Intermediates for producing semi-synthetic cephalosporins and methods of production
United States Patent [191 Sellstedt [451 Apr. 1, 1975 INTERMEDIATES FOR PRODUCING SEMI-SYNTHETIC CEPHALOSPORINS AND METHODS OF PRODUCTION [75] Inventor: John H. Seilstedt, Pottstown, Pa.  
 [73] Assignee: American Home Products Corp.,  
 New York, NY.  
 [22] Filed: July 11, 1973 [21] Appl. No.: 378,308  
  Related U.S. Application Data [62] Division of Ser. No. 197,142, Nov. 9, 1971.  
 [52] U.S. Cl 260/243 C, 424/246, 260/2391,  
  424/271 [51] Int. Cl. C07d 99/24, C07d 99/16 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,809,699 5/l974 lshimaru 260/306.7  
 Primary ExaminerNicholas S. Rizzo [57] ABSTRACT Novel 6-APA, 7-ACA, and 7-ADCA derivatives are described which comprise phosphorylated derivatives of 6-APA, 7-ACA, or 7-ADCA and the corresponding acylated derivatives thereof. The novel compounds are prepared by the reaction of 6-APA, 7-ACA, 7- ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor and subsequently acylating the thus formed phosphorylated compound, to form a phosphorylated acylated derivative which upon hydrolysis with water splits off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalosporin having useful antibacterial activity.  
 6 Claims, No Drawings INTERMEDIATES FOR PRODUCING SEMI-SYNTHETIC CEPHALOSPORINS AND METHODS OF PRODUCTION This application is a division of application Ser. No. 197,142 filed Nov. 9, l97l. 1  
  This invention relates to novel phosphorylated 6- APA, 7-ACA, and 7-ADCA derivatives, acylated derivatives thereof and the process for their production.  
  One aspect of the present invention relates to the&#39; production of semi-synthetic penicillins and cephalosporins in high yields from compounds such as 6-amino penicillanic acid, 7-amino cephalosporanic acid, and 7-amino-3-desacetoxy cephalosporanic acid.  
  Another aspect ofthe present invention relates to the acylation of novel phosphorylated 6amino penicillanic acids, 7-amino cephalosporanic acids, and 7-amino-3- desacetoxy cephalosporanic 7-amino in the absence of an acid acceptor.  
  Yet another aspect of the present invention relates to novel acylated and phosphorylated derivatives of 6- amino penicillanic acid, 7-amino cephalosporanic acid, 7-amino-3-desacetoxy cephalosporanic acid and related compounds.  
  These and other aspects of the present invention will become apparent from the following description.  
  In its broadest aspects the present invention covers compounds having the following structure:  
  1 2 RLN- and wherein:  
 R is a member selected from the class consisting of hydrogen and an organic acyl radical; R is selected from the class consisting of hydrogen and a radical of the formula 7 CH2 x or (CH2)? x wherein X is selected from the class consisting of oxygen, CH and sulfur; m is an integer from 1 to 6; R is hydrogen or (lower)alkyl.  
 The preferred novel compounds of the present invention are those having the following formulae:  
 R is selected from the class consisting of hydrogen and organic acyl; R is selected from the class consisting of hydrogen and with the proviso that R and R are not both hydrogen; R is selected from the class consisting of hydrogen and acetoxy.  
  The term (lower)alkyl&#34; as employed herein alone or in conjunction with other designated groups is intended to encompass straight chain or branch chain alkyl groups consisting of from one through six carbon atoms (e.g., methyl, ethyl, propyl, butyl, isobutyl, hexyl, 2-ethylpropyl, etc.)  
  The term halogen as used herein is intended to encompass chlorine, bromine, iodine and fluorine. The term aryl encompasses monocyclic and bicyclic rings having six to ten ring carbon atoms such as phenyl, naphthyl, etc. The term aryl(lower) alkyl&#34; is illustrated by benzyl, phenethyl, etc.  
  The term (lower)alkanoyloxy is illustrated by acetoxy, propionoyloxy and butanolyloxy. The term quaternary ammonium is illustrated by pyridinium, quinolinium, picolinum, etc. The term tertiary amine is illustrated by any of the well-known radicals such as triethylamine, tribenzylamine, N-ethylpiperidine which are described in the penicillin and cephalosporin art as capable of forming an amine salt with the carboxyl group.  
