GB2183236A - 2-(Carbomoyloxymethyl)-1-alkylcarbapenem compounds - Google Patents

Abstract

Compounds of formula (I> <IMAGE> wherein, R<1> is hydrogen or a hydroxy-protecting group; R<2> is lower alkyl; R<3> is hydrogen or lower alkyl; and R<4> is hydrogen or a salt- or ester-forming group, are active against Gram-positive and Gram-negative bacteria.

Description

SPECIFICATION Carbamoyloxymethyialkylcarbapenum compounds The present invention relates to carbamoyloxymethylalkylcarbapenem compounds. More particularly, it relates to (1S,5R,6S)-6-[(1R)- 1 -hydroxyethyl]-2-optionally alkylated carbamoyloxymethyl- 1- alkyl- 1 -carbapen-2-em-3-carboxylic acid and to derivatives thereof, to formulations containing them, to methods of preparing such compounds, and to uses thereof.

Following the discovery of thienamycin by Merck group, powerful antibacterial carbapenem compounds have been extensively researched and developed. A recent trend is to intoduce alkyl at position 1 (e.g., European Patents Nos. 5889, 10316, 30032, 54917, and 60077, U.S.

Patent Nos. 4262010 and 4262009). The compounds of the present invention have not been previously described.

The present applicants introduced a carbamoyloxymethyl group in place of a hetero atom group at position 2 of 1-alkylcarbapenem compounds to find products which are more strongly antibacterial against resistant staphylococci and Escherichia coli than imipenem. Further, the urinary recovery from intravenous administration is almost doubled as compared to representative penem or carbapenem compounds (e.g. impinema, 6-(1-hydroxyethyl)-2-carbamoyloxy-me- thylpen-2-em-3-carboxylic acid) and 6-( 1 -hydroxyethyl)- 1 -methyl-2-thiadiazolythiomethyl- 1 -carbapen-2-em-3-carboxylic acid.

Thus, according to the invention there is provided a compound of formula (I)

wherein R1 is hydrogen or a hydroxy-protecting group; R2 is lower alkyl; R3 is hydrogen or lower alkyl; and R4 is hydrogen or a salt- or ester-forming group.

The compounds of the invention are active against Gram-positive and Gram-negative bacteria.

The hydroxy-protecting group R1 is preferably tri(1C to 5C)-alkylsilyl (e.g. trimethylsilyl, tbutyldimethylsilyl).

The lower alkyl R2 contains preferably 1 to 5, especially 1 to 3 carbon atoms (e.g. methyl, ethyl, propyl).

The lower alkyl R3 contains preferably 1 to 5, especially 1 to 3 carbon atoms (e.g. methyl, ethyl, propyl).

The salt forming group R4 can preferably be one conventional in penicillin and cephalosporin chemistry e.g. a pharmaceutically acceptable ion which may belong to group I to Ill and period 2 to 4 in the Periodic Table. This can preferably be a light metal [e.g. alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium, calcium), or aluminium]. A salt with 1C 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 R4 may be a protecting ester forming group or a pharmaceutical ester forming group and may be one conventional for carboxy protection in penicillin and cephalosporin chemistry and can be introduced and removed without adverse effect on other part of the molecule.The group is preferably 2C to 19C and includes, for example, an optionally substituted 1C to 8C alkyl ester (e.g., methyl, methoxymethyl, ethyl, ethoxymethyl, iodoethyl, propyl, isopropyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, butyl, isobutyl, trichloroethyl, t-butyl, hexyl ester), 2C to 8C alkenyl ester (e.g., vinyl, propenyl, allyl, prenyl ester), 7C to 19C aralkyl ester (e.g., benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenethyl, trityl, di-t-butylhydroxybenzyl, phthalidyl, phenacyl ester), 6C to 12C aryl ester (e.g., phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, indanyl ester), an ester with a 1C to 12C N-hydroxyamino compound (ester with e.g., acetone oxime, acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide), 3C to 12C silyl ester (e.g., trimethylsilyl, t-butyldimethylsilyl, or dimethylmethoxysilyl ester) or 3C to 12C stannyl ester (e.g., trimethylstannyl ester). The group R4 may be further substituted. The protecting ester forming group R4 may be absent in certain group objective compounds. So its structure has not in itself any specific meaning as far 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 ester forming group R4 can preferably be a so-called pharmaceutical ester group, and may include orally or parenterally available 2C to 15C ester groups, for example, a 1-oxygen substituted-2C to 15C alkyl {e.g., straight, brached, cyclic, or partially cyclic alkanolyoxyalkyl (e.g., acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloylxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl), 3C to 15C alkoxycarbonyloxyalkyl (e.g., ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, t-butoxycarbonyloxyethyl, isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyisopropyl), 2C to 8C alkoxyalkyl (e.g., methoxymethyl), 4C to 8C 2-oxacylcloalkyl (e.g., tetrahydrofuranyl, tetrahydropyranyl)}, 8C to 12C aralkyl (e.g., phenacyl, phthalidyl), 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 esters may be optionally further substituted.

In above definition of the symbols, the carbon number referred to includes that for substituent.

Preferable compounds of this invention have R2 as methyl, R1 as hydrogen, R3 as hydrogen or methyl, and R4 as hydrogen sodium, or pivaloyloxymethyl. Such compounds are namely; (1 S,5F,6S)-6-[( R)- 1 -hydroxyethyl]-2-carbamoyloxymethyl- 1 -methyl- 1 -carbapen-2-em-3-carboxylic acid, (1 S,5F,6S)-6-[( 1 -R)-hydroxyethyl]-2-methylcarbamoyloxymethyl- -methyl-l -carbapen-2-em-3carboxylic acid and the sodium salt and pivaloyloxymethyl ester thereof.

