HK1059435B - Coupling process and intermediates useful for preparing cephalosporins - Google Patents

Description

Coupling process and intermediates for the preparation of cephalosporins

Background

The present invention relates to a novel process for the preparation of 3-cyclic ether substituted cephalosporins. The invention also relates to novel processes for the preparation of zwitterionic, p-nitrobenzyl and allyl esters useful in the preparation of cephalosporins. The invention also relates to 3-cyclic ether substituted cephalosporins. These compounds have certain beneficial properties, such as crystalline form and high enantiomeric excess (e.e.).

The 3-cyclic ether substituted cephalosporins prepared by the process of the present invention have prolonged and high levels of antibacterial activity and good parenteral absorption in humans and animals. The 3-cyclic ether substituted cephalosporins prepared by the process of the present invention comprise a cyclic ether substituent at the 3-position of the cephalosporin nucleus.

GB 1405758 describes an alternative process for the preparation of certain 3-ring-ether substituted cephalosporins.

J. antibiotics (1994), vol.47(2), page 253 and WO 92/01696 also describe alternative processes for the preparation of compounds of formula (I) as defined herein below and compounds for use in such processes.

U.S. Pat. Nos. 6,020,329 and 6,077,952 describe salts, polymorphs, solvates and hydrates of 3-cyclic ether substituted cephalosporins.

U.S. Pat. No. 6,001,997 describes an alternative preparation of 3-cyclic ether substituted cephalosporins.

U.S. provisional patent application entitled "Process and ester derivatives for the preparation of cephalosporins", filed on App. 11/30/2000, mentions intermediates and processes for the preparation of 3-cyclic ether substituted cephalosporins.

Each of the above publications, patents and patent applications is hereby incorporated by reference in its entirety.

The present inventors have discovered a novel compound of formula I as defined herein below. The present inventors have also discovered a high yield process for preparing the compound of formula I.

Summary of The Invention

The invention relates to a preparation method of 3-cyclic ether substituted cephalosporin shown in formula I or pharmaceutically acceptable salt thereof

Wherein

Group CO₂R¹Is a carboxylic acid or a salt of a carboxylic acid; and

R²having the formula:

wherein

A¹Is selected from C_5-10Aryl radical, C_1-10Heteroaryl and C_1-10A heterocyclic group;

A²is hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_6-10Aryl radical, C_1-6Alkyl (CO) (C)_1-6) alkyl-O-, HO (CO) (C)_1-6) Alkyl, mono (C)_6-10Aryl) (C_1-6Alkyl), di (C)_6-10Aryl) (C_1-6Alkyl) or tri (C)_6-10Aryl) (C_1-6Alkyl groups);

the method comprises reacting a compound of formula II

With a compound of formula III in the presence of a solvent and a base:

R²L III；

wherein

R²As defined above, and L is a leaving group. Optionally, the above process may be carried out in the presence of a coupling agent and a catalyst.

Preferably the group OA of the compound of the formula III²In the cis position of the amide bond, i.e., the preferred Z-configuration.

Suitable solvents for the above process for converting a compound of formula II to a compound of formula I of the present invention include water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1, 2-dichloroethane or mixtures thereof. In one embodiment of the invention, the solvent is tetrahydrofuran. In another embodiment of the invention, the solvent is ethyl acetate. Preferably, the solvent is water, acetone or a mixture thereof. More preferably, the solvent is a mixture of acetone and water. Most preferably, the solvent is a 1.3: 1 mixture of acetone and water.

Suitable bases for the above conversion in the process of the invention include diisopropylethylamine or sodium hydroxide. Preferably, the base is sodium hydroxide, most preferably 15% aqueous sodium hydroxide.

Suitable coupling agents for use in the above-described transformations of the invention include N, N ' -diethylcarbodiimide, N ' -dipropylcarbodiimide, N ' -diisopropylcarbodiimide, N ' -dicyclohexylcarbodiimide, N-ethyl-N ' - [3- (dimethylamino) propyl ] carbodiimide, N ' -carbonyldiimidazole or N, N ' -carbonyldithiazole. A preferred coupling agent is N, N' -dicyclohexylcarbodiimide. Preferably, the above transformation is carried out in the absence of any coupling agent.

Suitable catalysts for the above-described reactions of the present invention include Lewis acids. Suitable lewis acids are selected from boron trihalides such as boron tribromide and aluminium halides such as aluminium chloride. Preferably the above conversion is carried out in the absence of any catalyst.

The above-described conversion of the present invention may be carried out at a temperature of from about-40 ℃ to about +30 ℃, preferably from about +20 ℃ to about +30 ℃. The above process may be carried out for a period of about 1 hour to about 24 hours, preferably about 3 hours.

Suitable leaving groups L for compounds of formula III above in the above transformations include hydroxy, halogen, azido, mono (C)_1-6Alkyl) carbonate, (C)_1-6Alkyl) carboxylic acid esters, (C)_6-10Aryl) carboxylates, mono (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_1-6Alkyl) thiophosphate (C)_1-6Alkyl) sulfonyl, mono (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, di (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, (C)_1-6Alkyl) - (CO) -S-, cyano-C_1-6Alkoxy radical, C_6-10Aryloxy, 3-benzothiazoyloxy, 8-quinolyloxy or N-oxy-succinimidyl.

In one embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from the group consisting of hydroxy, halogen and azido.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from mono(C_1-6Alkyl) carbonate, (C)_1-6Alkyl) carboxylic acid esters, (C)_6-10Aryl) carboxylates, mono (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_6-10Aryl) (C_1-6Alkyl) carboxylates and di (C)_1-6Alkyl) thiophosphate.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from (C)_1-6Alkyl) sulfonyl, mono (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, di (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl and (C)_1-6Alkyl) - (CO) -S-.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from cyano-C_1-6Alkoxy radical, C_6-10Aryloxy, 3-benzothiazolyloxy, 8-quinolyloxy and N-oxy-succinimidyl.