  The acyl group defined by R is derived from an organic carboxylic acid or a suitable functional reactive derivative thereof.  
  When R is acyl, the preferred acyl radicals are selected from groups having the following formulae:  
 ear 0 t- G II-i wherein:  
 R is selected from the class consisting of hydrogen, (lower)alkyl and phenyl; R and R are selected from the group consisting of hydrogen and (lower)alkoxy;;  
 R&#39; is selected from the class consisting of hydrogen,  
 (lower)alkyl and phenyl;  
 R and R are selected from the class consisting of hydrogen and halogen;  
 R and R are selected from the class consisting of hydrogen, halogen, (lower)alkyl, (lower)alkoxy, phenyl and phenoxy;  
  In the foregoing process the starting material (e.g., o-APA, 7-ACA or 7-ADCA) which may be obtained by any number of procedures described in the art (e.g., See U.S. Pat. Nos. 3,499,909 and 2,941,995) is reacted with a phosphorus halide of formula II in the presence of inert organic solvent and an acid acceptor to form a compound of formula 111 or VlI respectively. This reaction is preferably carried out at a temperature above l C. and not higher than about 25 C. The molar ratio of an acid binding agent to a starting material such as 6-APA is about 0.75:2 and the molar ratio of acid binding agent to a compound of formula 11 is 1:1.  
  Suitable acid binding agents are tertiary amines such as triethyl amine, dimethylaniline, quinoline, pryidine, lutidine, alkali metalcarbonates; alkaline earth carbonates or other acid binding agents known in the art. The preferred acid binding agent is a strong tertiary amine. As used herein strong amines are those characterized by having dissociation constants in the range of&#39; from to 10 or having comparable basicity, as distinguished from weak amines which are characterized by having dissociation constants in the range of from 10 to 10 A wide range of anhydrous non-hydroxylic organic solvents are useful in the reaction of 6-APA or 7-ACA with a phosphorylating agent including hydrocarbons such as benzene and toluene; chlorinated solvents such as methylene chloride, chloroform and chlorobenzene; ethers such as diethyl ether, dioxane, tetrahydrofuran; and other conventional solvents such as methylisobutylketone, dimethylformamide, ethyl acetate, acetonitrile, etc.  
  The reaction between 6-APA, 7-ACA, or 7-ADCA and a phosphorus halide is carried out preferably at a temperature at which the reaction proceeds to completion in a reasonably short time period, i.e., between +10 C. and +10 C.  
  A compound of formula III and VII prepared according to this invention can be isolated by removing the hydrohalide base by filtration and distillation of the solvent, or if the intermediate is to be converted at once to a penicillin or cephalosporin, the reaction mixture can be acylated directly without filtration or concentration.  
  The product or products obtained from the reaction of a compound of formula 1 or V1 with a phosphorylating agent is dependent on the molar ratio of the reactants as to whether an anhydride of the penicillanic acid is formed. Thus, if the molar ratio of a compound of formula ll to formula 1 is greater than 1:1, the predominant material obtained is a compound of formula 111, particularly as the molar ratio increases to about 2:1 and higher. On the other hand where the molar ratio is 1:1 or less (e.g., 0.5:1 the predominant compound is f H s ca 6 CH;  
  O ll 0: N C-OH The fact that mixtures of phosphorylated compounds can be produced under certain reaction conditions does not interfere with the process of acylation and subsequent formation of the desired semi-synthetic penicillin or cephalosporin.  
  Novel phosphorylated acylated compounds within the scope of formula A and B may be prepared by the acylation of a compound of formula III or VII in accordance with the reaction sequence shown above in diagram A and B, respectively.  
  Suitable acylating agents include carboxylic acid halides, carboxylic acid anhydrides, mixed anhydrides with other carboxylic or inorganic acids; esters such as thiol esters and phenol esters; lactones; and carboxylic acids with carbodiimides or N,N  
 carboxyldiimidazoles.  