The free carboxy-, salt-, or pharmaceutical ester-compound of formula (1) is a potent antibacterial against aerobic or anaerobic bacteria. It may be used as a bacteriocidal, bacteriostatic, disinfecting, or antiperishing agent a bacterial growth inhibitor in human, animal, plant, or perishable subjects, a human or animal growth promoting additive in foodstuff, or an agent for treating or preventing human, veterinary, or poultry infection caused by sensitive bacteria and for testing sensitivity of bacteria to the antibacterial (I).Thus, the said compound (I) is effective against aerobic Gram-positive bacteria, (e.g., Bacillus cereus, Bacillus subtilis, Corynebacterium diphtheriae, Staphylococcus aureus, Staphylococcus epidermis, 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 influenza, 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 enterocoliticas, and anaerobic bacteria (e.g., Chlostridium difficile, Clostridium no vyi, Eubacterium cylindroides, Ba ctero ides fragilis, Fusobacterium nucleatum, Propionibac terium spp., Veillonella parvula).

The compound (I) in the form of a carboxylic acid or a light metal salt (i.e. having R4 as hydrogen or an alkali metal atom) can be administered intravenously, intramuscularly or subcutaneously (as e.g. a solution or suspension), or orally, if required in admixture with an excipient (e.g. solubilizing agent, stabilizer or emulsifying agent). A pharmaceutical ester of formula (I) can be given intravenously, intramuscularly, subcutaneously, orally (as e.g. a capsule, dry syrup, emulsion, powder, solution, suspension, tablet or troche), or topically (as e.g. an ear, nasal, or ocular drug, ointment, injection, pap preparation, spray or suppository).

A protected compound (I) is also useful as a starting material for synthesizing other antibacterials or as an agent for testing the sensitivity of bacteria.

The compounds of the invention may be used in treating or preventing 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 administration of an effective amount of the said compound (I) at a typical human daily dose of 0.1 to 6 gram (injection), 0.4 to 4 gram (orally), or 0.01 to 10 mg (topically), if required in formulation with a conventional additive or coacting substance (e.g., cilastatin, beta-lactamase inhibitor, other antibacterial).

This invention also provides an antibacterial pharmaceutical composition containing the said compound (I) in various enteral or parenteral dosage forms, 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, inhalent, injection, ointment, suspension, syrup, solution). The capsule, granule and tablet may be coated. They can be in a unit dosage form.

The carrier should be harmless to both the compound (I) and patients. Representative examples such a carrier include among others, for a solid preparation, a binder (e.g., acacia, carboxymethylcellulose, gelatin, polyvinylpyrrolidone, sodium alginate, sorbitol, starch, syrup, tra gacanth), 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 laurylfulfate, 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., aluminium stearage 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, or stabilizing agent. The pharmaceutical compositions may be produced conventionally.

The compounds according to the present invention may be prepared as follows; 1) Carbamic ester formation

(wherein R1, R2, R3, and R4 are as defined in Claim 1) (1 S,5R,6S)-6-[( 1 R)- 1 -hydroxyethyl]-2-hydroxymethyl- 1 -alkyl- 1 -carbapen-2-em-3-carboxylic acid or its derivative (II) may be esterified conventionally with a carbamoylating reagent of the formula R3HNCO-Hal or R3NCO (where Hal is halogen) to give Compound (I).

Here, the carbamoylating reagent can be a conventional one (e.g., N-protected carbamoyl halide, cyanate, isocyanate, alkyl isocyanide, alkylcarbamoyl halide). The reagent can conventionally be used, for example, in the presence of a subreagent [e.g., acid scavenger (e.g., aromatic base, tertiary amine), Lewis acid (e.g., aluminium chloride, bis(trialkylstannyl) oxide), or the like].

This reaction may usually be carried to 50"C for 30 minutes to 10 hours.

2) Salt formation A compound (i) having hydrogen as R4 can form a salt compound (I) (wherein R4 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 one 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 may usually be 1 to 10 minutes lower than 50"C, but it may be longer if no appreciable side reaction occurs.

3) Esterification A compound (I) having hydrogen as R4 or its salt can be esterified conventionally with a halide of the ester group represented by the formula R4-Hal (wherein R4 is the ester group and Hal is halogen) in the presence of an acid scavenger or the corresponding diazo compound in an inert solvent to afford the corresponding ester (I) in a manner, for example as given below: a) Reacting e.g. a halide or sulfonate of the ester group with an alkali metal salt of the carboxylic acid at -50"C to 50"C; b) Reacting an alcohol of the ester group with the carboxylic acid or its reactive derivative in the presence of a condensing reagent; or c) Reacting a diazo compound of the ester group with the carboxylic acid at 0 C to 50"C.

An especially important process is esterification to a (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-optionally alkylated carbamoyloxymethyl-1-alkyl-1-carbapen-2-em-3-carboxylic acid pharmaceutical

(wherein Rt, R2, R3, and R4 are as defined in Claim 1) ester (I) by treating the corresponding (1 S,5R,6S)-6-[( 1 R)- 1 -hydroxyethyl]-2-hydroxymethyl- 1 -alkyl- 1 -carbapen-2-em-3-carboxylic acid (IV) or its salt with an esterifying reagent of the formula R4-Hal (wherein Hal is halogen and R4 is a pharmaceutical ester group).

