Alkylcarbamoyloxymethylcephem compounds
This invention relates to an alkylcarbamoyloxymethylcephem compound. More specifically, it relates to 7β-[2-(2-aminothiazol-4-yl)-2-alkenamido]-3-(alkylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid or its derivative represented by the following formula ##STR2## (wherein R is hydrogen or an amino-protecting group, 
     R 1  is 1C to 8C alkyl, 
     R 2  is 1C to 8C alkyl, 
     R 3  is hydrogen, a salt- or ester-forming atom or group, and 
     X is sulfur or sulfinyl) 
     [EXPLANATION OF THE SYMBOLS] 
     In above formula (I), the amino-protecting group R may contain 1 to 19 carbon atoms and can be 1C to 8C alkyl (e.g., trichloroethyl, methoxyethoxymethyl, tetrahydropyranyl), 7C to 19C aralkyl (e.g., diphenylmethyl, trityl, methoxybenzyl), 1C to 8C alkylthio, 6C to 8C arylthio (e.g., nitrophenylthio), 5C to 8C cycloalkylidene, 1C to 8C acyl [e.g., 1C to 8C alkanoyl (e.g., formyl, acetyl, chloroacetyl, trifluoroacetyl), 2C to 8C alkoxycarbonyl (e.g., that having methyl, ethyl, propyl, cyclopropylethyl, isoproyl, butyl, isobutyl, pentyl, hexyl, trichloroethyl, pyridylmethyl, cyclopentyl, or cyclohexyl as the lower alkyl part), 8C to 19C aralkoxycarbonyl (e.g., that having benzyl, diphenylmethyl, or nitrobenzyl as the aralkyl part), 7C to 12C aroyl (e.g., benzoyl, nitrobenzoyl), succinyl, phthaloyl], 3 C to 9 C trialkylsilyl, 3 C to 9C alkoxydialkylsilyl, 3C to 9C trialkylstannyl, or the like, and that forming RNH being 1C to 8C alkylideneamino or 7C to 12C aralkylideneamino (e.g., benzylideneamino, methylbenzylideneamino, nitrobenzylideneamino). 
     The alkyl as R 1  or R 2  is an unsubstituted 1C to 8C alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl, isooctyl). 
     The ester-forming group R 3  can be one useful for carboxy protection in the penicillin and cephalosporin fields known which can be introduced and removed without adverse effect on other parts of the molecule. It is preferable that having 2C to 19C and forming, for example, a 1C to 8C alkyl ester (e.g., methyl, methoxymethyl, ethyl, ethoxymethyl, trichloroethyl, iodoethyl, propyl, isoproyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, butyl, isobutyl, tert-butyl, or hexyl ester), 2C to 8C alkenyl ester (e.g., vinyl, propenyl, or allyl ester), 7C to 19C aralkyl ester (e.g., benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenethyl, trityl, di-tert-butylhydroxybenzyl, phthalidyl, or phenacyl ester), 6C to 12C aryl ester (e.g., phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, or indanyl ester), ester with a 1C to 12C N-hydroxyamino compound (e.g., ester with acetone oxime, acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, or N-hydroxyphthalimide), 3C to 12C silyl ester (e.g., trimethylsilyl, tert-butyldimethylsilyl, or dimethylmethoxysilyl ester), 3C to 12C stannyl ester (e.g., trimethylstannyl ester), or the like. The carboxy protecting ester group may have a substituent. This group is absent in the objective compounds. So, its structure has not in itself any specific meaning as long as it protects the carboxy during the synthesis. Thus it can be replaced by a wide variety of equivalent groups (e.g., amide or acid anhydride with carbonic or carboxylic acid) or the like. 
     The salt forming group R 3  can preferably be that forming a pharmaceutically acceptable ion and belonging to group I to III and period 2 to 4 in the Periodical Table. This can preferably be a light metal [e.g., alkali metal (e.g., sodium, potassium, lithium), alkaline earth metal (e.g., magnesium, calcium), aluminum, or the like]. A salt with 1 C to 12C alkylamine (e.g., trimethylamine, triethylamine, methylmorpholine) or 4C to 9C aromatic base (e.g., pyridine, collidine, picoline, quinoline, dimethylaniline) is available for synthetic purposes. 
     The ester forming group R 3  can be a so-called pharmaceutically acceptable ester group, for example, a 1-oxygenated-2C to 15C alkyl {e.g., alkanoyloxyalkyl (e.g., acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl), 3C to 15C alkoxycarbonyloxyalkyl (e.g., ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, tert-butoxycarbonyloxyethyl, isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyisopropyl), 2C to 8C alkoxyalkyl (e.g., methoxymethyl), 4C to 8C 2-oxacycloalkyl (e.g., tetrahydrofuranyl, tetrahydropyranyl)}, 8C to 12C aralkyl (e.g., phenacyl, phthalid-yl), 6C to 12C aryl (e.g., phenyl, xylyl, indanyl), 2C to 12C alkenyl (e.g., allyl, 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl), or the like. 
     In above definition of the symbols, the carbon number referred to includes that for the substituent. 
     The alkyl part can be a straight, branched, or cyclic alkyl which may be substituted (e.g., by hydroxy, alkoxy, acyloxy, amino, acylamino, dialkylamino, cyano, carboxamino, formimidoylamino, oxo, acyl, alkyl, halogen, protected carboxy, carbamoyl). 
     The acyl part can also be straight, branched, or cyclic alkanoyl, monocyclic or dicyclic aroyl, aralkanoyl, arylalkenoyl, alkylsulfonyl, arylsulfonyl, carbamoyl, carbalkoxy, carbaralkoxy, sulfo, or the like acyl, which may optionally have nitrogen, oxygen, or sulfur as a hetero atom in its skeleton. The acyl may have a substituent as defined above. 
     The aryl part can be 5 to 6 membered monocyclic or bicyclic and carbocyclic or heterocyclic aryl and may have a substituent as given above. The typical heterocyclic group are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, thiatriazolyl, tetrazolyl, pyridyl, quinolyl, pyridopyridyl, and the like. 
     [SPECIFIC COMPOUNDS] 
     A preferable compound (I) has hydrogen or tert-butoxycarbonyl as R, methyl, ethyl, propyl, or isopropyl as R 1 , methyl, ethyl, propyl, or isopropyl as R 2 , hydrogen, sodium, diphenylmethyl, a pharmacologically acceptable ester group (e.g., acetoxymethyl, 1-(acetoxy)ethyl, 1-(cyclohexylcarbonyloxy)-1-cyclohexylmethyl, 1-(cyclohexylmethoxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(isopentyloxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropyloxycarbonyloxy)propyl, (4-methyl-2-oxo-1,3-dioxol-5-yl)methyl, pivaloyloxymethyl, 1-(pivaloyloxy)ethyl, or 1-(tert-butoxycarbonyloxy)ethyl as R 3 , and sulfur as X. 
     A representative compound has R as hydrogen, R 1  as methyl, R 2  as methyl, and R 3  as hydrogen, sodium, acetoxymethyl, 1-(acetoxy)-ethyl, 1-(cyclohexylcarbonyloxy)-1-cyclohexylmethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, or pivaloyloxymethyl; R as hydrogen, R 1  as ethyl, R 2  as methyl, and R 3  as hydrogen, sodium, acetoxymethyl, 1-(acetoxy)ethyl, 1-(ethoxy-carbonyloxy)ethyl, 1-(isopentyloxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, (4-methyl-2-oxo-1,3-dioxol-5-yl)methyl, 1-(pivaloyloxy)ethyl, pivaloyloxymethyl, or 1-(tert-butoxycarbonyloxy)ethyl; R as hydrogen, R 1  as ethyl, R 2  as ethyl, and R 3  as hydrogen, sodium, or pivaloyloxymethyl; R as hydrogen, R 1  as ethyl, R 2  as isopropyl, and R 3  is hydrogen, sodium, pivaloyloxymethyl, or 1-(cyclohexylmethoxycarbonyloxy)propyl; R as hydrogen, R 1  as propyl, R 2  as methyl, and R 3  as hydrogen, sodium, or pivaloyloxymethyl; or R as hydrogen, R 1  as isopropyl, R 2  as methyl, and R 3  as hydrogen, sodium, or pivaloyloxymethyl. 
     [PRIOR ARTS] 
     Some 3-alkylcarbamoyloxymethylcephalosporins are described in U.S. Pat. No. 3,484,437. Some compounds closely related to the free carboxylic acid of Compound (I) are described in U.S. Pat. Nos. 4,014,869 and 4,416,880. However, compound (I) having alkyl as R 2  and especially a pharmaceutically acceptable ester group as R 3  has never been disclosed. 
     [TECHNICAL MERITS] 
     The compounds (I) having methyl as R 2  is superior to those having hydrogen as R 2  of copending U.S. application Ser. No. 845,305, filed Mar. 27, 1986 in their oral availability (represented by blood level maximum of 28.7 μg/ml for a compound having methyl as R 2  whereas that of 9.3 μg/ml for a compound having hydrogen as R 2  when R 1  is ethyl and R 3  is pivaloyloxymethyl), antibacterial potency against Gram-positive bacteria, excretion, distribution, or the like characteristics. 
     [USE] 
     A free carboxy-, salt-, or pharmacological ester-compound (I) is a potent antibacterial against aerobic or anaerobic bacteria. It may be used as a bacteriocidal, bacteriostatic, disinfecting, or antiperishing agent, bacterial growth inhibitor in human, animal, plant, or perishable subjects, a human or animal growth promoting additive in foodstuffs, or an agent for treating or preventing a human, veterinary, or poultry infection caused by sensitive bacteria and for testing senstitivity of bacteria to the antibacterial (I). 
     Thus, the said compound (I) is an antibacterial against aerobic Gram-positive bacteria (e.g., Bacillus cereus, Bacillus subtilis, Corynebacterium diphtheriae, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus faecalis) and Gram-negative bacteria (e.g., Citrobacter diversus, Citrobacter freundii, Enterobacter aerogens, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Morganella morganii, Proteus vulgaris, proteus rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Salmonella paratyphi, Salmonella typhi, Serratia marcescens, Shigella sonnei, Yersinia enterocolitica), and anaerobic bacteria (e.g., Clostridium difficile, Clostridium novyi, Eubacterium cylindroides, Bacteroides fragilis, Fusobacterium nucleatum, Propionibacterium spp., Veillonella parvula). 
     [METHOD FOR TREATMENT] 
     Compound (I) as carboxylic acid or its light metal salt can be given intravenously, intramuscularly or subcutaneously (as e.g., solution, suspension), or orally, if required in admixture with an excipient (e.g., solubilizing agent, emulsifying agent). A pharmacological ester (I) can be given intravenously, intramuscularly, subcutaneously, orally (as e.g., capsule, dry syrup, emulsion, powder, solution, suspension, tablet, troche), externally, or topically (as e.g., ear, nasal, or ocular drug, ointment, injection, pap preparation, spray, suppository). 
     A protected compound (I) is also useful as a starting material for synthesizing other antibacterials or as an agent for testing sensitivity of bacteria. 
     This invention also provides a method for treating or preventing a human or veterinary bacterial infection (e.g., abscess, bronchitis, dermatitis, ear infections, empyema, enteritis, gastroenteritis, nasopharyngitis, osteomyelitis, pneumonitis, pneumonia, pustulosis, pyelonephritis, respiratory tract infection, rhinitis, septicemia, tonsillitis, ulceration, urinary tract infection, wound and soft tissue infection) caused by sensitive bacteria by administering an effective amount of the said compound (I) at a typical daily dose of 0.1 to 6 gram (injection), 0.1 to 4 gram (orally), or 0.1 to 10 mg (topically), if required formulating with a conventional additive, coacting substance (e.g., other antibacterial), or the like. 
     This invention also provides an antibacterial pharmaceutical composition containing the said compound (I) in a various enteral or parenteral dosage form, solely or in admixture with a carrier or coacting substance. The composition may contain 0.01 to 99% of compound (I) dissolved, dispersed, or suspended in a solid or liquid pharmaceutical carrier. 
     The composition may be a solid preparation (e.g., capsule, dry syrup, granule, lyophilized material, pellet, pill, powder, suppository, troche, tablet) or liquid preparation (e.g., dispersion, elixir, emulsion, inhalant, injection, ointment, suspension, syrup, solution). The capsule, granule, and tablet may be coated. They can be in a unit dosage form. 
     The carrier is inert to both the compound (I) and patients. Representative examples of such carrier include, among others, for a solid preparation, a binder (e.g., acacia, carboxymethylcellulose, gelatin, glucose, polyvinylpyrrolidone, sodium alginate, sorbitol, starch, syrup, tragacanth), bulking agent (e.g., bentonite, calcium carbonate, calcium phosphate, glycine, kaolin, lactose, polycarboxymethylene, salt, sorbitol, starch, sugar, talc), diluent (e.g., calcium carbonate, kaolin, lactose, starch, sucrose), disintegrator (e.g., agar, carbonate, sodium laurylsulfate, starch), lubricant (e.g., boric acid, cacao oil, magnesium stearate, paraffin, polyethyleneglycol, silica, sodium benzoate, stearic acid, talc), and wetting agent (e.g., hydroxypropylcellulose); for a solution, a solvent (e.g., alcohol, buffer, methyl oleate, peanut oil, sesame oil, water), emulsifying agent (e.g., acacia, lethicin, sorbitan monooleate), suspending agent (e.g., aluminum stearate gel, carboxymethylcellulose, gelatin, glucose, hydrogenated fats, hydroxyethylcellulose, methyl cellulose, sorbitol, sugar syrup), buffer, dispersing agent, and solubilizing agent: and for both, a perservative (e.g., methyl or ethyl p-hydroxybenzoate, sorbic acid), absorption promoter (e.g., glycerin mono- or di-octanoate), antioxidant, aromatic substance, analgesic, edible coloring agent, stabilizing agent, or the like. 
     The said pharmaceutical preparation can be prepared in a conventional manner. 
     [SYNTHESIS] 
     The compound (I) according to this invention can be prepared by a conventional method as given below. 
     (1) Amidation 
     A conventional amidation of amine (II) (i.e., 7β-amino-3-alkylcarbamoyloxymethyl-3-cephem-4-carboxylic acid) or its reactive derivative with carboxylic acid (III) (i.e., optionally protected 2-(2-aminothiazol-4-yl)-2-alkenoic acid) or its reactive derivative gives compound (I) or its derivative. ##STR3## 