  Illustrative of some specific preferred acylating agents are phenoxyacetyl chloride, 2,6-  
 dimethoxybenzoyl chloride, benzene sulfonyl chloride, Z-phenoxypropionyl chloride, Z-phenoxy-butyl chloride, D() phenylglycl chloride HCl, l-aminocyclopentune-carboxylic acid chloride HCl, l-aminocyclohexanecarboxylic acid chloride HCl, 2-amino-2- carboxyindane acid chloride HCl, 2-ethoxy naphthoyl bromide and 3-(2,o-dichlorophenyl)-5-methylisoxazole carbonyl chloride, etc.  
  ln carrying out the acylation step, it has been suprisingly found that an acid acceptor need not be present during the reaction. Heretofore such a reagent was deemed essential for sucessfully carrying out the acylation procedure as illustrated by U.S. Pat. Nos. 3,595,855; 3,249,622. In addition, where a strong amine is used in reacting a compound of formula 1 with a compound of formula II, it is desirable to avoid the presence of any excess strong amine because the strong amine has a deleterious effect on the yield of semisynthetic penicillin produced. The acylation process is carried out in the presence of an inert anhydrous organic solvent. Suitable solvents may be the same as earlier exemplified for the reaction producing the phosphorylated derivatives of 6-APA, 7-ACA, 7-ADCA, etc.  
  The acylated penicillins and cephalosporins of formulae 1V and IX are readily hydrolyzed by treating with water, to split off the protective group from the amino group and the carboxyl group to form a semisynthetic penicillin or cephalosporin embraced by formulae V and X, respectively.  
  The acylation of a compound of formula III or Vll first results in the formation of an intermediate of formula IV(a) or Vlll, respectively. These intermediates repidly convert to a compound of formula IV and 1X, respectively as a result of expulsion of l R l&#39;ialogen from the nitrogen atom. This expulsion is due to the presence of an anion (e.g., Cl) upon formation of the intermediate of formula lV(a) or VIII, respectively, which attacks the phosphorus atom linked to the nitrogen. It is possible that the presence of a weak base during the acylation would bind the anion and thereby avoid the expulsion of l 5 R -halogen In the latter case hydrolysis of a compound of formula 1 1 IV(a) or VIII, respectively, would result in direct formation of a compound of formula V or X, rather than intermediate IV or IX.  
  The hydrolysis is carried out at a pH between 0.5 and 2 at a temperature below about 15, preferably between and C. The hydrolysis is carried out by treatment with water.  
  Where the acylating agent used is in the form of an acid addition salt, the penicillin or cephalosporin of formula V or X is recovered upon hydrolysis as an acid addition salt (e.g., chloride) which may then be converted to the free base by methods well known in the art. In the event the ultimate penicillin to be obtained is a-aminobenzyl penicillin (ampicillin), it has been found advantageous to change the chloride to an aryl sulfonic acid salt of the aminopenicillin either by adding an appropriate sulfonic acid to the reaction mixture comprising the selected organic solvent and water, or to the aqueous extracts separated as described immediately above. In this connection, 25 percent excess of the sulfonic acid has been used to advantage in preparing the corresponding salt of ampicillin.  
  The aryl sulfonic salt of the a-aminobenzyl penicillin may then be converted to the penicillin per se by reaction with a base such as triethylamine or diethylamine in approximately 85 percent isopropanol. In the case of ampicillin specifically, the sulfonic acid salt, wet with water and ethyl acetate, may be added to isopropanol containing a molar equivalent of triethylamine at 7580C., whereby the anhydrous form of ampicillin described and claimed in US. Pat. No. 3,144,445 is formed and collected by filtration from the hot mixture.  
  Alternatively, the corresponding penicillin may be obtained, but in hydrated form, by raising the pH of the aqueous reaction mixture containing the hydrochloride salt of said penicillin to the iso-electric point.  
  The starting materials defined by formula 11 may be prepared by procedures described in the literature. For example, the preparation of 2-chloro-l,3,2-dioxaphospholane is described by Lucas et al., J. Am. Chem. Soc. 72, 5491-5497 (1950). Other compounds within the scope of formula 11 may be prepared by the procedures described by Brown et al., J. Chem. Soc. 878-881 (1970).  
  The following examples are given by way of illustration and are not to be construed as limitations of this invention.  