4) Deprotection of protected carboxy A compound (I) having protected carboxy as R4 may be deprotected conventionally in an inert solvent to give carboxylic acid (I). This deprotection includes, for example, the following proce dures: a) A highly reactive ester 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, sulfonylether, or the like as a carboxyprotecting group may be deprotected by treatment for example, with a mineral acid, Lewis acid (e.g., aluminium 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.

5) Hydroxy deprotection A compound (I) having trialkylsilyl as R' can be deprotected with acid to obtain the corresponding 6-( 1 -hydroxyethyl)-2-carbamoyloxymethyl- 1 -alkyl- 1 -carbapen-2-em-3-carboxylic acid or its derivative (III) as follows (wherein R1 is trialkylsilyl, and R2, R3, and R4 are as defined above):

The acid can be a mineral acid or trifluoroacetic acid or silicic acid.

6) Starting materials The starting material (1 S,5R,6S)-6-(1 R)- 1 -hydroxyethyl]-2-hydroxymethyl- 1 -alkyl- 1 -carbapen-2em-3-carboxylic acid or its derivative (II), can be prepared, for example, from (3S,4R)-3-[(1 R)-1-t- butyldimethylsilyloxyethyl]-4-acetoxy-2-azetidinone [according to W. J.Leanza et al.: Tetrahedron, volume 39, page 2505 (1983)] by the following successive treatments: 1) [3-carbon chain introduction] with triphenylcrotyltin and boron trifluoride in dichloromethane at room temperature overnight to give (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 -buten-3-yl)-2-azetidinone, 2) [epoxidation] with m-chloroperbenzoic acid in dichloromethane overnight at room temperature to give (3S,4R)-3-[(4R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 ,2-epoxy-3-butyl)-2-azetidinone; 3) [epoxide fission] with boron trifluoride etherate in a mixture of dichloromethane and acetic acid at 0 C for 2 hours to give (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxy-ethyl]-4-( 1 -acetoxy-2-hydroxy-3-butyl)-2- azetidinone; 4) [oxidation] with dimethyl sulfoxide, trifluoroacetic anhydride, and triethylamine in dichloromethane at --78"C for 1 hour to give (3S,4R)-3-[(1R)-1-t-butyidimethylsilyloxyethyl]-4-(1- acetoxy-2-oxo-3-butyl)-2-azetidinone; 5) [glyoxylate addition] with glyoxylic acid p-methoxybenzyl ester and triethylamine in tetrahydrofuran at room temperature overnight to give (3S,4R)-3-[(1R)- 1 -t-butyldimethylsilyoxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 hydroxymethyl)-2-azetidinone; 6) [chlorination] with thionyl chloride and 2,6-lutidine in tetrahydrofuran at --60"C for 1.5 hours to give (3S,4R)-3-[(1R)-1-t-butyidimethylsilyoxyethyl]-4-[(3R)-1-ace- toxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -chloromethyl)-2-azetidinone; 7) [ylide formation] with triphenylphosphine and 2,6-lutidine in dioxane at room temperature overnight to give (3S,4R)-3-[(1 R)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methox ybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidione; 8) [acetoxy hydrolysis] with sodium methoxide in methanol at OOC for 1 hour to give (3S,4R)-3-[(1R)-1-t-butyidimethylsilyoxye- thyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxcarbonyl- 1 -triphenylph6sphoranylide- nemethyl)-2-azetidinone; 9) [silyl hydrolysis] with concentrated hydrochloric acid in acetonitrile at 0 C for 2 hours to give (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-butyl]- l-(l-p- methoxybenzyloxy-carbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone; and 10) [ring culture] heating in toluene at 90"C for 1.5 hours to give (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-1 methyl-2-hydroxymethyl- 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester.

Another pathway includes a successive treatment of the product of 7) via 11) [silyl hydrolysis] with hydrochloric acid in acetonitrile at 0 C for 3 hours to give (3S,4R)-3-[(1R)-1-hydroxyethyl]-4 [(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenZylphosphoranylideneme- thyl)-2-azetidinone; and 12) [ring closures heating in toluene at 95"C for 1.5 hours to give ( 1 S,5R,6S)-6-[(1 R)- 1 -hydroxyethyl]- 1 -methyl-2-acetoxymethyl- 1 -carbapen-2-em-3-carboxylic acid pmethoxybenzyl ester.

Alternatively, the product 7) may be treated via 14) [silyl hydrolyis] with concentrated hydrochloric acid in acetonitrile at OOC for 2 hours to give (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(3R)-1- acetoxy-2-oxo-3-butylj- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranilidenemethyl)-2-azetidinone; 15) [trimethylsilyl introduction] with trimethylsilyl chloride and triethylamine in dichloromethane at 0 C for 30 minutes to give (3S,4R)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(3R)-1-acetoxy- 2-oxo-3-butyl- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (4.9 g); 16) [acetoxy hydrolysis] with sodium methoxide in methanol at --20"C to give (3S,4R) 3-[(1R)-1 -trimethylsilyoxyethyl]-4-( 1 -hydroxy-2-oxo-3-butyl)-2-azetidinone; and 17) [ring closure and silyl hydrolysis] heating in toluene at 96"C for 2 hours to give (1S,5R,6S)-6-[(1 R)-l-trimethyl- silyloxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester and its work up with hydrochloric acid gives (1S,5R,6S)-6-[(1 R)-hydroxyethyl]-l -methyl-2-hydrox- ymethyl- 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester.