In another embodiment of the above conversion of the present invention, the leaving group of the compound of formula III is selected from the group consisting of halogen, methanesulfonyl, diethylthiophosphate and 3-benzothiazolyloxy.

In a preferred embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is di (C)_1-6Alkyl) thiophosphate, more preferably diethylthiophosphate.

The present invention also relates to an alternative process for the preparation of a 3-cyclic ether substituted cephalosporin of formula I above or a pharmaceutically acceptable salt thereof which comprises reacting a compound of formula V:

wherein

R²Having the formula

Wherein

A¹Is C_6-10Aryl radical, C_1-10Heteroaryl or C_1-10A heterocyclic group;

A²is hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_6-10Aryl radical, C_1-6Alkyl (CO) (C)_1-6) alkyl-O-, HO (CO) (C)_1-6) Alkyl, mono (C)_6-10Aryl) (C_1-6Alkyl), di (C)_6-10Aryl) (C_1-6Alkyl) or tri (C)_6-10Aryl) (C_1-6Alkyl groups); and

R³is p-nitrobenzyl or allyl, preferably allyl.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched moieties, or combinations thereof. Alkyl groups, wherever present, may be optionally substituted with suitable substituents.

The term "cycloalkyl" as used herein, unless otherwise indicated, includes mono-or bicyclic carbocyclic rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo [2.2.1 ] n]Heptyl, bicyclo [3.2.1]Octyl and bicyclo [5.2.0]Nonyl, etc.); optionally containing 1 or 2 double bonds and optionally being substituted with 1 to 3 suitable substituents as defined below: fluorine, chlorine, trifluoromethyl, (C)_1-4) Alkoxy group, (C)_6-10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)_1-4) Alkyl, more preferably fluoro, chloro, methyl, ethyl and methoxy.

The term "alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.

The term "halogen" as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.

The term "aryl" as used herein, unless otherwise indicated, refers to an organic group derived from an aromatic hydrocarbon by removal of one or more hydrogens, such as phenyl or naphthyl, said group optionally substituted with 1 to 3 suitable substituents such as: fluorine, chlorine, cyano, nitro, trifluoromethyl, (C)_1-6) Alkoxy group, (C)_6-10) Aryloxy group, (C)_3-8) Cycloalkoxy, trifluoromethoxy, difluoromethoxy or (C)_1-6) An alkyl group.

As used herein, unless otherwise indicated, the term "heteroaryl" includes organic radicals derived from heteroaromatic compounds by removal of one or more hydrogens, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, 1, 5-naphthyridinyl, oxadiazolyl, oxazolyl, 2, 3-naphthyridinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, dihydropyrazyl, dihydropyranyl, and furanyl, Quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein (C)_6-10) Heteroaryl is optionally substituted on any ring carbon atom capable of forming an additional bond with 1 or two substituents independently selected from: F. cl, Br, CN, OH, (C)_1-4) Alkyl, (C)_1-4) Perfluoroalkyl group, (C)_1-4) Perfluoroalkoxy, (C)_1-6) Alkoxy and (C)_3-8) A cycloalkoxy group. The above groups derived from the above listed compounds may be C-linked or N-linked, if possible. For example, the group derived from a pyrrole group may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).

As used herein, unless otherwise indicated, the term "heterocyclyl" includes organic radicals derived from non-aromatic heterocyclic compounds by removal of one or more hydrogens, e.g., 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]-HengA group selected from the group consisting of azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1, 3-dioxolanyl, 1, 4-dithianyl, hexahydroazepinyl, hexahydropyrimidyl, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1, 2, 3, 6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thiaxazinyl, and trithianyl. The abovementioned radicals from the compounds listed above may, if possible, be C-linked or N-linked. For example, a piperidine-derived group may be piperidin-1-yl (N-linked) or piperidin-4-yl (C-linked). The above groups derived from the above compounds may be optionally substituted, if possible, with suitable substituents such as: oxygen, F, Cl, Br, CN, OH, (C)_1-4) Alkyl, (C)_1-4) Perfluoroalkyl group, (C)_1-4) Perfluoroalkoxy, (C)_1-4) Alkoxy or (C)_3-8) A cycloalkoxy group.

The term "suitable substituent" means a chemically and pharmaceutically acceptable functional group, i.e., a group that does not adversely affect the inhibitory activity of the compounds of the present invention. These suitable substituents may be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to, halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxy groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroarylalkoxy groups, carboxy groups, amino groups, alkyl-and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, and the like.

The term "carboxylate" as used herein includes metal salts (e.g. aluminium, alkali metal salts such as sodium or potassium, preferably sodium), alkaline earth metal salts (e.g. calcium or magnesium) and ammonium salts. The ammonium salt may be substituted with: c_1-6Alkylamines (e.g. triethylamine), hydroxy- (C)_1-6) Alkylamines (such as 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine), cycloalkylamines (such as dicyclohexylamine), procaine, dibenzylamine, N-dibenzylethylenediamine, 1-phenamine (ephenamine), N-methylmorpholine, N-ethylpiperidine, N-benzyl- β -phenylethylamine, dehydroabietylamine, N' -didehydro-abietylamine, ethylenediamine or a base of the pyridine type (such as pyridine, collidine or quinoline) or other amines known to form salts with known penicillins and 3-cyclic ether substituted cephalosporins. Other useful salts include lithium and silver salts. Salts within the scope of the compounds of the formula I can be prepared in a customary manner by salt exchange.

The term "active compound" as used herein refers to a compound of formula I.