  EXAMPLE 1 p D() oz-aminobenzylpenicillin 6-Aminopenicillanic acid (10.81 g, 0.05 mole) is stirred for one half hr. in 100 ml. of dichloromethane at 05C. containing 13.85 ml. of triethylamine. At 0-5C., a solution of 12.65 g. (0.1 mole) of 2-chloro- 1,3,2-dioxaphospholane in 50 m1. of dichloromethane is added over 1 hr., and the mixture is stirred an additional one-half hr. at 05 C. The resulting product is 6-(l,3,2-dioxaphospholan-2-yl amino) penicillanic acid, l,3,2,-dioxaphospholan -2-yl ester. D- ()phenylglycyl chloride hydrochloride (10.63 g., 0.05 mole) is added to the stirred mixture over 2 min., and stirring is continued for one-half at 05 C. under nitrogen. The cooling bath is removed and the temperature is allowed to go to 17 C. and held at this temperature for a total acylation time of 3 hr. The resulting acylated product is 6-(2-amino-2-phenyl-acetamido) penicillanic acid, l,3,2-dioxaphosphalan-2-yl ester. The mixture is poured into 300 ml. of water at 05 C.  
  12 and stirred for 15 min., with the pH going to 0.7. Celite is added, the mixture is filtered, and the filtrate is separated and the water layer (340 ml.) is bioassayed vs. S. Lutea. The addition of 5 ml. of this solution to 245 ml. of 1 percent pH 6 buffer gives an assay value of 700 &#39;y/ml. of ampicillin.  
  The B-naphthalene sulfonic acid salt is prepared from the 340 ml. of solution by adding ethyl acetate (40 ml.) and cooling to 0-10 C. followed by addition of 29.4 g. ofa 37,68 percent solution ofBnaphthalene sulfonic acid over 10 min. and holding the pH at 1.5 to 1.7 with the addition of 5N sodium hydroxide. This mixture is stirred overnight at 5 (filtered, stirred in 60 ml. of ethyl acetate for 5 min., filtered and sucked dry, giving 27.3 g. the B-naphthalene sulfonic acid salt of D()aaminobenzylpenicillin. It was bioassayed vs. S. Lutea indicating the presence of 560 of ampicillin.  
 EXAMPLE 2 l-aminocyclohexane penicillin 6-Aminopenicillanic acid (43.25 g., 0.7 mole) is stirred in dichloromethane (400 ml. containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered to 05 C., and 50.6 g. (0.4 mole) 2-chloro-l,3,2-dioxo-.  
 phospholane in 200 ml. of dichloromethane is added over 1 hr., and stirring is continued at 05 C. for one half hr. l-aminocyclohexanecarboxylic acid chloride hydrochloride (40 g., 0.2 mole) is added, and the mixture is stirred while the internal temperature is allowed to slowly go to 10 C. over one half hr., and the reaction is continued for an additional 2 /2hr. at 10C. The mixture is poured into 200 ml. of cold (05 C.) water and the mixture is stirred in an ice bath for 15 min. lsopropanol ml.) and celite (15 g.) are added, the mixture is filtered by suction, and the cake is washed with 40 ml. of isopropanol. The two-phase filtrate is poured into a 2 liter round bottom 3-neck flask, and while stirring at l520 C., the pH is raised to 5.4-5.5 with 5N NaOH, giving white crystals of dihydrate of the above titled compound.  
 EXAMPLE 3 D()-a-aminobenzylpenicillin 6-Aminopenicillanic acid (43.25 g., 0.2 mole) is stirred in dichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered to 05C., and 50.6 g. (0.4 mole) 2-chloro-1, 3,2-dioxophospholane in 200 ml. of dichloromethane is added over 1 hr., and continue to stir at 05 C. for one half hr. D()Phenylglycycl chloride hydrochloride (43.6 g., 0.2 mole) is added over about 1 min., and the mixture is stirred at 05 C. for three-fourths hr. The ice bath is lowered so that only the lower l-2 cm. of the flask is in the ice water, and the internal temperature is allowed to slowly (about 25 min.) go to 10 c., and then held at this point for a total temperature raising time and reaction time of 2 hr. The mixture is poured into 800 ml. of room temperature water, and the flask is rinsed with 200 ml. of water. The mixture is stirred with the vessel in an ice-bath for 15 min., Super Celis added, the mixture is filtered by suction, and the cake is washed with 200 ml. water. The layers are separated, and the aqueous phase is placed in a 2 liter round bottom flask containing 200 ml. ethyl acetate. The internal temperature is lowered to 0-l0 C. and the pH is adjusted to 2 by the addition of 5N sodium hydroxide.  