7) Reaction conditions The synthesis 1) to 6) may preferably be carried out at -700C to 100"C, especially -30"C to 50"C, for 10 minutes to 30 hours. Preferably, they 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 suitable industrial solvents or mixtures thereof.

8) Work up The objective products can be recovered from the reaction mixture and 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).

The following Preparation and Examples illustrate the embodiment of the invention. The physical constants of the products are listed in the tables in which IR shows wave numbers in cm~1 scale and NMR shows J values (chemical shift) in ppm scales and J values (coupling constant) in Hz scale. The examples and preparations are non-limiting in nature.

(Abbreviations) Ac=acetyl; Bu=butyl; ExNo.=Example No.; Me=methyl; nd=not determined; pH=phenyl; PMB=p-methoxybenzyl; POM=pivaloyloxymethyl; Prep No.=Preparation No.; t-=tertiary-; and TMS=tnmethylsilane.

PREPA RA TIONS Preparation 1 [3-carbon chain introduction] A solution of (3S,4R)-3-[( 1 F)- 1 -t-butyldimethylsilyloxymethyl]-4-acetoxy-2-azetidinone (9.1 g, 32 millimole, prepared according to the method of W. J. Leanza et al.: Tetrahedron, volume 39, page 2505 (1983)), triphenylcrotyltin (16.7 g), and boron trifluoride etherate (5.2 ml) in dichloromethane (100 ml) is stirred overnight at room temperature. The reaction mixture is filtered and the filtrate is washed with saturated aqueous sodium hydrogen carbonate, and con-centrated.

The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (4:1) to give (3S, 4R)-3-[( IR)- 1 -t-butyl-dimethylsilyloxyethyl]-4-( 1 -buten-3-yl)-2-azetidinone (amorphous, 7.8 g, 1:1 mixture of isomers at position 3 of 4-side chain).

Preparation 2 [epoxidation] A solution of (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxethyl]-4-( 1 -buten-3-yl)-2-azetidinone (1:1 mixture of isomers at position 3 of 4-side chain) (13.5 g) and m-chloroperbenzoic acid (20.5 g) in dichloromethane (100 ml) is stirred over-night at room temperature. The product is isolated by a conven-tional method to give (3S,4R)-3-[(4R)-1 -t-butyldimethylsilyloxy-ethyl]-4-( 1,2-epoxy-3-bu- tyl)-2-azetidinone (a mixture of isomers) (14 g).

Preparation 3 [epoxide fission] A solution of (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-ll ,2-epoxy-3-butyl)-2-azetidinone (a mixture of isomers) (14 g) and boron trifluoride etherate (5.98 ml) in a mixture of dichloromethane (50 ml) and acetic acid (50 ml) is stirred at 0 C for 2 hours. The reaction mixture is washed with water, the organic layer is taken and concentrated under reduced pressure. The residue is purified by chromatography over silica gel using a mixture of benzene and ethyl acetate (1:1) to give (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 -acetoxy-2-hydroxy-3-butyl)-2-azetidinone (a mixture of isomers, 10 g).

Preparation 4 [oxidation] To a solution of (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 -acetoxy-2-hydroxy-3-butyl)- 2-azetidinone (a mixture of isomers at 4-side chain, 6.2 g, 17 millimoles), dimethyl sulfoxide (3.6 ml), and trifluoroacetic anhydride (3.5 ml) in dichloromethane (24 ml) is added triethylamine (7.7 ml) and the mixture is stirred at -78"C for 1 hour, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and concentrated in vacuum. The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (2: 1) to give (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 -acetoxy-2-oxo-3-butyl)-2-azetidinone (mixture of isomers at 4-side chain, 4.0 g).

Preparation 5 [glycolate addition] A solution of (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-( 1 -acetoxy-2-oxo-3-butyl)-2-atetidi- none (1:1 mixture of isomers at position 3 of 4-side chain 4.9 g), glyoxylic acid p-methoxybenzyl ester (4.5 g) and triethylamine (2.4 ml) in tetrahydrofuran (20 ml) is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium suifite, and concentrated. The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:1) to give (3S,4R)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]- 4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -hydroxymethyl)-2-azetidinone (amorphous, a mixture of isomers at positions 1 and 4, 7.7 g).

Preparation 6 [chlorination] A solution of (3S,4R)-3-[( iF)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1--acetoxy-2-oxo-3-butyl]- 1 (1 -p-methoxybenzyloxycarbonyl- 1 -hydroxymethyl)-2-azetidinone (a mixture of isomers at positions 1 and 4, 7.7 g), thionyl chloride (1.5 ml), and 2,6-lutidine (5.6 ml) in tetrahydrofuran (20 ml) is stirred at --60"C for 1.5 hours. The mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and concentrated in vacuum to give (3S,4R)-3-[(1R)-1-t- butyldi-methylsilyloxyethyl]-4-[(3R)-l -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 chloromethyl-2-azetidinone (amorphous, a mixture of isomers in side chain at positions 1 and 4, 7.3 g).

Preparation 7 [ylide formation] A solution of (3S,4R)-3-[( 1 F)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 (1 -p-methoxybenzyloxycarbonyl- 1 -chloromethyl-2-azetidinone (a mixture of isomers in side chain at positions 1 and 4, 7.3 g), triphenylphosphosphine (5 g), and 2, 6 lutidine (5.4 ml) in dioxane (20 ml) is let stand at room temperature overnight. The mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and concentrated.The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (4: 1) to give (3S,4R)-3-[(1 R)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxyben zyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (3.7 g).

