Title of Invention

NEW PROCESS FOR PREPARING VINYL CEPHALOSPORIN

Abstract

A process for preparing Cefdinir of Formula II comprising the steps of, reacting thiazolyl acetic acid of Formula III; wherein R represents acetyl or trityl, with bis(5-methyl-1 ,3,4-thiadiazol-2..i yl)disulfide of Formula IV, in the presence oftriphenyl phosphine and an organic base in a solvent to I Produce thioester derivative of thiazolyl acetic acid of formula I wherein R is defined above; (ii) acylating the compound of Formula V; wherein R<sup>1</sup> represents H or silyl group with thioester derivative of Formula I to produce protected Cefdinir of Formula VI, wherein R is defined above; deprotecting compound of Formula VI to produce Cefdinir of Formula II.

Full Text

BACKGROUND OF THE INVENTION Cefdinir of Formula II is an oral, semi-synthetic cephalosporin antibiotic characterized by having a broad spectrum of antibacterial activity particularly against Staphylococci and Streptococci and a high stability against various P-lactamases. It further exhibits an enhanced activity against gram-positive bacteria as well and is chemically known as 7p-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid. Several synthetic methods are known in literature for preparation of cefdinir. For example, US Patent 4,559,334 describes a synthetic method starting from benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate, which is reacted with 4-bromoacetoacetyl bromide, the resulting product is nitrosated to oxime and cyclized to obtain protected cefdinir. Deprotection yielded cefdinir (Refer Scheme-1). However, this synthetic method suffers from several disadvantages such as use of raw materials which are not available easily, low yielding steps and isolation involving chromatography and lyophilisation. Overall yield reported is 10-11%. Spanish Patent ES 2 013 828 describes an alternate route to prepare cefdinir overcoming the difficulties in US Patent 4,559,334 (Refer Scheme-2). (Z)-2-(2-Amino-4-thiazolyl)-2-acetyloxyiminoacetic acid was prepared and converted into corresponding acid chloride hydrochloride (A) via reaction with phosphorus pentachloride and condensed with 7-amino-3-vinyl-3-cephem-4-carboxylic acid in the presence of silylating agent to yield 0-acetyl cefdinir which was deprotected to yield cefdinir. However, in our hands we observed that the preparation of (Z)-2-(2-amino-4-thiazolyl)-2-acetyloxyiminoacetylchloride hydrochloride was not consistent, possibly due to the nature of side chain and formation of more impurities. Moreover this reaction resulted in incomplete conversion and formation of anti-isomer was also observed. Further, this process requires very low temperature leading to additional burden on equipment. US Patent 6,093,814 describes a process wherein tritylated cefdinir is prepared and isolated as 0-trityl cefdinir p-toluenesulfonic acid 2N,N-dimethylacetamide solvate and further converted into cefdinir either by treatment with formic acid or trifluoroacetic acid (Refer Scheme-3). The disadvantages of this process are use of ethers to isolate O-trityl cefdinir p-toluenesulfonic acid 2N,N-dimethylacetamide solvate which greatly enhances danger of fire hazard on a commercial scale and poor solvent recovery. Detritylation to obtain cefdinir by using perhalogenated acids has been described by Otsuka Chemical Company in EP 1 273 587 Al. However, this process also gave low yields and further handling and disposal of perhalogenated acids poses an industrial hazard. US application 2004/0034233 Al describes a process for the preparation of anhydride 2-(2-aminothiazol-4-yl)-2-hydroxy compound, and further this compound is treated with halogenating agent to produce acid chloride and this acid chloride is reacted with 7-amino-3-vinyl-3-cephem carboxylic acid to yield cefdinir. WO 