     A typical reactive derivative of amine (II) has 7-amino activated by silyl (e.g., trimethylsilyl, methoxydimethylsilyl, tert-butyldimethylsilyl), stannyl (e.g., trimethylstannyl), alkylene (as a part of enamino consisting of the amino with, e.g., aldehyde, acetone, acetylacetone, acetoacetate ester, acetoacetonitrile, acetoacetanilide, cyclopentanedione, acetylbutyrolactone), alkyliene (e.g., 1-haloalkylidene, 1-haloaralkylidene, 1-alkoxyalkylidene, 1-alkoxyaralkylidene, 1-alkoxy-1-phenoxyalkylidene, alkylidene, aralkylidene), acid (as a salt of the amino with, e.g., mineral acid, carboxylic acid, sulfonic acid), easily removable acyl (e.g., alkanoyl), or the like and that protected at other function of the molecule. 
     The carboxylic acid (III) is used in the presence of a known condensing reagent [for example, carbodiimide (e.g., N,N&#39;-diethylcarbodiimide, N,N&#39;-dicyclohexylcarbodiimide), carbonyl compound (e.g., carbonyldiimidazole), isoxazolinium salt, acylamino compound (e.g., 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), halide (e.g., cyanuric chloride, diphenylphosphoryl chloride, methanesulfonyl chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride, tripyridiniumtriazine trihalide), or the like]. This reaction may preferably be carried out in an aprotic solvent using carboxylic acid (III) (1 to 2 molar equivalents) and a condensing reagent (1 to 2 molar equivalents) per amine (II). 
     The reactive derivative includes acid anhydride {for example, symmetric anhydride, mixed anhydride [with a mineral acid (e.g., phosphoric acid, sulfuric acid, carbonic half ester), organic acid (e.g., lower alkanoic acid, aralkanoic acid, lower alkyl- or aryl-sulfonic acid)], intramolecular acid anhydride (e.g., ketene, isocyanate), acid halide (i.e., mixed anhydride of the acid with hydrogen halide)}, reactive ester [enol ester (e.g., vinyl ester, isopropenyl ester), aryl ester (e.g., phenyl ester, halophenyl ester, nitrophenyl ester), heterocyclic ester (e.g., pyridyl ester, 1-hydroxybenzotriazolyl ester), ester with N-hydroxy compound, ester with diacylhydroxylamine (e.g., N-hydroxysuccinimidoyl ester, N-hydroxyphthalimidoyl ester), thiol ester (e.g., aralkylthiol ester, heterocyclic thiol ester), or the like], reactive amide [e.g., aromatic amide (e.g., amide with imidazole, triazole, 2-ethoxy-1-ethyl-1,2-dihydroquinoline), diacylanilide], and the like. The acid scavenger to be used with the said reactive derivatives include an inorganic base (e.g., oxide, hydroxide, carbonate, hydrogen carbonate, or the like of alkali metal, alkaline earth metal), organic base (e.g., tert-amine, aromatic base), oxirane (e.g., alkylene oxide, aralkylene oxide), adsorbent (e.g., Celite), or the like. This reaction may preferably be carried out in an aprotic solvent using a reactive derivative of carboxylic acid (II) (1 to 2 molar equivalents) and an acid scavenger (0 to 2 molar equivalents) per amine (II). Acid halide and enzymatically reactive ester can be used in an aqueous solvent. 
     (2) Alkylcarbamic ester formation 
     A 3-hydroxymethyl compound (II) (i.e., 7β-[2-(2-aminothiazol-4-yl)-2-alkenamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid) or its derivative is conventionally esterified with an alkylcarbamoylating reagent of the formula R 2  NHCO-Hal or R 2  NCO (wherein R 2  is as defined in claim 1 and Hal is halogen) to afford compound (I). ##STR4## 
     Here, the alkylcarbamoylating reagent can be a conventional alkylcarbamoylating reagent (e.g., alkyl isocyanate, alkylcarbamoyl halide). The reagent can be used conventionally, for example, in the presence of a subreagent [e.g., acid scavenger (e.g., aromatic base, tertiary amine), Lewis acid (e.g., aluminum chloride, bis(alkylstannyl)oxide), or the like]. This reaction is usually carried out in a solvent at 0° C. to 50° C. for 30 minutes to 10 hours to give the objective alkylcarbamic ester. 
     (3) Esterification 
     A compound (I) having hydrogen as R 3  can be esterified conventionally in an inert solvent to give an ester compound (I), for example, by a method as given below: 
     (a) A reaction of the halide, sulfonate, or the like of the ester group with an alkali metal salt of the carboxylic acid at -50° C. to 50° C.; 
     (b) A reaction of the alcohol of the ester group with the carboxylic acid or its reactive derivative in the presence of a condensing reagent; or 
     (c) A reaction of a diazo compound of the ester group with the carboxylic acid at 0° C. to 50° C. 
     Especially important esterification is that comprises treating 7β-[2-(2-amino-thiazol-4-yl)-2-alkenamido]-3-alkylcarbamoyloxymethyl-3-cephem-4-carboxylic acid represented by the following formula: ##STR5## or its salt with a halide of a pharmaceutically acceptable group represented by the formula R 3  --Hal (wherein R 3  is a pharmaceutically acceptable ester group and Hal is halogen) in the presence of an acid scavenger to afford the corresponding pharmaceutically acceptable ester (I). 
     (4) Amino- and/or Carboxy Deprotection 
     A compound (I) is usually produced through its amino- and/or carboxy-protected compound. So, on some stage to the objective compound, a deprotection is a requisite step in its production. One of the preferable processes is a deprotection of an amino- and/or carboxy-protected compound using acid, aqueous base, or Lewis acid in an inert solvent, as given below: 
     (4-a) Deprotection of Protected Carboxy 
     A compound (I) having protected carboxy can be deprotected conventionally in an inert solvent to give carboxylic acid (I). This deprotection includes, for example, the following procedures: 
     (a) A highly reactive ester, anhydride, etc., as a carboxy-protecting group can be deprotected by contacting it with acid, base, buffer solution, ion-exchange resin, or the like in an aqueous solvent. Some insufficiently reactive groups may be activated conventionally to deprotect easily (e.g., trichloroethyl ester with metal and acid; p-nitrobenzyl ester by hydrogenation, dithionate, or metal and acid; and phenacyl ester by irradiation); 
     (b) An aralkyl ester as a carboxy-protecting group can be deprotected by a conventional hydrogenation in the presence of a catalyst (e.g., palladium, platinum, nickel); 
     (c) A tert-alkyl ester, 2-alkenyl ester, aralkyl ester, sulfonylethyl ester, tert-alkoxycarbonylamido, aralkoxycarbonylamido, or the like as an amino- or carboxy-protecting group may be deprotected by treating, for example, with a mineral acid, Lewis acid, (e.g., aluminum chloride, tin tetrachloride, titanium tetrachloride), sulfonic acid (e.g., benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid), strong carboxylic acid (e.g., trifluoroacetic acid), or the like, if required in the presence of a cation scavenger (e.g., anisole, benzenethiol); 
     (d) A 2-alkenyl ester as a carboxy-protecting group can be deprotected by the action of triarylphosphine-palladium complex; 
     (e) A phenacyl ester, 2-alkenyl ester, hydroxyaralkyl ester, or the like as a carboxy-protecting group can be deprotected by the action of a base or nucleophilic reagent; or 
     (f) Other equivalent deprotection of a carboxy-protecting group. 
     (4-b) Deprotection of an Amino-Protecting Group 
     A compound (I) having an amino-protecting group can be deprotected conventionally in an inert solvent, for example, as given below: 
     (a) An alkoxycarbonyl group (e.g., tert-butoxycarbonyl) as an amino-protecting group can be deprotected with a strong acid (e.g., trifluoroacetic acid, trifluoromethanesulfonic acid), Lewis acid (e.g., aluminum chloride, tin tetrachloride, titanium tetrachloride, zinc chloride), or the like acid at -30° C. to 50° C., if required in the presence of a cation scavanger (e.g., anisole, benzenethiol); (b) An aralkoxycarbonyl (e.g., carbobenzoxy, methylcarbobenzoxy, diphenylmethoxycarbonyl) as an amino-protecting group can be removed by the action of hydrogen (e.g., catalytic hydrogenation using palladium, nickel, or the like catalyst) or the said Lewis acid and cation scavenger at 0° C. to 50° C.; (c) A lower alkanoyl (e.g., formyl, acetyl, chloroacetyl), Schiff base forming group (i.e., a divalent carbon function, e.g., ethylidene, propylidene, benzylidene, substituted benzylidene), aralkyl (e.g., trityl, substituted trityl), arylthio (e.g., phenylsulfenyl), tetrahydropyranyl, silyl or stannyl (e.g., trimethylsilyl, trimethylstannyl), or the like group as an amino-protecting group can be deprotected by the action of acid (e.g., hydrochloric acid, sulfuric acid, methanesulfonic acid) at -20° C. to 50° C.; or (d) Other specific method for some specific group (e.g., thiourea or N-alkylcarbamate for haloacetyl, hydrazine for dibasic acyl, phosphorus pentachloride and alkanol for amide). 
     (5) Salt Formation 
     A compound (I) having hydrogen as R 3  can form a salt compound (I) (wherein R 3  is a salt forming group) with a base or with a salt of weakly acidic carboxylic acid by an ion exchange reaction. The procedure can be that conventional in the art, e.g., by neutralizing the free acid with a base (e.g., light metal hydroxide, carbonate, or hydrogen carbonate) or by treating with light metal lower carboxylate (e.g., sodium acetate, sodium lactate, sodium 2-ethylhexanoate) in a polar organic solvent (e.g., alcohol, ketone, ester) and then adding a sparingly dissolving solvent to separate the salt. The reaction time is usually 1 to 10 minutes at lower than 50° C., but it may be longer if no appreciable side reaction occurs. 
     (6) Protection of Amino 
     The amino group in compound (I) can be protected at its amino in a conventional manner as given below: 
     (a) An alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, trialkylsilyl, or the like group as an amino-protecting group can be introduced by treating the amine with a halide or symmetric or asymmetric anhydride of the protecting group (1 to 5 equivalents) in the presence of an acid scavenger at -30° C. to 50° C.; (b) An alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, arylsulfenyl, aralkyl, trialkylsilyl, trialkylstannyl, or the like group as an amino-protecting group can be introduced by treating the amine with a halide of the group (1 to 5 molar equivalents) in the presence of an acid scavenger (1 to 10 molar equivalents) in a solvent at -30° C. to 100° C.; (c) A tetrahydropyranyl, tetrahydrofurayl, or the like group as an amino-protecting group can be introduced by reacting the amine with dihydropyran, dihydrofuran, etc., in a solvent; or (d) A trialkylsilyl group as an amino-protecting group can be introduced by treating the amine with disilazane, acetamide, or the like compound (e.g., hexamethyldisilazane, bistrimethylsilylacetamide). 
     (7) Oxidation to Sulfoxide 
     A compound (I) having a sulfide group in its molecule can be oxidized conventionally, for example, with the following oxidizing reagent to give the corresponding sulfoxide (I) (when the starting sulfide has a double bond at position 2, this migrates to position 3 in the sulfoxide product). (a) Peracid (e.g., industrially available permineral acid, percarboxylic acid, persulfonic acid); (b) Ozone; (c) Hydrogen peroxide; or (d) Peroxide (e.g., boron peroxide, nickel peroxide, sodium peroxide, urea peroxide). 
     Thus, compound (I) having sulfur as X is treated with an oxidizing reagent (e.g., hydrogen peroxide, percarboxylic acid, inorganic percid) in an inert solvent (e.g., halogenohydrocarbon, ester, water) to give the corresponding sulfoxide (I). Preferably the starting compound (I) is oxidized with the oxidizing reagent (1 to 2 molar equivalents) at -10° C. to 50° C. to give the sulfoxide. The reaction can be carried out, if required, in the presence of a catalyst (e.g., alkanoic acid, phosphoric acid, phosphoric ester, a salt of acid of the VIIth group atom in the periodical table). 
     (8 ) Reduction of Sulfoxide 
     Compound (I) having sulfinyl in the molecule can be reduced conventionally to give the corresponding sulfide (I). 
     Thus, compound (I) having sulfinyl as X is treated with 2 to 5 molar equivalents of a reducing reagent (e.g., trivalent phosphorus compound, stannous compound, hydrogen iodide) in an inert solvent (e.g., dimethylformamide, dichloromethane, dioxane) at -20° to 50° C. to give the corresponding sulfide (I). 
     (9) Reaction Conditions 
     The said syntheses (1) to (8) are usually carried out at -70° C. to 100° C., especially -30° C. to 50° C., for 10 minutes to 30 hours. Preferably, these are carried out under dry condition in a solvent. Other conventional conditions are applicable. 
     The reaction solvent can be a hydrocarbon (e.g., pentane, hexane, octane, benzene, toluene, xylene), halogenohydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene), ether (e.g., diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran), ketone (e.g., acetone, methyl ethyl ketone, cyclohexanone), ester (e.g., ethyl acetate, isobutyl acetate, methyl benzoate), amide (e.g., formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide), carboxylic acid (e.g., formic acid, acetic acid, propionic acid), organic base (e.g., diethylamine, triethylamine, pyridine, picoline, collidine, quinoline), alcohol (e.g., methanol, ethanol, propanol, hexanol, octanol, benzyl alcohol), water, or the like industrial solvent or a mixture. 
     (10) Work Up 
     The objective products can be recovered from the reaction mixture after removing contaminants (e.g., unreacted starting material, by-products, solvents) by a conventional method (e.g., extracting, evaporating, washing, concentrating, precipitating, filtrating, drying) and isolated by a usual work up (e.g., adsorbing, eluting, distilling, precipitating, separating, chromatographying). 
     Among the geometric isomers in relation to the trisubstituted double bond in the side chain at position 7, that having thiazole ring and hydrogen in the cis position is more useful than that having them in the trans position in antibacterial potency. 
    