Preparation 8 [acetoxy hydrolysis] A solution of (3R,4R)-3-[(1 R)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 (1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethy)-2-azetidinone (1.0 g) in methanol (20 ml) is treated with sodium methoxide (1 molar equivalent) at 0 C for 1 hour. The reaction mixture is diluted with ethyl acetate (100 ml), washed with water, concentrated in vaccum, and purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:1) to give (3S,LeR)-3-[(1R)-1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-butyl]- 1-(1- p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (0.676 g).

Preparation 9 [silyl deprotectioni A solution of (3S,4R)-3-[( 1 F)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-butyl]- 1 (1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (0.676 g) and concentrated hydrochloric acid (0.6 ml) in acetonitrile (20 ml) is stirred at 0 C for 2 hours. The reaction mixture is diluted with ethyl acetate (100 ml), washed with saturated aqueous sodium hydrogen carbonate, and concentrated in vacuum to give (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2azetidinone (0.52 g).

Preparation 10 [ring closure] A solution of (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- 1 -hydroxy-2-oxo-3-buty]- 1 -(1 -p-methoxy benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (0.52 g) in toluene (50 ml) is kept at 90"C for 1.5 hours to cyclize. The reaction mixture is concentrated and the residue is purified by silica gel chromatography using a mixture of ethyl acetate, dichloromethane, and acetonitrile (1: 1: 2) to give (1 S,5R,6S)-6-[(1 R)- 1 -hydroxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.152 g).

Preparation 11 [silyl hydrolysis] A solution of (3S,4R)-3-[( iF)- 1 -t-butyldimethylsilyloxyethyle]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 (1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphorantylidenemethyl)-2-azetidinone (0.44 g), prepared by the method of Preparation 7, and concentrated hydrochloric acid (0.4 ml) in acetonitrile (15 ml) is stirred at 0 C for 3 hours to give (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- l-acetoxy-2- oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (0.37 g).

Preparation 12 [ring closure] A solution of (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-a (0.34 g) in toluene (34 ml) is heated at 95"C for 1.5 hours to give (1S,5R,6S)-6-[(1 R)-l -hydroxyethyl]-l -methyl-2-acetoxyme- thyl-1-carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.28 g).

Preparation 13 [silyl hydrolysis] A solution of (3 R, 4R)-3-[( 1 R)- 1 -t-butyldimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 (1-p-methoxybenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (5.8 g), prepared by the method of Preparation 7 and concentrated hydrochloric acid (6 ml) in acetonitrile (200 ml) is stirred at 0 C for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and concentrated in vacuum to give (3S,4R)-3-[( 1 R)- 1 -hydroxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- 1 -(1 -p-methoxy-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (4.9 g).

Preparation 14 [silyl introduction] To a solution of (3S,4R)-3-[(1R)-1 -hydroxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]- l-(l-p-methox- ybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (4.9 g) in dichloromethane (100 ml) are added trimethylsilyl chloride (2 ml) and triethylamine (2.4 ml) and the mixture is stirred at 0 C for 30 minutes. The reaction mixture is washed with water and concentrated to give (3S,4R)-3-[(1R)-1 -trimethylsilyloxyethyl]-4-[(3R)- 1 -acetoxy-2-oxo-3-butyl]-( 1 -p-methoxybenzy- loxycarbonyl-1 -triphenylphosphoranylidenemethyl)-2-azetidinone (4.9 g).

Preparation 15 [acetoxy hydrolysis] To a solution of (3S,4R)-3-[(1R)-1 -trimethylsilyloxyethyl]-4-1(3R)- 1 -acetoxy-2-oxo-3-butyl]- l-(l-p- methoxybenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (4.9 g) in methanol (30 ml) is added sodium methoxide (0.5 molar equivalents) at -200C. The reaction mixture is diluted with ethyl acetate, washed with water, and concentrated. The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:1) to give (3S,4R)-3-[(1R)-1 trimethylsilyloxyethyl]-4-[( 1 R)- 1 -hydroxy-2-oxo-3-butyl]- 1 -(1 -p-methoxybenzyloxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-2-azetidinone (amorphous, 3.4 g).

Preparation 16 [ring closure] A solution of (3S,4R)-3-[(1R)-1 -trimethylsilyloxyethyl]-4-[( 1 F)- 1 -hydroxy-2-oxo-3-butyl]- 1 -(1 -p- methoxybenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-2-azetidinone (2 g) in toluene (20 ml) is kept at 96"C for 2 hours. The reaction mixture is concentrated and the residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (2:1) to give (1 S,5R,6S)-6-[(1 R)- 1 -trimethylsilyloxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen-2-em-3-carboxylic acid and p-methoxybenzyl ester (0.960 g).This product dissolved in ethyl acetate is shaken with hydrochloric acid in methanol to give, after usual work up, (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester identical with the product of Preparation 10 in quantiative yield.

EXAMPLES Example 1 [carbamoyl introduction] A solution of (1 S,5F,6S)-6-[( iF)- 1 -hydroxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen-2-em-3carboxylic acid p-methoxybenzyl ester (0.152 g) in dichloromethane (3 ml) and trichloroacetyl isocyanide (0.51 ml, 1 equivalent) is stirred at --20"C for 1.5 hours. The reaction mixture is diluted with ethyl acetate (20ml), washed with water, and concentrated under reduced presure.

The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:2) to give (1S,5R,6S)-6-[(1R)- 1 -hydroxyethyl]-1 -methyl-2-(N-trichloroacetylcarbamoyloxy)methyl 1 -carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.124 g) and the starting material (0.033 g).