04/016623 Al describes a process for the preparation of cefdinir using cefdinir crystalline salts. The cefdinir crystalline sahs are prepared by reacting 2-(2-amino-4-thiazolyl)-2-[(methylcarbonyloxyimino)imino]acetic acid-mercaptobenzothiazolyl ester with 7-amino-3-vinyl-3-cephem-4-carboxylic acid. In our co-pending patent application No. 441/MAS/03, the cefdinir is prepared by reacting 7-amino-3-vinyl-3-cephem carboxylic acid with 2-mercaptobenzothiazolyl (Z)-2-(2-amino-4-thiazolyl)-2-acetyloxyimino acetate. Thus, it is evident that the intermediates described in the prior art to prepare cefdinir include an acid chloride, a reactive thiophosphate, a reactive ester and the like. However, these intermediates have some disadvantages such as low yields, expensive input raw materials and handling problem in commercial production. Hence, there is a need to develop new acylating agent which is capable of transferring the 2-aminothiazolyl moiety to 7-amino-3-cephem compound in good yield without producing any side product and without requiring complicated protection / deprotection operations. OBJECTIVE The objective of the present invention is to provide a new thioester derivative of thiazolyl acetic acid of the Formula I, which would be better than the earlier reactive derivatives and also suitable for being used in the manufacture of cefdinir. Another objective of the present invention is to provide a process for the synthesis of thioester derivative of Formula I from thiazolyl acetic acid of Formula III and bis(5-methyl-l,3,4-thiadiazol-2-yl)disulphide of Formula IV. Yet another objective of the present invention is to provide a process for the preparation of cefdinir of Formula (II) from the said novel thioester at 20°C temperature. SUMMARY OF THE INVENTION The present invention provides a new thioester derivative of thiazolyl acetic acid of Formula I wherein R represents acetyl or trityl. The present invention also provides a process by which the said thioester derivatives can be prepared by reacting thiazolyl acetic acid of general Formula III wherein R is as defined above; with bis(5-methyl-l,3,4-thiadiazol-2-yl)disulphide of Formula IV using triphenyl phosphine in the presence of an organic base and a solvent. The present invention also provides a process for the preparation of cefdinir which comprises reacting the thioester derivative of Formula I with 7-amino-3-vinyl-3-cephem carboxylic acid derivative of Formula V DETAILED DESCRIPTION OF THE INVENTION In yet another embodiment of the present invention, organic base used for the reaction of compound III with compound IV is selected from triethylamine, trimethylamine, N-methyl morpholine, N-alkylpiperidines, N-alkyl anilines and mixtures thereof, but preferably triethylamine is used. The solvent is selected from halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane etc preferably dichloromethane is used. The reaction is carried out at a temperature in the range of 0-35°C preferably in the range of 5-20°C. In yet another embodiment of the present invention, when R represents acetyl and R1 represents hydrogen, the reaction of compound I with compound V is carried out in the presence of an organic base and aqueous organic solvent. In yet another embodiment of the present invention, organic base is selected from triethylamine, trimethylamine, N-methyl morpholine, N-alkylpiperidines, N-alkyl anilines and mixtures thereof, but preferably triethylamine is used. In yet another embodiment of the present invention, aqueous organic solvent is selected from tetrahydrofuran, acetonitrile, acetone, dioxane, N,N-dimethylformamide etc., but preferably tetrahydrofuran is used. In yet another embodiment of the present invention, reaction is carried out at a temperature in the range of 10-35°C, preferably in the range of 