 Then 1()() ml. of a 37.7 percent B-naphthalene siilfonic acid solution is added in about minutes while keeping the pH at 1.5 to 1.7 with 5N NaOH. After stirring ohr. at ()5 C., and no stirring for 12 hr., the mixture period and stirring is continued at ()5(. for one half hr. D-(---)-phenylglycyl chloride hydrochloride (21.3 g., 0.1 mole) is added all at once and the mixture is stirred at ()-5 (Y for min. The ice bath is lowered is filtered, and the cake is washed with about 100 ml. 5 hat nly the l er 1-2 cm. of the flask is in the ice of cold H 2 water After ki as dr as ibl the water, and the internal temperature is allowed to slowly cake is stirred in 250 ml. of ethyl acetate for 5 minutes, go to 10C. over about 2 hr., and the mixture is poured the mixture is filtered, and the cake is washed with 2 X into 451) ml. of room temperature water. and theflask 50 ml. ethyl acetate. giving 137 g. of the above titled is rinsed with ml. of water. The mixture is stirred product. A portion of the sample is dried indicating It ith the C C in 1 1 C0 hlllh for 15m SUPCF 0 is 53.5 percent NVM with a corresponding yield of 66 added, the mixture is filtered by suction. and the cake percent, but bioassay vs. S. Lutea indicates 380 y/mg. is washed with 100 ml. of water. The layers are sepa-&#39; with a corresponding yield of percent. This material rated, and the aqueousphase is placed in a 1 liter round is converted to anhydrous ampicillin in percent yield bottom flask containing ml. of ethylacetate. The by the standard isopropanol/triethylaminc procedure l5 int rnal tempe a re s C Cd l0 01 C.&#39;1md the pH as d ih d i [L3 P N 3 487 071 is raised to 2 by the addition of 5N NaOH. Then sulfonic g. of a 37 percent B-naphthalene sulfonic acidso- EXAMPUL 4 lution is added within 5 to 10 min. while keeping the l)()-tx-aminobenzylcephalosporiii pH at 1.5 to 1.7 with 5N NaOH. After stirring overnight I t I 30 at 0-5C., the mixture is filtered. and the cake is In a manner similar to the process tor preparation of washed with cold pH2 water (30 ml.). After sucking as ampicillin in hxample 1, but using 7-amino-cepha1os- I n 1 I y 6; I 0 a I m1 I 6 dry as possible the cake is stirred in ml. of ethyl acl f t .jl b l a I etate for 5 min.. the mixture is filtered, and the cake l l l H up washed twice with ethyl acetate, giving 382g. of the porm is isolated by ad ustmg the pH 01 the aqueous 7g I t I him my i d hr rim ti n h 1h wt 5 7s B-naphthalene sultonit. acid salt of D( )-ap i L I i aminobenzylpenicillin. A portion of the sample is dried EXAMPLE 5 indicating the presence of 6.36 g. of NVM, with a cor- I 4 &#39;1 s i t naphthalene suuomc Held Sun 0 rlecstponding 4 percent yield of the above titled prod D()-0z-aminobenzylpenicillin 30 6-Aminopenicillanic acid (21.7 g., 0.1 mole) is EXAMPLE 6 stirred in dichloromethane (200 ml.) at t)5 C., and Following the procedure of Example 1, a series of 14.0 ml. (0.1 mole) of triethylamine is added, and the phosphorylated penicillin compounds are prepared by mixture is stirred for one half hr. At ()-5 C., a solution reacting 2 moles of a phosphorylating agent of formula is dripped in of 2-chloro-l,3,2-dioxophopho1ane 12.7 35 C with one mole of o-APA to produce a compound of g., (1.1 mole) in dichloromethane 100 ml.) over a 1 hr. formula D.  