Example 2 [carbamoyl deprotection] A mixture of (1 S,5R,6S)-6-[(1 R)- 1 -hydroxyethyl]- 1 -methyl-2-(N-trichloroacetylcarbamoyloxy)me- thyl-1-carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.124 g) and silica gel (0.20 g) in methanol (5 ml) is stirred at room temperature overnight and filtered to remove solid material.

The filtrate is diluted with ethyl acetate (20 ml), washed with water, and concentrated in vacuum. The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:3) to give (1S,5R,6S)-6-[(1R)- l-hydroxyethyl]-l -methyl-2-carbamoylmethyl- l-car- bapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.052 9).

Example 3 [carboxy deprotection] A solution of (1 S,5R,6S)-6-[(1 R)-1 -hydroxyethyl]-1 -methyl-2-carbamoyloxymethyl-1 -carbapen-2- em-3-carboxylic acid p-methoxybenzyl ester (0.052 g) and aluminum chloride (0.035 g) in a mixture of anisole (4 ml) and dichloromethane (1 ml) is stirred at --40"C for 1 hour. The reaction mixture is diluted with 0.01 M-phosphate buffer (pH 7.0, 5 ml) containing sodium hydrogen carbonate and filtered. The filtrate is purified by chromatography over stylene-divinylbenzene copolymer adsorbent (Diaion HP-20) to give (1S,5R,6S)-6-[(1 R)-l -hydroxyethyl]-l -methyl-2-carba- moyloxymethyl-1-carbapen-2-em-3-carboxylic acid sodium salt (0.02 g).

Example 4 [N-methylcarbamoyl introduction and silyl removal] A solution of (1 S,5R,6S)-6-[(1 R)- 1 -trimethylsilyloxyethyl]- 1 -methyl-2-hydroxymethyl- 1 -carbapen2-em-3-carboxylic acid p-methoxybenzyl ester (0.309 g) in tetrahydrofuran (5 ml), methyl isocyanide (0.287 ml), and bis(tri-n-butylin) oxide (0.026 ml) is stirred at room temperature for 2 hours. The reaction mixture is diluted with ethyl acetate (30 ml), washed with diluted hydrochloric acid, and the organic layer is taken. The layer is concentrated in vacuum.The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:2) to give (iS, 5F,6S)-6-[( 1 R)- 1 -hydroxyethyl]- 1 -methyl-2-N-methylcarbamoyloxymethyl- 1 -carbapen-2-em-3carboxylic acid p-methoxybenzyl ester (amorphous, 0.372 g).

Example 5 [carboxy deprotection] A solution of (1S,5R,6S)-6-[(1R)- I-hydroxyethyll-l -methyl-2-N-methylcarbamoyloxymethyl- l-car- bapen-2-em-3-carboxylic acid p-methoxybenzyl ester (0.372 g) and aluminum chloride (0.49 g) in a mixture of anisole (5 ml) and dichloromethane (2 ml) is stirred at -40"C for 1 hour. The reaction mixture is diluted with 0.01M-phosphate buffer (pH 7.0, 5 ml) containing sodium hydrogen carbonate (1.11 g), and filtered. The filtrate is purified by chromatography over stylene-divinylbenzene copolymer adsorbent (Diaion HP-20) to give (1S,5R,6S)-6-[(1R)-1-hydroxye thyl]-1-methyl-2-N-methyl-carbamoyloxymethyl-1-carbapen-2-em-3-carboxylic acid sodium salt (0.173 g).

Example 6 [pharmaceutical ester] To a solution of (1 S,5R,6S)-6-[(1 R)- 1 -hydroxyethyl]- 1 -methyl-2-carbamoyloxymethyl- 1 -carbapen2-em-3-carboxylic acid sodium salt (0.060 g) in dry dimethylformamide (0.3 ml) stirred under nitrogen at --30"C is added iodomethyl pivalate (0.05 ml). The mixture is stirred for 1.5 hours and diluted with ethyl acetate and diluted aqueous sodium hydrogen carbonate. The organic layer is taken, washed with water, dried and concentrated in vacuum. The residue is purified by silica gel chromatography using a mixture of benzene and ethyl acetate (1:1 to 1:4) to afford (1 S, 5F,65)-6-[( 1 R)- 1 -hydroxyethyl]- 1 -methyl-2-carbamoyl-oxymethyl- 1 -carbapen-2-em-3-carboxylic acid pivaoyloxymethyl ester (0.027 g).

Table I Azetidinone compounds (Part I)

No R1 (R)-R O@ R5 R6 IR # (CHCl3) : cm-1 NMR # (CDCl3) : ppm Prep Na 1 -Sime3t-Bu -CHCH-CH3 -H nd. 0.07 (s, 6H). 0.87(s. 9H). 0.95(d, J=7Hz. 2 3H). 1.16(d. J=6Hz. 3H). 0.30-1.70 (m.

1H). 2.45-2.90 (m, 4H). 3.60 (m, 1H).

4.10 (m. 1H). 6.30 (hr. 1H).

2 -SiMe,t-Be CHMeCHOHCH, OAc -H nd. 0.07 (s, 6H), 0.87 (s, 9H). 0.95(d, J=7Hz. 3 3H). 1.25(d, J=6Hs, 3H). 2.10(s. 3H).

2.50(m. III). 2.70(br. 1H). 3.50-4.50(m.

5H). 6.25(br. 1H).

