    
1. The starting material was obtained by reaction of                      
3-chloro-5,6,7,8-tetrahydrocinnoline (see Journal of Org.                 
Chemistry 1955, Vol. 20, p.707) with trimethyloxonium tetra-              
fluoroborate in CH.sub.2 Cl.sub.2 overnight.                              
2. The condensation was performed in water at pH 7.6                      
(ambient temperature) with NaHCO.sub.3 as base.                           
3. HPLC eluant, MeOH/water/HOAc, 30-40:69-59:1, v/v/v.                    
4. n.m.r. in solvent B: 1.54(s, 6H); 1.86(m, 4H); 2.81(m, 4H);            
3.60(br.s, 2H); 3.96(s, 3H); 4.55(br.s, 2H); 5.16(d, 1H);                 
5.88(d, 1H); 7.04(s, 1H); 7.73(s, 1H).                                    
5. The starting heterocycle may be prepared as follows: To a              
stirred solution of 7.7-dichlorobicyclo-[3,2,0]heptan-6-one               
(see Tetrahedron, 1971, Vol. 27, p.615)(52.7 mmoles) in                   
MeOH(25 ml) at 0° C. was added dropwise hydrazine hydrate          
(3.3 ml.). Stirring was continued at 0° C. for 0.75 hours,         
the solvent was evaporated, the residue was taken up in water             
and extracted with CH.sub.2 Cl.sub.2, and the organic phases              
were combined, washed with water and dried (MgSO.sub.4).                  
Evaporation of the solvent gave cis-1,1-dichloromethylcyclo-              
pentane carbohydrazide (yield 54%) having the following                   
n.m.r. in CDCl.sub.3 : 2.0(m, 6H); 2.8(m, 2H); 3.92(br.s,                 
2H); 5.96(d, 1H); 7.0(br.s, 1H). The above hydrazide                      
(28.7 mmoles) was dissolved in aqueous EtOH (40 ml.; 3:1 v/v)             
and heated at reflux for 1.75 hours. The reaction mixture                 
was diluted with water and extracted with                                 
CH.sub.2 Cl.sub.2. The combined CH.sub.2 Cl.sub.2 extracts                
were washed with water and dried (MgSO.sub. 4), the solvent was           
evaporated to a small volume and ether was added to give                  
4,5-dihydro-4,5-trimethylenepyridazin-3(2H)-one (yield 87%).              
N.m.r. in CDCl.sub.3 : 1.5-2.4(m, 6H); 2.6-3.0(m, 2H);                    
6.95(d, 1H); 7.7(br.s, 1H). This dihydropyridazinone derivative           
(17.7 mmoles) was dissolved in HOAc (15 ml.) and bromine                  
(17.6 mmoles) was added slowly with stirring. The reaction                
mixture was then heated 0.4 hours at 100° C., cooled and           
the HOAc evaporated. The residue was taken up in water and                
the pH adjusted to 10 with 12N NaOH. After stirring for 3                 
hours at room temperature, the reaction mixture was extracted             
with CH.sub.2 Cl.sub.2, the combined CH.sub.2 Cl.sub.2                    
extracts were washed with water, dried (MgSO.sub.4), and                  
the solvent was evaporated. The crude product was applied to              
a column of Kieselgel 60 (120 g). Elution with ether-MeOH,                
5-7:95-93 v/v, gave 4,5-trimethylenepyridazin-                            
3(2H)-one in 24% yield. N.m.r. in CDCl.sub.3 : 2.13(q, 2H);               
2.91(t, 4H); 7.78(s, 1H). The above pyridazinone derivative               
(13.5 mmoles) was treated with 15 ml. of phosphorous oxychloride          
at 80° C. for 2 hours. After evaporation to dryness, the           
residue was taken up in water, neutralised with NaHCO.sub.3               
and extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2               
was evaporated and the residue was applied to a column of                 
Kieselgel 60 (50 g). Elution with ether/MeOH, 95:5 v/v, gave              
3-chloro-4,5-trimethylenepyridazine (yield 42%). N.m.r. in                
CDCl.sub.3 : 2,2(q, 2H); 3.06(t, 2H); 3.08(t, 2H);                        
9.02(s, 1H). This compound was then treated with                          
trimethyloxonium tetrafluoroborate in CH.sub.2 Cl.sub.2                   
at ambient temperature for 0.5 hour to give a 9:1 mixture                 
of 1-methyl and 2-methyl-4,5-trimethylenepyridazinium                     
tetrafluoroborate in 90% yield. N.m.r. in CDCl.sub.3 of                   
the 1-methyl derivative is: 2.39(q, 2H); 3.26(t, 2H);                     
3.43(t, 2H); 4.59(s, 3H); 9.51(s, 2H).                                    
6. The condensation was performed in DMF/water at                         
60° C. for 6 hours in the presence of NaHCO.sub.3.                 
7. HPLC eluant: MeOH/water/HOAc, 25:74:1, v/v/v.                          
8. n.m.r. in solvent B: 1.51(s, 3H); 1.54(s, 3H); 2.17(m, 2H);            
2.9(m, 4H); 3.52(m, 2H); 4.21(s, 3H); 4.67(m, 1H); 4.84(m, 1H);           
5.1(d, 1H); 5.82(d, 1H); 7.05(s, 1H); 8.95(s, 1H).                        
 
    
     EXAMPLES 181-191 
     The general process described in Example 1 was repeated using the appropriate 3-aminomethyl-cephalosporin derivative and the appropriate heterocycle. The following compounds were obtained: 
     
         __________________________________________________________________________
 ##STR205##                                                               
Example No.                                                               
       R.sup.1  R.sup.2                                                   
                  R.sup.3          Yield %                                
                                        Footnote                          
__________________________________________________________________________
181    C(CH.sub.3).sub.2 CO.sub.2 H                                       
                H                                                         
                   ##STR206##      13   1, 2, 3                           
182    C(CH.sub.3).sub.2 CO.sub.2 H                                       
                H                                                         
                   ##STR207##      20   4, 5, 6                           
183    &#34;        Et                                                        
                   ##STR208##      24   4, 7, 8                           
184                                                                       
        ##STR209##                                                        
                Et                                                        
                   ##STR210##      31   4, 9, 10                          
185                                                                       
        ##STR211##                                                        
                H                                                         
                   ##STR212##      60   4, 11, 12                         
186    C(CH.sub.3).sub.2 CO.sub.2 H                                       
                H                                                         
                   ##STR213##      27   13, 14, 15                        
187    &#34;        Et                                                        
                   ##STR214##      36   13, 16, 17                        
188                                                                       
        ##STR215##                                                        
                H                                                         
                   ##STR216##      54   13, 18, 19                        
189    C(CH.sub.3).sub.2 CO.sub.2 H                                       
                H                                                         
                   ##STR217##      35   20, 21, 22                        
190                                                                       
        ##STR218##                                                        
                H                                                         
                   ##STR219##           23, 24, 25                        
191    &#34;        H                                                         
                   ##STR220##           26, 27, 28                        
__________________________________________________________________________
1. 6-Fluoro-2,3-dihydro-1H-imidazo(1,2,3)-pyridazinium bromide was        
prepared according to the                                                 
procedure described in Croat. Chem. Acta 41, 135 (1969) using             
3,6-difluoropyridazine as starting                                        
material. The hydrobromide salt in MeOH was further treated with          
diazomethane to liberate the                                              
free base, 6-fluoro-2,3-dihydroimidazo(1,2-b)pyridazine. Upon evaporation 
of the MeOH, the                                                          
compound was dissolved in CH.sub.2 Cl.sub.2 /nitromethane (5:3 v/v) and   
trimethyloxonium                                                          
tetrafluoroborate was added to the reaction mixture. After 4 hours at     
ambient temperature,                                                      
the mixture was filtered, and the filtrate was evaporated to give         
6-fluoro-2,3-dihydro-1-                                                   
methylimidazo(1,2-b)pyridazinium tetrafluoroborate.                       
2. HPLC eluant, MeOH/water/HOAc, 25:74:1 v/v/v.                           
3. n.m.r. in solvent B: 1.54(s, 6H); 2.99(s, 3H); 3.2-4.6(m, 8H); 5.13(d, 
1H); 5.82(d, 1H);                                                         
7.05(s, 1H); 7.4(d, 1H); 7.5(d, 1H).                                      
4. The starting material was 6-chloro-thiazolo-[3,2-b]pyridazinium        
perchlorate,                                                              
(see J. Org Chem 34, 996, (1969).                                         
5. HPLC eluant, MeOH/water HOAc, 20:79:1, v/v/v.                          
6. n.m.r. in solvent B: 1.55(s, 6H); 3.3(d, 1H); 3.55(d, 1H); 3.95(d,     
1H); 4.4(d, 1H);                                                          
5.15(d, 1H); 5.55(d, 1H); 7.45(d, 1H); 8.47-8.6(m, 3H).                   
7. The product was purified by chromatography on Diaion HP20 resin,       
eluting with increasing                                                   
proportions of CH.sub.3 CN in water.                                      
8. n.m.r. in solvent B: 1.16(br t, 3H); 1.51(s, 6H); 3.5(m, 2H); 3.6(m,   
2H); 4.45(d, 1H);                                                         
3.65(d, 1H); 5.18(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.9(d, 1H); 8.54(d,    
1H); 8.66(d, 1H);                                                         
8.7(d, 1H).                                                               
9. HPLC eluant, MeOH/water/HOAc, 20-30:79-69:1 v/v/v.                     
10. n.m.r. in solvent B: 1.15(br t, 3H); 1.91-2.4(m, 6H); 3.6(m, 4H);     
4.5(d, 1H);                                                               
4.8(d, 1H); 5.17(d, 1H); 5.85(d, 1H); 6.98(s, 1H); 7.85(d, 1H); 8.65(d,   
1H); 8.5(d, 1H);                                                          
8.6(d, 1H).                                                               
11. HPLC eluant, MeOH/water/HOAc, 30:69:1, v/v/v.                         
12. n.m.r. in solvent B: 1.7(m, 4H); 2.1(m, 4H); 3.5(d, 1H); 3.7(d, 1H);  
4.1(d, 1H); 4.6(d, 1H);                                                   
5.14(d, 1H); 5.84(d, 1H); 7.04(s, 1H); 7.45(d, 1H); 8.6(d, 1H); 8.47(d,   
1H); 8.52(d, 1H).                                                         
13. The starting material was 6-chloro-3-methylthiozolo[3,2-b]pyridazinium
 perchlorate                                                              
(see J. Org. Chem. 34, 996(1964)).                                        
14. HPLC eluant, MeOH/water/HOAc, 25:74:1, v/v/v.                         
15. n.m.r. in solvent B: 1.52(s, 3H); 1.54(s, 3H); 3.55(m, 2H); 4.1(d,    
1H); 4.65(d, 1H);                                                         
5,15(d, 1H); 5.85(d, 1H); 7.0(s, 1H); 7.47(d, 1H)); 8.62(d, 1H); 8.23(s,  
1H).                                                                      
16. HPLC eluant, MeOH/water/HOAc, 30:69:1, v/v/v.                         
17. n.m.r. in solvent B: 1.15(br.t, 3H); 1.5(br.s, 6H); 2.51(s, 3H);      
3.4(q, 2H); 3.65(m, 2H);                                                  
4.5(d, 1H); 4.8(d, 1H); 5.17(d, 1H); 5.87(d, 1H); 7.0(s, 1H); 7.87(d,     
1H); 8.64(d, 1H); 8.2(s, 1H).                                             
18. HPLC eluant MeOH/water/HOAc, 30:69:1, v/v/v.                          
19. n.m.r. in solvent B: 1.7(m, 4H); 2.1(m, 4H); 2.52(s, 3H); 3.56(d,     
1H); 3.6(d, 1H); 4.3(d, 1H);                                              
4.6(d, 1H); 5.15(d, 1H); 5.86(d, 1H); 7.04(s, 1H); 7.47(d, 1H); 8.61(d,   
1H); 8.61(d, 1H); 8.22(s, 1H).                                            
20. The starting material was prepared by treating 6-fluoroimidazo(1,2-b)p
yridazine, (obtained by                                                   
a process described in Tetrahedron, 23, 387 (1967), with trimethyloxonium 
tetrafluoroborate in                                                      
CH.sub.2 Cl.sub.2 at ambient temperature for 5 hours. The precipitate was 
filtered, to give                                                         
6-fluoro-1-methylimidazo(1,2-b)pyridazinium tetrafluoroborate.            
21. HPLC eluant, MeOH/water/HOAc, 20:79:1, v/v/v.                         
22. n.m.r. in solvent B: 1.56(br.s, 6H); 3.61(m, 2H); 3.98(s, 3H); 4.1(d, 
1H); 4.6(d, 1H); 5.15(d, 1H);                                             
5.83(d, 1H); 7.02(s, 1H); 7.31(d, 1H); 8.04(d, 1H); 8.09(d, 1H); 8.21(d,  
1H).                                                                      
23. For starting material see Example 229, Footnote 2.                    
24. HPLC eluant was MeOH/water/HOAc, 25:74:1, v/v/v.                      
25. n.m.r. in solvent B: 1.7(m, 4H); 2.14(m, 4H); 3.48(d, 1H); 3.7(d,     
1H); 4.15(s, 3H); 4.14(d, 1H);                                            
4.45(d, 1H); 5.14(d, 1H); 5.85(d, 1H); 7.05(s, 1H); 7.52(d, 1H); 8.35(d,  
1H); 9.47(s, 1H).                                                         
26. For starting material, see Example 222, Footnote 5.                   
27. HPLC eluant was MeOH/water/HOAc, 30:69:1, v/v/v.                      
28. n.m.r. in solvent B: 1.7(m, 4H); 2.15(m, 4H); 2.44(d, 1H); 2.65(d,    
1H); 4.05(s, 3H); 4.55(d, 1H);                                            
4.95(d, 1H); 5.15(d, 1H); 5.82(d, 1H); 7.05(s, 1H); 7.92(s, 2H); 8.9(s,   
1H).                                                                      
 