  5 R 1 CH 6 -6 l, 1&#39;? R 3 -N- C113 o= t -OE &#39;R 3 (a) CH CH C1 Cri CH I t t 01 t t (c) cii e ca tp Br cii qi cii cl --S Cl C S C H C H (e) C H C 11 Cl 2 5 2 5 EXAMPLE 8 Following the procedure of Example 1, a series of 15 phosphorylated penicillin compounds are prepared by reacting 0.5 mole of a phosphorylating agent of formula C with one mole of 6-APA to produce a com pound of formula F.  
 -Continued EXMAPLE 7 Following the procedure of Example 4. a series of phosphonvlated penicillin compounds are prepared by reacting 2 moles of a phosphorylating agent of formula C with one mole of 7-ACA or 7-ADCA to produce a compound of formula E.  
 (a) CH3 Continued i (c) crr o ca q Br on o c:-: I  
 ( 3 Cl Q s s l e) x C 3 01 E 0 1-1 0 2 l I E (1) c1 2 i i K/IK i i ii i l EXAMPLE 9 EXAMPLE 10 Following the procedure of Example 1, the following Following the procedure of Example 4 a series of acylating agents are used in place of D()phenyl glyphosphonylated cephalosporin compounds are precine chloride hydrochloride to obtain the following acpared by reacting 0.5 mole of a phosphorylating agent ylated phosphorylated penicillin derivatives. Those of formula C with one mole of 7-ACA 0r 7ADCA to having an amino group are obtained as the hydrochloproduce a compound of formula G. ride salt.  
  T5 l RLP X R P-L l I I/ \I i l i g L---N\/CF7R2 o=cou c G g hc c-: or I I (d I Cl C J .1. 1 j 3 I I (o) Br 5 .r: I .O/ i o t I v (C) q) r M (P 5 $1 (a) ce cn c C.L I occe c&#39; cu o i l u l CH 1 s 3 i N15 u-O-P 0.15  
 acvlatihrr. aaenz i v R I 0 z. .lc. NH? H hydrochloride salt Oi l-eqrahoc jcioc pehtahe carooxylic acid chloride 0 e n hydrochloride salt of l-ammocyclo-Q- w xe -lcarooxylic acid chloride 5 2 T&#34; hydrochloride salt of i-eminQ-i I I indane carboxylic acid chloride L752 q I hydrochloride salt of l-arninol, 3, 4- 3..  
 tetrahydronaphthoic acid chloride hydrochloride salt of l-emino-Y-eznoxy- -l 2 3 &#39;r-tetrah dz&#39;o-l-haohanoic acid I J J chloride hydrochloride salt of Z-amino- 2-i.nde.necarboxylic acid chloride hydrochloride salt of 2-amino-lphenoxy-E-indane carboxylic acid chloride hydrochloride salt of l-ainino-l,2,3,4- tetrahydro-3,6-dimethyl-l-naphthoic acid chloride hydrochloride salt of l-amino-3-cycloentene -lcarboxylic acid 3-(phenyl)-5-methyl-4-isoxazolecarbonyl chloride Continued O 3-(2 ,6-dichlorophenyl )-5-methyl- 4-isoxazole-carbonyl chloride I C-- v c1 3 2,6-di-methoxy-benzoic acid chloride Z-ethoxy-l-napnthoyl chloride m (EH3 H O CH&#39;C- oc-phenoxy butyrlc acld chlorlde 35 EXAMPLE 1 1 agents identifed below are used to obtain the following acylated phosphorylated cephalosporins. Those having Following the procedure of Example 4, the acylating the amino group are obtained as the hydrochloride salt.  