    
     (11) EXAMPLES 
     Following examples illustrate the embodiment of the invention. The physical constants of the products are listed in the tables. In the tables, IR shows wave numbers in cm -1  scale and NMR shows δ values (chemical shift) in ppm scale and J values (coupling constant) in Hz scale. 
     In the examples, the amount shown by part is the weight of the substance per 1 weight of the betalactam starting material. The equivalent is the molar number of the substance per 1 mole of the starting betalactam. 
     The work up procedure in the examples is usually carried out conventionally as follows: The reaction mixture is diluted with water, acid, dichloromethane, or the like. When the product is neutral, the organic layer is taken, washed with water, dried, and concentrated under reduced pressure to give residual mass. The mass is, if required after purifying by silica gel chromatography, crystallized, precipitated or filtrated to afford the product. The physical contants of the products are listed on the tables after Examples. All are the cis isomer in relation to the double bond in the side chain at position 7 unless otherwise specified. 
     
         ______________________________________                                    
[Abbreviations]                                                           
______________________________________                                    
AOE = 1-(acetoxy)ethyl                                                    
                   AOM = acetoxymethyl                                    
BCE = 1-(tert-butoxycarbonyloxy)ethyl                                     
BH = diphenylmethyl                                                       
                   BOC = tert-butoxycarbonyl                              
Bu = butyl                                                                
DOL = (4-methyl-2-oxo-1,3-dioxol-5-yl)methyl                              
ECE = 1-(ethoxycarbonyloxy)ethyl                                          
Et = ethyl                                                                
HCE = 1-(cyclohexyloxycarbonyloxy)ethyl                                   
HOH = 1-(cyclohexylcarbonyloxy)-1-cyclohexylmethyl                        
HmCP = 1-(cyclohexylmethoxycarbonyloxy)propyl                             
ICE = 1-(isopropoxycarbonyloxy)ethyl                                      
ICP = 1-(isopropoxycarbonyloxy)propyl                                     
Me = methyl                                                               
POE = 1-(pivaloyloxy)ethyl                                                
POM = pivaloyloxymethyl                                                   
PeCP = 1-(isopentyloxycarbonyloxy)propyl                                  
Ph = phenyl        Pr = propyl                                            
SO = 1-oxide                                                              
Chf = chloroform   DCM = dichloromethane                                  
THF = tetrahydrofuran                                                     
                   DMA = N--dimethyl-                                     
DMF = N,N--dimethylformamide                                              
                   acetamide                                              
S.M. = starting material                                                  
                   Exp. No. = Example No.                                 
TFA = trifluoroacetic acid                                                
                   m-CPBA = m-chloro-                                     
Y1d. = yield       perbenzoic acid                                        
nd = not determned Temp = temperature                                     
                   hr = hour                                              
                   rt = room temperature                                  
______________________________________                                    
 
    
     EXAMPLE 1 
     (Amidation) 
     A 7β-amino compound (2) (1 equivalent) is treated with a carboxylic acid (3) corresponding to the 7β-side chain or its reactive derivative to give amide (1), for example, by a conventional method as exemplified below: ##STR6## 
     (1) In a mixture of carbon tetrachloride (30 parts), N-methylmorpholine (1.5 equivalents), trisdiethylaminophosphine (1.1 equivalents), and carboxylic acid (3) (1.1 equivalents), kept at -20° C. to 10° C. for 1 to 5 hours. 
     (2) In a mixture of dichloromethane (5 to 30 parts), trifluoroacetic acid anhydride (1.5 equivalents), pyridine (3 equivalents), and carboxylic acid (3) (1.5 equivalents), stirred at 0° C. to room temperature for 1 to 5 hours. 
     (3) In a mixture of dichloromethane (10 to 30 parts), diphenylphosphoryl chloride (1.2 equivalents), N-methylmorpholine (2.5 equivalents), and carboxylic acid (3) (1.2 equivalents), stirred at -50° to 0° C. for 1 to 3 hours. 
     (4) In a mixture of dichloromethane (10 to 50 parts), cyanuric chloride (1.1 equivalents), pyridine (4 equivalents), and carboxylic acid (3) (1.1 equivalents), stirred at -30° C. to 10° C. for 5 minutes to 2 hours. 
     (5) In a mixture of dichloromethane (3 to 30 parts), phosphorus oxy-chloride (1.1 equivalents), triethylamine (1.5 equivalents), and carboxylic acid (3) (1.1 equivalents), stirred at -10° C. to 10° C. for 20 minutes to 2 hours. 
     (6) Amine (2) is treated with trimethylsilyl chloride and an acid scavenger to obtain the corresponding N-trimethylsilylamino compound and this is treated with phosphorus oxychloride (1.5 equivalents), carboxylic acid (3) (1.2 equivalents), and dimethylaniline (4equivalents) in dichloromethane (5 to 30 parts) at 0° C. to room temperature for 30 minutes to 2 hours. 
     (7) In a mixture of dichloromethane (5 to 30 parts), thionyl chloride (1.5 equivalents), pyridine (2.5 equivalents), and carboxylic acid (3) (1.1 equivalents), stirred at -30° C. to 0° C. for 1 to 5 hours. 
     (8) In a mixture of chloroform (3 to 30 parts), toluene (1 part), carboxylic acid (3) (1.1 equivalents), picoline (2 equivalents), and oxalyl chloride (1 equivalents), stirred at -50° C. to 10° C. for 10 minutes to 2 hours. 
     (9) In a mixture of dichloromethane (20 to 50 parts), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (2.1 equivalents), N,N&#39;-dicyclo-hexylcarbodiimide (2.5 equivalents), and carboxylic acid (3) (2 equivalents), stirred at room temperature for 1 to 15 hours. 
     (10) In a mixture of dichloromethane (3 to 20 parts), carboxylic acid (3) (1.1 equivalents), 1,3,5-tripyridiniumtriazine trichloride (4 equivalents), stirred at -10° C. to 10° C. for 1 to 5 hours. 
     (11) In a mixture of carbonyldiimidazole (1.1 equivalents), tetrahydrofuran (5 to 50 parts), dimethylacetamide (5 parts), and carboxylic acid (3) (1.1 equivalents), stirred at 0° C. to room temperature for 1 to 5 hours. 
     (12) In a mixture of dimethylformamide (5 to 30 parts), dimethylaniline (1.3 equivalents), carboxylic acid (3), and the Vilsmeyer reagent made from dimethylformamide (1.1 equivalents), stirred at room temperature for 1 to 5 hours. 
     (13) In a mixture of dichloromethane (10 to 50 parts), dimethylformamide (5 parts), N,N&#39;-dicyclohexylcarbodiimide (1.1 equivalents), picoline (1.2 equivalents), and carboxylic acid (3) (1.1 equivalents), heated under reflux for 2 to 24 hours. 
     (14) To a solution of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid (1.49 g) in dichloromethane (60 ml) are added triethylamine (0.83 ml) and methanesulfonyl chloride (0.4 ml) at -65° C., and the mixture is stirred for 3 hours at -65° C. To the mixture is added diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.26 g) and N-methylmorpholine (0.55 ml) in dichloromethane (60 ml). After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed with water, dried, and concentrated to give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (3.12 g). Yield: 85%. 
     (15 ) To a mixture of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoic acid (1.56 g), diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g), and N-methylmorpholine (2.0 ml) in dichloromethane (50 ml) is added diphenylphosphoryl chloride (1.27 g) at -30° C. After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed, dried, and purified by chromatography give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g). Yield: 73%. 
     (16) In a mixture of ethyl acetate (8 to 30 parts), 1,2-dichloroethane (10 parts), N-methylmorpholine (1.5 equivalents), and the symmetric anhydride of carboxylic acid (3) (1.1 equivalents), heated under reflux for 10 minutes to 2 hours. 
     (17) In a mixture of chloroform (10 to 30 parts) and dimethoxyethane (10 parts), triethylamine (1.5 equivalents), and the mixed anhydride (2 equivalents) of carboxylic acid (3) and isobutoxyformic acid (1.5 equivalents), stirred at -5° C. to 10° C. for 30 minutes to 6 hours. 
     (18) In a mixture of dichloromethane (10 to 30 parts), pyridine (1.5 equivalents), and mixed anhydride of carboxylic acid (3) and methanesulfonic acd (1.1 equivalents), stirred under warming from -70° C. to room temperature for 1 to 3 hours. Yield: 90 to 95%. 
     (19) In a mixture of ethyl acetate (10 to 30 parts), pyridine (1.5 equivalents), and the mixed anhydride of carboxylic acid (3) and diethyl hydrogen phosphate (1.5 equivalents), stirred at 0° C. to 10° C. for 1 to 5 hours. 
     (20) In a mixture of ethyl acetate (10 to 30 parts), dichloromethane (10 to 30 parts), N-methylmorpholine (1 equivalent), and mixed anhydride of carboxylic acid (3) and dichlorophosphoric acid (1.1 equivalents), stirred at 0° C. to room temperature for 1 to 3 hours. 
     (21) In a mixtur of lutidine (1.5 equivalents), dichloromethane (10 to 30 parts), and the mixed anhydride of carboxylic acid (3) and monochlorophosphoric acid dimethylamide (1.1 to 2 equivalents), stirred at 0° C. to 30° C. for 1 to 4 hours. 
     (22) Amine (2) having carboxy at position 4 of the cephem ring is dissolved in water (10 to 30 parts) containing sodium hydrogen carbonate (2.5 equivalents). Carboxylic acid (3) chloride (1.1 equivalents) is dropwise added thereto. The mixture is kept at -5° C. to room temperature for 30 minutes to 2 hours. 
     (23) Amine (2) having carboxy at position 4 of the cephem ring is treated with trimethylsilyl chloride and triethylamine (1.2 equivalents each) in dichloromethane (10 to 30 parts), and then treated with pyridine (4 equivalents) and carboxylic acid (3) chloride (1.1 equivalents) at -30° C. for 30 minutes to 2 hours, and then the resulting silyl ester is hydrolyzed with acid. 
     (24) In a solution of picoline (4 equivalents) and carboxylic acid (3) chloride (1.2 equivalents) in dichloromethane (5 to 30 parts), stirred at -30° C. to 0° C. for 30 minutes to 2 hours. 
     (25) In a mixture of dimethylformamide (2 parts), ethyl acetate (10 to 30 parts), triethylamine (1.1 equivalents), and carboxylic acid (3) chloride (1.1 equivalents), stirred at 0° C. to 20° C. for 30 minutes to 3 hours. 
     (26) In a mixture of dichloromethane (20 to 50 parts), pyridine (3 equivalents), and benzotriazol-1-yl ester of carboxylic acid (3) (3 equivalents), stirred at 10° C. to 50° C. for 5 to 30 hours. 
     (27) In a mixture of dioxane (10 parts) and phthalimidoyl ester of carboxylic acid (3) (2 equivalents), stirred at 10° C. to 50° C. for 2 to 8 hours. 
     (28) In a mixture of methyl isobutyl ketone (10 to 30 parts) and succinimidoyl ester of carboxylic acid (3) (1.5 equivalents), stirred at 0° C. to 40° C. for 2 to 9 hours. 
     (29) In a manner similar to above, amides (I) on Tables 1 to 5 are prepared. 
     EXAMPLE 2 
     (Sodium Salt) 
     (1) To a solution of a carboxylic acid on Table 2 in acetone (10 to 30 parts) is added a solution of sodium ethylhexanoate (1 to 2 equivalents) in isobutanol. The mixture is diluted with ethyl acetate and ether. The separating crystals are collected by filtration to give the corresponding sodium salt. 
     (2) Similarly, to a suspension of a carboxylic acid on Table 3 (1  g) in water is added aqueous sodium carbonate to make a solution of pH 6.5. This is desalted, and poured into a 10 ml vial, and lyophylized to give a sodium salt preparation as above. 