3 -SiMe,t-Be -CHMeCOCH3OAc(R) -C(=PPh3)COOPMB 2920, 1740. 1610. nd. 7 Table 1 Azetidinone compounds (Part 2)

No R1 (R)-R O@ R5 R6 IR # (CHCl3) : cm-1 NMR # (CDCl3) : ppm Prep Na 4 -SiMe3t-Bu -CHMeCOCH3OH (R) -C(=PPh3)COOPMB 1750, 1635, 1605. nd. 8 5 -H -CHMeCOCH3OH(R) -C(=PPh3)COOPMB 3300, 1730, 1620. nd. 9 6 -H -CHMeCOCHOAc (R) -C(=PPh3)COOPMB 3400. 1740. 13 7 -SiMe3 -CHMeCOCH3OAc (R) -C(=PPh3)COOPMB 1740. 14 8 -SiMe3 -CHMeCOCH3OH (R) -C(=PPh3)COOPMB 3500. 1740. 15 Table I Carbapenem compounds (Part 1)

No R R R30 R4 IR#(CHCl2):cm-1 NMR # (CDCl3):ppm Prep [(R)-RO] No 1 -H -Me H -PMB 3350. 2950. 1770. 0.16 (d. J=7Hz, 3H). 1.30(d. J=6Hz, 3H). 2.00(brs, 2H), 10 1605. 3.21(m, 1H). 3.27(dd, J=2Hz. J=6Hz, 1H). 3.80(s. 3H).

4.10-4.35(m, 2H). 4.35. 4.64 (ABq. J=8Hz, 2H), 5.21(s, 2H).

6.85, 7.35(A3B2q J=9Hz. 4H).

2 -H -Me COMe -PMB 3450. 1780. 1740. 1.15 (d. J=7Hz, 3H), 1.30(d, J=6Hz, 3H). 2.00(brs. 1H).

1720. 2.07(s, 3H), 3.22 (m, 1H), 3.28(dd, J=2Hz, J=6Hz, 1H). 12 3.80(s, 3H), 4.05-4.35(m, 2H). 4.85, 5.35 (ABq. J=8Hz, 2H).

521(s. 2H). 6.85, 7.35(A2B2q. J=9Hz. 4H).

Table I Carbapenem compounds (Part 2)

No R R R30 R4 IR#(CHCl2):cm-1 NMR # (CDCl3):ppm ExMn [(R)-RO] 3 -SiMe, -Me H -PMB 3400, 1775. 0.06(s, 6H). 0.10(s, 9H). 1.16(d. J=7Hz. 3H), 1.20(d, Prep J=6Hz. 3H). 3.25 (m, 1H). 3.30(dd. J=2Hz. J=6Hz. 1H). 16 3.80 (s. 3H). 4.02-4.30(m, 2H). 4.35, 4.61 (ABq. J=8Hz. 2H).

4.40 (br. 1H). 5.21(s, 2H). 6.85, 7.35(A,B,q. J=9Hz, 4H).

4 -H -Me CONCOCCl3 -PMB 3450, 2950, 1800 0.18(d. J=7Hz, 3H). 1.32(d, J=6Hz, 3H). 2.00(brs, 1H). 1 1775, 1725, 1605 3.25(m, 1H). 3.30(dd, J=Hz, J=6Hz, 1H). 3.80 (s. 3H).

4.05-4.35 (m, 2H), 5.00. 5.61(ABq. J=8Hz. 2H). 5.21(s. 2H).

6.85. 7.35(A2B2q. J=9Hz, 4H). 8.40(bra, 1H).

5 -H -Me CONH3 -PMB 3450, 1775. 1720 0.14(d, J=7Hz, 3H), 1.27(d, J=6Hz, 3H). 2.50(brs. 2H). 2 1605. 3.20(m, 1H), 3.25(dd, J=2Hz. J=6Hz, 1H). 3.80(s, 3H).

4.05-4.35(m,2H). 4.85 (5.33(ABq. J=8Hz. 2H). 5.10(brs.

1H). 5.20(s, 2H). 6.85, 7.35 (A2B2q. J=9Hz. 4H).

6 -H -Me CONH3 -Na UV(H2O)#:269mm 1.56 (d. J=7Hz. 3H). 1.72(d, J=6Hz. 3H). 3.70(m, 1H). 3 [&alpha;]@51(H2O) 3.87(dd. J=2 Hz. J=6Hz. 1H). 4.55-4.75(m, 2H). 5.18, 5.65(ABq. J=8Hz. 2H). (3O. TMS external standard) Table I Carbapenem compounds (Part 3)

no r r r30 r4 ir#(chcl2):cm-1 nmr # (cdcl3):ppm exmn [(r)-ro] 7 -H -Me CONHMe -PMB 3450. 1775. 1720. 1.14(d. J=7Hz. 3H). 1.28(d. J=6Hz. 3H). 2.60(br. 1H). 4 2.75 (d. J=4 Hz. 3H). 3.20 (m. 1H). 3.25(dd, J=2Hz. J=6Hz.

1H). 3.80(s. 3H). 4.04-4.30(m. 2H). 4.80(m. 1H). 4. 85.

5.35 (ABq. J=8Hz. 2H). 5.20(s. 2H). 6.85. 7.35 (A,B,q.

J=9Hz. 4H).

8 -H -Me CONHMe -Na UV(H,O) #:270nm 1.56 (d. J=7Hz. 3H). 1.73 (d. J=6Hz. 3H). 3. 16(s. 3H). 5 (&alpha;]@47.(H3O) 3.70(m. 1H). 3.88(dd. J=2Hz. J=6Hz. 1H). 4.50-4.75(m, 2H).