 acylating agent D(-&#39;)pnenyl glycine chloride, 1 Ii hydrochloride 1 .C&#34;- C- Z-thienylacetic acid Continued \&#34;)P Y glycine chloride, hydrochloride 1 a O-c-W phenoxyacetic acid chloride fi o-ca -co-c-ca-,  
  It is to be understood that the only limitation on the O Y H s acld&#34;lfh h&#39; &#34;u&#39; d h] y ra ma 0 t esynt etic pemcl ms an cep aospo 70 rins is that they be essentially non-toxic upon in vitro 0 Q or in vivo application. 0 N CH g The synthetic penicillins and cephalosporins pre- 2 pared from the intermediates of the present invention have activity against gram positive and/or gram nega- 75 /O&#39; tive bacteria and may be utilized in pharmacological O C O- P\ compositions in association with pharmacologically ac- 0 ceptable carrier, e.g., in suitable injectable forms, ineluding solutions and suspensions; or orally as tablets, capsules, and the like, utilizing conventional solvents,  
  3O suspensoids, excipients, and the like. These compounds 0 H E P N- 3. A compound accroding to claim 1 which is:  
 may be administered orally or parenterally Naturally,  
  S the dosage of these compounds will vary somewhat O f with the form of administration and the particular com- 0: v N CH3 pound chosen. Further, it will vary with the particular 35 subject under treatment.  
 What is claimed is: C P 1 l. A compound of the formula: \O  
  4. A method which comprises reacting a compound of the formula:  
  O: N CHR 6 2 I O C-O-P R wherein: O C  
 R is selected from the class consisting of hydrogen, 5()  
 (lower)alkanoyloxy containing two to eight carbon wherein R is selected from the class consisting of hyatoms, and a quaternary ammonium radical; R and drogen. alkali metal and tertiary amine; R is selected R are selected from the class consisting of (lowerfrom the class consisting of hydrogen, (lower)allalkyl, phenyl, naphthyl, phenyl( lower alkyl) and kanoyloxy containingtwo to eight carbon atoms, and naphthyl(lower)alkyl; and R and R when joined 55 a quaternary ammonium radical; with a phosphorytogether with the phosphorus atom form the ring lating agent of the formula:  
 &#39; CH X R7 X 2 R l or R is selected from the class consisting of hydrogen and ,5 R5 (lower)alkyl; m is an interger from 1 to 6; and X is selected from the class consisting of oxygen, methylene and sulfur. a wherein: R and R are each selected from the class 2. A compound according to claim 1 which is: consisting of (lower)alkyl, phenyl, naphthyl, phenyl(- l halogen P R lower)alkyl and naphthyl(lower)alkyl; R and R when wherein X is oxygen and m is one. joined together with the phosphorus atom form the 6. A process according to claim 4 which comprises ring: reacting a cephalosporin selected from the class con- 1 7 2 X t R 7 v R H x f or X is selected from the class consisting of oxygen, methsisting of 7amino-cephalosporanic acid and 7-amino-3- ylene and sulfur; m is an interger from 1 to 6; and R desacetoxy cephalosporanic acid under anhydrous conis selected from the class consisting of hydrogen and ditions and in the presence of an acid binding agent (lower)alkyl. S with a 2-halo-1,3,2-dioxaphospholane or a lower alkyl 5. A process according to claim 4 wherein R and R substituted derivative thereof at a temperature between are joined together with the phosphorus atom to form about l0C. and +C, the molar ratio of said the ring: 2-halo-l,3,2-dioxaphospholane are lower alkyl deriva- CH .x\ tive thereto to said cephalosporin being at least 1:].  
 UNITED STATES PATENT OFFECE CETIFICATE 0F CORRECTYON PATENT NO. 3 75 152 DATED April 1, 1975 lNvENTORtS) John H. Sellstedt It is certified that error appears tn the above-rdenhtied patent and that saic Letters Patent are hereby corrected as shown below;  
 Column 1, line 17, &#34;7 amino&#34; should be -acids-;  
 &#39; Column 5, formula III, two bonds are missing from the structural formula which should be Column 9, line 9, &#34;-25C should be --+25&#34;C--;  
 Column 10, line 46, delete &#34;amino group&#34; line 52, &#39;repidly&#34; should be -rapidly-;  
 Column 12, line 17 after &#34;560&#34; insert /mg-;  
 line 21, &#34;O .7 mole&#34; should be 0.2 mole;  
 Column 14, line 16, delete &#34;su1-&#34; line 17, delete &#34;fonic g&#34; and insert 60 g--;  
 Signed and Sealed this second Day Of September 1975 [SEAL] Attest:  
 RUTH C. MASON C. MARSHALL DANN Arresting Officer (mnmissimu&#39;r nj&#39;Parenls and Trademarks