    
     EXAMPLE 192 ##STR221## 
     The starting material was 3-fluoro-6-methoxy-1-methyl-pyridazinium tetrafluoroborate, which was obtained by treatment of 6-fluoro-2-methylpyridazin-3-one with trimethyloxonium tetrafluoroborate in CH 2  CL 2  at ambient temperature. 
     The condensation reaction was carried out in DMF/water in the presence of NaHCO 3  at ambient temperature for 0.5 hours. Yield 12%. 
     HPLC eluant, MeOH/water/HOAc, 25:74:1, v/v/v. 
     n.m.r. in solvent B: 1.54 (s, 6H); 3.6 (br.s, 2H); 3.93 (s, 3H); 3.45 (d, 1H); 3.85 (d, 1H), 5.16 (d, 1H); 5.88 (d, 1H); 7.04 (s, 1H); 7.98-8.17 (m, 2H). 
     EXAMPLE 193 ##STR222## 
     This compound was obtained as follows: To 5-amino-3-chloropyridazine (see Yakugaku Zasshi 82, 857-60, (1962); Chem. Abstracts 59, 1631j) in nitromethane was added trimethyloxonium tetrafluoroborate. After 3 hours at ambient temperature the solvent was evaporated, and the ether was added to give a mixture of 5-amino-3-chloro-1-methylpyridazinium and 5-amino-3-chloro-2-methylpyridazinium tetrafluoroborates, which were used without further separation. The standard procedure was used for the condensation, which was carried out in a DMF/water mixture in the presence of NaHCO 3  at 70° C. for 1.25 hours. The final compound was worked up by HPLC using MeOH/water/HOAc, 22.5:76.5:1 v/v/v, as eluant. Yield 25%. n.m.r. of the single isomer product in solvent B: 1.53 (br.s, 6H); 3.59 (m, 2H); 3.83 (s, 3H); 4.56 (m, 2H); 5.15 (d, 1H); 5.9 (d, 1H); 6.23 (d, 1H); 7.0 (s, 1H); 7.92 (d, 1H). 
     EXAMPLES 194-195 
     The general process described in Example 1 was repeated, using the appropriate 3-aminomethylcephalosporin derivative and the appropriate heterocycle, to give the following compounds: 
     
         ______________________________________                                    
 ##STR223##                                                               
Example No.                                                               
          R              Yield %   Footnotes                              
______________________________________                                    
194                                                                       
           ##STR224##    37        1, 2, 3                                
195                                                                       
           ##STR225##    23        4, 5, 6                                
______________________________________                                    
Footnotes:                                                                
1. For the quaternary heterocyclic starting material, see Example         
182, Footnote 4.                                                          
2. HPLC eluant, MeOH/water/HOAc, 20-25:79-74:1, v/v/v.                    
3. n.m.r. in solvent B: 1.48(s, 6H); 3.45(d, 1H); 3.71(d, 1H);            
4.11(d, 1H); 4.57(d, 1H); 5.12(d, 1H); 5.84(d, 1H); 7.46(d, 1H);          
8.47(d, 1H); 8.57(d, 2H).                                                 
4. For the quarternary heterocyclic starting material, see Example        
13, Footnote 6.                                                           
5. HPLC eluant, MeOH/water/HOAc, 20:79:1, v/v/v.                          
6. n.m.r. in solvent B: 1.47(s, 6H); 3.5(m, 2H); 3.6(s, 3H);              
3.91(d, 1H); 4.42(d, 1H); 5.09(d, 1H); 5.83(d, 1H); 7.26(s, 2H).          
7. The 3-aminomethyl cephalosporin starting material was obtained         
by adding the corresponding known 3-azidomethyl cephalosporin             
derivative to 90% v/v aqueous TFA and stirring for 3 hours at             
ambient temperature. After cooling at 0°, Raney nickel             
(wet 2.0 g) was added and the mixture was stirred for 0.5 hours at        
0° and 1 hour at ambient temperature. The mixture was filtered,    
the filtrate evaporated and the crude product purified by                 
chromatography on a Diaion HP 20 column, eluting with                     
increasing proportions of acetonitrile in water. Appropriate              
fractions were combined, evaporated to a small volume and                 
freez-dried to give the required compound (0.81 g; yield 43%)             
having the following n.m.r. in solvent B: 1.49(s, 6H);                    
3.5-4.0(m, 4H); 5.18(d, 1H); 5.9(d, 1H).                                  
 
    
     EXAMPLES 196-218 
     The general procedure described in Examples 1-4 was used, except that the reaction was carried out at ambient temperature for 5 hours before quenching with HOAc. The appropriate 3-aminomethylcephalosporin was used, the reaction was worked up by chromatography on Diaion CHP20P resin to purify. The following compounds were made: 
     