15-30°C. In yet another embodiment of the present invention, the new intermediate of Formula - VII is provided, which is used in the preparation of cefdinir. X"^ represents an organic amine cation, wherein the organic amine is selected from triethylamine, trimethylamine, A^-methyl morpholine, TV^-alkylpiperidines, A^-alkyl anilines, pyridine, 1,8-diaza bicyclo undecane, 4-dimethyl amino pyridine. This intermediate is formed when the reaction of compound I with compound V is carried out in presence of organic base. In yet another embodiment of the present invention, when R represents acetyl and trityl, R" represents trialkylsilyl, the reaction is carried out in the presence of silylating agent and aprotic organic solvent. In yet another embodiment of the present invention, silylating agent is selected from hexamethyldisilazane, bis (trimethyl)silyl acetamide, mono(trimethyl)silyl acetamide, trimethylsilyl chloride or mixtures thereof, preferably mono(trimethyl)silyl acetamide is used. In yet another embodiment of the present invention, aprotic organic solvent is selected from dichloromethane, toluene, acetonitrile, alkylethers etc., preferably dichloromethane is used. In yet another embodiment of the present invention, reaction is carried out at a temperature in the range of 10-35°C, preferably in the range of 15-30°C. The invention is illustrated with the following examples EXAMPLE-I PREPARATION OF 7P-I(Z)-2-(AMINO-4-THIAZOLYL)-2-HYDROXYIMINO ACETAMID01-3-VINYL-3-CEPHEM-4-CARBOXYLIC ACID (CEFDINIR) STEP-I PREPARATION OF 2-MERCAPTO-5-METHYL-1,3,4-THIADIAZOLYL-(Z)-2-(2-AMINO-4-THIAZOLYL)-2-ACETYLOXYIMINO ACETATE (Z)-2-(2-Amino-4-thiazolyl)-2-acetyloxyimino acetic acid (100 g) (0.437 moles) was added to methylene chloride (600 ml) at 20-25°C, then triethylamine (48 g) (0.48 moles) was added and stirred the contents for 2 h. To this mixture bis (5-methyl-l, 3,4-thiadiazol-2-yl) disulphite (125.8 g) (0.48 moles) was added at 25°C. The reaction mass was cooled to 10-15°C. Triphenyl phosphine (125.8 g) (0.48 moles) was added in 2 min, and the reaction mass was stirred for 2 h during which time product precipitated. The slurry was cooled to 0-5 °C and filtered the precipitated product. Dried the product at 35-40°C under reduced pressure to obtain the title compound. YIELD: 125 g STEP-II PREPARATION OF 7P-I(Z)-2-(AMINO-4-THIAZOLYL)-2-ACETYLOXY-IMINO ACETAMID01-3-VINYL-3-CEPHEM-4-CARBOXYLIC ACID TRIETHYLAMINE SALT 7-Amino-3-vinyI-3-cephem-4-carboxylic acid (25 g) (0.11 moles) was added to tetrahydrofuran (250 ml) at 20-25°C, followed by the addition of 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-amino-4-thiazolyl)-2-acetyloxyimino acetate (44 g) (0.122 moles) and stirred the reaction mass for 10 min at 20-25°C. Cooled the reaction mass to 15°C. DM water (125 ml) and triethylamine (13 g) (0.122 moles) were added in 45 min. Thereafter, methylene chloride (250 ml) and DM water (125 ml) were added and separated the organic layer and reextracted with DM water (125 ml). The combined aqueous layer obtained was mixed with acetonitrile (10 times with respect to aqueous layer) then concentrated at H" NMR (DMSO-dfi): 51.2 (9H, t, -CH2-CH3), 62.0 (3H, s,-CH3-CN), 83.0 (6H, q, -CH2-CH3), 53.5(2H, m, -S-CH2), 55.1 (IH, d, -CH=CH2), 55.4 (IH, d, -CH=CH2), 57.5 (2H, s, -NH2), 59.7 (IH, d, -CONH). STEP-III PREPARATION OF 7P-[(Z)-2-(AMINO-4-THIAZOLYL)-2-HYDROXYIMINO ACETAMID01-3-VINYL-3-CEPHEM-4-CARBOXYLIC ACID (CEFDINIR) 7p-[(Z)-2-(amino-4-thiazolyl)-2-acetyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid triethylamine salt is dissolved in methylene chloride (250 ml) at 20-25°C. Ammonium chloride (16.5 g) (0.308 moles) and 20% w/v aq. potassium carbonate solution (87.5 ml) were added at 20°C. The reaction mass was stirred for 1 h and adjusted the pH to 2.5-3.0 using 10% w/w sulphuric