     (3) The sodium salt (1 g) prepared under sterile condition is dissolved in sterile water (4 g) and given twice a day orally or intravenously to a patient suffering from Staphylococcus aureus infection for treating this disease. The minimal inhibitory concentration of this sodium salt determined by the standard method of Japan Society of Chemotherapy is 0.4 to 0.8 μg/ml against Staphylococcus aureus JC-1, 0.006 to 0.0125 μg/ml against Streptococcus pyogenes C-203, and 0.1 to 0.4 μg/ml against Escherichia coli H. 
     (4) In a manner similar to above, sodium salts (I) on Table 2 are prepared. 
     EXAMPLE 3 
     (Deprotection of Protected Carboxy) 
     (1) A solution of the corresponding diphenylmethyl ester in a mixture of dichloromethane (0 to 30 parts), trifluoroacetic acid (1 to 9 parts), and anisole (0.5 to 10 parts) is stirred under ice water cooling or at room temperature for 0.5 minutes to 5 hours. The solution is concentrated to remove the solvent and reagent. The residue is washed with a mixture of ether and hexane to give a carboxylic acid on Table 2 and 3 in 70 to 90% yield. When the starting material has tert-butoxycarbonylamido, this can also be removed to give the corresponding trifluoroacetate of the amino. 
     (2) To a solution of the corresponding diphenylmethyl ester in a mixture of dichloromethane (5 to 30 parts) and anisole (2 to 20 parts) is added aluminum chloride, tin tetrachloride, or titanium tetrachloride (3 to 12 equivalents) at -10° C. to 10° C., and the mixture is stirred at -10° C. to 40° C. for 1 to 24 hours. The mixture is washed with diluted hydrochloric acid and water, dried and concentrated to give a carboxylic acid on Table 3 in 80 to 90% yield. A tert-butoxycarbonylamino when present, is deprotected to give amino simultaneously. 
     (3) To a solution of the corresponding diphenylmethyl ester in anisole (2 to 10 parts) are added 90% formic acid (5 to 6 parts). The mixture is stirred at 50° C. to 60° C. for 1 to 4 hours to give a carboxylic acid on Table 2 in 40 to 50% yield. 
     EXAMPLE 4 
     (Esterification) 
     (1) (Acetoxymethyl ester) To a solution of the corresponding carboxylic acid potassium salt in N,N-dimethylformamide (2 to 10 parts) is added dropwise bromomethyl acetate (1 to 2 equivalents) at -10° C. to 20° C. After stirring for 15 minutes to 2 hours, the mixture is diluted with ethyl acetate, washed with ice water and aqueous sodium hydrogen carbonate, dried, and concentrated. The residue is crystallized from ethyl acetate to give an acetoxymethyl ester on Table 4. Yield: 60 to 70%. 
     (2) (1-Acetoxyethyl ester) To a solution of the corresponding carboxylic acid in N,N-dimethylformamide (2 to 10 parts) are added potassium carbonate (1 to 2 equivalents) and potassium fluoride (1 to 2 equivalents) at -15° C., and the mixture is stirred for 10 minutes. To the mixture is added dropwise bromoethyl acetate (3 equivalents) and the mixture is stirred at -15° to 0° C. for 1 to 2 hours. The reaction mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give a 1-acetoxyethyl ester on Table 4. Yield: 40 to 70%. 
     (3) (Pivaloyloxymethyl ester) To a solution of the corresponding carboxylic acid potassium salt in N,N-dimethylformamide (2 to 10 parts) is added dropwise iodomethyl pivalate (1 to 2 equivalents) at -40° C. to 30° C. After stirring for 15 minutes to 4 hours, the mixture is diluted with ethyl acetate, washed with ice water and aqueous sodium hydrogen carbonate, dried, and concentrated under reduced pressure. The residue is purified by column chromatography to give a pivaloyloxymethyl ester on Table 4. Yield: 60 to 85%. 
     (4) (1-Pivaloyloxyethyl ester) To a solution of the corresponding carboxylic acid in N,N-dimethylformamide (5 to 10 parts) are added potassium carbonate (1 to 2 equivalents) at -30° C., and the mixture is stirred for 10 minutes. To the mixture is added dropwise 1-iodoethyl pivalate (1 to 3 equivalents) and the mixture is stirred at -15° to 0° C. for 1 to 2 hours. The reaction mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by chromatography over silica gel to give a 1-(pivaloyloxy)ethyl ester on Table 4. Yield: 40 to 70%. 
     (5) (1-Ethoxycarbonyloxyethyl ester) To a solution of the corresponding carboxylic acid sodium salt in N,N-dimethylformamide (5 to 10 parts) is added dropwise 1-iodoethyl ethoxyformate (1 to 2 equivalents) at 0° C. After stirring at -15° C. to 0° C. for 1 to 2 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by chromatography over silica gel to give a 1-(ethoxycarbonyloxy)-ethyl ester in Table 4. Yield: 30 to 50%. 
     (6) (4-methyl-2-oxo-1,3-dioxol-5-ylmethyl ester) To a solution of the corresponding carboxylic acid sodium salt in N,N-dimethylformamide (5 to 10 parts) is added dropwise 5-bromomethyl-4-methyl-1,3-dioxol-2-one (1 to 2 equivalents). After stirring at -5° C. to 5° C. for 1 to 3 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by chromatography over silica gel to give a 4-methyl-2-oxo-1,3-dioxol-5-ylmethyl ester on Table 4. Yield: 40 to 60%. 
     (7) In a manner similar to above, other pharmacologically acceptable esters (I) on Table 4 {i.e., 1-(cyclohexylcarbonyloxy)-1-cyclohexylmethyl ester, 1-(cyclohexylmethoxycarbonyloxy)propyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, 1-(isopentenyloxycarbonyloxy)propyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)propyl ester, and 1-(tert-butoxycarbonyloxy)ethyl ester} are prepared from the corresponding carboxylic acid using the same molar ratio of halide of the ester group. 
     (8) An amino-unprotected pharmacologically acceptable ester (100 mg), corn starch (150 mg), and magnesium stearate (5 mg) are granulated conventionally and filled in a capsule. This capsule (1 or 2 capsules, 2 to 3 times per day) is administered orally to treat an infection caused by Staphylococcus aureus. 
     (9) (Diphenylmethyl ester) To a solution of the corresponding carboxylic acid in a mixture of dichloromethane (10 parts) and methanol (10 parts) is added diphenyldiazomethane (1.2 equivalents). After stirring at room temperature for 1 hour, the mixture is washed with diluted hydrochloric acid and water, dried, and concentrated under reduced pressure. The residue is a diphenylmethyl ester on Table 1. 
     EXAMPLE 5 
     (Alkylcarbamoyl Ester Formation) ##STR7## 
     To a solution of the corresponding 3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (2) in tetrahydrofuran (5 to 20 parts) are added alkyl isocyanate (3 to 10 equivalents) and pyridine (1 to 7 equivalents) or di-(tri-n-butylstannyl) oxide (0.05 to 1 equivalent) and the mixture is stirred for 1 to 5 hours. The reaction mixture is diluted with aqueous 5% sodium hydrogen carbonate and separating aqueous layer is taken. This is acidified to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The residue is purified by column chromatography over silica gel to give a 3-N-alkylcarbamoyloxymethyl compound (1) on Table 2. Yield: 50 to 80%. 
     The produced acid may be dissolved by adding aqueous sodium hydrogen carbonate (1 equivalent) and lyophilized to give the corresponding sodium salt. 
     EXAMPLE 6 
     (Deprotection of Protected Amino) 
     (1) To a solution of the corresponding tert-butoxycarbonylamino compound in dichloromethane (0 to 20 parts) are added trifluoroacetic acid (0.3 to 20 parts) and anisole (0.5 to 10 parts), and the mixture is stirred at -10° C. to 40° C. for 10 minutes to 3 hours. The mixture is concentrated to remove the solvent and reagent and the resulting residue is washed with benzene or ether to give an amino compound on Table 3 or 5. Yield: 70 to 80%. 
     (2) To a solution of the corresponding tert-butoxycarbonylamino compound in dichloromethane (5 to 9 parts) are added anisole (2 to 8 parts) and aluminum chloride, titanium tetrachloride, or tin tetrachloride (3 to 12 equivalents), and the mixture is stirred at -10° C. to 10° C. for 1 to 24 hours. The mixture is extracted with hydrochloric acid. The extract is passed through a column of adsorbent, and concentrated to give an amino compound in Table 3 or 5. Yield: 60 to 80%. 
     EXAMPLE 7 
     (Reduction of Sulfoxide) 
     To a solution of the corresponding sulfoxide in dichloromethane (5 to 50 parts) is added phosphorus tribromide (1 to 3 equivalents) at -40° C. to -10° C. and the mixture is stirred for 30 minutes to 5 hours. The reaction mixture is diluted with dichloromethane, washed with aqueous sodium hydrogen carbonate and water, dried, and concentrated to give a sulfide. 
     EXAMPLE 8 
     (Sulfoxide Introduction) 
     To a solution of the corresponding sulfide in chloroform (10 to 20 parts) is added m-chloroperbenzoic acid (1 equivalent), and the mixture is stirred for 20 to 90 minutes. The reaction mixture is washed with aqueous sodium hydrogen carbonate, dired, and concentrated under reduced pressure to give a sulfoxide on Table 4. Yield: 60 to 80%. 
     PREPARATION 1 
     (1) To a solution of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-hexenoic acid (2.064 g) in dichloromethane (30 ml) are added triethylamine (1.02 ml) and methanesulfonyl chloride (0.56 ml) at -65° C., and the mixture is stirred for 3 hours at -65° C. The reaction mixture is mixed with 7β-aminocephalosporanic acid (2.35 g), triethylamine (2.4 ml), and dichloromethane (40 ml), and stirred at -70° C. to -5° C. for 2 hours. The reaction mixture is acidified with 10% hydrochloric acid, washed with water, dried, and concentrated to give 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-hexanoylamino]cephalosporanic acid (3.58 g). Yield: 95.5%. 
     (2) To a solution of 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-hexenoylamino]cephalosporanic acid (3.58 g) in methanol (35 ml) is added dropwise aqueous 1N-sodium hydroxide (16 ml) at -30° C., and the mixture is stirred at -30° C. to -20° C. for 1 hour. The reaction mixture is acidified with 1N-hydrochloric acid (16 ml) and the separated crystals are collected to give 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-hexenoylamino]-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (2.67 g). Yield: 77.2%. 
     IR (Nujol)ν: 3220, 1755, 1725, 1660, 1605, 1550. 
     NMR (CDCl 3  --CD 3  OD)δ: 0.95(t, J=8 Hz, 3H), 1.55 (s, 9H), 1.55(q, J=8 Hz, 2H), 2.35(brq, J=8 Hz, 2H), 3.52(brs, 2H), 3.82(brs, 2H), 5.03(d, J=5 Hz, 1H), 5.79(d, J=5 Hz, 1H), 6.44(t, J=8 Hz, 1H), 6.79 (s, 1H). 
     PREPARATION 2 
     (1) To a solution of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoic acid (4.48 g) in dichloromethane (60 ml) are added triethylamine (2.2 ml) and methanesulfonyl chloride (1.23 ml) at -65° C., and the mixture is stirred for 3 hours. The reaction mixture is mixed with 7β-aminocephalosporanic acid (5.1 g), triethylamine (5.2 ml), and dichloromethane (100 ml) and stirred at -70° C. to -5° C. for 2 hours. The reaction mixture is acidified with 10% hydrochloric acid, washed with water, dried, and concentrated to give 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]cephalosporanic acid (5.12 g). Yield: 62.9%. 
     IR (Nujol)ν: 3400, 1780, 1720, 1670, 1600. 
     NMR (CDCl 3  --CD 3  OD)δ: 1.05(d, J=7 Hz, 6H), 1.52 (s, 9H), 2.04(s, 3H), 2.73˜3.13(m, 1H), 3.4(m, 2H), 4.91, 5.13(ABq, J=13 Hz, 2H), 5.09(d, J=5 Hz, 1H), 5.86(d, J=5 Hz, 1H), 6.22(d, J=10 Hz, 1H), 6.78 (s, 1H). 
     (2) To a solution of 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]cephalosporanic acid (5.12 g) in methanol (50 ml) is added dropwise aqueous 1N-sodium hydroxide (22.6 ml) at -30° C., and the mixture is stirred at -30° C. to -20° C. for 1 hour. The reaction mixture is acidified with 1N-hydrochloric acid (22.6 ml) and the separating crystals are collected to give 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (2.67 g). Yield: 77.2%. 
     IR (Nujol)ν: 3250, 1755, 1725, 1660, 1600. 
     NMR (CDCl 3  --CD 3  OD)δ: 1.06(d, J=7 Hz,, 6H), 1.53 (s, 9H), 2.5˜3.1(m, 1H), 3.4(m, 2H), 3.81(s, 2H), 5.02(d, J=5 Hz, 1H), 5.77(d, J=5 Hz, 1H), 6.22(d, J=10 Hz, 1H), 6.80(s, 1H). 
     