         __________________________________________________________________________
 ##STR226##                                                               
Example No.                                                               
       R.sup.1   R.sup.2          Yield %                                 
                                       Footnotes                          
__________________________________________________________________________
196    CH.sub.2 CO.sub.2 H                                                
                  ##STR227##      46   1, 2                               
197    CH.sub.2 CO.sub.2 H                                                
                  ##STR228##      40   3, 4                               
198                                                                       
        ##STR229##                                                        
                  ##STR230##      34   1, 5, 6                            
199                                                                       
        ##STR231##                                                        
                  ##STR232##      40   1, 6, 7                            
200                                                                       
        ##STR233##                                                        
                  ##STR234##      28   3, 6, 8                            
201                                                                       
        ##STR235##                                                        
                  ##STR236##      22   3, 6, 9                            
202                                                                       
        ##STR237##                                                        
                  ##STR238##      29   3, 10                              
203                                                                       
        ##STR239##                                                        
                  ##STR240##      20   11, 12                             
204    CH.sub.2 CONHCH.sub.3                                              
                  ##STR241##      67   1, 13, 14                          
205    CH.sub.2 CON(CH.sub.3).sub.2                                       
                  ##STR242##      64   1, 15, 16                          
206    CH.sub.2 CONHCH.sub.2 CF.sub.3                                     
                  ##STR243##      57   1, 17, 18                          
207                                                                       
        ##STR244##                                                        
                  ##STR245##      69   1, 19, 20                          
208    C.sub.2 H.sub.5                                                    
                  ##STR246##      18   11, 21                             
209                                                                       
        ##STR247##                                                        
                  ##STR248##      60   1, 22, 23                          
210                                                                       
        ##STR249##                                                        
                  ##STR250##      46   1, 23, 24                          
211                                                                       
        ##STR251##                                                        
                  ##STR252##      33   3, 25                              
212                                                                       
        ##STR253##                                                        
                  ##STR254##      69   26, 27                             
213                                                                       
        ##STR255##                                                        
                  ##STR256##      57   28, 29                             
214                                                                       
        ##STR257##                                                        
                  ##STR258##      56   30, 31                             
215                                                                       
        ##STR259##                                                        
                  ##STR260##      53   30, 32                             
216                                                                       
        ##STR261##                                                        
                  ##STR262##      61   30, 33                             
217                                                                       
        ##STR263##                                                        
                  ##STR264##      42   34, 35                             
218                                                                       
        ##STR265##                                                        
                  ##STR266##      52   1, 36                              
__________________________________________________________________________
Footnotes                                                                 
1. Starting material was 3-chloro-1-methylpyridazinium iodide.            
2. n.m.r. in solvent A: 3.36(d, 1H); 3.59(d, 1H); 4.08(d, 1H); 4.24(s,    
3H); 4.48(d, 1H); 4.53(s, 2H);                                            
5.03(d, 1H); 5.71(d, 1H); 6.8(s, 1H); 7.6(m, 1H); 7.88(m, 1H); 8.88(m,    
1H).                                                                      
3. Starting material was 7-methylthiothiazolo-[3,2-a]pyrimidinium         
tetrafluoroborate.                                                        
4. n.m.r. in solvent A: 3.35(d, 1H); 3.6(d, 1H); 4.25(d, 1H); 4.51(s,     
2H); 4.64(d, 1H); 5.03(d, 1H);                                            
5.73(d, 1H); 6.81(s, 1H); 7.04(d, 1H); 7.65(d, 1H); 8.08(d, 1H); 8.79(d,  
1H).                                                                      
5. n.m.r. in solvent A: 1.4(d, 3H); 3.39(d, 1H); 3.61(d, 1H); 4.08(d,     
1H); 4.23(s, 3H); 4.53(d, 1H);                                            
4.6(q, 1H); 5.06(d, 1H); 5.8(d, 1H); 6.81(s, 1H); 7.6(m, 1H); 7.93(m,     
1H); 8.9(m, 1H).                                                          
Retention time 3.6 minutes on a reversed phase Partisil 10/25 ODS-2       
column, using                                                             
MeOH/H.sub.2 O/TFA, 35:65:0.2, v/v/v as eluant.                           
6. The 3-aminomethylcephalosporin may be prepared as follows: To a        
stirred suspension of 2-                                                  
(2-formamidothiazol-4-yl)-2-oxoacetic acid (6.1 g) in DMF (50 ml) was     
added pyridine (2.65 ml)                                                  
and 4N aqueous hydrochloric acid (8.52 ml.), followed by dropwise         
addition of t-butyl 2-amino-                                              
oxypropionate (5.28 g). After stirring for 18 hours at ambient            
temperature, the mixture was                                              
diluted with water, acidified, and worked up in a conventional manner by  
extraction into EtOAc.                                                    
Crude product was dissolved in a mixture of ether (80 ml) and EtOAc (40   
ml), and N-methyl-                                                        
morpholine (7.6 ml) added. The precipitate was filtered to give           
2-[(Z)-1-(tert-butoxy-                                                    
carbonyl)ethoxy-imino]-2-(2-formamidothiazol-4-yl)acetic acid as its      
N-methyl-morpholine salt,                                                 
having the following n.m.r. in d.sub.6 DMSO: 1.35(d, 3H); 1.41(s, 9H);    
2.35(s, 3H); 2.56(t, 4H);                                                 
3.65(t, 4H); 4.55(q, 1H); 7.35(s, 1H); 8.46(s, 1H).                       
Oxalyl chloride (2.61 ml) and DMF (2.3 ml) were added to CH.sub.2         
Cl.sub.2 (100 ml) at -10° C.,                                      
and stirred for 30 minutes. The above N-methylmorpholine salt (12.06 g)   
was added, followed by                                                    
N-methylmorpholine (0.60 ml), and stirring continued for 30 minutes.      
Meanwhile, in a separate                                                  
flask, a suspension of 7-amino-3-azidomethyl-ceph-3-em-4-carboxylic acid  
(7.27 g) in CH.sub.2 Cl.sub.2                                             
(40 ml) was treated with N,O-bis(trimethylsilyl)acetamide (14.1 ml), and  
stirred for 1 hour to                                                     
give a clear solution, which was transferred by syringe to the acid       
chloride solution. After                                                  
stirring for 1 hour at -10° C., the temperature was allowed to     
come to ambient. The                                                      
mixture was poured into water (100 ml) and organics extracted into EtOAc. 
Removal of solvent                                                        
gave 3-azido-methyl-7-[ 2-((Z)-1-(t-butoxycarbonyl)ethoxyimino)-2-(2-forma
midothiazol-4-yl)-                                                        
acetamido]ceph-3-em-4-carboxylic acid, as a mixture of diastereoisomers,  
having the following                                                      
n.m.r. in solvent A: 1.35(s, 9H); 1.37 and 1.38(2xd, 3H); 3.41(2xd, 1H);  
3.61(d, 1H); 3.82(2xd, 1H);                                               
4.34(d, 1H); 4.56(2xq, 1H); 5.14(2xd, 1H); 5.83(d, 1H); 7.32(2xs, 1H);    
8.39(s, 1H).                                                              
A solution of the above 3-azidomethyl compound (16.5 g) in a mixture of   
isopropanol (110 ml),                                                     
water (20 ml) and concentrated hydrochloric acid (7.5 ml) was stirred for 
3 days at ambient                                                         
temperature. After cooling to 0° C., the pH was raised to 3 using  
triethylamine, solvents were                                              
evaporated, the residue treated with water (100 ml.) and organics         
extracted into EtOAc. Evapor-                                             
ation gave 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-(t-butoxycarbonyl)ethoxyimi
no)acetamido]-3-                                                          
azidomethylceph-3-em-4-carboxylic acid, as a mixture of diastereoisomers, 
having the following                                                      
n.m.r in solvent A: 1.4 and 1.42(2xc, 3H); 1.44(s, 9H); 3.46(2xd, 1H);    
3.66(d, 1H); 3.88(2xd, 1H);                                               
4.39(d, 1H); 4.55(q, 1H); 5.18(d, 1H); 5.84(d, 1H); 6.74(2xs, 1H).        
The above deprotected 3-azidomethylcephem (12.2 g) was added to 90% v/v   
aqueous TFA (60                                                           
ml) pre-cooled to 0° C., and stirred for 30 minutes. Raney nickel  
(wet, 2.5 g) was added, and the                                           
mixture stirred 20 minutes, allowing the temperatre to rise to ambient.   
The mixture was filtered,                                                 
solvents evaporated and the residue dissolved in water, and the pH raised 
to 3 with sodium                                                          
acetate. Careful chromatography on Diaion HP20SS, eluting successively    
with water, then                                                          
water/CH.sub.3 CN, 97.5:2.5 v/v and water/CH.sub.3 CN 95:5 v/v, allowed   
substantial separation of the                                             
two diastereoisomers of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-
carboxyethoxy-                                                            
imino)acetamido]ceph-3-em-4-carboxylic acid. The more polar (m.p.)        
isomer, having retention                                                  
time 3.05 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column,    
using MeOH/H.sub.2 O/                                                     
HOAc 20:80:1 v/v/v as eluant, had the following n.m.r. in solvent A:      
1.37(d, 3H); 3.23(d, 1H);                                                 
3.44(d, 1H); 3.53(d, 1H); 3.65(d, 1H); 4.52(q, 1H); 4.99(d, 1H); 5.8(d,   
1H); 6.79(s, 1H).                                                         
The less polar (l.p.) isomer, having retention time 4.7 minutes under     
identical conditions to the                                               
above, had the following n.m.r. in solvent A: 1.43(d, 3H); 3.2(d, 1H);    
3.42(d, 1H); 3.53(d, 1H);                                                 
3.64(d, 1H); 4.52(q, 1H); 5.0(d, 1H); 5.72(d, 1H); 6.81(s, 1H).           
7. n.m.r. in solvent A: 1.42(d, 3H); 3.45(d, 1H); 3.64(d, 1H); 4.08(d,    
1H); 4.24(s, 3H); 4.56(d, 1H);                                            
4.63(q, 1H); 5.12(d, 1H); 5.81(d, 1H); 6.79(s, 1H); 7.6(m, 1H); 7.95(m,   
1H); 8,95(m, 1H). Retention                                               
time 4.6 min. on a reversed phase Partisil PXS 10/25 ODS-2 column, using  
MeOH/H.sub.2 O/TFA,                                                       
35:65:0.2 v/v/v, as eluant.                                               
8. n.m.r. in solvent A: 1.38(d, 3H); 3.31(d, 1H); 3.59(d, 1H); 4.27(d,    
1H); 4.56(q, 1H); 4.59(d, 1H);                                            
5.02(d, 1H); 5.77(d, 1H); 6.78(s, 1H); 7.05(d, 1H); 7.66(d, 1H); 8.1(d,   
1H); 8.69(d, 1H). Retention                                               
time 3.3 minutes on a reversed phase Partisil 10/25 ODS0-2 column, using  
MeOH/H.sub.2 O/TFA,                                                       
40:60:0.2, v/v/v, as eluant.                                              
9. n.m.r. in solvent A: 1.41(d, 3H); 3.36(d, 1H); 3.61(d, 1H); 4.23(d,    
1H); 4.6(m, 3H); 5.05(d, 1H);                                             
5.74(d, 1H); 6.8(s, 1H); 7.03(d, 1H); 7.67(d, 1H); 8.11(d, 1H); 8.7(d,    
1H). Retention time 4.3                                                   
minutes on a reversed phase Partisil 10/25 ODS-2 column, using            
MeOH/H.sub.2 O/TFA, 40:60:0.2,                                            
v/v/v, as eluant.                                                         
10. n.m.r. in solvent A: 2.38(t, 4H); 3.35(d, 1H); 3.62(d, 1H); 4.27(d,   
1H); 4.66(d, 1H); 5.06(d, 1H);                                            
5.76(d, 1H); 6.76(s, 1H); 7.04(d, 1H); 7.66(d, 1H); 8.1(d, 1H); 8.7(d,    
1H).                                                                      
11. The basic procedure of Examples 1-4 was used, except the reaction     
mixture was heated at                                                     
60° C. for 2 hours, and product was isolated by chromatography on  
Diaion HP20SS. The starting                                               
heterocycle was 6-amino-3-fluoro-1-methylpyridazinium tetrafluoroborate.  
12. n.m.r. in solvent A: 2.33(m, 4H); 3.28(d, 1H); 3.56(d, 1H); 3.65(s,   
3H); 3.83(d, 1H); 4.27(d,                                                 
1H); 5.0(d, 1H); 5.68(d, 1H); 6.7(s, 1H); 8.23(s, 2H).                    
13. n.m.r. in solvent A: 2.66(s, 3H); 3.35(d, 1H); 3.61(d, 1H); 4.08(d,   
1H); 4.26(s, 3H); 4.47(s, 2H);                                            
4.51(d, 1H); 5.03(d, 1H); 5.72(d, 1H); 6.87(s, 1H); 7.62(m, 1H); 7.94(m,  
1H); 8.91(d, 1H).                                                         
14. The 3-aminomethylcephalosporin may be prepared as follows: Using the  
general procedure of                                                      
Footnote 6 above, 2-((Z)-N-methylcarbamoylmethoxyimino)-2-(2-tritylaminoth
iazol-4-yl)acetic                                                         
acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carboxylic acid  
to give the                                                               
appropriate 7-amido-3-azidomethylcephalosporin. This was then reduced,    
with accompanying                                                         
removal of the trityl group, by the same general procedure to give        
3-aminomethyl-7-[2-(2-amino-                                              
thiazol-4-yl)-2-((Z)-N-methylcarbamoylmethoxyimino)acetamido]ceph-3-em-4-c
arboxylic acid,                                                           
used without further characterisation in subsequent stages.               
15. n.m.r. in solvent A: 2.8(s, 3H); 2.92(s, 3H); 3.3(d, 1H); 3.61(d,     
1H); 4.06(d, 1H); 4.24(s, 3H);                                            
4.49(d, 1H); 4.81(s, 2H); 5.02(d, 1H); 5.71(d, 1H); 6.82(s, 1H); 7.6(m,   
1H); 7.93(dd, 1H); 8.89(d,                                                
1H).                                                                      
16. The 3-aminomethylcephalosporin may be prepared as follows: Using the  
general procedure of                                                      
Footnote 6 above, 2-((Z)-N,N-dimethylcarbamoylmethoxyimino)-2-(2-tritylami
nothiazol-4-                                                              
yl)acetic acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carboxy
lic acid, to give                                                         
the appropriate 7-amido-3-azidomethylcephalosporin. This was reduced, by  
the same general                                                          
procedure, to give, after chromatography on Diaion HP20SS resin and       
eluting with isopropanol/                                                 
water, 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2((Z)-N,N-dimethylcarbamoy
lmethoxy-                                                                 
imino)acetamido]ceph-3-em-4-carboxylic acid, used without further         
characterisation for                                                      
subsequent stages.                                                        
17. n.m.r. in solvent A: 3.34(d, 1H); 3.63(d, 1H); 3.94(m, 2H); 4.08(d,   
1H); 4.25(s, 3H); 4.55(d,                                                 
1H); 4.6(s, 2H); 5.05(d, 1H); 5.74(d, 1H); 6.87(s, 1H); 7.63(m, 1H);      
7.94(dd, 1H); 8.92(d, 1H).                                                
18. The starting material may be obtained as follows: 2,2,2-Trifluoroethyl
amine hydrochloride                                                       
(27.1 g) was suspended in dichloromethane (300 ml), cooled to 5°,  
and triethylamine (55.6 ml)                                               
was run in. A solution of bromoacetyl bromide (18 ml) in dichloromethane  
(200 ml) was run in                                                       
over the course of 3 hours. After a conventional extractive work-up, the  
crude product was                                                         
distilled to give N-(2,2,2-trifluoroethyl)-2-bromoacetamide, n.m.r. in    
CDCl.sub.3 : 3.93(m, 4H);                                                 
6.9(br, 1H).                                                              
Ethyl 2-(Z)-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate             
hydrochloride (19.7 g) was                                                
dissolved in DMSO (150 ml), treated with potassium carbonate (15.4 g),    
and the above bromo-                                                      
acetamide (12.7 g) was added. After stirring for 24 hours, the reaction   
mixture was diluted with                                                  
water (500 ml) and worked-up by conventional extraction. Product was      
purified by chromato-                                                     
graphy on silica gel, to give ethyl 2-[(Z)-N-(2,2,2-trifluoroethyl)carbamo
ylmethoxyimino]-2-(2-                                                     
tritylaminothiazol-4-yl)acetate, n.m.r. in CDCl.sub.3 : 1.38(t, 3H);      
3.94(m, 2H); 4.41(q, 2H), 4.82(s,                                         
2H); 6.63(s, 1H); 7.0 (m, 2H); 7.35(m, 15H).                              
The ester was dissolved in methanol, and hydrolysed at ambient            
temperature by addition of                                                
aqueous sodium hydroxide. The sodium salt precipitated and was filtered   
off. After resuspension                                                   
in water and acidification with 2N hydrochloric acid, there was obtained  
2-[(Z)-N-(2,2,2-tri-                                                      
fluoroethyl)carbamoylmethoxyimino]-2-(2-tritylaminothiazol-4-yl)acetic    
acid. Following the                                                       
procedure outlined in Footnote 14 above, this was condensed with          
7-amino-3-azidomethylceph-3-                                              
em-4-carboxylic acid, and the product was reduced, to give                
3-aminomethyl-7-[2-(2-aminothiazol-                                       
4-yl)-2-[(Z)-N-(2,2,2-trifluoroethyl)carbamoylmethoxyimino]acetamido]-ceph
-3-em-4-carboxylic                                                        
acid, used without further purification for subsequent stages.            
19. Product obtained as a 6:4 mixture of diastereoisomers, n.m.r. in      
solvent A: 2.26(m, 2H);                                                   
3.22(m, 2H); 3.32(d, 1H); 3.59(d, 1H); 4.06(d, 1H); 4.25(s, 3H); 4.48(d,  
1H); 4.68 and 4.74(2xt,                                                   
1H); 5.01(d, 1H); 5.66(d, 1H); 6.78 and 6.81(2xs, 1H); 7.61(br. 1H);      
7.93(dd, 1H); 8.91(d, 1H).                                                
20. The 3-aminomethylcephalosporin may be prepared as follows: Using the  
general procedure                                                         
outlined in Footnote 6 above, 2-((Z,RS)-2-oxopyrrolidin-3-yloxy-imino)-2-(
2-tritylaminothiazol-                                                     
4-yl)acetic acid was condensed with 7-amino-3-azidomethylceph-3-em-4-carbo
xylic acid to give                                                        
3-azidomethyl-7-[2-((Z,RS)-2-oxopyrrolidin-3-yloxyimino)-2-(2-tritylaminot
hiazol-4-                                                                 
yl)acetamido]ceph-3-em-4-carboxylic acid, n.m.r. in solvent A: 2.53(m,    
2H); 3.3-3.6(m, 4H);                                                      
4.09(d, 1H); 4.45(d, 1H); 5.05(m, 2H); 5.88(d, 1H); 6.75(s, 1H); 7.33(m,  
15H).                                                                     
The azide was reduced by the standard procedure to give                   
3-aminomethyl-7-[2-(2-aminothiazol-                                       
4-yl)-2((Z,RS)-2-oxopyrrolidin-3-yloxyimino)acetamido]-ceph-3-em-4-carboxy
lic acid as a 6:4                                                         
mixture of diastereoisomers, n.m.r. in solvent A: 2.3(m, 2H); 3.1-3.8(m,  
6H); 4.73 and 4.78(2xt,                                                   
1H); 5.02(d, 1H); 5.72(d, 1H); 6.81 and 6.83(2xs, 1H).                    
21. n.m.r. in solvent A: 1.23(t, 3H); 3.32(d, 1H); 3.6(d, 1H); 3.71(s,    
3H); 4.05(m, 4H); 5.01(d, 1H);                                            
5.68(d, 1H); 6.71(s, 1H); 7.28(s, 2H).                                    
22. n.m.r. in solvent A: 0.93(t, 3H); 1.78(quintet, 2H); 3.34(d, 1H);     
3.58(d, 1H); 4.06(br, 1H);                                                
4.22(s, 3H); 4.42(t, 1H); 4.46(br, 1H); 5.02(d, 1H); 5.75(d, 1H);         
7.59(br, 1H); 7.91(br, 1H); 8.9(d,                                        
1H). Retention time 5.8 minutes on a reversed phase Partisil PXS 10/25    
ODS-2 column, using                                                       
MeOH/water/TFA 40:60:0.2 v/v/v as eluant.                                 
23. The 3-aminomethylcephalosporin may be prepared as follows: Hydrazine  
hydrate (15 ml) was                                                       
added dropwise to a stirred solution of t-butyl 2-(N-phthalimido-oxy)-buty
rate (45.8 g) in                                                          
dichloromethane (600 ml) at ambient temperature. After 2 hours, a mixture 
of 25% aqueous                                                            
ammonia (120 ml) and water (200 ml) was added, and t-butyl-2-aminoxybutyra
te isolated by a                                                          
conventional extractive procedure. By following the procedure of Footnote 
6, this was                                                               
converted to 2-[(Z)-1-(t-butoxycarbonyl)propoxyimino]-2-(2-formamidothiazo
l-4-yl)-acetic acid,                                                      
precipitated as its triethylamine salt, having the following n.m.r. in    
d.sub.6 -DMSO: 0.94(t, 3H);                                               
1.21(t, 9H); 1.46(s, 9H); 1.73(quintet, 2H); 3.03(q, 6H); 4.3(t, 1H);     
7.25(s, 1H); 8.51(s, 1H).                                                 
Following the procedure of Footnote 6, the above acetic acid was          
condensed with 7-amino-3-                                                 
azido-methylceph-3-em-4-carboxylic acid, the formyl group was removed by  
hydrolysis, and the                                                       
resulting product was reduced to the 3-aminomethylcephem. Careful         
chromatography on Diaion                                                  
HP20SS, eluting successively with water, water/CH.sub.3 CN, 97.5:2.5 v/v, 
water CH.sub.3 CN, 95:5 v/v                                               
and water/CH.sub.3 CN, 92.5:7.5 v/v, allowed substantial separation of    
the diasteroisomers of                                                    
3-aminomethyl-7-[2-aminothiazol-4-yl)-2-((Z)-1-carboxy-propoxyimino)acetam
ido]ceph-3-em-4-                                                          
carboxylic acid. The more polar (m.p.) isomer, having retention time 3.02 
minutes on a reversed                                                     
phase Partisil PXS 10/25 ODS-2 column, using MeOH/H.sub.2 O/HOAc 30:70:1  
v/v/v as eluant, had                                                      
the following n.m.r. in solvent A: 0.95(t, 3H); 1.8(m, 2H); 3.28(d, 1H);  
3.43(d, 1H); 3.58(d, 1H);                                                 
3.69(d, 1H); 4.45(t, 1H); 5.02(d, 1H); 5.75(d, 1H); 6.79(s, 1H).          
The less polar (l.p.) isomer, having retention time 3.76 minutes under    
identical conditions to the                                               
above, had the following n.m.r, in solvent A: 1.0(t, 3H); 1.83(m, 2H);    
3.28(d, 1H); 3.43(d, 1H);                                                 
3.58(d, 1H); 3.69(d, 1H); 4.43(t, 1H); 5.03(d, 1H); 5.71(d, 1H); 6.77(s,  
1H).                                                                      
24. n.m.r. in solvent A: 0.94(t, 3H); 1.79(quintet, 2H); 3.34(d, 1H);     
3.56(d, 1H); 4.05(br, 1H);                                                
4.22(s, 3H); 4.37(t, 1H); 4.47(br, 1H); 5.03(d, 1H); 5.69(d, 1H); 6.77(d, 
1H); 7.6(br, 1H); 7.92(br,                                                
1H); 8.9(d, 1H)). Retention time 6.8 minutes on a reversed phase Parisil  
PXS 10/25 ODS-2                                                           
column, using MeOH/water/TFA 40:60:0.2 v/v/v as eluant.                   
25. n.m.r. in solvent A: 1.65(m, 4H); 2.03(m, 4H); 3.34(d, 1H); 3.61(d,   
1H); 4.25(d, 1H); 4.65(d,                                                 
1H); 5.03(d, 1H); 5.72(d, 1H); 6.75(s, 1H); 7.03(d, 1H); 7.67(d, 1H);     
8.1(d, 1H); 8.7(d, 1H).                                                   
26. Starting material was 2,3-dihydro-7-methylthiothiazolo[2,3-a]pyrimidin
ium tetrafluoroborate.                                                    
27. n.m.r. in solvent A: 1.67(m, 4H); 2.04(m, 4H); 3.27(d, 1H); 3.58(d,   
1H); 3.69(t, 2H); 4.22(d,                                                 
1H); 4.55(d, 1H); 4.6(t, 2H); 5.04(d, 1H); 5.73(d, 1H); 6.67(d, 1H);      
6.75(s, 1H); 8.12(d, 1H).                                                 
28. The starting material was prepared by dissolving 1-(2-cyanothiazol-4-y
l)methyl-4-methylthio-                                                    
pyridinium chloride (242 mg) in a mixture of dichloromethane (11 ml) and  
TFA (2 ml), cooling                                                       
in ice, and treating with 3-chloroperoxybenzoic acid (232 mg). After      
stirring for 40 minutes                                                   
solvents were evaporated and the residue was treated with water (8 ml)    
and extracted with ether                                                  
(3 portions of 5 ml). The aqueous layer containing 1-(2-cyanothiazol-4-yl)
methyl-4-methyl-                                                          
sulphinylpyridinium salts was used as such.                               
29. n.m.r. in solvent A: 1.82(m, 2H); 2.37(t, 4H); 3.29(d, 1H); 3.52(d,   
1H); 4.21(d, 1H); 4.41(d,                                                 
1H); 5.04(d, 1H); 5.53(s, 2H); 5.72(d, 1H); 6.75(s, 1H); 6.95(dd, 1H);    
7.34(dd, 1H); 8.17(dd, 1H);                                               
8.29(s, 1H); 8.34(dd, 1H).                                                
30. The starting material was prepared as in Footnote 28, but starting    
from 4-methylthio-1-(1,2,3-                                               
thiadiazol-4-yl)methylpyridinium methanesulphonate.                       
31. n.m.r. in solvent A: 1.82(m, 2H); 2.38(t, 4H); 3.28(d, 1H); 3.51(d,   
1H); 4.2(d, 1H); 4.41(d, 1H);                                             
5.05(d, 1H); 5.71(d, 1H); 5.82(s, 2H); 6.73(s, 1H); 6.94(dd, 1H);         
7.35(dd, 1H); 8.25(d, 1H); 8.43(d,                                        
1H); 9.26(s, 1H).                                                         
32. n.m.r. in solvent A: 1.41(d, 3H); 3.27(d, 1H); 3.51(d, 1H); 4.21(d,   
1H); 4.51(d, 1H); 4.59(q,                                                 
1H); 5.06(d, 1H); 5.74(d, 1H); 5.86(s, 2H); 6.76(s, 1H); 6.95(dd, 1H);    
7.35(dd, 1H); 8.27(d, 1H);                                                
8.45(d, 1H); 9.27(s, 1H).                                                 
Retention time 5.0 minutes on a reversed phase Partisil PXS 10/25 ODS-2   
column using MeOH/                                                        
water/TFA 35:65:0.2 v/v/v as eluant.                                      
33. n.m.r. in solvent A: 0.92(t, 3H); 1.78(quintet, 2H); 3.27(d, 1H);     
3.36(d, 1H); 4.21(d, 1H);                                                 
4.42(d, 1H); 4.44(t, 1H); 5.04(d, 1H), 5.72(d, 1H); 5.86(s, 2H); 6.76(s,  
1H); 6.95(dd, 1H); 7.32(dd,                                               
1H); 8.27(d, 1H); 8.45(d, 1H); 9.26(s, 1H). Retention time 7.6 minutes on 
a reversed phase Partisil                                                 
PXS 10/25 ODS-2 column, using MeOH/water/TFA 35:65:0.2 v/v/v as eluant.   
34. The starting material was prepared as in Footnote 28, but starting    
with 1-(E-3-cyano-2-                                                      
methylallyl)-4-methylthiopyridinium bromide, and using two equivalents of 
3-chloroperoxy-                                                           
benxoic acid, to give substantially 1-(E-3-cyano-2-methylallyl)-4-methanes
ulphonylpyridinium                                                        
bromide.                                                                  
35. n.m.r. in solvent A: 0.95(t, 3H); 1.8(quintet, 2H); 1.96(d, 3H);      
3.29(d, 1H); 3.54(d, 1H);                                                 
4.24(d, 1H); 4.43(d, 1H); 4.45(t, 1H); 4.93(s, 2H); 5.06(d, 1H); 5.23(d,  
1H); 5.74(d, 1H); 6.78(s,                                                 
1H); 6.96(dd, 1H); 7.31(dd, 1H); 8.01(dd, 1H); 8.19(dd, 1H).              
Retention time 4.3 minutes on a reversed phase Partisil PXS 10/25 ODS-2   
column, using MeOH/                                                       
Water/TFA 40:60:0.2 v/v/v as eluant.                                      
36. n.m.r. in solvent A: 1.67(br, 4H); 2.0(br, 4H); 3.31(d, 1H); 3.61(d,  
1H); 4.24(s + m, 4H);                                                     
4.46(d, 1H); 5.01(d, 1H); 5.71(d, 1H); 6.72(s, 1H); 7.6(m, 1H); 7.82(m,   
1H); 8.84(d, 1H).                                                         
 