The compounds of formula I contain chiral centers and therefore exist in different enantiomeric forms. The present invention relates to all optical isomers, enantiomers, stereoisomers and mixtures thereof of the compounds of formula I. The compounds of the invention also exist in different tautomeric forms. The present invention relates to all tautomers of formula I. The cephalosporin nucleus is known to the person skilled in the art to exist as a mixture of tautomers in solution. The different ratios of tautomers in solid and liquid form depend on the different substituents on the molecule and the particular crystallization technique used to isolate the compound.

Preferably the group OA of the compound of the formula III²In the cis position of the amide bond, i.e., the preferred Z-configuration.

Suitable deprotecting agents for the above-described process for converting a compound of formula V to a compound of formula I of the invention include sodium dithionite or tetrakis-triphenylphosphine palladium (0).

Suitable solvents for the above transformations include acetone, water, tetrahydrofuran, dichloromethane or mixtures thereof. In one embodiment of the invention, the solvent is dichloromethane, tetrahydrofuran or mixtures thereof. In another embodiment of the invention, the solvent is tetrahydrofuran. In a preferred embodiment of the above conversion of the present invention, the solvent is dichloromethane.

The above-described conversion may be carried out at a temperature of about 0 ℃ to about 45 ℃. The above-described conversion may be carried out for a period of about 1 hour to about 24 hours.

In one embodiment of the above transformation, R³Is p-nitrobenzyl. Within this embodiment, a suitable deprotecting agent is sodium dithionite. In this embodiment, the above-mentioned conversion is suitably carried out at a temperature of about 40 ℃. Within this embodiment, the above process is suitably carried out for about 4 hours.

In a preferred embodiment of the above transformation, R³Is allyl. Within this embodiment, the preferred deprotecting agent is tetrakis-triphenylphosphine palladium (0). Within this embodiment, the above process is carried out at a temperature of from about 20 ℃ to about 35 ℃, preferably from about 27 ℃ to about 30 ℃. Within this embodiment, it is preferred that the above process be carried out for about 5 hours.

The present invention also includes a process for preparing a compound of formula II above, comprising reacting a compound of formula IV with a suitable deprotecting agent in the presence of a solvent:

wherein R is³Is p-nitrobenzyl or allyl, preferably p-nitrobenzyl, and X is halogen, preferably chlorine.

Suitable solvents for the process of converting a compound of formula IV to a compound of formula II of the present invention include acetone, water, tetrahydrofuran, dichloromethane or mixtures thereof. In one embodiment of the invention, the solvent is acetone, water, tetrahydrofuran or mixtures thereof. Preferably, the solvent is a mixture of acetone and water. More preferably, the solvent is a 3: 1 mixture of acetone and water.

Suitable deprotecting agents for the above transformations include sodium dithionite, catalytic hydrogenants (e.g., hydrogen on 10% palladium on carbon), or tetrakis-triphenylphosphine palladium (0).

The above conversion may be carried out at a temperature of about 0 ℃ to about 45 ℃. The above conversion may be carried out for a period of about 1 hour to about 24 hours.

In a preferred embodiment of the above transformation, R³Is p-nitrobenzyl. Within this embodiment, the preferred deprotecting agent is sodium dithionite. Preferably, the above process is carried out at a temperature of about 45 ℃. Preferably, the above process is carried out for a period of about 1 hour.

In another embodiment of the invention, R³Is allyl. Within this embodiment, a suitable deprotecting agent is tetrakis-triphenylphosphine palladium (0). Suitable solvents include dichloromethane and tetrahydrofuran. The above process may be carried out at a temperature of about 20 ℃ to about 35 ℃.

The present invention also relates to a process for the preparation of a compound of formula V above, said process comprising reacting a compound of formula IV above (wherein R is³Is p-nitrobenzyl or allyl, preferably allyl; and X is halogen, preferably chlorine) with a compound of formula III as defined above in the presence of a solvent. Optionally the above process may be carried out in the presence of an optional coupling agent or an optional catalyst.

Suitable solvents for the above-described conversion of the compound of formula IV to the compound of formula V include dichloromethane, tetrahydrofuran or mixtures thereof.

In one embodiment of the above transformation of the present invention, a coupling agent is used. Within this embodiment, suitable coupling agents include N, N ' -diethylcarbodiimide, N ' -dipropylcarbodiimide, N ' -diisopropylcarbodiimide, N ' -dicyclohexylcarbodiimide, N-ethyl-N ' - [3- (dimethylamino) propyl ] carbodiimide, N ' -carbonyldiimidazole or N, N ' -carbonyldithiazole. A preferred coupling agent is N, N' -dicyclohexylcarbodiimide. Preferably, the above conversion is carried out in the absence of any coupling agent.

In another embodiment of the above conversion of the present invention, a catalyst is used. Within this embodiment, the catalyst may be a lewis acid. Suitable lewis acids are boron trihalides, such as boron tribromide, or aluminium halides, such as aluminium chloride. Preferably, the above conversion is carried out in the absence of any catalyst.

The above-described conversion may be carried out at a temperature of from about-40 ℃ to about +40 ℃. The above-described conversion may be carried out for a period of about 1 hour to about 24 hours.

In one embodiment of the above transformation of the present invention, R³Is p-nitrobenzyl. Within this embodiment, the above-described conversion is suitably carried out at a temperature of from about +20 ℃ to about +30 ℃. In this embodiment, the above conversion is suitably carried out for about 3 hours.

In a preferred embodiment of the above transformation of the invention, R³Is allyl. In this embodiment, the solvent is preferably dichloromethane. Within this embodiment, it is preferred that the above-described conversion be carried out at a temperature of from about 20 ℃ to about 40 ℃. Within this embodiment, it is preferred that the above conversion be carried out for about 24 hours.