                                           TABLE 1                                 
__________________________________________________________________________
PHYSICAL CONSTANTS OF THE PRODUCTS                                        
 ##STR8##                                                                 
Protected Compound                                                        
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
               IR(CHCl.sub.3)ν:cm.sup.-1                               
                         NMR(CDCl.sub.3) δ :ppm                     
                                                    Ex.                   
__________________________________________________________________________
                                                    No.                   
1  BOC                                                                    
      Me Me BH nd        1.51(s, 9H), 2.08(d, J=7Hz, 3H), 2.67(d, J=4Hz,  
                         3H),                       (4-9)                 
                         3.23(brs, 2H), 4.77, 5.06(ABq, J=14Hz, 2H),      
                         4.9(m,                                           
                         1H), 4.94(d, J=4Hz, 1H), 5.73(dd, J=4Hz, J=9Hz,  
                         1H),                                             
                         6.50(q, J=7Hz, 1H), 6.62(s, 1H), 6.80(s, 1H),    
                         7.1˜7.5 (m, 10H), 8.03(d, J=9Hz, 1H).      
2  BOC                                                                    
      Me Me BH 1772, 1718, 1662,                                          
                         1.53(s, 9H), 1.91(d, J=7.5Hz, 3H), 2.68(d,       
                         J=5.0Hz,                   (4-9)                 
               1146.     3H), 3.15 (s, 2H), 4.82(d, J=4.5Hz, 1H), 4.76,   
   trans                 5.02(ABq, J= 14.4Hz, 2H), 5.56(dd, J=4.5Hz,      
                         J=8.0Hz,                                         
                         1H), 6.51(s,1H), 6.72(s, 1H), 7.21˜7.40(m, 
                         12H),                                            
                         7.97(d, J=8.0Hz, 1H).                            
3  BOC                                                                    
      Et Me BH 3450, 3400, 2950,                                          
                         1.10(t, J=8Hz, 3H), 1.52(s, 9H), 2.56(quintet,   
                         J=8                        (4-9)                 
               1775, 1715, 1665,                                          
                         Hz, 2H), 2.70(d, J=5Hz, 3H), 3.25 (brs, 2H),     
                         4.80,                      (1-14)                
               1150.     5.06 (ABq, J=14Hz, 2H), 4.98(d, J=5Hz, 1H), 5.75 
                         (dd, J=5Hz, J=9Hz, 1H), 6.42(t, J=(Hz, 1H),      
                         6.70(s,                                          
                         1H, 6.85(s, 1H), 7.30˜7.40(m, 10H),        
                         7.86(d, J=9Hz,                                   
                         1H), 9.60(brs,1H).                               
4  BOC                                                                    
      Et Et BH nd        1.07(t, J=8Hz, 3H), 1.10(t, J=8Hz, 3H), 1.52(s,  
                         9H),                       (4-9)                 
                         2.54 (quintet, J=8Hz, 2H), 3.12(quintet, J=8Hz,  
                         2H),                                             
                         3.22(brs, 2H), 4.80(brs, 1H), 4.78, 5.01(ABq,    
                         J= 14Hz, 2H), 4.95(d, J=5 Hz, 1H), 5.70(dd,      
                         J=5Hz,                                           
                         J=8Hz, 1H), 6.40(t, J=8Hz, 1H), 6.68 (s, 1H),    
                         6.82(s, 1H), 7.20˜7.42 (m, 10H), 7.84(d,   
                         J=8Hz, 1H).                                      
5  BOC                                                                    
      n-Pr                                                                
         Me BH 3450, 3400, 1785,                                          
                         0.97(t, J=7Hz, 3H), 1.51(brq, J=7Hz, 2H),        
                         1.53(s,                    (4-9)                 
               1725, 1670.                                                
                         9H), 2.53(q, J=7Hz, 2H), 2.68(d, J=5Hz, 3H),     
                         3.23(brs, 2H), 4.79, 5.04(ABq, J=13Hz, 2H),      
                         4.97(d,                                          
                         J=5Hz, 1H), 5.71(dd, J=5Hz, J=8Hz, 1H), 6.42(t,  
                         J=7Hz, 1H), 6.67(s, 1H), 6.83(s, 1H), 7.33(m,    
                         10H),                                            
                         7.89(d, J=8Hz, 1H).                              
6  BOC                                                                    
      i-Pr                                                                
         Me BH 3450, 3400, 1780,                                          
                         1.08(d, J=7Hz, 6H), 1.52(s, 9H), 2.65(d, J=5Hz,  
                         3H),                       (1-15)                
               1720, 1670.                                                
                         2.9˜3.4 (m, 1H), 3.21(brs, 2H), 4.78,      
                         5.00(ABq,,                 (4-9)                 
                         J=14 Hz, 2H), 4.96(d, J=5Hz, 1H), 5.71(dd,       
                         J=5Hz,                                           
                         J=8Hz, 1H), 6.22(d, J=10Hz, 1H), 6.71(s, 1H),    
                         6.84(s, 1H), 7.3(m, 10H), 7.70(d, J=8Hz,         
__________________________________________________________________________
                         1H).                                             
 
    
     
                                           TABLE 2                                 
__________________________________________________________________________
N--Protected carboxy compound and its salts                               
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
              IR(CHCl.sub.3)ν: cm.sup.-1                               
                        NMR(CDCl.sub.3) δ: ppm                      
                                                   Ex. No.                
__________________________________________________________________________
(Part 1)                                                                  
1  BOC                                                                    
      Me Me H nd        1.54(s, 9H), 1.98(d, J=7Hz, 3H), 2.72(s, 3H),     
                        3.45,                      (3-1)                  
                        3.66(ABq, J=18Hz, 2H), 4.92, 5.11(ABq, J=12Hz,    
                        2H),                       (5-1)                  
                        5.03(d, J=4Hz, 1H), 5.83(d, J=4Hz, 1H), 6.50(q,   
                        J=7Hz, 1H), 6.81(s, 1H). [CDCl.sub.3 --CD.sub.3   
                        OD]                                               
2  BOC                                                                    
      Me Me Na                                                            
              nd        2.29(d, J=7.5Hz, 3H), 3.12(s, 3H),                
                        3.56˜4.12(m, 2H),    (2-1)                  
   trans                4.23(s, 2H), 5.52(d, J=4.5Hz, 1H), 6.12(d,        
                        J=4.5Hz,                   (5-1)                  
                        1H), 7.41(s, 1H), 7.45(q, J=7.5Hz, 1H).[D.sub.2   
                        O/TMS                                             
                        external standard]                                
3  BOC                                                                    
      Et Me H 3450, 3400, 1780,                                           
                        1.08(t, J=8Hz, 3H), 1.54(s, 9H), 2.42(quintet,    
                        J=8                        (5-1)                  
              1720, 1670, 1540,                                           
                        Hz, 2H), 2.74(s, 3H), 3.40, 3.57(ABq, J=18Hz,     
                        2H),                                              
              1365, 1150.                                                 
                        4.85, 5.07(ABq, J=13Hz, 2H), 5.05(d, J=5Hz, 1H),  
                        5.83(d, J=5Hz, 1H), 6.40(t, J=8Hz, 1H), 6.76(s,   
                        1H).                                              
                        [CDCl.sub.3 --CD.sub.3 OD]                        
4  BOC                                                                    
      Et Me Na                                                            
              3400, 1760, 1710,                                           
                        1.08(t, J=7Hz, 3H), 1.53(s, 9H), 2.30(quintet,    
                        J=7                        (2-1)                  
              1655, 1603, 1540.                                           
                        Hz, 2H), 2.68(s, 3H), 3.33, 3.56(ABq, J=17Hz,     
                        2H),                       (5-1)                  
              [KBr]     4.74, 4.88(ABq, J=6Hz, 2H), 5.07(d, J=5Hz, 1H),   
                        5.76(d, J=5Hz, 1H), 6.49(t, J=7Hz, 1H), 6.79(s,   
                        1H)                                               
                        [CD.sub.3 OD].                                    
(Part 2)                                                                  
5  BOC                                                                    
      Et Et H nd        1.08(t, J=8Hz, 3H), 1.12(t, J=8Hz, 3H), 1.53(s,   
                        9H),                       (3-1)                  
                        2.42(quintet, J=8Hz, 2H), 3.15(q, J=8Hz, 2H),     
                        3.40,                      (5-1)                  
                        3.56(ABq, J=21Hz, 2H), 4.86, 5.07(ABq, J=13Hz,    
                        2H),                                              
                        5.05(d, J=5Hz, 1H), 5.83 (d, J=5Hz, 1H), 6.40(t,  
                        J=8Hz, 1H), 6.76(s, 1H). [CDCl.sub.3 --CD.sub.3   
                        OD]                                               
6  BOC                                                                    
      Et i-Pr                                                             
            Na                                                            
              3330, 1765, 1720,                                           
                        1.05(t, J=7Hz, 3H), 1.13(d, J=7Hz, 6H), 1.53(s,   
                        9H),                       (2-1)                  
              1655, 1615, 1540.                                           
                        230(quintet, J=7Hz, 2H), 3.35, 3.54(ABq,          
                                                   (5-1)z,                
              [Nujol]   2H), 3.7(m, 1H), 4.74, 4.86(ABq, J=6Hz, 2H),      
                        5.07(d,                                           
                        J=4Hz, 1H), 5.77(d, J=4Hz, 1H), 6.50(t, J=7Hz,    
                        1H),                                              
                        6.78(s, 1H). [CD.sub.3 OD]                        
7  BOC                                                                    
      n-Pr                                                                
         Me H 3230, 1780, 1720,                                           
                        0.95(t, J=8Hz, 3H), 1.40˜1.63(m, 2H),       
                        1.54(s, 9H),               (3-1)                  
              1660. [Nujol]                                               
                        2.22˜2.47 (m, 2H), 2.72(s, 3H), 3.51(m,     
                        2H), 4.84,                 (5-1)                  
                        5.12(ABq, J=15Hz, 2H), 5.09(d, J=5Hz, 1H),        
                        5.84(d,                                           
                        J=5Hz, 1H), 6.45(t, J=8Hz, 1H), 6.87(s,           
                        1H). [CDCl.sub.3 --CD.sub. 3 OD]                  
8  BOC                                                                    
      i-Pr                                                                
         Me H nd        nd                         (3-1)                  
                        This product was subjected to the treatment of    
                        next                       (5-1)                  
                        step without isolation.                           
__________________________________________________________________________
 