    
     EXAMPLE 219 
     The general procedure of Examples 7-14 was repeated using DMF as solvent at ambient temperature, with the appropriate starting materials. Products were worked up by chromatography on Diaion CHP20P resin, eluting with CH 3  CN/water mixtures. The following compounds were made. 
     
         ______________________________________                                    
 ##STR267##                                                               
Example                          Yield Foot-                              
No.    R.sup.1    R.sup.2        %     notes                              
______________________________________                                    
219                                                                       
        ##STR268##                                                        
                   ##STR269##    48    1, 2, 3                            
______________________________________                                    
Footnotes                                                                 
1. Starting material was 1-methyl-4-methylthiothieno[2,3-                 
d]pyrimidinium tetrafuloroborate.                                         
2. n.m.r. in solvent A: 1.29(t, 3H); 1.38(d, 3H); 3.21(d, 1H);            
3.44(d, 1H); 4.01(s + m, 5H); 4.56(q, 1H); 4.86(d, 1H); 5.05(d,           
1H); 5.22(d, 1H); 5.74(d, 1H); 6.75(s, 1H); 7.8(d, 1H); 7.9(d, 1H);       
8.81(s, 1H).                                                              
Retention time 5.1 minutes on a reversed phase Partisil PXS 10/25         
ODS-2 column, using MeOH/H.sub.2 O/TFA 40:60:0.2 as eluant.               
3. The cephalosporin intermediate may be prepared as follows:             
To a stirred solution of triethylamine (0.18 ml) in MeOH (50 ml)          
was added 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-              
carboxyethoxyimino)-acetamido]ceph-3-em-4-carboxylic acid                 
(more polar isomer, 0.6 g), followed by sodium cyanoborohydride           
(0.08 g). A solution of acetaldehyde (0.07 ml) in MeOH (5 ml)             
was added over 40 minutes, then the solvent was removed and the           
residue was dissolved in water (100 ml). After reducing the pH            
to 3.5, the solution was loaded onto a column of Diaion CHP20P            
resin. Elution with 95:5 H.sub.2 O:CH.sub.3 CN gave 7-[2-(2-amino-        
thiazol-4-yl)-2-((Z)-1-carboxyethoxyimino)acetamido]-3-ethyl-             
aminomethylceph-3-em-4-carboxylic acid (more polar isomer),               
having the following n.m.r. in solvent A: 1.19(t, 3H); 1.43(d, 3H);       
2.94(q, 2H); 3.37(d, 1H); 3.41(d, 1H); 3.6(d, 1H); 3.76(d, 1H);           
4.61(q, 1H); 5.03(d, 1H); 5.75(d, 1H); 6.78(s, 1H).                       
Retention time 3.25 minutes on a reversed phase Partisil PXS              
10/25 ODS-2 column, using MeOH/water/HOAc 25:75:1 as                      
eluant.                                                                   
 
    
     EXAMPLE 220 
     Dry dichloromethane (5 ml) was cooled to -10° and oxalyl chloride (1.15 mM), followed by DMF (1.15 mM), was added, and the mixture was stirred at -15° to -10° for 1 hour. To this was then added 1-(Z)-chloroethylene-2-(2-formamidothiazol-4-yl)acetic acid (1 mM), followed by N-methylmorpholine (1.15 mM), and the mixture was stirred for 1 hour at -15° to -10°. 
     In another flask a solution of 7-amino-3-(1-methyl-4-pyridinio)aminomethylceph-3-em-4-carboxylic acid (1.15 mM), as its partial salt with 1.76 moles TFA, in dimethylacetamide (6 ml) was treated with N-methylmorpholine (2.08 mM), and the pink suspension was syringed into the flask containing the activated acid, is followed by N-methylmorpholine (1.15 mM). After stirring for 1 hour, at -10° and 1 hour at ambient temperature, the mixture was filtered. The solution was evaporated to dryness, and deformylated by solution in methanol (20 ml) and treating with concentrated hydrochloric acid (0.5 ml), at ambient temperature for 2 hours. After removal of the methanol, the residue was dissolved in water, the pH was adjusted to 5.2 with aqueous NaHCO 3 , and the product was purified by chromatography on Diaion CHP20P resin to give 7-[2-(2-aminothiazol-4-yl)-2-(Z)-chloromethyleneacetamido]-3-(1-methyl-4-pyridinio)aminomethylceph-3-em-4-carboxylic acid, in 5% yield, having the following n.m.r. in solvent A: 3.27 (d, 1H); 3.5 (d, 1H); 3.84 (s, 3H); 4.19 (d, 1H); 4.41 (d, 1H); 5.07 (d, 1H); 5.66 (d, 1H); 6.38 (s, 1H); 6.82 (s, 1H); 6.89 (d, 1H); 7.26 (d, 1H); 8.01 (d, 1H); 8.18 (d, 1H). 
     EXAMPLES 221-228 
     To a stirred suspension of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (240 mg, 0.5 mmole) and triethylamine (200 ul, 1.4 mmole) in EtOH (10 ml) at 25° was added 1-methyl-4-methylthioquinazolinium iodide (160 mg. 0.5 mmole). After 1.5 hours the solution was evaporated to dryness under reduced pressure, the residue dissolved in water (10 ml), the solution acidified with excess 5% v/v aqueous HOAc and the insoluble material filtered off. The filtrate was applied to a Dianion HP20 column and the product purified by gradient elution with MeOH. Using this general process and the appropriate quaternary heterocycle, the following compounds were obtained: 
     