Suitable leaving groups L for compounds of formula III in the above-described transformations of the invention include hydroxy, halogen, azido, mono (C)_1-6Alkyl) carbonate, (C)_1-6Alkyl) carboxylic acid esters, (C)_6-10Aryl) carboxylates, mono (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_1-6Alkyl) thiophosphate, (C)_1-6Alkyl) sulfonyl, mono (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, di (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, (C)_1-6Alkyl) - (CO) -S-, cyano-C_1-6Alkoxy radical, C_6-10Aryloxy, 3-benzothiazoyloxy, 8-quinolyloxy or N-oxy-succinimidyl.

In one embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from the group consisting of hydroxy, halogen and azido.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from mono (C)_1-6Alkyl) carbonate, (C)_1-6Alkyl) carboxylic acid esters, (C)_6-10Aryl) carboxylates, mono (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_6-10Aryl) (C_1-6Alkyl) carboxylates and di (C)_1-6Alkyl) thiophosphate.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from (C)_1-6Alkyl) sulfonyl, mono (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, di (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl and (C)_1-6Alkyl) - (CO) -S.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from cyano-C_1-6Alkoxy radical, C_6-10Aryloxy, 3-benzothiazolyloxy, 8-quinolyloxy and N-oxy-succinimidyl.

In another embodiment of the above transformation of the invention, the leaving group L of the compound of formula III is selected from the group consisting of halogen, methanesulfonyl, diethylthiophosphate and 3-benzothiazoyloxy.

In a preferred embodiment of the above transformation of the invention, the leaving group of the compound of formula III is mono (C)_1-6Alkyl) carbonates, more preferably acetates.

The invention also relates to compounds of formula II

In one embodiment of the invention, the compounds of formula II have an enantiomeric or diastereomeric purity of 96% to 100%, preferably 97%.

The invention also relates to compounds of formula V

Wherein R is²As defined above; and R is³Is p-nitrobenzyl or allyl, preferably allyl.

In one embodiment of the invention, the compounds of formula V have an enantiomeric or diastereomeric purity of 96% to 100%, preferably 97%.

In a general or less general embodiment of each of the above embodiments, the R²A of (A)¹Part is C_6-10Aryl radicals, such as phenyl. In other general or less general embodiments of the invention, the R group²A of (A)¹Part is C selected from_1-10Heteroaryl group: furyl, thienyl, pyridyl, aminothiazolyl, and aminothiadiazolyl, wherein the amino moiety of the aminothiazolyl or aminothiadiazolyl is optionally protected. In other general and less general embodiments of the invention, the R group²A of (A)¹Part is C_1-10Heterocyclic radicals, e.g. 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]-heptyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1, 3-dioxolanyl, 1, 4-dithianyl, hexahydroazepinyl, hexahydropyrimidyl, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1, 2, 3, 6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thiaxanyl or trithianyl. Preferably the R is²A of (A)¹And the moiety is aminothiazolyl.

In other general and less general implementations of the inventionIn the scheme, the R²A of (A)²Part being hydrogen or C_1-6An alkyl group. A preferred embodiment of the present invention includes each of the above-described general and less general embodiments: wherein R is²A of (A)²Part is C_1-6Alkyl, more preferably methyl.

In a preferred embodiment of each of the foregoing general and sub-general embodiments of the invention, the compound of formula III has formula IIIa:

wherein L is a leaving group, for example halogen, methanesulfonyl, a dialkyl thiophosphate such as diethyl thiophosphate or 3-benzothiazolyloxy.

In a most preferred embodiment of each of the above embodiments of the present invention, the compound of formula III has formula IIIa as defined above, wherein L is diethyl phosphorothioate or acetate.

R can be accomplished using methods known in the art²To different R²And any formation of a pharmaceutically acceptable salt.

In the above and below processes, the protecting group must be removed. Deprotection can be accomplished by any conventional method known in the art while minimizing undesirable side reactions. The isolation of undesired by-products can be accomplished using standard methods known to those skilled in the art (see, for example, "Protection of the Amino Group", in protective groups in Organic Synthesis, second edition, T.W.Greene and P.G.M.Wuts, Ed., Wiley and Sons, Inc.1991, pp.309-405).

The invention also relates to a process for the preparation of 3-cyclic ether substituted cephalosporins using zwitterionic intermediates.

Detailed Description

The process of the invention and the preparation of the compounds of the invention are illustrated in the following reaction schemes. Unless otherwise indicated, in the following schemes and discussions, substituents R are unless otherwise indicated¹、R²、R³、L、A¹、A²And X is as defined above.

Route 1

Route 2

Route 3

Scheme 1 refers to the preparation of compounds of formula I. Referring to scheme 1, compounds of formula I can be prepared by reacting a compound of formula II with a compound of formula III in the presence of a base and a solvent,

R²-L (III)

wherein L is a leaving group.

Suitable leaving groups include hydroxy, halogen, azido, mono (C)_1-6Alkyl) carbonate, (C)_1-6Alkyl) carboxylic acid esters, (C)_6-10Aryl) carboxylates, mono (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_6-10Aryl) (C_1-6Alkyl) carboxylates, di (C)_1-6Alkyl) thiophosphate, (C)_1-6Alkyl) sulfonyl, mono (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, di (C)_1-6Alkyl) (C_6-10Aryl) sulfonyl, (C)_1-6Alkyl) - (CO) -S-, cyano-C_1-6Alkoxy radical, C_6-10Aryloxy, 3-benzothiazoyloxy, 8-quinolyloxy or N-oxy-succinimidyl. Preferably, the leaving group is di (C)_1-6Alkyl) thiophosphate, such as diethyl thiophosphate.

Suitable bases include diisopropylethylamine or sodium hydroxide, preferably sodium hydroxide, most preferably 15% aqueous sodium hydroxide.

Suitable solvents include water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1, 2-dichloroethane, or mixtures thereof; a mixture of water and acetone is preferred, and a 1: 1.3 mixture of water and acetone is most preferred.