    
     
                                           TABLE 3                                 
__________________________________________________________________________
Carboxy compound and its salts                                            
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
              IR(CHCl.sub.3)ν: cm.sup.-1                               
                        NMR(CDCl.sub.3) δ: ppm                      
                                                   Ex. No.                
__________________________________________________________________________
(Part 1)                                                                  
1  H  Me Me H 3300, 1700, 1705,                                           
                        1.92(d, J=7Hz, 3H), 2.68(s, 3H), 3.47,            
                                                   (6-1)ABq,              
   TFA        1660, 1528. [KBr]                                           
                        J=17Hz, 2H), 4.75, 5.09(ABq, J=12Hz, 2H), 5.11(d, 
                        J=4Hz, 1H), 5.82(d, J=4Hz, 1H), 6.43(q, J=7Hz,    
                        1H),                                              
                        6.48(s, 1H). [CD.sub.3 OD]                        
2  H  Me Me H 1772, 1702sh,                                               
                        2.23(d, J=7Hz, 3H), 2.88(d, J=6.5Hz, 3H),         
                        3.86(brs,                  (3-1)                  
   TFA        1663. [Nujol]                                               
                        2H), 4.99, 5.28(ABq, J=12.6Hz, 2H), 5.45(d,       
                        J=4.5Hz,                   (6-1)                  
   trans                1H), 6.11(d, J=4.5 1H), 6.94(s, 1H), 7.22q        
(Part 2)                                                                  
5  H  Et i-Pr                                                             
            H 3300, 1772,                                                 
                        1.08(t, J=7Hz, 3H), 1.13(d, J=7Hz,                
                                                   (6-1)                  
   TFA        1650br, 1530.                                               
                        2.34(quintet, J=7Hz, 2H), 3.51, 3.68(ABq, J=21Hz, 
              [KBr]     2H), 3.7(m, 1H), 4.81, 5.12(ABq, J=12Hz, 2H),     
                        5.17(d, J=5Hz, 1H), 5.84(d, J=5Hz, 1H), 6.37(t,   
                        J=                                                
                        7Hz, 1H), 6.68(s, 1H). [CD.sub.3 OD]              
6  H  n-Pr                                                                
         Me H 3300, 3250, 1780,                                           
                        0.97(brt, J=7Hz, 3H), 1.53(brq, J=7Hz, 2H),       
                                                   (3-1)                  
              1755, 1695, 1660,                                           
                        (brq, J=7Hz, 2H), 2.73(s, 3H), 3.48,              
                                                   (6-1)ABq,              
              1635. [Nujol]                                               
                        J=18Hz, 2H), 4.88, 5.16(ABq, J=12Hz, 2H), 5.13(d, 
                        J=5Hz, 1H), 5.83(d, J=5Hz, 1H), 6.41(t, J=7Hz,    
                        1H),                                              
                        6.46(s, 1H). [CDCl.sub.3 --CD.sub.3 OD]           
7  H  i-Pr                                                                
         Me H 3280, 1765, 1700,                                           
                        1.10(d, J=7Hz, 6H), 2.50˜2.95(m, 1H),       
                        2.74(s, 3H),               (3-1)                  
              1655, 1635.                                                 
                        3.30˜3.80 (m, 2H), 4.91, 5.13(ABq, J=13Hz,  
                        2H),                       (6-1)                  
              [Nujol]   5.11(d, J=5Hz, 1H), 5.85 (d, J=5Hz, 1H), 6.21(d,  
                        J=10Hz, 1H), 6.42(s, 1H). [CDCl.sub.3 --CD.sub.3  
                        OD]                                               
__________________________________________________________________________
 
    
     
                                           TABLE 4                                 
__________________________________________________________________________
N--Protected pharmacologically acceptable ester                           
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
                IR(CHCl.sub.3)ν: cm.sup.-1                             
                          NMR(CDCl.sub.3) δ: ppm                    
                                                     Ex.                  
__________________________________________________________________________
                                                     No.                  
(Part 1)                                                                  
 1 BOC                                                                    
      Me Me AOM 3445, 3400, 1785,                                         
                          1.52(s, 9H), 1.97(d, J=7Hz, 3H), 2.09(s, 3H),   
                          2.75                       (4-1)                
                1722, 1677, 1540.                                         
                          (d, J=5Hz, 3H), 3.48(s, 2H), 4.76, 5.07(ABq,    
                          J=18Hz,                                         
                          2H), 5.00(d, J=4Hz, 1H), 5.36(m, 1H), 5.82(s,   
                          2H),                                            
                          5.91(m, 1H), 6.46(q, J=7Hz, 1H), 6.75(s, 1H),   
                          7.99                                            
                          (d, J=9Hz, 1H), 9.50(brs, 1H).                  
 2 BOC                                                                    
      Me Me AOE 3440, 1782, 1753,                                         
                          1.46˜1.60(m, 3H), 1.52(s, 9H), 2.00(d,    
                          J=7Hz, 3H),                (4-2)                
                1720, 1672.                                               
                          2.07(s, 3H), 2.76(d, J=5Hz, 3H), 3.33,          
                          3.57(ABq, J=                                    
                          18Hz, 2H), 4.78, 5.10(ABq, J=13Hz, 2H), 5.01(d, 
                          J=4                                             
                          Hz, 1H), 5.60˜5.95(m, 2H), 6.23(s, 1H),   
                          6.47(q, J=                                      
                          7Hz, 1H), 7.88(d, J=9Hz, 1H), 8.21(brs, 1H).    
 3 BOC                                                                    
      Me Me POM 3450, 3400, 1780,                                         
                          1.20(s, 9H), 1.51(s, 9H), 2.01(d, J=7Hz, 3H),   
                          2.76                       (4-3)                
                1745sh, 1720,                                             
                          (d, J=5Hz, 3H), 3.42, 3.51(ABq, J=17Hz, 2H),    
                          4.79,                                           
                1670, 1540.                                               
                          5.06(ABq, J=16Hz, 2H), 5.03(d, J=4Hz, 1H),      
                          5.19(q,                                         
                          J=5Hz, 1H), 5.86(s, 2H), 5.8(m, 1H), 6.52(q,    
                          J=7Hz,                                          
                          1H), 6.72(s, 1H), 8.02(d, J=7Hz, 1H), 9.87 (br, 
                          1H).                                            
(Part 2)                                                                  
 4 BOC                                                                    
      Me Me HOH 3460, 1785, 1740,                                         
                          1.00˜2.0(m, 21H), 2.02(d, J=7Hz, 3H),     
                          2.2˜2.4(m,           (4-7)                
                1720, 1675, 1542.                                         
                          1H), 2.75(d, J=5Hz, 3H), 3.42, 3.51(ABq,        
                          J=18Hz,                                         
                          2H), 4.78, 5.05(ABq, J=16Hz, 2H), 5.02(d,       
                          J=4.5Hz,                                        
                          1H), 5.20(q, J=5Hz, 1H), 5.8(m, 1H), 6.51(d,    
                          J=7Hz,                                          
                          1H), 6.52(q, J=7Hz, 1H), 6.71(s, 1H), 8.02(d,   
                          J=7Hz,                                          
                          1H), 9.87(brs, 1H).                             
 5 BOC                                                                    
      Me Me ECE 3410, 1785, 1761,                                         
                          1.29(t, J=7Hz, 3H), 1.52(s, 9H),                
                          1.54˜1.66(m, 3H),    (4-5)                
                1720, 1675, 1150.                                         
                          1.99(d, J=8Hz, 3H), 2.76(d, J=5Hz, 3H), 3.34,   
                          3.63                                            
                          (ABq, J=18Hz, 2H), 4.21(q, J=7Hz, 2H), 4.75,    
                          5.03                                            
                          (ABq, J=13Hz, 2H), 5.00(d, J=4Hz, 1H),          
                          5.60˜6.03(m,                              
                          2H), 6.41(t, J=8Hz, 1H), 6.45(s, 1H), 8.20(d,   
                          J=9Hz,                                          
                          1H), 9.13(brs, 1H).                             
 6 BOC                                                                    
      Me Me ICE 3440, 3380, 1780,                                         
                          1.30(d, J=6Hz, 6H), 1.53(s, 9H),                
                          1.50˜1.61(m, 3H),    (4-7)                
                1755, 1720, 1678.                                         
                          2.01(d, J=8Hz, 3H), 2.78(d, J=5Hz, 3H), 3.41,   
                          3.61                                            
                          (ABq, J=18Hz, 2H), 4.65˜5.21(m, 2H),      
                          5.15(d, J=5Hz,                                  
                          1H), 5.33(q, J=5Hz, 1H), 5.79(dd, J=5Hz, J=9Hz, 
                          1H),                                            
                          6.45(q, J=8Hz, 1H), 6.71(m, 1H), 6.75(s, 1H),   
                          6.82                                            
                          (m, 1H), 7.70(d, J=9Hz, 1H), 7.86(brs, 1H).     
(Part 3)                                                                  
  7                                                                       
   BOC                                                                    
      Me Me HCE 3450, 3400, 1780,                                         
                          1.0˜2.0(m, 10H), 1.51(s, 9H), 1.52(d,     
                          J=6Hz, 3H),                (4-7)                
                1760, 1718, 1665,                                         
                          2.08(d, J=8Hz, 3H), 2.78(d, J=5Hz, 3H), 3.40,   
                          3.60                                            
                1540, 1150.                                               
                          (ABq, J=18Hz, 2H), 4.4˜5.3(m, 3H),        
                          5.02(d, J=4.5Hz,                                
                          1H), 5.26(dd, J=4.5Hz, J=8Hz, 1H), 5.28(q,      
                          J=5Hz,                                          
                          1H), 6.62(q, J=8Hz, 1H), 6.73(s, 1H), 6.85(q,   
                          J=6Hz,                                          
                          1H), 7.96(brs, 1H), 8.01(d, J=8Hz, 1H).         
 8 BOC                                                                    
      Et Me AOM 3450, 3400, 1780,                                         
                          1.06(t, J=7Hz, 3H), 1.52(s, 9H), 2.09(s, 3H),   
                          2.4(m,                     (4-1)                
                1720, 1675, 1540.                                         
                          2H), 2.72 (d, J=5Hz, 3H), 3.46(s, 2H), 4.75,    
                          5.07                                            
                          (ABq, J=14Hz, 2H), 4.98(d, J=4Hz, 1H), 5.35(m,  
                          1H),                                            
                          5.8(m, 1H), 5.82(s, 2H), 6.41(t, J=7Hz, 1H),    
                          6.74                                            
                          (s, 1H), 7.98(d, J=9Hz, 1H), 9.87(brs, 1H).     
 9 BOC                                                                    
      Et Me AOE 1780, 1755, 1721,                                         
                          1.07(t, J=7Hz, 3H), 1.52(s, 9H),                
                          1.45˜1.60(m, 3H),    (4-2)                
                1668.     2.07(s, 3H), 2.30˜2.66(m, 2H), 2.75(d,    
                          J=4Hz, 3H),                (7-1)                
                          3.33, 3.56(ABq, J=18Hz, 2H), 4.77, 5.10(ABq,    
                          J=14Hz, 2H), 4.99(d, J=4Hz, 1H),                
                          5.60˜5.97(m, 1H),                         
                          6.41(t, J=7Hz, 1H), 6.23(s, 1H),                
                          6.80˜7.20(m, 1H),                         
                          7.85(d, J=9Hz, 1H).                             
(Part 4)                                                                  
10 BOC                                                                    
      Et Me AOE 1796, 1752, 1720,                                         
                          1.09(t, J=7Hz, 3H), 1.52(s, 9H), 1.53(d, J=6Hz, 
                          3H),                       (8-1)                
                1663.     2.09(s, 3H), 2.33˜2.77(m, 2H), 2.76(d,    
                          J=5Hz, 3H),                                     
            SO            3.32, 3.92(ABq, J=18Hz, 2H), 4.60(d, J=4Hz,     
                          1H),                                            
                          4.73, 5.23(ABq, J=14Hz, 2H), 6.18, 6.29(dd,     
                          J=4Hz,                                          
                          1H), 6.46(t, J=7Hz, 1H), 6.76(s, 1H),           
                          6.29˜7.23(m,                              
                          1H), 8.80(d, J=9Hz, 1H).                        
11 BOC                                                                    
      Et Me POM 3450, 3400, 1780,                                         
                          1.07(t, J=8Hz, 3H), 1.22(s, 9H), 1.53(s,        
                                                     (4-3)                
                1750, 1720, 1665,                                         
                          2.46(quintet, J=8Hz, 2H), 2.75(d, J=5Hz, 3H),   
                          3.41,                                           
                1540, 1365, 1150.                                         
                          3.52(ABq, J=18Hz, 2H), 4.75˜4.95(m, 1H),  
                          4.77,                                           
                          5.03(ABq, J=14Hz, 2H), 5.01(d, J=5Hz, 1H),      
                          5.88(dd,                                        
                          J=5Hz, J=8Hz, 1H), 5.84, 5.92(ABq, J=6Hz, 2H),  
                          6.42                                            
                          (t, J=8Hz, 1H), 6.74(s, 1H), 7.67(d, J=8Hz,     
                          1H).                                            
12 BOC                                                                    
      Et Me POE 1785, 1745sh,                                             
                          1.08(t, J=7Hz, 3H), 1.20(s, 9H), 1.52(s, 9H),   
                          1.53                       (4-4)                
                1730, 1672.                                               
                          (d, J=6Hz, 3H), 2.27˜2.67(m, 2H), 2.78(d, 
                          J=5Hz,                                          
                          3H), 3.33, 3.62(ABq, J=18Hz, 2H), 4.78,         
                          5.12(ABq,                                       
                          J=14Hz, 2H), 5.05(d, J=4Hz, 1H),                
                          5.67˜6.03(m, 1H),                         
                          6.43(t, J=7Hz, 1H), 6.75(s, 1H),                
                          6.80˜7.20(m, 1H),                         
                          7.23˜7.96(m, 1H).                         
(Part 5)                                                                  
13 BOC                                                                    
      Et Me ECE 1783, 1760, 1722,                                         
                          1.07(t, J=7Hz, 3H), 1.30(t, J=7Hz, 3H), 1.53(s, 
                          9H),                       (4-5)                
                1670.     1.53˜1.66(m, 3H), 2.15˜2.30(m, 2H), 
                          2.76(d, J=5Hz,             (7-1)                
                          3H), 3.33, 3.61(ABq, J=18Hz, 2H), 4.21(q,       
                          J=7Hz,                                          
                          2H), 4.77, 5.10(ABq, J=14Hz, 2H), 4.99(d,       
                          J=4Hz,                                          
                          1H), 5.60˜6.03(m, 1H), 6.41(t, J=7Hz,     
                          1H),                                            
                          6.70˜7.10(m, 1H), 7.15˜7.85(m, 1H). 
14 BOC                                                                    
      Et Me ECE 1800, 1760, 1722,                                         
                          1.08(t, J=7Hz, 3H), 1.31(t, J=6Hz, 3H), 1.52(s, 
                          9H),                       (8-1)                
                1668.     1.60(d, J=6Hz, 3H), 2.30˜2.70(m, 2H),     
                          2.75(d, J=5                                     
            SO            Hz, 3H), 3.32, 3.92(ABq, J=18Hz, 2H), 4.27(q,   
                          J=6Hz,                                          
                          2H), 4.68(d, J=4Hz, 1H), 4.78, 5.22(ABq,        
                          J=13Hz,                                         
                          2H), 6.23(q, J=4Hz, 1H), 6.48(t, J=7Hz, J=9Hz,  
                          1H),                                            
                          6.76(s, 1H), 6.83˜7.20(m, 1H), 8.68(d,    
                          J=9Hz, 1H).                                     
15 BOC                                                                    
      Et Me ICP 3445, 3400, 1778,                                         
                          0.94(t, J=7Hz, 3H), 1.07(t, J=8Hz, 3H), 1.30(d, 
                          J=6                        (4-7)                
                1755, 1720, 1673.                                         
                          Hz, 6H), 1.53(s, 9H), 1.6˜2.1(m, 2H),     
                          2.45(dq, J=8                                    
                          Hz, J=8Hz, 2H), 2.77(d, J=5Hz, 3H), 3.40,       
                          3.59(ABq,                                       
                          J=18Hz, 2H), 4.65˜5.30(m, 2H), 5.15(d,    
                          J=5Hz, 1H),                                     
                          5.32(q, J=5Hz, 1H), 5.79(dd, J=5Hz, J=9Hz, 1H), 
                          6.44                                            
                          (t, J=8Hz, 1H), 6.70(m, 1H), 6.75(s, 1H),       
                          6.83(t, J=                                      
                          7Hz, 1H), 7.70(d, J=9Hz, 1H), 7.86(brs, 1H).    
(Part 6)                                                                  
16 BOC                                                                    
      Et Me PeCP                                                          
                3440, 3390, 1780,                                         
                          0.93(t, J=7Hz, 3H), 0.95(t, J=7Hz, 3H),         
                          1.0˜2.0(m,           (4-7)                
                1753, 1720, 1670,                                         
                          6H), 1.06(t, J=7Hz, 3H), 1.21(d, J=6Hz, 3H),    
                          1.52(s,                                         
                1150.     9H), 2.4(m, 2H), 2.77(d, J=5Hz, 3H), 3.46(s,    
                          2H),                                            
                          4.80, 5.00(ABq, J=15Hz, 2H), 4.8(m, 1H),        
                          4.98(d, J=4                                     
                          Hz, 1H), 5.28(q, J=5Hz, 1H), 5.35(m, 1H),       
                          6.23(m,                                         
                          1H), 6.41(t, J=7Hz, 1H), 6.74(s, 1H), 7.99(d,   
                          J=9Hz,                                          
                          1H), 9.87(brs, 1H).                             
17 BOC                                                                    
      Et Me DOL 3450, 3400, 1818,                                         
                          1.17(t, J=7Hz, 3H), 1.52(s, 9H), 2.18(s, 3H),   
                          2.45                       (4-6)                
                1782, 1722, 1670,                                         
                          (quintet, J=7Hz, 2H), 2.75(d, J=5Hz, 3H), 3.41, 
                1540.     3.58(ABq, J=19Hz, 2H), 4.74, 5.09(ABq, J=14Hz,  
                          2H),                                            
                          4.99(s, 2H), 5.03(d, J=4Hz, 1H), 5.1(m, 1H),    
                          5.87(dd, J=4Hz, J=9Hz, 1H), 6.43(t, J=7Hz, 1H), 
                          6.78(s, 1H), 7.81(d, J=9Hz, 1H), 9.56(brs, 1H). 
18 BOC                                                                    
      Et Et POM 3450, 3420, 2970,                                         
                          1.07(t, J=8Hz, 3H), 1.12(t, J=7Hz, 3H), 1.23(s, 
                          9H),                       (4-3)                
                2940, 1790, 1750,                                         
                          1.53(s, 9H), 2.46(quintet, J=8Hz, 2H),          
                          4.18(quintet,                                   
                1725, 1680, 1545,                                         
                          J=7Hz, 2H), 3.40, 3.53(ABq, J=18Hz, 2H),        
                          4.35(brs,                                       
                1510, 1375, 1150.                                         
                          1H), 4.78, 5.05(ABq, J=14Hz, 2H), 5.01(d,       
                          J=5Hz,                                          
                          1H), 5.86(dd, J=5Hz, J=9Hz, 1H), 5.86(s, 2H),   
                          6.42                                            
                          (t, J=8Hz, 1H), 6.75(s, 1H), 7.74(d, J=9Hz,     
                          1H),                                            
                          8.71 (brs, 1H).                                 
(Part 7)                                                                  
19 BOC                                                                    
      Et i-Pr                                                             
            POM 3400, 3200, 1792,                                         
                          1.08(t, J=7Hz, 3H), 1.15(d, J=7Hz, 6H), 1.23(s, 
                          9H),                       (4-3)                
                1745, 1720, 1670,                                         
                          1.53(s, 9H), 2.47(quintet, J=7Hz, 2H), 3.40,    
                1540.     3.52(ABq, J=16Hz, 2H), 3.7(m, 1H), 4.76,        
                          5.07(ABq,                                       
                          J=14Hz, 2H), 4.80(d, J=7Hz, 1H), 5.00(d, J=4Hz, 
                          1H),                                            
                          5.86(s, 2H), 5.87(dd, J=4Hz, J=9Hz, 1H),        
                          6.42(t,                                         
                          J=7Hz, 1H), 6.74(s, 1H), 7.86(d, J=9Hz, 1H),    
                          9.23(brs, 1H).                                  
20 BOC                                                                    
      Et i-Pr                                                             
            HmCP                                                          
                3410, 3200, 1793,                                         
                          0.95(t, J=7Hz, 3H), 0.9˜2.1(m, 13H),      
                          1.08(t, J=7Hz,             (4-7)                
                1745, 1722, 1675,                                         
                          3H), 1.15(d, J=7Hz, 6H), 1.53(s, 9H),           
                          2.47(quintet,                                   
                1540.     J=7Hz, 2H), 3.40, 3.52(ABq, J=16Hz, 2H),        
                          3.54(m,                                         
                          2H), 3.7(m, 1H), 4.76, 5.07(ABq, J=14Hz, 2H),   
                          5.00                                            
                          (d, J=4Hz, 1H), 5.87(dd, J=4Hz, J=9Hz, 1H),     
                          6.42(t,                                         
                          J=7Hz, 1H), 6.72(t, J=5Hz, 1H), 6.74(s, 1H),    
                          7.86(d,                                         
                          J=9Hz, 1H), 9.23(brs, 1H).                      
21 BOC                                                                    
      n-Pr                                                                
         Me POM 3450, 3400, 1785,                                         
                          0.93(t, J=7Hz, 3H), 1.21(s, 9H), 1.50(brq,      
                                                     (4-3)                
                1745, 1720, 1670.                                         
                          1.52(s, 9H), 2.42(brq, J=7Hz, 2H), 2.77(d,      
                          J=5Hz,                                          
                          3H), 3.43, 3.55(ABq, J=18Hz, 2H), 4.78,         
                          5.07(ABq,                                       
                          J=13Hz, 2H), 5.02(d, J=5Hz, 1H), 5.87 (s, 2H),  
                          5.88(dd, J=5Hz, J=8Hz, 1H), 6.44(t, J=8Hz, 1H), 
                          6.76                                            
                          (s, 1H), 7.82(d, J=8Hz, 1H),                    
(Part 8)                                                                  
22 BOC                                                                    
      i-Pr                                                                
         Me POM 3450, 3400, 1785,                                         
                          1.05(d, J=7Hz, 6H), 1.22(s, 9H), 1.52(s, 9H),   
                          2.77                       (4-3)                
                1750, 1720, 1670.                                         
                          (d, J=5Hz, 3H), 2.83˜3.22(m, 1H), 3.44,   
                          3.58(ABq,                                       
                          J=18Hz, 2H), 4.79, 5.10(ABq, J=14Hz, 2H),       
                          5.03(d,                                         
                          J=5Hz, 1H), 5.87(s, 2H), 5.90(dd, J=5Hz, J=8Hz, 
                          1H), 6.25(d, J=10Hz, 1H), 6.77(s, 1H), 7.75(d,  
                          J=                                              
                          8Hz, 1H),                                       
__________________________________________________________________________
 