         __________________________________________________________________________
 ##STR270##                                                               
Example                            Yield                                  
No.  R.sub.1      R.sub.2                                                 
                     R.sub.3                                              
                        R.sub.4    %   Footnotes                          
__________________________________________________________________________
221  CH.sub.3     CH.sub.3                                                
                     CH.sub.3                                             
                        H          11  1, 2, 3                            
222  CH.sub.3     H  H  H           9  4, 5, 6                            
223  CH.sub.2 CHCH.sub.2                                                  
                  H  H  H          44  7, 8, 6                            
224                                                                       
      ##STR271##  H  H  H          33  9, 10, 6                           
225  CH.sub.3     H  H  CH.sub.2 CH.sub.3                                 
                                   29  11, 12, 13,                        
                                       5, 6                               
226  CH.sub.2 CHCH.sub.2                                                  
                  H  H  CH.sub.2 CH.sub.3                                 
                                   22  14, 15, 13,                        
                                       8, 6                               
227  CH.sub.2 CHCH.sub.2                                                  
                  H  H                                                    
                         ##STR272##                                       
                                   46  16, 17, 18, 19, 8, 6               
228  CH.sub.3     H  H                                                    
                         ##STR273##                                       
                                   35  20, 21, 22, 5, 6                   
__________________________________________________________________________
Footnotes                                                                 
1. n.m.r. in solvent A: 1.41(s, 3H); 1.43(s, 3H); 2.52(m, 6H); 3.49(d,    
1H); 3.72(d, 1H); 3.94(s,                                                 
3H); 4.26(d, 1H); 4.82(d, 1H); 5.02(d, 1H); 5.76(d, 1H); 6.75(s, 1H);     
8.74(s, 1H).                                                              
2. The 1,5,6-trimethyl-4-methylthiothieno[2,3-d]pyrimidinium iodide may   
be prepared as                                                            
follows: A solution of 5,6-dimethyl-4-methylthiothieno[2,3-d]pyrimidine   
in CH.sub.2 Cl.sub.2 was                                                  
treated with trimethyloxonium tetrafluoroborate and stirred, under argon, 
at room tempera-                                                          
ture overnight. The solution was evaporated to dryness to give a white    
solid. N.mr. in d.sub.6                                                   
DMSO: 2.6(s, 6H); 2.8(s, 3H); 4.2(s, 3H); 9.4(s, 1H).                     
3. 5,6-Dimethyl-4-methylthiothieno[2,3-d]-pyrimidine may be prepared as   
follows: A solution                                                       
of 5,6-dimethyl-1H-thieno[2,3-d]pyrimidin-4-one in CH.sub.3 CN was        
treated, at reflux for 3 hr,                                              
with Lawesson&#39;s reagent. The reaction mixture was poured into water and   
extracted with                                                            
ethyl acetate. The organic extracts were combined and extracted several   
times with 2N                                                             
NaOH. The aqueous extracts were acidified with HCl and re-extracted with  
ethyl acetate,                                                            
the extracts washed with water, dried and evaporated to dryness. The      
crude 5,6-dimethyl-                                                       
1H-thieno[2,3-d]pyrimidin-4-thione so obtained (M.sup.+  = 196) was       
alkylated with                                                            
methyl iodide in aqueous sodium hydroxide to give, after chromatography   
on silica, 5,6-                                                           
dimethyl-4-methylthiothieno[2,3-d]pyrimidine. n.m.r. in CDCl.sub.3 :      
2.5(s, 6H); 2.6(s,                                                        
3H); 8.7(s, 1H). This product was quaternised by heating with excess      
methyl iodide under                                                       
reflux for 18 hours.                                                      
4. n.m.r. in solvent A: 1.4(s, 3H); 1.44(s, 3H); 3.46(d, 1H); 3.62(d,     
1H); 4.02(s, 3H); 4.55(d,                                                 
1H); 4.9(d, 1H); 5.02(d, 1H); 5.82(d, 1H); 6.72(s, 1H); 7.90(s, 1H);      
8.85(s, 1H).                                                              
5. The 1-methyl-4-methylthiothieno[2,3-d]pyrimidinium tetrafluoroborate   
was prepared from 4-                                                      
methylthiothieno[2,3-d]pyrimidine and trimethyloxonium tetrafluoroborate  
by a procedure                                                            
analogous to that described in footnote 2. n.m.r. in d.sub.6 DMSO: 2.9(s, 
3H); 4.34(s, 3H); 7.88(d,                                                 
1H); 8.28(d, 1H); 9.52(s, 1H).                                            
6. The 4-methylthiothieno[2,3-d]pyrimidine was prepared from              
1H-thieno[2,3-d]pyrimidine-4-one                                          
by a two-stage procedure analogous to that described in footnote 3.       
n.m.r. in CDCL.sub.3 : 2.72                                               
(s, 3H); 7.35(d, 1H); 7.45(d, 1H); 8.85(s, 1H).                           
7. n.m.r. in solvent A: 1.36(s, 3H); 1.38(s, 3H); 3.36(d, 1H); 3.6(d,     
1H); 4.56(d, 1H); 4.88(d,                                                 
1H); 5.04(d, 3H); 5.42(d, 1H); 5.48(d, 1H); 5.75(d, 1H); 6.04(m, 1H);     
6.75(s, 1H); 7.86(d,                                                      
1H); 7.93(d, 1H); 8.92(s, 1H).                                            
8. The 1-allyl-4-methylthiothieno[2,3-d]pyrimidinium bromide was prepared 
from 4-methylthio-                                                        
thieno[2,3-d]pyrimidine and allyl bromide in refluxing acetonitrile. The  
excess allyl bromide                                                      
and solvent were removed by evaporation. n.m.r. in d.sub.6 DMSO: 2.9(s,   
3H); 5.45(d, 2H);                                                         
5.6(d, 1H); 5.75(d, 1H); 6.18(m, 1H); 7.88(d, 1H); 8.32(d, 1H); 9.72(s,   
1H).                                                                      
9. n.m.r. in solvent A: 1.42(s, 3H); 1.44(s, 3H); 3.40(d, 1H); 3.62(d,    
1H); 4.6(d, 1H); 4.92(d,                                                  
1H); 5.08(d, 1H); 5.76(d, 1H); 5.84(s, 2H); 6.74(s, 1H); 7.75(d, 1H);     
7.8(d, 1H); 7.92(d, 1H);                                                  
8.24(d, 1H); 9.18(s, 1H).                                                 
10. The 4-methylthio-1-p-nitrobenzylthieno[2,3-d]-pyrimidinium bromide    
was prepared as                                                           
follows: 4-Methyl-thiothieno[2,3-d]pyrimidine in CH.sub.3 CN was treated  
with p-nitrobenzyl                                                        
bromide and the solution refluxed for 8 hr. The solution was evaporated   
to dryness and the                                                        
residue triturated with CH.sub.2 Cl.sub.2. The insoluble solid was        
filtered off, and                                                         
dried. n.m.r. in d.sub.6 DMSO: 2.94(s, 3H); 6.16(s, 2H); 7.82(dd, 2H);    
8.2(d, 1H); 8.25(d, 1H);                                                  
9.8(s, 1H).                                                               
11. To a stirred suspension of 3-ethylaminoethyl-7-[2-(2-aminothiazol-4-yl
)-2-(( .sub.-- Z)-1-carboxy-1-                                            
methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (260 mg. 0.5 mM)  
in DMF                                                                    
(5 ml) was added Et.sub.3 N (150 μl, 1.1 mM) followed by               
1-methyl-4-methylthiothieno[2,3-d]-                                       
pyrimidinium tetrafluoroborate (150 mg, 0.53 mM). The mixture was stirred 
at room temper-                                                           
ature overnight before being poured into H.sub.2 O (100 ml). The pH of    
the solution was adjusted                                                 
to 3.5 with glacial acetic acid and the solution applied to a Diaion      
HP20SS column. The                                                        
product was eluted using H.sub.2 O and CH.sub.3 CN and the appropriate    
fractions were freeze-dried.                                              
12. n.m.r. in solvent A: 1.35(br t, 3H); 1.43(s, 3H); 1.44(s, 3H);        
3.38(d, 1H); 3.54(d, 1H); 4.06                                            
(m, 2H); 4.06(s, 3H); 4.79(d, 1H); 5.16(d, 1H); 5.28(d, 1H); 5.85(d, 1H); 
6.71(s, 1H); 7.82(d,                                                      
1H); 7.95(d, 1H); 8.85(s, 1H).                                            
13. The 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.--        
Z)-1-carboxy-1-methylethoxyimino)-                                        
acetamido]ceph-3-em-4-carboxylic acid was prepared as follows:            
3-Aminomethyl-7-[2-                                                       
(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-1-carboxy-1-methylethoxyimino)acetam
ido]cep-3-em-                                                             
4-carboxylic acid (2 g, 4 mM) was suspended in MeOH (200 ml), and         
Et.sub.3 N (570 μl,                                                    
4.1 mM) followed by sodium cyanoborohydride were added. The mixture was   
stirred,                                                                  
under argon, at room temperature and treated, dropwise, during 40 min.    
with a solution                                                           
of acetaldehyde (276 μl, 4.9 mM) in methanol (2 ml). After 3 hr. the   
methanol was                                                              
evaporated under reduced pressure and the product was purified by         
chromatography on                                                         
Diaion HP20SS using H.sub.2 O and CH.sub.3 CN in a graded elution. The    
appropriate                                                               
fractions were combined and freeze dried. N.m.r. in solvent A: 1.15(t,    
3H); 1.44(s, 3H);                                                         
1.46(s, 3H); 2.82(q, 2H); 3.36(d, 1H); 3.45(d, 1H); 3.59(d, 1H); 3.76(d,  
1H); 5.0(d, 1H);                                                          
5.77(d, 1H); 6.74(s, 1H).                                                 
14. The procedure described in Footnote 11 was followed, but starting     
with 1-allyl-4-                                                           
methylthiothien-[2,3-d]pyrimidinium bromide.                              
15. n.m.r. in solvent A: 1.32(t, 3H); 1.45(br s, 6H), 3.24(d, 1H);        
3.46(d, 1H); 4.10(m,                                                      
2H); 4.91(d, 1H); 5.08(d, 1H); 5.26(d, 1H); 5.45(d, 1H); 5.52(d, 1H);     
5.72(d, 1H);                                                              
6.05(m, 1H); 6.7(s, 1H); 7.79(d, 1H); 7.92(d, 1H); 8.89(s, 1H).           
16. The procedure described in Footnote 11 was followed, but starting     
with 3-(2-fluoro-1 .sub.-- H-                                             
imidazol-4-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.--   
Z)-1-carboxy-1-                                                           
methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid and               
1-allyl-4-methylthio-                                                     
thieno[2,3-d]pyrimidinium bromide.                                        
17. n.m.r. in solvent A: 1.42(s, 3H); 1.46(s, 3H); 3.12(d, 1H); 3.37(d,   
1H); 4.93(d, 1H);                                                         
4.97(d, 1H); 5.0-5.1(m, 4H); 5.18(d, 1H); 5.44(d, 1H); 5.5(d, 1H);        
5.72(d, 1H); 6.02                                                         
(m, 1H); 6.72(s, 1H); 6.82(s, 1H); 7.79(d, 1H); 8.04(d, 1H); 8.87(s,      
1H).                                                                      
18. 3-(2-Fluoro-1H-imidazol-4-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-
yl)-2-(( .sub.-- Z)-1-                                                    
carboxy-1-methylethoxyimino)-acetamido]ceph-3-em-4-carboxylic acid was    
prepared from                                                             
3-(2-fluoro-1-triphenylmethylimidazol-4-ylmethyl)aminomethyl-7-[2-(2-amino
thiazol-4-yl)-2-                                                          
(( .sub.-- Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxyl
ic acid by treatment in                                                   
CH.sub.2 Cl.sub.2 at room temperature with p-toluene sulphonic acid       
H.sub.2 O. The                                                            
reaction mixture was poured into water and the aqueous layer applied to a 
Diaion HP20SS                                                             
column. The product was obtained by gradient elution with CH.sub.3        
CN/H.sub.2 O and freeze-                                                  
drying the appropriate fractions. N.m.r. in solvent A: 1.45(br s, 6H);    
3.42(d, 1H); 3.54(d,                                                      
1H); 3.68(d, 1H); 3.83(d, 1H); 3.92(s, 2H); 5.03(d, 1H); 5.75(d, 1H);     
6.76(s, 1H); 6.93(s, 1H).                                                 
19. The 3-(2-fluoro-1-triphenylmethylimidazol-4-ylmethyl)aminomethyl-7-[2-
(2-aminothiazol-4-                                                        
yl)-2-(( .sub.-- Z)-1-carboxy-1-methylethoxyimino)-acetamido]ceph-3-em-4-c
arboxylic                                                                 
acid was prepared from 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((      
.sub.-- Z)-1-carboxy-                                                     
1-methylethoxy imino)acetamido]ceph-3-em-4-carboxylic acid and            
2-fluoro-4-formyl-1-triphenyl-                                            
methylimidazole by a procedure analogous to that described in footnote    
N.m.r. in solvent A: 1.44(s, 3H); 1.46(s, 3H); 3.32(d, 1H); 3.4(d, 1H);   
3.58(d, 1H); 3.75(d,                                                      
1H); 3.92(s, 2H); 5.0(d, 1H); 5.71(d, 1H); 6.75(s, 1H); 6.8(s, 1H);       
7.13(d, 6H); 7.43(m, 9H).                                                 
20. The procedure described in Footnote 11 was followed but starting with 
3-(pyrid-3-ylmethyl)                                                      
aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(( .sub.-- Z)-1-carboxy-1-methyle
thoxyimino)acetamido]-                                                    
ceph-3-em-4-carboxylic acid.                                              
21. N.m.r. in solvent A: 1.42(s, 6H); 3.35(br d, 1H); 3.54(br d, 1H);     
4.04(s, 3H); 5.02(d, 1H);                                                 
5.05-5.55(m, 4H); 5.74(d, 1H); 6.72(s, 1H); 7.35(m, 1H); 7.79(br d, 1H);  
7.92(m, 2H); 8.48                                                         
(br s, 1H); 8.93(s, 1H).                                                  
22. 3-(Pyrid-3-ylmethyl)aminomethyl-7-[2-(2-aminothiazol-4-yl)-2((        
.sub.-- Z)-1-carboxy-1-                                                   
methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid was prepared      
following the                                                             
procedure described in Footnote 3, but with 3-formylpyridine as the       
aldehyde. N.m.r. in                                                       
solvent A: 1.4(s, 3H); 1.44(s, 3H); 3.39(d, 1H); 3.48(d, 1H); 3.65(d,     
1H); 3.73(d, 1H); 4.12(s,                                                 
2H); 5.02(d, 1H); 5.76(d, 1H); 6.76(s, 1H); 7.38(m, 1H); 7.87(d, 1H);     
8.54(br s, 1H); 8.62(s,                                                   
1H).                                                                      
 
    
     EXAMPLES 229-233 
     To a stirred suspension of the appropriate 3-aminomethylceph-3-em-4-carboxylic acid (0.82 mmole) and triethylamine (1.8 mmole) in DMF (10 ml) at 25° was added the appropriate 6-chloro-1,2,4-triazolo[4,3-b]-pyridazinium iodide (0.84 mmole). After stirring overnight, the mixture was poured into water (100 ml), the pH adjusted to 3.5 with glacial acetic acid and the solution filtered. The filtrate was applied to a Diaion HP20P resin column, and the product was obtained by gradient elution using water and acetonitrile. The appropriate fractions were freeze-dried. 
     
         __________________________________________________________________________
 ##STR274##                                                               
Example                 Yield                                             
No.      R.sub.1                                                          
             R.sub.2                                                      
                   R.sub.3                                                
                        %       Footnotes                                 
__________________________________________________________________________
229      2-CH.sub.3                                                       
             H     H     8      1, 2                                      
230      1-CH.sub.3                                                       
             H     H    21      3, 4                                      
231      1-CH.sub.3                                                       
             Cl    H    16      5, 6                                      
232      1-CH.sub.3                                                       
             H     CH.sub.2 CH.sub.3                                      
                        12      7, 8, 4                                   
233                             9, 10, 11                                 
 ##STR275##                                                               
__________________________________________________________________________
Footnotes                                                                 
1. n.m.r. in solvent A: 1.46(br s, 6H); 3.42(d, 1H); 3.65(d, 1H);         
4.0-4.2(br s, 4H);                                                        
4.3-4.5(br s, 1H); 5.04(d, 1H); 5.75(d, 1H); 6.74(s, 1H); 7.3(d, 1H);     
8.04(d, 1H);                                                              
approximately 11.0(s, 1H).                                                
2. The triazolopyridazinium salt may be prepared as follows:              
6-chloro-1,2,4-triazolo-                                                  
[4,3-b]pyridazine in methanol was treated with methyl iodide, and the     
solution was refluxed for 2 hr. Anhydrous ether was then added to the     
reaction mixture                                                          
and the precipitated solid so obtained was filtered off, washed with a    
little ether and                                                          
dried under vacuum, m. pt. 238-40°.                                
3. n.m.r. in solvent A: 1.42(s, 3H); 1.45(s, 3H); 3.38(d, 1H); 3.64(d,    
1H); 4.1(br s,                                                            
4H); 4.38(m, 1H); 5.02(d, 1H); 5.73(d, 1H); 6.74(s, 1H); 7.53(bs, 1H);    
8.35(d, 1H);                                                              
9.65(s, 1H).                                                              
4. The 6-chloro-1-methyl-1,2,4-triazolo[4,3-b]pyridazinium iodide may be  
prepared                                                                  
as follows: 6-chloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide    
were refluxed                                                             
in acetonitrile for 4 hr. The reaction mixture was cooled and the solid   
which had                                                                 
precipitated during the reaction was filtered off, washed with a little   
acetonitrile, and                                                         
dried, m pt 208-210°.                                              
5. n.m.r. in solvent A: 1.42(s, 3H); 1.44(s, 3H); 3.45(d, 1H); 3.66(d,    
1H); 4.1(m, 4H);                                                          
4.5(d, 1H); 5.04(d, 1H); 5.78(d, 1H); 6.74(s, 1H); 7.57(m, 1H); 8.34(d,   
1H).                                                                      
6. The 3,6-dichloro-1-methyl-1,2,4-triazolo[4,3-b]pyridazinium iodide was 
prepared                                                                  
from 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide in    
acetonitrile.                                                             
N.m.r. in d.sub.6 DMSO: 4.38(s, 3H); 8.45(d, 1H); 9.12(d, 1H).            
7. Prepared from 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((       
.sub.-- Z)-1-carboxy-1-                                                   
methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid.                  
8. n.m.r. in solvent A: 1.14(t, 3H); 1.42(s, 6H); 3.2(d, 1H); 3.46(d,     
1H); 3.6(m, 1H);                                                          
3.75(m, 1H); 4.18(s, 3H); 4.64(m, 2H); 5.06(d, 1H); 5.7(d, 1H); 6.72(s,   
1H); 8.2(br s,                                                            
1H); 8.52(d, 1H); 9.69(s, 1H).                                            
9. Sodium hydrogen carbonate was used in place of triethylamine. Yield    
3%.                                                                       
10. n.m.r. in solvent A: 1.42(s, 3H); 1.45(s, 3H); 3.42(d, 1H); 3.65(d,   
1H); 4.07(s, 3H);                                                         
4.24(d, 1H); 4.46(d, 1H); 5.01(d, 1H); 5.72(d, 1H); 6.74(s, 1H); 7.82(d,  
1H); 7.87(d,                                                              
1H); 8.64(dd, 1H); 8.91(dd, 1H).                                          
11. The 3-chloro-1-methyl-1,2,4-triazolo[4,3-b]pyradizinium iodide was    
prepared                                                                  
from 3-chloro-1,2,4-triazolo[4,3-b]pyridazine and methyl iodide in        
acetonitrile.                                                             
The product which separated from solution was filtered off washed with a  
little                                                                    
CH.sub.3 CN and ether and dried, m. pt. 225-227°.                  
 