5.19. 5.67 (ABq. J=8 Hz. 2H). (D2O. TMS external standard) 9 -H -Me CONH2 -POM 3550. 3430. 1780. 1.17 (d. J=7Hz. 3H). 1.22 (s. 9H). 1.30(d. J=6.3Hz. 3H). 6 1719. 1676. 1730. 1.8-2.6(brs. 1H). 3.13-3.48(m. 1H). 3.25 (dd, J=3Hz.

1586. 1284 (H3O). J=6.3Hz. 1H). 4.06-4.36(m, 1H). 4.23(dd. J=7Hz. J=3Hz.

1H). 4.88 (brs. 2H). 4.82, 5.34(ABq. 15 Hz. J=2Hz. 2H).

5.81, 5.95 (ABq. 5.8Hz. J=2Hz. 2H).

Claims (29)

1. A compound of the formula (I)

wherein, R' is hydrogen or a hydroxy-protecting group; R2 is lower alkyl; R3 is hydrogen or lower alkyl; and R4 is hydrogen or a salt- or ester-forming group)

2. A compound as claimed in Claim 1 wherein R' is hydrogen or trialkylsilyl.

3. A compound as claimed in Claim 1 or Claim 2 wherein R2 is 1C to 5C alkyl.

4. A compound as claimed in any one of Claims 1 to 3 wherein R3 is hydrogen or 1C to 5C alkyl.

5. A compound as claimed in any one of Claims 1 to 4 wherein R4 is hydrogen or a light metal atom, or an optionally substituted 1C to 8C alkyl, 2C to 8C alkenyl, 7C to 19C alkyl, 6C to 12C aryl, 1C to 12C iminooxy, 3C to 12C silyl, or 3C to 12C stannyl group.

6. A compound as claimed in any one of Claims 1 to 5 wherein R2 is methyl.

7. A compound as claimed in any one of Claims 1 to 6 wherein R3 is hydrogen or methyl.

8. A compound as claimed in any one of Claims 1 to 7 wherein R4 is hydrogen, sodium, pivaloyloxymethyl, or p-methoxybenzyl.

9. A compound that is (1S,5R,6S)-6-[(1R)- 1 -hydroxyethyl]-2-carbamoyloxymethyl- l-methyl-l- carbapen-2-em-3-carboxylic acid.

10. A compound that is (1 S,5R,6S)-6-[( 1 F)- 1 -hydroxyethyl]-2-methylcarbamoyloxymethyl- 1 - methyl-l -carbapen-2-em-3-carboxylic acid,

11. A pivaloyloxymethyl ester or sodium salt of a compound as claimed in Claim 9 or Claim 10.

12. A compound as claimed in Claim 1 wherein R', R2, R3, and/or R4 are/is selected from groups referred to hereinbefore in exemplification thereof.

13. A compound as claimed in Claim 1 and specifically referred to hereinbefore.

14. A process for preparing a compound as claimed in claims (1) which comprises reacting a compound of formula (II) or a derivative thereof with a reagent of formula R3NHCO-Hal or R3NCO wherein Hal is halogen.

15. A process as claimed in Claim 14 wherein the reagent is an N-protected carbamoyl halide, cyanate, or iso-cyanate or an alkyl isocyanide or alkylcarbamoyl halide.

16. A process as claimed in Claim 14 or Claim 15 wherein the reaction is carried out in the presence of an acid scavenger or Lewis acid in a solvent at 0 C to 50"C for 30 minutes to 10 hours.

17. A process as claimed in any one of Claims 14 to 16 wherein an R4 ester product is deprotected with Lewis acid and a cation scavenger to give free carboxylic acid and treated with a base to give a salt.

18. A process for preparing a compound as claimed in Claim 1 which comprises reacting a compound of formula (III) or a derivative thereof with an acid

(wherein R' is trialkylsilyl).

19. A process for preparing an ester as claimed in Claim 1 which comprises reacting a compound of formula (IV) or a salt thereof with an esterifying reagent of the formula R4-Hal (wherein Hal is halogen and R4 is a physiologically acceptable ester forming group):

20. A process for preparing a compound as claimed in claim 1 wherein R4 is a salt forming goup which comprises treating a compound of formula I wherein R4 is hydrogen with a base or with a salt of a weakly acidic carboxylic acid in an ion exchange reaction.

21. A process as claimed in any one of claims 14 to 20 and substantially as hereinbefore described.

22. A process as claimed in any one of claims 14 to 20 and substantially as hereinbefore described in any one of the Examples.

23. A pharmaceutical or veterinary formulation which comprises a compound as claimed' in any one of claims 1 to 13 formulated for pharmaceutical or veterinary use respectively.

24. A formulation as claimed in claim 23 also comprising an acceptable diluent, carrier or excipient.

25. A formulation as claimed in claim 23 or claim 24 and in unit dosage form.

26. A pharmaceutical or veterinary formulation as claimed in any one of claims 23 to 26 and substantially as hereinbefore described.

27. A compound as claimed in any one of claims 1 to 13 for use as a bacteriocidal, bacteriostatic, disinfecting, or antiperishing agent, a bacterial growth inhibitor in human, animal, plant, or perishable subjects, a human or animal growth promoting additive in foodstuff, or an agent for treating or preventing, human veterinary, or poultry infection caused by sensitive bacteria or for testing sensitivity of bacteria

28. A compound as claimed in claim 27 for use in a daily dosage of 0.01 mg to 6 g.

29. The use of a compound as claimed in any one of claims 1 to 13 in the preparation of a medicament for use in the treatment of bacterial infection.