    
     
                                           TABLE 5                                 
__________________________________________________________________________
Pharmacologically acceptable ester                                        
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
                IR(CHCl.sub.3)ν: cm.sup.-1                             
                          NMR(CDCl.sub.3) δ: ppm                    
                                                     Ex.                  
__________________________________________________________________________
                                                     No.                  
(Part 1)                                                                  
 1 H  Me Me AOM 3425, 1782, 1728,                                         
                          1.89(t, J=7Hz, 3H), 2.08(s, 3H), 2.57(d, J=6Hz, 
                          3H),                       (6-1)                
                1695, 1660, 1540.                                         
                          3.61(s, 2H), 4.61, 4.92(ABq, J=13Hz, 2H),       
                          5.21(d, J=                                      
                [Nujol]   4Hz, 1H), 5.78(dd, J=4Hz, J=9Hz, 1H), 5.84(s,   
                          2H),                                            
                          6.23(s, 1H), 6.41(q, J=7Hz, 1H), 6.98(brs, 2H), 
                          9.22                                            
                          (d, J=9Hz, 1H). [CD.sub.3 SOCD.sub.3 ]          
 2 H  Me Me AOE 3380, 1778, 1751,                                         
                          1.54(d, J=6Hz, 3H), 1.88(d, J=7Hz, 3H), 2.10(s, 
                          3H),                       (6-1)                
                1723, 1670.                                               
                          2.77(d, J=5Hz, 3H), 3.33, 3.56(ABq, J=19Hz,     
                          2H),                                            
                          4.78, 4.92(ABq, J=13Hz, 2H), 5.03(d, J=4Hz,     
                          1H), -                          5.23(q, J=5Hz,  
                                                     1H), 5.60(brs, 2H),  
                                                     5.95(dd, J=4Hz,      
                          J=9Hz, 1H), 6.34(s, 1H), 6.41(q, J=7Hz, 1H),    
                          6.92˜                                     
                          7.25(m, 1H), 8.05(d, J=9Hz, 1H).                
 3 H  Me Me POM 3480, 3400, 1787,                                         
                          1.21(s, 9H), 1.87(d, J=7Hz, 3H), 2.75(d, J=5Hz, 
                          3H),                       (6-1)                
                1750, 1730, 1670,                                         
                          3.42, 3.54(ABq, J=18Hz, 2H), 4.77, 5.07(ABq,    
                          J=15                                            
                1520.     Hz, 2H), 5.04(d, J=4Hz, 1H), 5.2(m, 1H),        
                          5.67(brs,                                       
                          2H), 5.85, 5.91(ABq, J=6Hz, 2H), 5.9 (m, 1H),   
                          6.21                                            
                          (s, 1H), 6.48(q, J=7Hz, 1H), 8.62(d, J=9Hz,     
                          1H).                                            
(Part 2)                                                                  
 4 H  Me Me HOH 3410, 1780, 1745,                                         
                          0.97˜1.98(m, 21H), 1.88(d, J=7Hz, 3H),    
                          2.3˜2.5(m,           (6-2)                
                1672, 1515.                                               
                          1H), 2.75(d, J=5Hz, 3H), 3.43, 3.55(ABq,        
                          J=18Hz,                                         
                          2H), 4.76, 5.06(ABq, J=15Hz, 2H), 5.05(d,       
                          J=4.5Hz,                                        
                          1H), 5.30(dd, J=4.5Hz, J=9Hz, 1H), 5.67(brs,    
                          2H),                                            
                          5.9(m, 1H), 6.21(s, 1H), 6.47(q, J=7Hz, 1H),    
                          6.53(d,                                         
                          J=6.5Hz, 1H), 8.62(d, J=9Hz, 1H).               
 5 H  Me Me ECE 3380, 1780, 1762,                                         
                          1.58(d, J=6Hz, 3H), 1.89(d, J=8Hz, 3H), 2.06(s, 
                          3H),                       (6-1)                
                1720, 1695, 1540.                                         
                          2.59(d, J=6Hz, 3H), 3.62(s, 2H), 4.62,          
                          4.91(ABq, J=                                    
                [Nujol]   14Hz, 2H), 5.22(d, J=4Hz, 1H), 5.83(s, 2H),     
                          5.89(dd,                                        
                          J=4Hz, J=9Hz, 1H), 6.23(s, 1H), 6.39(q, J=8Hz,  
                          1H),                                            
                          6.95(brs, 2H), 7.12(q, J=6Hz, 1H), 9.30(d,      
                          J=9Hz,                                          
                          1H). [CD.sub.3 SOCD.sub.3 ]                     
 6 H  Me Me ICE 3440, 1778, 1750,                                         
                          1.31(d, J=6Hz, 6H), 1.56(d, J=6Hz, 3H), 1.90(d, 
                          J=8                        (6-2)                
                1675, 1542.                                               
                          Hz, 3H), 2.76(d, J=5Hz, 3H), 3.40, 3.59(ABq,    
                          J=19Hz,                                         
                          2H), 4.80, 4.98(ABq, J=15Hz, 2H), 5.04(d,       
                          J=5Hz,                                          
                          1H), 5.27(q, J=5Hz, 1H), 5.48(brs, 2H),         
                          5.91(dd, J=                                     
                          5Hz, J=9Hz, 1H), 6.32(s, 1H), 6.39(q, J=8Hz,    
                          1H),                                            
                          6.71˜6.74(m, 2H), 8.00(d, J=9Hz, 1H).     
(Part 3)                                                                  
 7 H  Me Me HCE 3440, 3350, 1790,                                         
                          1.0˜2.1(m, 10H), 1.50(d, J=6.5Hz, 3H),    
                          2.05(d, J=8                (6-1)                
                1755, 1698, 1655,                                         
                          Hz, 3H), 2.76(d, J=5Hz, 3H), 3.40, 3.61(ABq,    
                          J=18Hz,                                         
                1155.     2H), 4.3˜4.7(m, 1H), 4.77, 5.07(ABq,      
                          J=15Hz, 2H),                                    
                          5.02(d, J=4Hz, 1H), 5.19(dd, J=4Hz, J=8Hz, 1H), 
                          5.30                                            
                          (q, J=5Hz, 1H), 5.38(brs, 2H), 6.62(q, J=8Hz,   
                          1H),                                            
                          6.62(s, 1H), 7.98(d, J=8Hz, 1H).                
 8 H  Et Me AOM 3440, 3360, 3280,                                         
                          1.00(t, J=7Hz, 3H), 2.07(s, 3H),                
                                                     (6-1)quintet,        
                1790, 1730, 1698,                                         
                          J=7Hz, 2H), 2.58(d, J=6Hz, 3H), 3.60(s, 2H),    
                          4.60,                                           
                1659, 1625, 1540.                                         
                          4.90(ABq, J=13Hz, 2H), 5.22(d, J=4Hz, 1H),      
                          5.80(dd,                                        
                [Nujol]   J=4Hz, J=9Hz, 1H), 5.84(s, 2H), 6.22(s, 1H),    
                          6.25(t,                                         
                          J=7Hz, 1H), 6.98(brs, 2H), 7.03(q, J=6Hz, 1H),  
                          9.26(d, J=9Hz, 1H). [CD.sub.3 SOCD.sub.3 ]      
 9 H  Et Me AOE 1780, 1750, 1720,                                         
                          1.07(t, J=7Hz, 3H), 1.53(d, J=6Hz, 3H), 2.10(s, 
                          3H),                       (6-1)                
                1665.     2.20˜2.63 (m, 2H), 2.78(d, J=5Hz, 3H),    
                          3.33, 3.63                                      
                          (ABq, J=19Hz, 2H), 4.88, 5.03(ABq, J=14Hz, 2H), 
                          5.04(d, J=4Hz, 1H), 5.27˜5.50(m, 2H),     
                          5.91, 6.02(dd,                                  
                          J=4Hz, J=9Hz, 1H), 6.35(s, 1H), 6.42(t, J=7Hz,  
                          1H),                                            
                          6.90˜7.28(m, 1H), 8.07(d, J=9Hz, 1H).     
(Part 4)                                                                  
10 H  Et Me POM 3410, 3330, 2970,                                         
                          1.05(t, J=8Hz, 3H), 1.22(s, 9H), 2.40(quintet,  
                          J=8                        (6-1)                
                1780, 1745, 1715,                                         
                          Hz, 2H), 2.77(d, J=5Hz, 3H), 3.44, 3.57(ABq,    
                          J=20Hz,                    (6-2)                
                1660, 1620, 1525,                                         
                          2H), 4.73˜4.96(m, 1H), 4.92, 5.07(ABq,    
                          J=15Hz, 2H),                                    
                1375, 1243, 1123.                                         
                          5.04(d, J=5Hz, 1H), 5.30(brs, 2H), 5.86,        
                          5.93(ABq,                                       
                [KBr]     J=6Hz, 2H), 5.95(dd, J=5Hz, J=8Hz, 1H), 6.34(s, 
                          1H),                                            
                          6.42(t, J=8Hz, 1H), 8.10(d, J=8Hz, 1H).         
11 H  Et Me POE 1785, 1745sh,                                             
                          1.04(t, J=7Hz, 3H), 1.20(s, 9H), 1.54(d, J=5Hz, 
                          3H),                       (6-1)                
                1725, 1670.                                               
                          2.17˜2.63(m, 2H), 2.76(d, J=5Hz, 3H),     
                          3.36, 3.63                                      
                          (ABq, J=18Hz, 2H), 4.27, 5.08(ABq, J=14Hz, 2H), 
                          5.05                                            
                          (d, J=4Hz, 1H), 5.40˜5.67(brm, 2H), 5.90, 
                          6.00(dd,                                        
                          J=4Hz, 1H), 6.32(s, 1H), 6.41(t, J=7Hz, 1H),    
                          6.83˜                                     
                          7.20(m, 1H), 8.19(d, J=9Hz, 1H).                
12 H  Et Me ECE 1782, 1760, 1723,                                         
                          1.05(t, J=7Hz, 3H), 1.31(t, J=7Hz, 3H), 1.58(d, 
                          J=6                        (6-1)                
                1670.     Hz, 3H), 2.13˜2.55(m, 2H), 2.75(d, J=5Hz, 
                          3H), 3.33,                                      
                          3.60(ABq, J=18Hz, 2H), 4.22(q, J=7Hz, 2H),      
                          4.78,                                           
                          5.07(ABq, J=14Hz, 2H), 5.01(d, J=4Hz, 1H),      
                          5.40˜5.70                                 
                          (br, 2H), 5.92(dd, J=4Hz, J=8Hz, 1H), 6.30(s,   
                          1H),                                            
                          6.38(t, J=7Hz, 1H), 6.75˜7.10(m, 1H),     
                          8.03˜8.27(m,                              
                          1H).                                            
(Part 5)                                                                  
13 H  Et Me ICP 3450, 1775, 1750,                                         
                          0.95(t, J=7Hz, 3H), 1.05(t, J=7Hz, 3H), 1.30(t, 
                          J=6                        (6-1)                
                1678, 1530.                                               
                          Hz, 6H), 1.7˜2.2(m, 2H), 2.38(dq, J=8Hz,  
                          J=8Hz, 2H),                                     
                          2.75(d, J=5Hz, 3H), 3.40, 3.56(ABq, J=18Hz,     
                          2H),                                            
                          4.82, 5.02(ABq, J=15Hz, 2H), 5.06(d, J=5Hz,     
                          1H), 5.28                                       
                          (q, J=5Hz, 1H), 5.42(brs, 2H), 5.92(dd, J=5Hz,  
                          J=9                                             
                          Hz, 1H), 6.33(s, 1H), 6.48(t, J=8Hz, 1H),       
                          6.72(m,                                         
                          2H), 8.00(d, J=9Hz, 1H).                        
14 H  Et Me BCE 3485, 3390, 1782,                                         
                          1.06(t, J=7Hz, 3H), 1.49(s, 9H), 1.56(d, J=6Hz, 
                          3H),                       (4-7)                
                1760, 1730, 1667,                                         
                          2.40(dq, J=7Hz, J=8Hz, 2H), 2.76(d, J=5Hz, 3H), 
                1525.     3.40, 3.57(ABq, J=18Hz, 2H), 4.83, 5.03(ABq,    
                          J=15Hz,                                         
                          2H), 5.03(d, J=5Hz, 1H), 5.26(q, J=5Hz, 1H),    
                          5.32                                            
                          (brs, 2H), 5.92(dd, J=5Hz, J=9Hz, 1H), 6.35(s,  
                          2H),                                            
                          6.40(t, J=8Hz, 1H), 6.90(m, 1H), 7.95(d, J=9Hz, 
                          1H).                                            
15 H  Et Me PeCP                                                          
                3410, 3350, 1780,                                         
                          0.94(t, J=7Hz, 6H), 1.05(t, J=8Hz, 3H), 1.22(d, 
                          J=6                        (6-1)                
                1752, 1715, 1665,                                         
                          Hz, 3H), 1.1˜2.0(m, 6H), 2.38(quintet,    
                          J=8Hz, 2H),                                     
                1123.     2.75(d, J=5Hz, 3H), 3.41, 3.57(ABq, J=18Hz,     
                          2H),                                            
                          4.80, 4.99(ABq, J=14Hz, 2H), 4.90(m, 1H),       
                          5.03(d, J=                                      
                          5Hz, 1H), 5.28(d, J=5Hz, 1H), 5.42(brs, 2H),    
                          5.90                                            
                          (dd, J=5Hz, J=8Hz, 1H), 6.32(s, 1H), 6.47(t,    
                          J=8Hz,                                          
                          1H), 7.30(m, 1H), 8.00(d, J=8Hz, 1H).           
(Part 6)                                                                  
16 H  Et Me DOL  3470, 3400, 3340,                                        
                          1.02(t, J=7Hz, 3H), 2.16(s, 3H), 2.3(m, 2H),    
                          2.73(d,                    (6-1)                
                1820, 1784, 1730,                                         
                          J=5Hz, 3H), 3.42, 3.56(ABq, J=20Hz, 2H), 4.73,  
                          5.08                                            
                1670, 1605, 1520.                                         
                          (ABq, J=14Hz, 2H), 5.01(s, 2H), 5.03(d, J=4Hz,  
                          1H),                                            
                          5.1(m, 1H), 5.71(brs, 2H), 5.89(dd, J=4Hz,      
                          J=9Hz,                                          
                          1H), 6.23(s, 1H), 6.35(t, J=7Hz, 1H), 8.43(d,   
                          J=9Hz,                                          
                          1H).                                            
17 H  Et Et POM 3400, 3340, 2970,                                         
                          1.05(t, J=8Hz, 3H), 1.12(t, J=7Hz, 3H), 1.22(s, 
                          9H),                       (6-1)                
                1780, 1745, 1720,                                         
                          2.38(quintet, J=8Hz, 2H), 3.18(quintet, J=7Hz,  
                          2H),                                            
                1660, 1620, 1525,                                         
                          3.43, 3.52(ABq, J=18Hz, 2H), 4.93(brs, 1H),     
                          4.78,                                           
                1375, 1240. [KBr]                                         
                          5.05(ABq, J=14Hz, 2H), 5.02(d, J=5Hz, 1H),      
                          5.28(s,                                         
                          2H), 5.83, 5.90(ABq, J=6Hz, 2H), 5.92(dd,       
                          J=5Hz,                                          
                          J=9Hz, 1H), 6.33(s, 1H), 6.40(t, J=8Hz, 1H),    
                          8.02(d,                                         
                          J=9Hz, 1H).                                     
18 H  Et i-Pr                                                             
            POM 3500, 3440, 3400,                                         
                          1.03(t, J=7Hz, 3H), 1.13(d, J=7Hz, 6H), 1.28(s, 
                          9H),                       (6-2)                
                1787, 1750, 1723,                                         
                          2.33(quintet, J=7Hz, 2H), 3.41, 3.55(ABq,       
                          J=17Hz,                                         
                1670, 1605, 1505.                                         
                          2H), 3.7(m, 1H), 4.76, 5.06(ABq, J=14Hz, 2H),   
                          4.83(d, J=7Hz, 1H), 5.02(d, J=4Hz, 1H),         
                          5.51(brs,                                       
                          2H), 5.84, 5.91(ABq, J=5Hz, 2H), 5.90(dd,       
                          J=4Hz,                                          
                          J=9Hz, 1H), 6.29(s, 1H), 6.40(t, J=7Hz, 1H),    
                          8.28(d,                                         
                          J=7Hz, 1H).                                     
(Part 7)                                                                  
19 H  Et i-Pr                                                             
            HmCP                                                          
                3430, 3390, 1780,                                         
                          0.94(t, J=7Hz, 3H), 0.9˜2.0(m, 13H),      
                          1.03(t, J=7Hz,             (6-1)                
                1755, 1720, 1672,                                         
                          3H), 1.13(d, J=7Hz, 6H), 2.33(quintet, J=7Hz,   
                          2H),                                            
                1605.     3.41, 3.55(ABq, J=17Hz, 2H), 3.53(d, J=7Hz,     
                          2H),                                            
                          3.71(m, 1H), 4.76, 5.06(ABq, J=14Hz, 2H),       
                          4.83(d, J=                                      
                          7Hz, 1H), 5.02(d, J=4Hz, 1H), 5.51(brs, 2H),    
                          5.90                                            
                          (ddJ=4Hz, J=9Hz, 1H), 6.29(s, 1H), 6.40(t,      
                          J=7Hz,                                          
                          1H), 6.70(m, 1H), 8.28(d, J=7Hz, 1H).           
20 H  n-Pr                                                                
         Me POM 3450, 3400, 1785,                                         
                          0.92(t, J=7Hz, 3H), 1.22(s, 9H), 1.49(brq,      
                          J=7Hz,                     (6-1)                
                1750, 1725, 1670,                                         
                          2H), 2.35(brq, J=7Hz, 2H), 2.77(d, J=5Hz, 3H),  
                1600.     3.43, 3.57(ABq, J=18Hz, 2H), 4.79, 5.12(ABq,    
                          J=14Hz,                                         
                          2H), 5.06(d, J=5Hz, 1H), 5.54(s, 2H), 5.84,     
                          5.92(ABq, J=5Hz, 2H), 5.89(dd, J=5Hz, J=8Hz,    
                          1H),                                            
                          6.33(s, 1H), 6.42(t, J=7Hz, 1H), 8.14(d, J=8Hz, 
                          1H),                                            
21 H  i-Pr                                                                
         Me POM 3450, 3390, 1785,                                         
                          1.04(d, J=7Hz, 6H), 1.20(s, 9H), 2.25(d, J=5Hz, 
                          3H),                       (6-1)                
                1745, 1720, 1670,                                         
                          2.70˜3.13(m, 1H), 3.42, 3.53(ABq, J=19Hz, 
                          2H),                                            
                1600.     4.78, 5.07(ABq, J=14Hz, 2H), 5.02(d, J=5Hz,     
                          1H),                                            
                          5.29(q, J=5Hz, 1H), 5.60(brs, 2H), 5.92(dd,     
                          J=5Hz,                                          
                          J=8Hz, 1H), 5.98(s, 2H), 6.22(d, J=10Hz, 1H),   
                          6.36(s, 1H), 7.83(d, J=8Hz, 1H),                
__________________________________________________________________________
 
    
     
                                           TABLE 6                                 
__________________________________________________________________________
Carboxy-deprotection                                                      
 ##STR9##                                                                 
 ##STR10##                                                                
                    S. M.                                                 
                        Solvent                                           
                             F.sub.3 CCOOH                                
                                   Subreagent                             
                                         Time                             
                                            Temp                          
                                                Yld.                      
                                                   Crop                   
No.                                                                       
   R  R.sup.1                                                             
           R.sup.2                                                        
              Exp. No.                                                    
                    (mg)                                                  
                        (ml) (ml)  (ml)  (hr)                             
                                            (°C.)                  
                                                (%)                       
                                                   (mg)                   
__________________________________________________________________________
1  H  Me   Me (3-1), (6-1)                                                
                    200 --   2.0   anisole 0.3                            
                                         3/2                              
                                            rt  61  101                   
2  H  Me trans                                                            
           Me (3-1), (6-1)                                                
                     60 DCM 0.4                                           
                             1.0   anisole 2.5                            
                                         3/2                              
                                            rt  62 29                     
3  H  Et   Me (3-1), (6-1)                                                
                     40 DCM 1.0                                           
                             1.0   anisole 0.5                            
                                         5/2                              
                                            rt  73 30                     
4  H  Et   Et (3-1), (6-1)                                                
                     70 DCM 1.5                                           
                             1.5   anisole 0.75                           
                                         3/2                              
                                            rt  64 36                     
5  BOC                                                                    
      Et   Et (3-1) 500 DCM 5                                             
                             1.0   anisole 0.5                            
                                         1/2                              
                                            0   97 397                    
6  H  Et   i-Pr                                                           
              (3-1), (6-1)                                                
                    100 --   1.0   anisole 0.1                            
                                         3/2                              
                                            rt  53 53                     
7  H  n-Pr Me (3-1), (6-1)                                                
                    100 --    0.62 anisole 0.2                            
                                         1  rt  54 35                     
8  BOC                                                                    
      n-Pr Me (3-1) 1200                                                  
                        DCM 5                                             
                             5.0   anisole 2.5                            
                                         1  0   100                       
                                                   965                    
9  H  i-Pr Me (3-1), (6-1)                                                
                    120 --    0.72 anisole 0.25                           
                                         1  rt  64 50                     
10 BOC                                                                    
      i-Pr Et (3-1) 442 DCM 3                                             
                             2.0   anisole 1.0                            
                                         1  0   98 348                    
__________________________________________________________________________
 
    
     