    
     EXAMPLE 234 
     The process described in Example 221 was repeated using the appropriate 3-ethylaminomethyl cephem and quaternary heterocycle to give the following compound: 
     
         __________________________________________________________________________
 ##STR276##                                                               
Example No. R        Yield %   Footnotes                                  
__________________________________________________________________________
234                                                                       
             ##STR277##                                                   
                     44        1, 2, 3                                    
__________________________________________________________________________
Footnotes                                                                 
1. n.m.r. in solvent A: 1.34(m, 3H); 1.42(br s, 6H); 2.08(s, 3H); 3.38(d, 
1H);                                                                      
3.53(d, 1H); 4.02(m, 2H); 4.80(d, 1H); 5.14(d, 1H); 5.2-5.45(overlapping  
s, d, 3H); 5.68(s, 1H); 5.84(d, 1H); 6.7(s, 1H); 7.79(d, 1H); 7.9(d, 1H); 
8.84(s, 1H).                                                              
2. The chemical shifts quoted probably refer to the major E isomer, but   
there is also                                                             
evidence of the minor Z in the n.m.r. spectrum.                           
3. The starting material was prepared from 4-methylthiothieno[2,3-d]pyrimi
dine and                                                                  
2-bromomethyl-1-cyanoprop-1-ene (mixture of E and Z isomers in the ratio  
9:1)                                                                      
in CH.sub.3 CN. The precipitate was filtered off and washed with CH.sub.3 
CN and dried.                                                             
N.m.r. in d.sub.6 DSMO: 2.1(s, 3H); 2.92(s, 3H); 5.64(s, 2H); 5.86(s,     
1H); 7.86(d, 1H);                                                         
8.24(d, 1H); 9.6(s, 1H).                                                  
 
    
     EXAMPLE 235 ##STR278## 
     3-Aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (242mg, 0.5 mmole) was suspended in DMF (3 ml) and water (1 ml) and treated with 2-methylthio-1,2,4-thiadiazolo[2,3-a]pyridinium bromide (132 mg, 0.5 mmole) and then with sodium hydrogen carbonate (240 mg, 2.5 mmole) suspended in water (0.5 ml). The solution was stirred at room temperature overnight before being diluted with water (25 ml) and applied to a Diaion HP20SS column. Following gradient elution with acetonitrile/water the product was obtained by freeze-drying the appropriate fractions. Yield 11%. N.m.r. in solvent A: 1.45 (s, 3H); 1.46 (s, 3H), 3.64 (d, 1H); 3.76 (d, 1H); 4.34 (d, 1H); 4.88 (d, 1H); 5.07 (d, 1H); 5.78 (d, 1H); 6.73 (s, 1H);  7.0 (m, 1H); 7.13 (d, 1H); 7.72 (m, 1H); 8.17 (dd, 1H). 
     EXAMPLES 236-243 
     A solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamidolceph-3-em-4-carboxylic acid (0.5 mm) and NaHCO 3  (2.5 mM) in water (5 ml) was treated with an appropriate chloro- or methylsulphinyl-substituted quaternary heterocycle, at room temperature for 18 hrs. The solution was acidified with HOAC and sufficient sodium acetate added to redissolve any precipitate. The product was isolated by chromatography on an HP20 gravity column, eluting with CH 3  CN/H 2  O mixtures and then freeze-drying the appropriate fractions. The following compounds were obtained: 
     
         ______________________________________                                    
 ##STR279##                                                               
Example                   Yield                                           
No.    R                  %        Footnotes                              
______________________________________                                    
236                                                                       
        ##STR280##        34       1, 2                                   
237                                                                       
        ##STR281##        36       3, 4                                   
238                                                                       
        ##STR282##        27       5, 6                                   
239                                                                       
        ##STR283##        26       7, 8                                   
240                                                                       
        ##STR284##        33       9, 10                                  
241                                                                       
        ##STR285##        57       11, 12                                 
242                                                                       
        ##STR286##        48       13, 14                                 
243                                                                       
        ##STR287##        16       15, 16                                 
______________________________________                                    
Footnotes                                                                 
1. n.m.r. in solvent A: 1.45(2xs, 6H); 3.4(q, 2H); 4.3(q. 2H);            
5.05(d, 1H); 5.45(s, 2H); 5.7(d, 1H); 6.7(s, 1H); 6.9-8.5(6xm, 8H).       
2. The starting pyridinium salt was obtained by adding 4-hydroxy-         
pyridine (10 mM) to a stirred suspension of hexane-washed sodium          
hydride (10 mM) in DMF (15 ml). To this solution was added a              
solution of 4-chloromethylpyridine (10 M) in ether (5 ml), (ob-           
tained by treating the corresponding 4-chloromethylpyridine               
hydrochloride with NaHCO.sub.3 in aqueous solution, extracting            
with ether and drying), and the mixture was stirred at room               
temperature for 18 hrs. The solvents were evaporated, and the             
residue was purified by MPLC, on Merck silica gel 9385, eluting           
with MeOH/CH.sub.2 Cl.sub.2, 8-10:92-90, to give 1-(2-pyridylmethyl)-     
pyrid-4-one. Yield 65%. N.m.r. in CDCl.sub.3 : 5.0(s, 2H); 7.2-7.8(m,     
4H); 6.35(d, 2H); 8.6 (d, 2H). This pyridone (1.5 mM) and tosyl           
chloride (1.65 mM) were heated in DMF at 80° for 45 minutes,       
the solvent was evaporated, and the residue triturated with               
CH.sub.2 Cl.sub.2 to give 4-chloro-1-(2-pyridylmethyl)pyridinium          
tosylate                                                                  
in 70% yield. N.m.r. in d.sub.6 DMSO: 2.3(s, 3H); 6.0(s, 2H); 7.1(d,      
2H); 7.5(d, 2H); 7.4-8.6(m, 6H); 9.15(d, 2H).                             
3. N.m.r. in solvent A: 1.45(2xs, 6H); 3.4(q, 2H), 4.3(q, 2H); 5.1(d,     
1H); 5.35(s, 2H); 5.8(d, 1H); 6.75(s, 1H); 6.95(q, 1H); 7.1(q, 1H);       
7.4(d, 2H); 8.2(d, 1H); 8.3(d, 2H); 8.4(d, 1H).                           
4. The starting pyridinium salt was obtained as follows: A solution       
of 4-chloromethyl-1-oxidopyridinium chloride (5 mM) in ether was          
basified with NaHCO.sub.3 solution. The ether solution was separated      
and dried, 4-methylthiopyridine was added, the solvent was                
evaporated and the residue was kept at room temperature for 18            
hrs. Trituration gave 4-methylthio-1-(1-oxido-pyrid-4-ylmethyl)py-        
ridinium chloride. N.m.r. in d.sub.6 DMSO: 2.7(s, 3H); 5.75(s, 2H);       
7.6(d, 2H); 8.0(d, 2H); 8.25(d, 2H); 9.05(d, 2H). This thiomethyl         
compound (2 mM) was suspended in CH.sub.2 Cl.sub.2 (10 ml) at 0°,  
and                                                                       
sufficient TFA was added to give a solution. A solution of                
MCPBA (2 mM) in CH.sub.2 Cl.sub.2 (3 ml) was added, and the solution      
was allowed to warm to room temperature, then stirred for 1 hr.           
The solvents were evaporated, and the residue was triturated              
several times with ether, to remove excess MCPBA, to give 4-              
methylsulphinyl-1-(1-oxidopyrid-4-ylmethyl)-pyridinium chloride,          
which was used without further purification or characterisation.          
5. N.m.r. in solvent A: 1.4(2xs, 6H); 3.35(q, 2H), 4.3(q, 2H);            
5.05(d, 1H); 5.45(s, 2H); 5.7(d, 1H); 6.7(s, 1H); 6.5-8.4(6xm, 8H).       
6. The starting pyridinium salt was prepared by the process of            
Footnote 4, except that the reactants were warmed together to             
form a homogeneous melt, then heated at 100° for 15 minutes,       
cooled and triturated with CH.sub.2 Cl.sub.2. N.m.r. in d.sub.6 DMSO:     
2.7(s,                                                                    
3H); 5.9(s, 2H); 7.5, 7.95 and 8.35(m, 6H); 8.95(d, 2H). The              
methylthio compound was then oxidised to the required methyl-             
sulphinyl compound as described in Footnote 4.                            
7. Reaction solvent was H.sub.2 O/CH.sub.2 CN, (4:1), N.m.r. in solvent   
A:                                                                        
1.45(2xs, 6H); 3.4(q, 2H), 4.3(q, 2H); 5.05(d, 1H); 5.4(s, 2H); 5.7(d,    
1H); 6.7(s, 1H), 6.95(q, 1H); 7.4(q, 1H); 7.55(s, 2H); 8.15(q, 1H);       
8.35(q, 1H).                                                              
8. The starting pyridinium salt was prepared by the process of            
Footnote 4, from 4-bromomethyl-2,6-dichloropyridine, except that          
this starting material reacted exothermically with 4-methylthio-          
pyridine, so the reaction mixture was kept below 40° until the     
reaction was largely complete, then heated at 100° for 5 minutes.  
The product was crystallised form HCl/EtOH. N.m.r. in d.sub.6             
DMSO: 2.75(t, 3H); 5.95(s, 2H); 7.75(s, 2H); 7.95(d, 2H); 9.05(d,         
2H). The methylthio compound was oxidised to the required                 
methylsulphinyl compound as in Footnote 4. N.m.r. in d.sub.6 -DMSO/       
CDCl.sub.3 : 2.95(s, 3H); 5.95(s, 2H); 7.7(s, 2H); 8.4(d, 2H); 9.3(d,     
2H).                                                                      
9. N.m.r. in solvent A: 1.4(2xs, 6H); 2.25(s, 3H); 3.4(q, 2H); 4.3(q,     
2H); 5.05(d, 1H); 5.3(s, 2H); 5.7(d, 1H); 6.7(s, H); 6.9(d, 1H);          
7.25(d), 8.05(d, 1H); 8.8(d, 1H).                                         
10. The starting pyridinium salt was obtained as follows:                 
5-Hydroxymethyl-6-methyluracil (15 mM) was suspended in                   
glacial acetic acid (10 ml) and the mixture was saturated with HCl        
gas, then heated under reflux for 1/2 hour until the solid material       
was dissolved, and filtered. On cooling, 5-chloromethyl-6-methyl-         
uracil was obtained, n.m.r. in d.sub.6 DMSO: 2.15(s, 3H); 4.45(s, 2H).    
This compound was treated with a solution of 4-methylthio-                
pyridine in CH.sub.2 Cl.sub.2, the solvent was evaporated, and the        
residue                                                                   
was heated at 100° for 10 minutes. It stayed solid throughout,     
but                                                                       
formed the required quaternary salt. Yield 93%. N.m.r. in d.sub.6         
DMSO: 2.25(s, 3H); 2.65(s, 3H); 5.3(s, 2H); 7.8(d, 2H); 8.7(d, 2H).       
This material was oxidised to the required 4-methylsulphinyl start-       
ing material, as in Footnote 4.                                           
11. N.m.r. in solvent A: 1.45(2xs, 6H); 2.1(s, 3H); 2.45(s, 3H);          
3.4(q, 2H); 4.3(q, 2H); 5.0(d, 1H); 5.2(s, 2H); 5.7(d, 1H); 6.75(s,       
1H); 6.9(q, 1H); 7.3(q, 1H); 8.0(q, 1H); 8.25(q, 1H).                     
12. The starting pyridinium salt was obtained by the process of           
Footnote 4. N.m.r. of 4-methylthiopyridinium salt, in d.sub.6 DMSO:       
2.15(s, 3H); 2.5(s), 2.7(s, 3H); 5.75(s, 2H); 7.95(d, 2H); 8.85(d, 2H).   
The compound was oxidised to the required 4-methylsulphinyl               
starting material as in Footnote 4.                                       
13. n.m.r. in solvent A: 0.8-1.0(m, 4H); 1.45(2xs, 6H); 1.9(partially     
obscured by solvent peaks); 3.4(q, 2H); 4.3(q, 2H); 5.0(s, 2H);           
5.05(d, 1H); 5.7(d, 1H); 6.0(s, 1H); 6.7(s, 1H); 6.9(d, 1H); 7.15(d,      
1H); 8.0(d, 1H); 8.15(d, 1H).                                             
14. The starting pyridinium salt was obtained as follows: 6-Chloro-       
methyl-2-cyclopropyl-4-hydroxypyridine (10 mM) and 4-methyl-              
thiopyridine (10 mM) were thoroughly mixed and heated at 100°      
for 1/2 hour. The mixture partly melted, then re-solidified. On           
cooling, the product was triturated with CH.sub.2 Cl.sub.2 to give the    
4-methylthiopyridinium salt. Yield 73%. N.m.r. in d.sub.6 DMSO            
0.6-1.1(m, 4H); 2.0(m, 1H); 2.7(s, 3H); 5.55(s, 2H); 6.2(s, 1H);          
7.95(d, 2H); 8.7(d, 2H). This product was oxidised to the required        
4-methylsulphinyl pyridinium salt, as in Footnote 4.                      
15. N.m.r. in solvent A: 1.4(s, 6H); 3.1(s, 3H); 3.4(q, 2H); 4.3(q,       
2H); 5.05(d, 1H); 5.3(s, 2H); 5.75(d, 1H); 6.75(s, 1H); 7.15(d, 1H);      
7.7(d, 1H); 6.9-8.45(m, 5H).                                              
16. The starting pyridinium salt, in this case the tetrafluoroborate,     
was obtained by reacting 5-bromomethyl-1-methylisatin with 4-             
methylthiopyridine to give 1-(1-methyl-5-isatinylmethyl)-4-               
methylthiopyridinium bromide, m.p. 227.5-228.5 (crystallised from         
EtOH). This salt was dissolved in MeOH/H.sub.2 O, 1:1 v/v (30 ml)         
and the solution was stirred while silver tetrafluoroborate (1 mM)        
in water (5 ml) was added. The yellow silver bromide was filtered         
off through kieselguhr, the filter cake was suspended in water (50        
ml) and again filtered, and the filtrates were combined and               
evaporated to give the required tetrafluoroborate salt.                   
 