The above reaction may be carried out at a temperature of about-40 ℃ to about 30 ℃, preferably about 20 ℃ to about 30 ℃. The above reaction may be carried out for a period of about 1 hour to about 24 hours, preferably about 3 hours.

Optionally, the above reaction may be carried out in the presence of an acid-binding agent, such as a tertiary amine (e.g., triethylamine), pyridine (e.g., 2, 6-lutidine or 4-dimethylaminopyridine), or dimethylaniline. Optionally, the above reaction can also be carried out in the presence of molecular sieves, inorganic bases (calcium carbonate or sodium bicarbonate) or ethylene oxide (oxirane) combined with the hydrogen liberated in the above reaction. The ethylene oxide is preferably C_1-6Alkyl-1, 2-alkylene oxides, such as ethylene oxide or propylene oxide.

Optionally, the above reaction may be carried out in the presence of a coupling agent. Suitable coupling agents include N, N ' -diethylcarbodiimide, N ' -dipropylcarbodiimide, N ' -diisopropylcarbodiimide, N ' -dicyclohexylcarbodiimide, N-ethyl-N ' - [3- (dimethylamino) propyl ] carbodiimide, N ' -carbonyldiimidazole and N, N ' -carbonyldithiazole. Preferably, the coupling agent is N, N' -diethylcarbodiimide. Preferably the reaction is carried out in the absence of any coupling agent.

Optionally, the above reaction may be carried out in the presence of a catalyst. Suitable catalysts include lewis acids such as boron trihalides or aluminum halides. Preferably the reaction is carried out in the absence of any catalyst.

The compounds of formula III may be prepared by methods known in the art. Suitable methods include those described in british patent 2107307B, british patent specification 1,536,281 and british patent specification 1,508,064. Preferably, the compound of formula III (i.e. R)²L), wherein R²Having the formula:

wherein A is¹Is 2-aminothiazol-4-yl; a. the²Is methyl and L is (C)_1-6Alkyl) sulfonyl such as methylsulfonyl or di (C)_1-6Alkyl) thiophosphates such as diethyl thiophosphate,

can be prepared from compounds of formula IIIb

And (C)_1-6Alkyl) sulfonyl halides, e.g. methanesulfonyl chloride or di (C)_1-6Alkyl) thiophosphoric acid such as diethylthiophosphoric acid.

Most preferably, the compound of formula III is diethylthiophosphoryl- [ Z ] -2-aminothiazol-4-yl-methoxyamino (DAMA), which may be prepared according to the procedures described in U.S. Pat. No. 5,567,813 and EP 628561.

Scheme 2 refers to the preparation of compounds of formula II. Referring to scheme 2, compounds of formula II can be prepared by reacting compounds of formula IV (wherein R is³Preferably p-nitrobenzyl ester, and X is preferably chlorine) with a suitable deprotecting agent in a solvent.

Suitable deprotecting agents include sodium dithionite or catalytic hydrogenants such as hydrogen on 10% palladium on carbon.

Suitable solvents include acetone, water, tetrahydrofuran, dichloromethane or mixtures thereof. Preferably, the solvent is a 3: 1 mixture of acetone and water.

The above reaction may be carried out at a temperature of about 0 ℃ to about 45 ℃, preferably about 45 ℃. The above reaction may be carried out for a period of about 1 hour to about 24 hours, preferably about 1 hour.

Can be prepared by a variety of synthetic methods, such as those described in U.S. provisional patent application entitled "methods and ester derivatives for the preparation of cephalosporins" filed at 11 months 2000.

Scheme 3 refers to an alternative preparation of the compounds of formula I. Referring to scheme 3, compounds of formula I may be prepared from compounds of formula V (wherein R is³Preferably allyl) with a suitable deprotecting agent in a solvent.

Suitable deprotecting agents include sodium dithionite or tetrakis-triphenylphosphine palladium (0).

Suitable solvents include acetone, water, tetrahydrofuran, dichloromethane or mixtures thereof. The preferred solvent is dichloromethane.

The above reaction may be carried out at a temperature of about 0 ℃ to about 45 ℃. The above reaction may be carried out for a period of about 1 hour to about 24 hours.

Compounds of formula V may be prepared by reacting compounds of formula IV (wherein R is³Preferably allyl, and X is preferably chlorine) with a compound of formula III in a solvent.

R²-L (III)

Suitable solvents for the above reaction include dichloromethane, tetrahydrofuran or mixtures thereof. Preferably, the solvent is dichloromethane.

Optionally, the above reaction may be carried out in the presence of a coupling agent. Suitable coupling agents include N, N ' -diethylcarbodiimide, N ' -dipropylcarbodiimide, N ' -diisopropylcarbodiimide, N ' -dicyclohexylcarbodiimide, N-ethyl-N ' - [3- (dimethylamino) propyl ] carbodiimide, N ' -carbonyldiimidazole or N, N ' -carbonyldithiazole. Preferably, the coupling agent is N, N' -diethylcarbodiimide. Preferably, the above reaction is carried out in the absence of any coupling agent.

Optionally, the above reaction may be carried out in the presence of a catalyst. Suitable catalysts include lewis acids such as boron trihalides or aluminum halides. Preferably, the above reaction is carried out in the absence of a catalyst.

The above reaction may be carried out at a temperature of about-40 ℃ to about +40 ℃, preferably about +20 ℃ to about +40 ℃. The above reaction may be carried out for a period of about 1 hour to about 24 hours, preferably about 24 hours.

The compounds of formula IV can be prepared as described above in the description of scheme 2.

The compounds of the present invention may be crystallized or recrystallized using a solvent such as an organic solvent. Solvates may be formed in these cases. The present invention includes within its scope stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water that may be produced by processes such as lyophilization.