                                           TABLE 7                                 
__________________________________________________________________________
Esterification                                                            
 ##STR11##                                                                
 ##STR12##                                                                
                       S.M.                                               
                           Solvent                                        
                                Reagent Subreagent                        
                                                Time                      
                                                    Temp Yld.             
                                                            Crop          
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
              R.sup.4                                                     
                  Exp. No.                                                
                       (mg)                                               
                           (ml) (mg)    (mg)    (hr)                      
                                                    (°C.)          
                                                         (%)              
                                                            (mg)          
__________________________________________________________________________
1  BOC                                                                    
      Me Me Na                                                            
              AOM (4-1)                                                   
                       575  DMF 3                                         
                                AOM-Br                                    
                                     180                                  
                                        --      1     0  45 281           
2  BOC                                                                    
      Me Me H AOE (4-2)                                                   
                       553 DMF 3                                          
                                AOE-Br                                    
                                     350                                  
                                        Na.sub.2 CO.sub.3                 
                                             160                          
                                                1     0  63 403           
3  BOC                                                                    
      Me Me Na                                                            
              POM (4-3)                                                   
                       800 DMF 5                                          
                                POM-I                                     
                                     700                                  
                                        --      1/2   0  48 447           
4  BOC                                                                    
      Me Me H HOH (4-7)                                                   
                       553 DMA 5                                          
                                HOH-I                                     
                                     450                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                4/3   0  43 334           
5  BOC                                                                    
      Me Me H ECE (4-5)                                                   
                       553 DMF 3                                          
                                ECE-Br                                    
                                     260                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                3/2   0  63 422           
6  BOC                                                                    
      Me Me H ICE (4-7)                                                   
                       553 DMF 5                                          
                                ICE-I                                     
                                     330                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                4/3 -10  58 397           
7  BOC                                                                    
      Me Me H HCE (4-7)                                                   
                       553 DMA 5                                          
                                HCE-I                                     
                                     387                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                1   - 10 62 447           
8  BOC                                                                    
      Et Me Na                                                            
              AOM (4-1)                                                   
                       600 DMF 5                                          
                                AOM-Br                                    
                                     200                                  
                                        --      1   -10  70 449           
9  BOC                                                                    
      Et Me H AOE (4-2)                                                   
                       1120                                               
                           DMF 10                                         
                                AOM-Br                                    
                                     650                                  
                                        K.sub.2 CO.sub.3                  
                                             325                          
                                                3/2 -15  47 600           
10 BOC                                                                    
      Et Me H POM (4-3)                                                   
                       138 DMF 1.4                                        
                                POM-I                                     
                                      62                                  
                                        K.sub.2 CO.sub.3                  
                                              67                          
                                                1/2 -30  82 136           
11 BOC                                                                    
      Et Me H POE (4-4)                                                   
                       300 DMF 3                                          
                                POE-I                                     
                                     250                                  
                                        K.sub.2 CO.sub.3                  
                                             110                          
                                                4/3 -30  49 180           
12 BOC                                                                    
      Et Me Na                                                            
              ECE (4-5)                                                   
                       600 DMF 6                                          
                                ECE-Br                                    
                                     260                                  
                                        --      1     0  26 180           
13 H  Et Me H BCE (4-7)                                                   
                       467 DMA 5                                          
                                BCE-I                                     
                                     360                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                4/3   0  48  274          
14 BOC                                                                    
      Et Me H ICP (4-7)                                                   
                       284 DMF 2                                          
                                ICP-I                                     
                                     180                                  
                                        K.sub.2 CO.sub.3                  
                                             100                          
                                                11/6                      
                                                    -10  61 218           
15 BOC                                                                    
      Et Me H PeCP                                                        
                  (4-7)                                                   
                       567 DMF-5                                          
                                PeCP-I                                    
                                     390                                  
                                        K.sub.2 CO.sub.3                  
                                             200                          
                                                2     0  36 267           
16 BOC                                                                    
      Et Me Na                                                            
              DOL (4-6)                                                   
                       1000                                               
                           DMF 10                                         
                                DOL-Br                                    
                                     660                                  
                                        --      2     0  50 532           
17 BOC                                                                    
      Et Et H POM (4-3)                                                   
                       175 DMF 1.4                                        
                                POM-I                                     
                                      62                                  
                                        K.sub.2 CO.sub.3                  
                                              75                          
                                                1/2 -30  72 150           
18 BOC                                                                    
      Et i-Pr                                                             
            Na                                                            
              POM (4-3)                                                   
                       500 DMF 5                                          
                                POM-I                                     
                                     200                                  
                                        --      1   -10  85 487           
19 BOC                                                                    
      Et i-Pr                                                             
            H HmCP                                                        
                  (4-7)                                                   
                       288 DMF 3                                          
                                HmCP-I                                    
                                     215                                  
                                        K.sub.2 CO.sub.3                  
                                             100                          
                                                3/2   0  33 129           
20 BOC                                                                    
      n-Pr                                                                
         Me H POM (4-3)                                                   
                       233 DMF 3                                          
                                POM-I                                     
                                     140                                  
                                        K.sub.2 CO.sub.3                  
                                             110                          
                                                2   -40  62 174           
21 BOC                                                                    
      i-Pr                                                                
         Me H POM (4-3)                                                   
                       348 DMF 4                                          
                                POM-I                                     
                                     200                                  
                                        K.sub.2 CO.sub.3                  
                                             166                          
                                                3/2 -35  68 282           
__________________________________________________________________________
 
    
     
                                           TABLE 8                                 
__________________________________________________________________________
Carboxy-protection                                                        
 ##STR13##                                                                
 ##STR14##                                                                
                   S.M.                                                   
                      Solvent                                             
                           Ph.sub.2 CN.sub.2                              
                                Subreagent                                
                                      Time                                
                                         Temp                             
                                             Yld.                         
                                                Crop                      
No.                                                                       
   R  R.sup.1                                                             
           R.sup.2                                                        
              Exp. No.                                                    
                   (mg)                                                   
                      (ml) (mg) (ml)  (hr)                                
                                         (°C.)                     
                                             (%)                          
                                                (mg)                      
__________________________________________________________________________
1  BOC                                                                    
      Me   Me (4-9)                                                       
                   370                                                    
                      DCM 5                                               
                           144  MeOH 1                                    
                                      1  rt   41                          
                                                200                       
2  BOC                                                                    
      Me trans                                                            
           Me (4-9)                                                       
                   100                                                    
                      DCM 2                                               
                            40  --    1/3                                 
                                         rt  61  80                       
3  BOC                                                                    
      Et   Et (4-9)                                                       
                   800                                                    
                      DCM 5                                               
                           295  MeOH 2                                    
                                      1  rt  75 770                       
__________________________________________________________________________
 
    
     
                                           TABLE 9                                 
__________________________________________________________________________
Carbamic esterification                                                   
 ##STR15##                                                                
 ##STR16##                                                                
                      S. M.                                               
                         Solvent                                          
                              R.sup.2 NCO    Time                         
                                                Temp                      
                                                    Yld.                  
                                                       Crop               
No.                                                                       
   R  R.sup.1                                                             
           R.sup.2                                                        
              R.sup.3                                                     
                Exp. No.                                                  
                      (mg)                                                
                         (ml) (ml) Subreagent                             
                                             (hr)                         
                                                (°C.)              
                                                    (%)                   
                                                       (mg)               
__________________________________________________________________________
1  BOC                                                                    
      Me   Me H (5-1)                                                     
                     1000                                                 
                         THF 10                                           
                              2.0  Pyridine 1.0 ml                        
                                             3/2                          
                                                rt  73 810                
2  BOC                                                                    
      Me trans                                                            
           Me Na                                                          
                (5-1)                                                     
                      130                                                 
                         THF 2                                            
                              0.074                                       
                                   (n-Bu.sub.3 Sn).sub.2 O 12             
                                             3/2                          
                                                rt  76 110                
3  BOC                                                                    
      Et   Me H (5-1)                                                     
                      392                                                 
                         THF 4                                            
                              0.7  Pyridine 0.4 ml                        
                                             1  rt  41 170                
4  BOC                                                                    
      Et   Me Na                                                          
                (5-1)                                                     
                      450                                                 
                         THF 10                                           
                              0.45 (n-Bu.sub.3 Sn).sub.2 O 40             
                                             3/2                          
                                                rt  73 370                
5  BOC                                                                    
      Et   Et H (5-1)                                                     
                     1070                                                 
                         THF 10                                           
                              1.6  Pyridine 0.8 ml                        
                                             9/2                          
                                                rt  75 870                
6  BOC                                                                    
      Et   i-Pr                                                           
              Na                                                          
                (5-1)                                                     
                     1000                                                 
                         THF 15                                           
                              0.93 (n-Bu.sub.3 Sn).sub.2 O 95             
                                             3/2                          
                                                rt  72 840                
__________________________________________________________________________
 
    
     
                                           TABLE 10                                
__________________________________________________________________________
Amino-deprotection                                                        
 ##STR17##                                                                
 ##STR18##                                                                
                     S. M.                                                
                         Solvent                                          
                              Reagent Subreagent                          
                                            Time                          
                                               Temp                       
                                                   Yld.                   
                                                      Crop                
No.                                                                       
   R  R.sup.1                                                             
         R.sup.2                                                          
            R.sup.3                                                       
                Exp. No.                                                  
                     (mg)                                                 
                         (ml) (ml)    (ml)  (hr)                          
                                               (°C.)               
                                                   (%)                    
                                                      (mg)                
__________________________________________________________________________
1  BOC                                                                    
      Me Me AOM (6-1)                                                     
                     250 --   F.sub.3 CCOOH 2.0                           
                                      anisole 0.5                         
                                            4/3                           
                                               rt  70 166                 
2  BOC                                                                    
      Me Me AOE (6-1)                                                     
                     320 --   F.sub.3 CCOOH 3.2                           
                                      anisole 0.7                         
                                            3/2                           
                                               rt  73 197                 
3  BOC                                                                    
      Me Me POM (6-1)                                                     
                     447 --   F.sub.3 CCOOH 4.0                           
                                      anisole 0.3                         
                                            1  rt  59 223                 
4  BOC                                                                    
      Me Me HOH (6-2)                                                     
                     311 DCM 1.0                                          
                              AlCl.sub.3 107 mg                           
                                      anisole 0.5                         
                                            1/3                           
                                               -20 80 217                 
5  BOC                                                                    
      Me Me ECE (6-1)                                                     
                     335 --   F.sub.3 CCOOH 3.5                           
                                      anisole 0.7                         
                                            3/2                           
                                               rt  75 215                 
6  BOC                                                                    
      Me Me ICE (6-2)                                                     
                     342 DCM 1.0                                          
                              AlCl.sub.3 110 mg                           
                                      anisole 0.5                         
                                            1/3                           
                                               -20 73 213                 
7  BOC                                                                    
      Me Me HCE (6-1)                                                     
                     420 --   F.sub.3 CCOOH 3.5                           
                                      anisole 1.0                         
                                            5/3                           
                                               rt  63 228                 
8  BOC                                                                    
      Et Me AOM (6-1)                                                     
                     400 --   F.sub.3 CCOOH 4.0                           
                                      anisole 0.5                         
                                            1  rt  68 230                 
9  BOC                                                                    
      Et Me AOE (6-1)                                                     
                     185 --   F.sub.3 CCOOH 0.8                           
                                      anisole 0.2                         
                                            1  rt  64 101                 
10 BOC                                                                    
      Et Me POM (6-2)                                                     
                     135 DCM 1.0                                          
                              AlCl.sub.3 80 mg                            
                                      anisole 0.5                         
                                            1/2                           
                                               -10 81  93                 
11 BOC                                                                    
      Et Me POE (6-1)                                                     
                     170 --   F.sub.3 CCOOH 0.8                           
                                      anisole 0.2                         
                                            1  rt  49  72                 
12 BOC                                                                    
      Et Me ECE (6-1)                                                     
                     127 --   F.sub.3 CCOOH 0.5                           
                                      anisole 0.1                         
                                            3/2                           
                                               rt  59  64                 
18 BOC                                                                    
      Et Me ICP (6-1)                                                     
                     215 --   F.sub.3 CCOOH 1.8                           
                                      anisole 0.5                         
                                            4/3                           
                                               rt  49  91                 
19 BOC                                                                    
      Et Me PeCP                                                          
                (6-1)                                                     
                     222 --   F.sub.3 CCOOH 2.2                           
                                      anisole 0.5                         
                                            4/3                           
                                               rt  44  85                 
7  BOC                                                                    
      Et Me DOL (6-1)                                                     
                     500 --   F.sub.3 CCOOH 4.0                           
                                      anisole 0.5                         
                                            1/2                           
                                               rt  56 240                 
8  BOC                                                                    
      Et Et POM (6-1)                                                     
                     150 --   F.sub.3 CCOOH 2.5                           
                                      --    1/2                           
                                               rt  67  87                 
9  BOC                                                                    
      Et i-Pr                                                             
            POM (6-2)                                                     
                     450 DCM 3.0                                          
                              AlCl.sub.3 255 mg                           
                                      anisole 1.0                         
                                            1/3                           
                                               -10 67 257                 
20 BOC                                                                    
      Et i-Pr                                                             
            HmCP                                                          
                (6-1)                                                     
                     125 --   F.sub.3 CCOOH 1.5                           
                                      anisole 0.3                         
                                            4/3                           
                                               rt  53  58                 
10 BOC                                                                    
      n-Pr                                                                
         Me POM (6-1)                                                     
                     174 --   F.sub.3 CCOOH 1.5                           
                                      anisole 0.4                         
                                            4/3                           
                                               rt  43  65                 
11 BOC                                                                    
      i-Pr                                                                
         Me POM (6-1)                                                     
                     282 --   F.sub.3 CCOOH 2.5                           
                                      anisole 0.5                         
                                            1  rt  60 145                 
__________________________________________________________________________
 
    
     
                                           TABLE 11                                
__________________________________________________________________________
Reduction of Sulfoxide                                                    
 ##STR19##                                                                
 ##STR20##                                                                
                    S. M.                                                 
                        Solvent                                           
                             Reagent    Time                              
                                           Temp                           
                                               Yld.                       
                                                  Crop                    
No.                                                                       
   R  R.sup.1                                                             
        R.sup.2                                                           
           R.sup.3                                                        
               Exp. No.                                                   
                    (mg)                                                  
                        (ml) (μl)                                      
                                  Subreagent                              
                                        (hr)                              
                                           (°C.)                   
                                               (%)                        
                                                  (mg)                    
__________________________________________________________________________
1  BOC                                                                    
      Et                                                                  
        Me AOE (7-1)                                                      
                    187  DCM 5                                            
                             PBr.sub.3 65                                 
                                  --    2/3                               
                                           -35  88                        
                                                  161                     
2  BOC                                                                    
      Et                                                                  
        Me ECE (7-1)                                                      
                    130 DCM 3                                             
                             PRr.sub.3 44                                 
                                  --    1/2                               
                                           -35 100                        
                                                  127                     
__________________________________________________________________________
 
    
     
                                           TABLE 12                                
__________________________________________________________________________
Sulfoxidation                                                             
 ##STR21##                                                                
 ##STR22##                                                                
                    S. M.                                                 
                        Solvent                                           
                             Reagent      Time                            
                                             Temp                         
                                                 Yld.                     
                                                    Crop                  
No.                                                                       
   R  R.sup.1                                                             
        R.sup.2                                                           
           R.sup.3                                                        
               Exp. No.                                                   
                    (mg)                                                  
                        (ml) (mg)   Subreagent                            
                                          (hr)                            
                                             (°C.)                 
                                                 (%)                      
                                                    (mg)                  
__________________________________________________________________________
1  BOC                                                                    
      Et                                                                  
        Me AOE (8-1)                                                      
                    600 Chf 12                                            
                             m-CPBA 192                                   
                                    --    2/3                             
                                             0   64 394                   
2  BOC                                                                    
      Et                                                                  
        Me ECE (8-1)                                                      
                    180 Chf  5                                            
                             m-CPBA --0   2/3                             
                                             0   70 130                   
__________________________________________________________________________