    
     EXAMPLE 244-245 
     7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylic acid (205 mg) was dissolved in a mixture of sodium bicarbonate (336 mg) in water (5 ml), and acetonitrile (5 ml). 4-Chloro-1-(4-nitrobenzyl)pyridinium chloride (168 mg) was added, stirred for 10 minutes to achieve solution, then stood at room temperature overnight. The solvent was evaporated, and the residue was purified by running on an RP18 column (in sodium salt form), eluting with H 2  O/CH 3  CN, 100-70:0-30, to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-[N-(1-p-nitrobenzyl-4-pyridinio)-N-ethyl]aminomethylceph-3-em-4-carboxylic acid. Yield 27.5%. N.m.r. in solvent A: 1.1 (t, 3H), 1.45 (2xs, 6H); 3.2-3.7 (m, 4H); 4.5-4.7 (q, 2H); 5.15 (d, 1H); 5.55 (s, 2 H); 5.85 (d, 1H); 6. 7 (s, 1H); 7.1-7.4 (m, 2H); 7.7 (d, 2H); 8.3 (d, 2H); 8.45 (d, 2H). 
     In a similar manner, using the corresponding N-carboxymethyl cephem, there was obtained 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)-acetamido]-3-[N-carboxymethyl-N-(1-p-nitrobenzyl -4-pyridinio]aminomethylceph-3-em-4-carboxylic acid. Yield 19%. 
     N.m.r. in solvent A: 1.4 (2xs, 6H); 3.25-3.6 (q, 2H); 4.4 (s, 2H); 4.6 (s, 2H); 5.15 (d, 1H); 5.55 (s, 2H); 5.85 (d, 1H); 6.7 (s, 1H); 7.05-7.2 (m, 1H); 7.4-7.55 (m, 1H); 7.6-7.7 (d, 2H); 8.2-8.3 (d, 2H); 8.4-8.6 (m, 2H). 
     EXAMPLE 246 
     The process of Example 244 was repeated, using the appropriate N-substituted cephem starting material, to give the following compound: ##STR288## 
     N.m.r. in solvent A: 1.15 (t, 3H); 1.7-1.9 (m, 2H); 2.2-2.5 (m, 4H); 3.0-3.5 (q, 2H); 3.5-3.8 (m, 2H); 4.4-4.8 (q, 2H); 5.05 (d, 1H); 5.5 (s, 2H); 5.7 (d, 1H); 6.7 (s, 1H); 7.05-7.25 (m, 1H); 7.6-7.7 (m, 3H); 8.2-8.3 (d, 2H); 8.35-8.4 (d, 2H). 
     EXAMPLE 247 
     3-Acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]ceph-3-em-4-carboxylic acid (460 mg) was suspended in water (20 ml) with sufficient NaHCO 3  to obtain a solution. 5-Amino-2-methylisoquinolinium iodide (244 mg) was added, and the solution was heated under argon for 3hrs. at 85°, maintaining the pH at 7.5 by small additions of HOAC or aqueous NaHCO3. The solution was cooled, made to pH5 with HOAC, and run onto a column of HP20SS resin. The column was eluted with H 2  O/CH 3  CN, 100-80:0-20. The fractions containing the product, 7-[2-(2-aminothiazol- 4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]-3-[(2-methyl-5-isoquinolinio)aminomethyl]ceph-3-em-4-carboxylic acid, were combined and lyophilised. N.m.r. in solvent A: 1.85 (m, 2H); 2.35 (m, 4H); 3.45 (m, 2H); 4.4 (m, 2H); 4.4 (s, 3H); 5.05 (d, 1H); 5.75 (d, 1H); 6.75 (s, 1H); 7.3 (d, 1H); 7.55 (d, 1H); 7.75 (t, 1H); 8.54 (d, 1H); 8.65 (d, 1H), 9.7 (s, 1H). 
     EXAMPLE 248 
     The process described in Example 221 was repeated, using 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(3-pyridylmethylaminomethyl)ceph-3-em-4-carboxylic acid and 1-allyl-4-chloropyridinium bromide as starting materials, to give 3-[N-(1-allyl-4-pyridinio)-N-(3-pyridylmethyl)aminomethyl]-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid. N.m.r. in solvent A: 1.65 (s, 3H), 1.7 (s, 3H); 3.35 (d, 1H); 3.7 (d, 1H); 4.7-5.3 (m, 7H), 5.4 (d, 1H); 5.5 (d, 1H); 5.95 (d, 1H); 6.1 (m, 1H); 7.0 (s, 1H); 7.1-7.5 (br m, 2H); 7.65 (t, 1H); 8.0 (d, 1H); 8.3 (m, 2H); 8.7 (s, 2H). 
     The cephem starting material was obtained as in Example 62, Footnote 14. 
     1-Allyl-4-chloropyridinium bromide was obtained by quaternising 4-chloropyridine with allyl bromide. 
     EXAMPLES 249-254 
     The process described in Example 54 was repeated, to obtain the following compounds: 
     
         __________________________________________________________________________
 ##STR289##                                                               
Example No.                                                               
       R      R.sup.1       Yield %                                       
                                 Footnotes                                
__________________________________________________________________________
249    Et                                                                 
               ##STR290##    6   1, 2                                     
250    Et                                                                 
               ##STR291##   22   3                                        
251    Et                                                                 
               ##STR292##   26   4                                        
252    (CH.sub.2).sub.2 CN                                                
               ##STR293##   20   5                                        
253    H                                                                  
               ##STR294##    9   6, 7                                     
254    (CH.sub.2).sub.2 CN                                                
               ##STR295##    9   8                                        
__________________________________________________________________________
Footnotes                                                                 
1. Initially, 1 eq. of quaternary heterocyclic salt and NaHCO.sub.3       
reacted with the                                                          
CAZAMCA derivative, and further portions of salt and NaHCO.sub.3 were     
sub-                                                                      
sequently added up to a total of 5 eq. and 10 eq. respectively.           
2. Eluant portion 20-35:80-65:1. N.m.r. in solvent B: 1.85(s, 3H);        
1.55(s, 6H); 3.5(m,                                                       
2H); 3.7(m, 2H); 4.55(d, 1H); 5.15(d, 1H); 5.2(d, 1H); 5.8(d, 1H);        
7.05(s, 1H); 7.45(d,                                                      
1H); 7.8(d, 1H); 8.2(d, 1H); 9.0(d, 1H).                                  
3. Reaction was carried out in DMF, using 2 eq. of Et.sub.3 N in place of 
NaHCO.sub.3.                                                              
Eluant portion 25-30:75-70:1. N.m.r. in solvent B: 1.2(t, 3H); 2.15(s,    
6H); 3.4-3.8(m,                                                           
4H); 4.5-4.8(m, 2H); 5.1(d, 1H); 5.9(d, 1H); 6.05(m, 1H); 7.1(s, 1H);     
7.25(s, 1H);                                                              
7.25(m, 1H); 8.35(d, 1H); 8.4(m, 1H); 8.9(m, 1H).                         
4. Reaction as in Footnote 3. Eluant proportion 20-25:80-75:1. N.m.r. in  
solvent B:                                                                
1.15(t, 3H); 1.55(s, 6H); 3.4(q, 2H); 3.4-3.8(m, 4H); 4.4-5.2(m, 4H);     
5.15(d, 1H);                                                              
5.95(d, 1H); 6.95(d, 1H); 7.05(s, 1H); 8.35(d, 1H).                       
5. Reaction as in Footnote 3. Eluant proportion 20:80:1. N.m.r. in        
solvent B: 1.55(s,                                                        
6H); 2.7-3.0(m, 2H); 3.3-4.2(m, 6H); 4.4-4.8(m, 3H); 5.0-5.3(m, 2H);      
5.85(d, 1H);                                                              
7.0(s, 1H); 7.15(s, 1H); 8.45(d, 1H).                                     
6. Reaction as in Footnote 1, for 2 hr. at room temperature. Eluant       
proportion as in                                                          
Footnote 4. N.m.r. in solvent B: 1.55(s, 6H); 3.55(s, 2H); 4.55(s, 2H);   
4.7(s, 3H);                                                               
5.2(d, 1H); 5.85(d, 1H); 7.05(s, 1H); 7.15(d, 1H); 7.35(d, 1H); 8.05(t,   
1H); 8.85(d,                                                              
1H); 9.35(d, 1H).                                                         
7. The starting material quarternary heterocyclic salt was obtained from  
5-amino-                                                                  
cinnoline and methyl iodide. N.m.r. in solvent B: 4.65(s, 3H); 7.2(d,     
1H); 7.25(d,                                                              
1H); 7.95(t, 1H); 8.9(d, 1H); 9.25(d, 1H).                                
8. Eluant was MeOH/aqueous ammonium carbonate buffer, 1.3:8.7 v/v. N.m.r. 
in                                                                        
solvent B; 1.55(s, 6H); 2.7-2.9(m, 2H); 3.3-3.7(m, 2H); 3.8-4.1(m, 2H);   
4.6-5.0(m,                                                                
4H); 5.2(d, 1H); 5.2-5.4(m, 2H); 5.9(d, 1H); 7.0(s, 1H); 7.3(d, 1H);      
8.3(d, 1H).                                                               
 