The compounds of formula (I) are useful for the preparation of 3-cyclic ether substituted cephalosporins, i.e. active compounds. The active compounds have activity against gram-positive and gram-negative bacteria. Methods for determining activity and methods for formulating and administering active compounds are disclosed in U.S. patent 6,020,329 published on 2/1/2000. Methods of treatment are also described in the above patents.

The following examples illustrate the preparation of the compounds of the present invention. The melting point is uncorrected. NMR data are reported in parts per million (ppm) and compared to deuterium fixation signals from the sample solvent (tritiated chloroform, unless otherwise indicated). Commercial reagents were used without further purification. The room temperature or ambient temperature is 20 ℃ to 25 ℃. For convenience and to maximize yield, all non-aqueous reactions were carried out under nitrogen atmosphere. Concentration under reduced pressure means the use of a rotary evaporator. TLC for thin layer liquid chromatography. HPLC stands for high pressure liquid chromatography. GC stands for gas chromatography.

Example 1

7- (2- (2-aminothiazol-4-yl) -2-methoxyimino) -3- (tetrahydrofuran-2- Yl) -8-oxo-5-thia-1-aza-bicyclo [4.2.0]Oct-2-ene-2-carboxylic acid sodium salt

The method A comprises the following steps: from 7-amino-8-oxo-3- (tetrahydrofuran-2-yl) -5-thia-1-aza-bis Cyclo [4.2.0]Starting with octa-1- (6), 2, 4-triene-2-carboxylic acid

7-amino-8-oxo-3- (tetrahydrofuran-2-yl) -5-thia-1-aza-bicyclo [4.2.0] octa-1 (6), 2, 4-triene-2-carboxylic acid (20g, 75mmol), water (300ml), acetone (400ml) was combined with a mixture of (Z) -2-amino- α - (methoxyimino) -4-thiazoleacetic anhydride and O, O-diethylhydrosulfuric phosphate (27g, 1.06 equivalents) to form a slurry. The pH of the slurry was adjusted to 7-7.5 using aqueous sodium hydroxide. After complete dissolution was achieved, the reaction mixture was stirred for 3 hours. Acetone (3200mL) was added to precipitate the product. The resulting slurry was granulated, filtered and dried under vacuum to give the title compound (29.0g, 80%).

The method B comprises the following steps: from allyl-7- (2- (2-aminothiazol-4-yl) -2-methoxyimino Yl) -3-tetrahydrofuran-2-yl) -8-oxo-5-thia-1-aza-bicyclo [4.2.0]Oct-2-ene 2-formic acid ester, benzenesulfinic acid (benzenesulfinic acid) salt

Methylene chloride (4.50 liters) was charged under a nitrogen atmosphere to a 10 liter glass flask, followed by tetrakis (triphenylphosphine) palladium (9.0g, 7.8 mmoles). Triphenylphosphine (1.0g, 3.8mmoles) was added and stirred to solution. Allyl-7- (2- (2-aminothiazol-4-yl) -2-methoxyimino) -3-tetrahydrofuran-2-yl) -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylate, benzenesulfinate (225.0g, 354mmoles) and heating to 27-30 ℃.

The reaction was monitored by HPLC and further catalyst was added as needed. When the reaction was complete, the resulting product was filtered and washed twice with dichloromethane (700 ml total). The yellow to tan product was then air dried to achieve a constant weight and then stored in a refrigerator. The yield ranged from 49-110.1%.

Example 2

7-amino-8-oxo-3- (tetrahydrofuran-2-yl) -5-thia-1-aza-bicyclo [4.2.0] Ocine-1 (6), 2, 4-triene-2-carboxylic acid

4-Nitro-benzyl 7-amino-8-oxo-3- (tetrahydrofuran-2-yl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylate (20g, 54mmol), water (30ml) and acetone (90ml) were combined to form a slurry. The pH of this slurry was adjusted to 7 with aqueous ammonia solution (15%). A solution of sodium bisulfite (32g, 3.8 equivalents) in water (40mL) was added to the resulting solution. The pH of the resulting solution was adjusted to 7 with an aqueous ammonia solution (15%) while maintaining the temperature between 40 ℃ and 45 ℃. After stirring for 1 hour at 45 ℃, the pH was adjusted to 3.5 again with aqueous hydrochloric acid (15%). The resulting slurry was granulated, filtered and dried to give the title compound (11.3g, 80%).

Preparation 1: (3-benzyl-7-hydro-4-thia-2, 6-diaza-bicyclo [ 3.2.0%]G-2- En-6-yl) -4-nitro-benzyl hydroxyacetate

Isopropanol (500mL), dichloromethane (1800mL) and (1R) - (4-nitrophenyl) methyl ester- α, 1-methylethylidene) -7-oxo-3- (phenylmethyl) -4-thia-2, 6-diazabicyclo [3.2.0] hept-2-ene-6-acetic acid (250g) were combined and the mixture was cooled at-70 ℃. Ozone is bubbled through the cooled reaction mixture until ozonolysis is complete. To the resulting solution was added a mixture of glacial acetic acid (625mL) and isopropanol (750mL), followed by a mixture of isopropanol (100mL), water (100mL) and sodium borohydride (22 g). After the reduction was completed, an aqueous solution of sodium metabisulfite was added, and then the pH was adjusted to 1.5-2.5 with hydrochloric acid (15%). The layers were separated and the organic layer was washed twice with sodium chloride (1000 mL). The organic layer was concentrated in vacuo and the resulting slurry was granulated, filtered and the filter cake washed with isopropanol. The product was dried in vacuo.

Preparation 2: hydroxy- { 2-oxo-4- [ 2-oxo-2- (tetrahydrofuran-2-yl) ethylthio]-3- Phenylacetylamino-azetidin-1-yl } -acetic acid 4-nitro-benzyl ester

Bromine (51g) and methanol (270mL) were combined, and a solution of 1- (tetrahydro-2-furanyl) -ethanone (30g) in methanol (30mL) was added dropwise at 30 ℃. Aqueous sodium thiosulfate solution was then added followed by dichloromethane (300 mL). The layers were separated and the organic layer was washed twice with aqueous sodium bicarbonate (300 ml). The resulting organic layer was concentrated, followed by addition of acetone (600mL) and p-toluenesulfonic acid (6 g). After heating to reflux for 2 hours, the reaction was cooled and 4-nitro-benzyl (3-benzyl-7-oxo-4-thia-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -hydroxy-acetate (100g) and additional p-toluenesulfonic acid (6g) were added. The resulting solution was stirred for 2 hours and then adjusted to pH 3-4 with pyridine. The reaction was concentrated, then water (180mL), dichloromethane (600mL), and hydrochloric acid (9mL, 15%) were added to adjust the pH to 1-2. The layers were separated and dichloromethane was replaced with methanol (600 mL). Isopropanol (300mL) was added to complete the precipitation and the resulting slurry was granulated, filtered and the filter cake washed with isopropanol. The product was dried in vacuo.

Preparation 3: 7-amino-8-oxo-3- (tetrahydrofuran-2-yl) -5-thia-1-chloro-bicyclo [4.2.0]Oct-2-ene-2-carboxylic acid 4-nitro-benzyl ester

Thionyl chloride (45ml, 0.615mol) was added dropwise to a solution of hydroxy- { 2-oxo-4- [ 2-oxo-2- (tetrahydrofuran-2-yl) -ethylfuranyl ] -3-phenylacetylamino-azetidin-1-yl } -acetic acid 4-nitro-benzyl ester (202g, 0.362mol) and 2, 6-lutidine (58ml, 0.500mol) in dichloromethane (4 l) at-20 ℃. After stirring for 1 hour, the solution was washed twice with saturated sodium chloride (1 l) and concentrated. To the concentrated solution was added a solution of trimethylphosphine in tetrahydrofuran (110ml, 3M, 330mmol), the solution was stirred for 1 hour and washed with diluted sodium bicarbonate and saturated sodium chloride. After stirring at reflux for 16 hours, the solution was washed with water and saturated sodium chloride. The solution was concentrated and cooled to-40 ℃ and then phosphorus pentachloride (104g, 0.5mol) was added dropwise. A solution of alpha-picoline (92ml) in dichloromethane (60ml) was added whilst maintaining the temperature between-40 ℃ and 30 ℃. The mixture was stirred for 1 hour, then isopropanol (660ml) was added. The reaction mixture was heated to 22 ℃, granulated, filtered and dried to give the title compound (250g, 45%).

Example 3

Allyl-7- (2- (2-aminothiazol-4-yl) -2-methoxyimino) -3-tetrahydrofurfuryl Pyran-2-yl) -8-hydro-5-thia-1-chloro-bicyclo [4.2.0]2-Octanyl-2-ene-2-carboxylate, benzene Sulfinate salt

Preparation 1: allyl-7-phenylacetamido-3- (tetrahydrofuran-2-yl) -8-oxo-5- Thia-1-aza-bicyclo [4.2.0]-oct-2-ene-2-carboxylic acid esters

Toluene (47 l) and allyl-2-tri-n-methylphosphinylidene) -2- (3-phenylacetamido-4- (tetrahydrofuran-2-ylcarbonyl-methylthio) azetidin-one-1-yl) acetate (1990g) were added to a 100 l glass container. The solution was purged with nitrogen and reflux was used. Any water present was collected and the solution was refluxed for 20 hours. After sampling for TLC/HPLC analysis, the solution was cooled to ambient temperature. The solution was then passed through silica gel 60(4.5kg) and the silica gel was further eluted with additional toluene (33 liters). The methanol was then stripped under vacuum at a maximum temperature of 60 ℃. Ethyl acetate was then added followed by stripping at a maximum temperature of 60 ℃. Tert-butyl methyl ether (2.5 l) was added to the semi-solid oil and the solution was stirred overnight. The crystalline product was filtered off and washed further with tert-butyl methyl ether (0.3 l). The mother liquor was concentrated and chromatographed again on silica gel (dissolved in 5 l of toluene, added to silica gel, eluted with 15 l of toluene) and crystallized in the same manner to give a second crop. The product was isolated as a white crystalline solid. The yield ranges from 70% to 80%.

Preparation 2: allyl-2-tri-n-methylphosphinidene (methylphosphonoranylidene) -2- (3-phenylacetylamino-4- (tetrahydrofuran-2-ylcarbonyl-methylthio) azetidine- Keto-1-yl) acetic acid esters

The allyl-2-hydroxy-2- (3-phenylacetamido-4- (tetrahydrofuran-2-ylcarbonyl-methylthio) azetidin-one-1-yl) acetate solution in tetrahydrofuran from preparation 3 of example 3 was further diluted with additional tetrahydrofuran (tetrahydrofuran totaling 12 liters). The solution was cooled to-20 ℃ under nitrogen and 2, 6-lutidine (654.0g, 6.09moles) was added followed by the addition of thionyl chloride (724.0g, 6.09moles) at the highest temperature of-20 ℃. Stir for 30 minutes, then heat the solution to-10 ℃ and sample for TLC. TLC indicated complete conversion of starting material to allyl-2-chloro-3- (3-phenylacetamido-4- (tetrahydrofuran-2-ylcarbonyl-methylthio) azetidin-one-1-yl) acetate. The precipitated product is then filtered off and washed further with tetrahydrofuran. The tetrahydrofuran solution was then concentrated in vacuo at a maximum temperature of 30 ℃, redissolved in fresh tetrahydrofuran (6 l) and cooled back to-10 ℃. After stirring overnight at ambient temperature, the solution was sampled, diluted with ethyl acetate (35 l) and washed with 5% sodium bicarbonate (20 l) and 20% saturated sodium chloride (20 l). The ethyl acetate was then vacuum stripped at a maximum temperature of 40 ℃ to give a thick black oil. The yield ranges from 88% to 90%.