    
     EXAMPLE 255 
     The process described in Example 61, Footnote 13 was repeated, using 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxycyclobutyloxyimino)acetamido]-3-ethyl-aminoethylceph-3-em-4-carboxylic acid as the cephem starting material, to give 3-[N-(1-[2-aminoethyl]-4-pyridinio)-N-ethylaminomethyl]-7-[2-((Z)-1-carboxycyclobutyloxyimino)acetamidolceph-3-em-4-carboxylic acid. The product was purified by MPLC on a HP20SS column eluting with H 2  O/CH 3  CN, 100-93:0-7. N.m.r. in solvent A: 1.1 (t, 3H); 1.85 (m, 2H); 2.35 (m, 4H); 3.05 (d, 1H); 3.3 (m, 2H); 3.45 (d, 1H); 3.55-3.8 (m, 2H); 4.35-4.5 (m, 3H); 4.8 (d, 1H); 5.05 (d, 1H); 5.7 (d, 1H); 6.75 (s, 1H); 7.1 (m, 1H); 7.65 (m, 1H); 8.2 (d, 2H). 
     EXAMPLE 256 
     The general process described in Example 6 was repeated, using the appropriate heterocyclic starting material and cephem derivative, to give the following compound in 31% yield: ##STR296## 
     HPLC eluant MeOH/water/HOAc, 30-35:69-64:1 v/v/v. 
     N.m.r. in solvent B: 1.3 (t, 3H); 1.7 (m, 4H); 2.15 (m, 4H); 2.95 (q, 2H); 3.55 (m, 2H); 4.2 (d, 1H); 4.6 (d, 1H); 5.1 (d, 1H); 5.85 (d, 1H); 7.05 (s, 1H); 7.45 (d, 1H); 8.1 (s, 1H); 8.55 (d, 1H). 
     The starting material was 6-chloro-3-ethylthiazolo[3,2-b]pyridazinium perchlorate which was prepared by the general procedure described in J. Org. Chem., 34, 996, (1964). 
     EXAMPLE 257 
     The process described in Example 247 was repeated, using the appropriate 3-acetoxymethyl cephem and 5-amino-2-methylisoquinolinium iodide as starting materials. The reaction was carried out in water at pH 7.5 (adjusted by addition of HOAC or NaHCO 3  as necessary), for 2.5 hrs. at 80°. HPLC eluant was MeOH/H 2  O/HOAc, 30-35:69-64:1 v/v/v. N.m.r. in solvent B: 1.7 (m, 4H); 2.15 (m, 4H); 3.6 (m, 2H); 4.4 (m, 5H); 5.15 (d, 1H); 5.85 (d, 1H); 7.05 (s, 1H); 7.15 (d, 1H); 7.5 (d, 1H); 7.6 (dd, 1H); 7.75 (dd, 1H); 8.5 (d, 1H); 8.65 (d, 1H); 9.75 (s, 1H). 
     The cephalosporin starting material may be obtained as follows: 
     To a stirred mixture of DMF (0.85 ml) in anhydrous CH 2  Cl 2  (40 ml) at -10° C. was added dropwise a solution of oxalyl chloride (0.87 ml) in anhydrous CH 2  Cl 2  (10 ml). Stirring was continued at -10° C. for 30 minutes. To this stirred suspension was added in one portion 2-[(Z)-(tert-butoxycarbonyl)cyclopentyloxyimino]- 2-(2-tritylaminothiazol-4-yl)acetic acid (5.97 g) followed by N-methylmorpholine (1.32 ml). Stirring was continued for 30 minutes at -10° C. 
     In another flask a suspension of 7-aminocephalosporanic acid (2.72 g) in anhydrous CH 2  Cl 2  (25 ml) was stirred for 1 hour with N,O-bis (trimethylsilyl) acetamide (4 ml) to give a clear solution. This was transferred by syringe to the above acid chloride solution which was stirred at -10° C. during the addition. The reaction mixture was then allowed to warm to room temperature and stirred for a further 1.5 hours. The reaction mixture was poured into water and extracted with CH 2  Cl 2 . The combined CH 2  Cl 2  extracts were washed with water, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to yield a foam. The crude product was dissolved in EtOAc and applied to a column of Kieselgel 60. Elution with EtOAc gave, after precipitation from CH 2  Cl 2  with n-hexane, 3-acetoxymethyl-7-[2-(2-tritylaminothiazol-4-yl)-2-((Z)-1-tert-butoxycarbonyl)cyclopentyloxyimino)acetamido]ceph-3-em-4-carboxylic acid (6.6g) as a white solid. This compound, (2.61g) was then stirred for 1 hour at 0° C. with a mixture of TFA (12 ml) and water (1.2 ml). The reaction mixture was evaporated to dryness, the residue taken up in water and extracted with EtOAc. The solvent was evaporated under reduced pressure to give a solid which was dissolved in a minimum MEOH and precipitated with ether to give 3-acetoxymethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-cyclopentyloxyimino)acetamido]ceph-3-em-4-carboxylic acid (1.1 g) as a white solid having the following n.m.r. in solvent B: 1.7 (m, 3H); 1.95 (s, 3H); 2.15 (m, 4H); 3.4 (d, 1H); 3.65 (d, 1H); 4.7 (d, 1H); 4.95 (d, 1H); 5.15 (d, 1H); 5.85 (d, 1H); 7.05 (d, 1H). 
     EXAMPLE 258 
     Method A of Example 108 was repeated, using the appropriate starting materials, and water as solvent to give the compound: ##STR297## in 17.5% yield. N.m.r. in solvent B: 2.4-2.7 (m, 4H); 3.4-3.85 (ABq, 2H); 4.3-4.7 (Abq, 2H); 5.25 (d, 1H); 5.55 (s, 2H); 5.9 (d, 1H); 6.95 (s, 1H); 7.15 (d, 1H); 7.35-7.5 (m, 1H); 7.6 (d, 2H); 8.05 (d, 2H); 8.3 (d, 1H); after MPLC on HP20SS (as the sodium salt), and precipitation from aqueous solution with acetic acid. 
     The starting quaternary pyridinium salt was the tetrafluoroborate described in Example 243, Footnote 16. 
     EXAMPLE 259 
     The process described in Example 221 was repeated, using the appropriate 3-ethylaminomethyl cephem and 1-methyl-4-methylthioquinazolinium iodide, to give ##STR298## 
     n.m.r. in solvent A: 1.4 (br s, 9H); 3.1-3.5 (dd, 2H); 3.98 (br s, 5H); 5.04 (d, 1H); 5.1-5.5 (m, 2H); 5.68 (d, 1H); 6.71 (s, 1H); 7.8 (t, 1H); 7.99 (d, 1H); 8.12 (t, 1H); 8.28 (d, 1H); 8.85 (s, 1H). 
     EXAMPLE 260 
     The process described in Example 236 was repeated, using the appropriate 3-aminomethyl cephem and 1-furfuryl-4-methylsulphinylpyridinium chloride, to give in 20% yield, ##STR299## 
     n.m.r. in solvent A: 1.42 (2xs 6H); 3.35 (q, 2H); 4.3 (q, 2H); 5.01 (d, 1H); 5.37 (s, 2H); 5.67 (d, 1H); 6.45 (q, 1H); 6.62 (d, 1H); 6.73 (s, 1H); 6.93 (m, 1H); 7.4 (m, 1H); 7.64 (m, 1H); 8.12 (d, 1H); 8.28 (d, 1H). 
     The starting pyridinium salt was obtained by the general process described in Example 237, Footnote 4. The 1-furfuryl-4-methylthiopyridinium chloride had n.m.r. in d 6  -DMSO: 2.72 (s, 3H); 5.92 (s, 2H); 6.52 (q, 1H); 6.84 (d, 1H); 7.75 (m, 1H); 8.0 (d, 2H); 8.96 (d, 2H). This compound was oxidised to the required sulphoxide, as described in Example 237, Footnote 4, and used without further purification. 
     EXAMPLE 261 
     The process described in Examples 1 to 4 was repeated, using the appropriate 3-ethylaminomethyl cephem and 3-chloro-1-methylpyridazinium iodide. The reaction was carried out for 18 hrs. at room temperature before quenching with HOAc, and isolating the product by chromatography on Diaion CHP20P resin, to give, in 51% yield, the more polar isomer of ##STR300## 
     n.m.r. spectrum in solvent A: 0.93 (t, 3H); 1.1 (t, 3H); 1.78 (quintet, 2H); 3.2 (d, 1H); 3.43 (d, 1H); 3.64 (m, 2H); 4.29 (s, 3H); 4.43 (t, 1H); 4.55 (d, 1H); 4.69 (d, 1H); 5.04 (d, 1H); 5.73 (d, 1H); 6.76 (s, 1H); 8.05 (m, 2H); 8.93 (t, 1H). Retention time 5.3 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column, using MeOH/water/TFA 40:60:0.2 v/v/v as eluant. 
     The cephalosporin starting material may be prepared as follows: To a stirred solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]ceph-3-em-4-carboxylic acid (more polar isomer, 2.6g) in 2.5% (w/v) pH 5.5 sodium acetate buffer (50 ml) was added sodium cyanoborohydride (0.34 g), followed by acetaldehyde (0.3 ml) in water (5 ml) over 40 minutes. The reaction mixture was then concentrated, diluted to 50 ml with water, and the pH adjusted to 3.5 with HOAc. Careful chromatography on Diaion HP20SS, eluting with H 2  O/CH 3  CN, (92.5:7.5) gave 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylic acid, having the following n.m.r. spectrum in solvent A: 0.96 (t, 3H); 1.18 (t, 3H); 1.81 (quintet, 2H); 2.94 (q, 2H); 3.38 (d, 1H); 3.42 (d, 1H);  3.61 (d, 1H); 3.78 (d, 1H), 4.46 (t, 1H); 5.03 (d, 1H); 5.76 (d, 1H); 6.88 (s, 1H). Retention time 4.2 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column, using MeOH/H 2  O/HOAc,,30:70:1, v/v/v, as eluant. 
     EXAMPLE 262 
     The general process described in Example 244 was repeated, using 1-(4-carbamoylbenzyl)-4-chloropyridinium bromide as the starting material, to give ##STR301## 
     n.m.r. in solvent A: 1.05-1.2 (t, 3H); 1.4 (2xs, 6H); 3.2-3.7 (m, 4H); 4.45-4.7 (q, 2H); 5.15 (d, 1H); 5.45 (s, 2H); 5.8 (d, 1H); 6.7 (s, 1H); 7.0-7.4 (m, 2H); 7.4-7.5 (d, 2H); 7.85-7.95 (d, 2H); 8.35-8.45 (d, 2H). 
     The starting pyridinium salt was obtained by quaternising 4-chloropyridine with 4-bromomethylbenzamide in DMF at room temperature for 4 hours. 
     EXAMPLES 263-269 
     The general procedure described in Examples 1-4 was repeated, except that the solvent was DMF and the base was Et 3  N. The appropriate 3-ethylaminomethylcephalosporin was used, and products were purified by chromatography on Diaion CHP20P resin. Retention times are quoted for a reversed phase Partisil PXS 10/25 ODS-2 column. 
     The following compounds were made: 
     
         __________________________________________________________________________
 ##STR302##                                                               
                                  Yield                                   
Example                                                                   
     R.sub.1  R.sub.2             (%) Footnotes                           
__________________________________________________________________________
263                                                                       
      ##STR303##                                                          
               ##STR304##         19  1, 2, 3                             
264                                                                       
      ##STR305##                                                          
               ##STR306##          5  1, 4, 5                             
265                                                                       
      ##STR307##                                                          
               ##STR308##         12  6, 7, 8                             
266                                                                       
      ##STR309##                                                          
               ##STR310##         60  7, 9, 10                            
267                                                                       
      ##STR311##                                                          
               ##STR312##         50  7, 11, 12                           
268                                                                       
      ##STR313##                                                          
               ##STR314##         50  13, 14, 15                          
269                                                                       
      ##STR315##                                                          
               ##STR316##         56  16, 17, 18                          
__________________________________________________________________________
1. Starting material was 6-amino-1-methylpyridazinium tetrafluoroborate.  
2. Reaction mixture heated 24 hours at 45° C. before quenching     
with acetic acid.                                                         
3. N.m.r. in solvent A: 0.93(t, 3H), 1.04(t, 3H), 1.8(m, 2H), 3.27(d,     
1H), 3.44(d, 1H), 3.48(m,                                                 
2H), 3.75(s, 3H), 4.32(d, 1H), 4.47(t, 1H), 4.57(d, 1H), 5.07(d, 1H),     
5.88(d, 1H), 6.88(s, 1H),                                                 
7.36(d, 1H), 7.75(d, 1H). Retention time 4.6 minutes, eluting with        
MeOH/H.sub.2 O/HOAc, 40:60:1,                                             
v/v/v.                                                                    
4. Reaction mixture heated at 65° C. for 3 hours before quenching  
with acetic acid. After a                                                 
preliminary purification on Diaion CHP20P, the product was re-purified by 
preparative HPLC                                                          
on a reversed phase Partisil ODS2 column, eluting in MeOH/H.sub.2 O/HOAc, 
75:25:1 v/v/v.                                                            
5. N.m.r. in solvent A: 1.05(t, 3H), 1.39(d, 3H), 3.24(d, 1H), 3.43(d,    
1H), 3.48(m, 2H), 3.74(s,                                                 
3H), 4.31(d, 1H), 4.53(d, 1H), 4.6(q, 1H), 5.07(d, 1H), 5.75(d, 1H),      
6.87(s, 1H), 7.33(d, 1H),                                                 
7.88(d, 1H). Retention time 4.5 minutes, eluting with MeOH/water/HOAc,    
65:35:1, v/v/v.                                                           
6. Starting material 6-fluoro-thiazolo[3,2-b]pyridazinium perchlorate.    
7. Reaction carried out at ambient temperature for 18 hours before        
quenching with HOAc.                                                      
8. N.m.r. in solvent A: 0.92(t, 3H), 1.15(t, 3H), 1.79(m, 2H), 3.32(d,    
1H), 3.51(d, 1H), 3.68(m,                                                 
2H), 4.45(t, 1H), 4.58(d, 1H), 4.79(d, 1H), 5.05(d, 1H), 5.77(d, 1H),     
6.76(s, 1H), 7.89(d, 1H),                                                 
8.46(d, 1H), 8.76(d, 1H), 8.78(d, 1H). Retention time 4.7 minutes,        
eluting with MeOH/H.sub.2 O/                                              
HOAc, 40:60:1, v/v/v.                                                     
9. Starting material was 1-methyl-4-methylthiothieno[2,3-d]pyrimidinium   
tetrafluoroborate.                                                        
10. N.m.r. in solvent A: 0.9(t, 3H), 1.3(m, 3H), 1.77(m, 2H), 3.24(d,     
1H), 3.46(d, 1H), 3.98(m,                                                 
2H), 4.0(s, 3H), 4.44(t, 1H), 4.84(d, 1H), 5.06(d, 1H), 5.25(d, 1H),      
5.77(d, 1H), 6.76(s, 1H),                                                 
7.76(d, 1H), 7.87(d, 1H), 8.77(s, 1H). Retention time 4.1 minutes,        
eluting with MeOH/H.sub.2 O/                                              
TFA, 45:65:0.1, v/v/v.                                                    
11. Starting material was 6,7-dihydro-2-methylthio-thiazolo [3,2-a]       
pyrimidinium tetrafluoro-                                                 
borate.                                                                   
12. N.m.r. in solvent A: 1.11(t, 3H), 1.39(d, 3H), 3.16(d, 1H), 3.43(d,   
1H), 3.66(m, 4H), 4.6(m,                                                  
4H), 4.96(d, 1H), 5.06(d, 1H), 5.78(d, 1H), 6.77(s, 1H), 6.83(d, 1H),     
8.23(d, 1H). Retention time                                               
5.0 minutes, eluting with MeOH/H.sub.2 O/TFA, 40:60:0.2, v/v/v.           
13. Prepared by the standard aqueous/DMF conditions of Examples 1-4,      
except that the                                                           
reaction was carried out for 65 hours at ambient temperature before       
quenching with HOAc.                                                      
14. Starting material was 1-allyl-4-chloropyridinium tosylate.            
15. N.m.r. in solvent A: 1.12(t, 3H), 1.39(d, 3H), 3.15(d, 1H), 3.45(d,   
1H), 3.63(m, 2H), 4.5(d,                                                  
1H), 4.58(q, 1H), 4.71(d, 1H), 4.78(d, 2H), 5.06(d, 1H), 5.25(d, 1H),     
5.33(d, 1H), 5.77(d, 1H),                                                 
6.03(m, 1H), 6.75(s, 1H), 7.1(br, 1H), 7.4(br, 1H), 8.19(d, 2H).          
Retention time 3.9 minutes,                                               
eluting with MeOH/H.sub.2 O/TFA, 40:60:0.1, v/v/v.                        
16. Prepared using the procedure of Footnote 13 above, except that the    
crude product was                                                         
chromatographed with out acidification on CHP20P, to give the product as  
a mono-sodium                                                             
salt, after precipitation from water by acetone.                          
17. Starting material was 4-chloro-1-(4-nitrobenzyl)-pyridinium           
tosylate.                                                                 
18. N.m.r. in solvent A: 1.11(t, 3H), 1.37(d, 3H), 3.1(d, 1H), 3.51(d,    
1H), 3.76(m, 2H), 4.48(d,                                                 
1H), 4.57(q, 1H), 4.77(d, 1H), 5.0(d, 1H), 5.52(s, 2H), 5.7(d, 1H),       
6.75(s, 1H), 7.1(br, 1H),                                                 
7.55(br, 1H), 7.63(d, 2H), 8.25(d, 2H), 8.36(d, 2H). Retention time 8.5   
minutes in MeOH/H.sub.2 O/                                                
TFA, 40:60:0.2, v/v/v.                                                    
 ##STR317##