Preparation 3: allyl-2-hydroxy-2- (3-phenylacetylamino-4- (tetrahydrofuran-2-) Alkylcarbonyl-methylthio) azetidin-1-yl) acetate

Methylene chloride (10.0 liters), tetrahydrofuran (1.0 liters) and allyl-2-hydroxy-2- (3-benzyl-4-thia-2, 6-diazabicyclo [3.2.0] hept-2-en-7-one) acetate (2016g, 6.05moles) were added to a 20 liter flask. To this solution was added 45% aqueous p-toluenesulfonic acid (500.0 g). After stirring for 3 hours, the solution was sampled for complete TLC. The solution was then transferred to a 50 l glass separation vessel, dichloromethane (5 l) was added, followed by water (2 l). The separated organic layer was then washed with water (4 l). The dichloromethane phase was then dried over sodium sulfate to give an anhydrous solution of allyl-2-hydroxy-2- (3-phenylacetamido-4-mercapto-azetidin-one-1-yl) acetate in dichloromethane, which was then used immediately. To the above solution was added a 86% solution of 2-bromoacetyltetrahydrofuran in dichloromethane (6.3 moles). The resulting solution was stripped to 50% of its volume at a maximum temperature of 30 ℃. Pyridine (503.1g, 6.36moles) was added at a maximum temperature of 10 ℃. The solution was stirred overnight, diluted with dichloromethane (10 l), washed twice with water (10 l total) and once with saturated sodium chloride (10%, 10 l). Dried over sodium sulfate and then the solution was concentrated under vacuum at a maximum temperature of 40 ℃ to ensure that there was no water. The solution was redissolved in tetrahydrofuran (5 l) for the next step. If storage is required, the tetrahydrofuran solution is stored and dried before use.

Preparation 4: 2-Bromoacetyltetrahydrofuran

A20 liter glass vessel was charged with dichloromethane (10.0 liters) followed by acetyltetrahydrofuran (838.0g, 7.34 moles). The solution was then cooled back to-10 ℃ and triethylamine (854.0g, 8.44moles) was added. The vessel was purged with nitrogen and trimethylsilane triflate (1713.0g, 7.71moles) was added dropwise at the maximum temperature of-8 ℃. The addition is generally completed within 45 minutes. After stirring for 15 minutes, samples were removed for TLC and GC analysis, which indicated complete reaction. N-bromosuccinimide (1340g, 7.53moles) was added to this solution in 6 portions over a period of about 45 minutes at a maximum temperature of-5 ℃. After stirring for 30 minutes, the solution was sampled for GC and TLC analysis, which indicated that the reaction was complete. The solution was then transferred to a 50 liter separation vessel and 5% sodium bicarbonate (5 liters) was carefully added. The solution was stirred and separated. The upper aqueous phase was discarded and the dichloromethane phase was washed with water, dried over sodium sulfate, filtered and stored in the refrigerator before being used in the next step.

Preparation 5: allyl-2-hydroxy-2- (3-benzyl-4-thia-2, 6-diazabicyclo) [3.2.0]Hept-2-en-7-one) acetic acid ester

A50 liter glass vessel was charged with methylene chloride (20.6 liters) followed by 3-benzyl-4-thia-2, 6-diazabicyclo [3.2.0] hept-2-en-7-one (1700g, 7.79 moles). To this suspension was added allyl glyoxylate monohydrate (1285g, 9.74moles) followed by sufficient triethylamine (approximately 175g) to bring the pH of the solution to 7.5-7.9. After stirring for 1 hour, the solution was sampled for TLC/HPLC analysis. Upon completion of the assay, the solution was quenched with 0.1M hydrochloric acid (2.75 liters) to a pH of 4.50-5.00. The upper aqueous phase was discarded and the dichloromethane phase was washed with water (8 l) and saturated sodium chloride (8 l). The solution was dried over sodium sulfate and concentrated to a thick oil. This oil was dispersed in hexane (5 l), filtered and reslurried in tert-butyl methyl ether (5 l), then filtered and further washed with tert-butyl methyl ether. Air drying gave a beige crystalline product. The yield ranged from 72-99%.

While the invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will recognize that various modifications, alterations, modifications, substitutions, deletions, or additions may be made to the methods and protocols without departing from the spirit and scope of the invention. It is the intention, therefore, to be limited only as indicated by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims (10)

1. A compound of formula (II)

2. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein

Group CO₂R¹Is a carboxylic acid or a salt of a carboxylic acid; and is

R²Having the formula:

the method comprises reacting a compound of formula II

With a compound of formula III:

R²L III；

wherein

R²As defined above; and is

L is two (C)_1-6Alkyl) thiophosphate.

3. A process for the preparation of a compound of formula II as defined in claim 1, which process comprises deprotecting a compound of formula IV

Wherein R is³Is p-nitrobenzyl, and X is halogen.

4. A process according to claim 2, further comprising the step of preparing a compound of formula II as described in claim 3.

5. The process of claim 2 wherein L is diethyl phosphorothioate.

6. The process of claim 2 wherein the base is sodium hydroxide.

7. The process according to claim 2, wherein the reaction is carried out in acetone.

8. A process according to claim 3, wherein X is chlorine.

9. A process according to claim 4, wherein X is chlorine.

10. A process according to claim 3 wherein the deprotection is carried out using sodium dithionite or a hydrogenating agent.