acid at 25°C. Stirred the precipitated product for 1 h and filtered. Dried the product at 35-40°C under reduced pressure to obtain the title compound. YIELD: 40 g EXAMPLE-II PREPARATION OF 7p-[(Z)-2-(AMINO-4-THIAZOLYL)-2-HYDROXYIMINO ACETAMIDOJ-3-VINYL-3-CEPHEM-4-CARBOXYLIC ACID (CEFDINIR) STEP-I PREPARATION OF 2-MERCAPTO-5-METHYL-1,3,4-THIADIAZOLYL-(Z)-2-(2-AMINO-4-THIAZOLYL)-2-ACETYLOXYIMINO ACETATE (Z)-2-(2-Amino-4-thiazolyl)-2-acetyloxyimino acetic acid (100 g) (0.437 moles) was added to methylene chloride (600 ml) at 20-25°C, then triethylamine (48 g) (0.48 moles) was added and stirred the contents for 2 h. To this mixture bis (5-methyl-l, 3,4-thiadiazol-2-yl) disulphide (125.8 g) (0.48 moles) was added at 25°C and cooled the reaction mass to 10-15°C. Triphenyl phosphine (125.8 g) (0.48 moles) was added in 2 min, and the reaction mass was stirred for 2 h, during which time product precipitated. The slurry was cooled to 0-5°C and filtered the precipitated product. Dried the product at 35-40°C under reduced pressure to obtain the title compoxmd. YIELD: 125 g STEP-II PREPARATION OF 7P-[(Z)-2-(AMINO-4-THIAZOLYL)-2-HYDROXYIMINO ACETAMIDO]-3-VINYL-3-CEPHEM-4-CARBOXYLIC ACID (CEFDINIR) 7-Amino-3-vinyl-3-cephem-4-carboxylic acid (25 g) (0.11 moles) was added to tetrahydrofuran (250 ml) at 20-25°C, followed by 2-mercapto-5-methyl-1,3,4-thiadiazolyI-(Z)-2-(2-amino-4-thiazolyl)-2-acetyloxyimino acetate (44 g) (0.122 moles) and stirred the reaction mass for 10 min at 20-25°C. Cooled the reaction mass to 15°C and added DM water (125 ml) and triethylamine (13 g) (0.122 moles) in 45 min. Thereafter, methylene chloride (250 ml) and DM water (125 ml) were added, separated the layers. The organic layer was reextracted with DM water (125 ml). The combined aqueous layer was washed with methylene chloride (125 ml). Ammonium chloride (16.5 g) (0.308 moles) and potassium carbonate solution (87.5 ml) (20% w/v) were added at 20°C. The reaction mass was stirred for 1 h and adjusted the pH to 2.5-3.0 using 10% w/w sulphuric acid at 25°C. Stirred the precipitated product for 1 h and filtered the precipitated product. Dried the product at 35-40°C under reduced pressure to obtain the title compound. YIELD: 40 g EXAMPLE-III PREPARATION OF 2-MERCAPTO-5-METHYL-1,3,4-THIADIAZOLYL-(Z)-2-(2-AMINO-4-THIAZOLYL)-2-TRITYLOXYIMINO ACETATE (Z)-2-(2-Amino-4-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid (25 g) (58.27 m moles) was added to methylene chloride (250 ml) at 25°C and cooled the reaction mixture to 15°C. Triethylamine(7 g) was added in 5 min and stirred the reaction mass for 1 h at 15-20°C. Added Bis (5-methyl-l, 3,4-thiadiazol-2-yl) disulphide (18.3 g) (16.9 mm) and triphenyl phosphine (18.3 ml) (16.9 m mol), cooled the reaction mass to 10°C and stirred for 30 min. The precipitated product was filtered and washed with 50 ml of chilled (10-15°C) methylene chloride. Dried the product at 35-40°C under reduced pressure to obtain the title compound. YIELD: 26 g WE CLAIM: 1. A process for preparing Cefdinir of Formula II comprising the steps of, (i) reacting thiazolyl acetic acid of Formula III, wherein R represents acetyl or trityl, with bis(5-methyl-l,3,4-thiadiazol-2-yl)disulfide of Formula IV, in the presence of triphenyl phosphine and an organic base in a solvent to produce thioester derivative of thiazolyl acetic acid of Formula I, (iii) deprotecting compound of Formula VI to produce Cefdinir of Formula II. 2. The process according to claim 1 wherein the organic base used in step (i) is selected from triethylamine, N-methyl morpholine, N-alkylpiperdines, triethylamine, n-butylamine, and mixtures thereof 3. The process according to claim 1 wherein the said solvent used in step (i) is selected from the group consisting of chloroform, methylene dichloride, 1,2- dichloroethane or mixtures thereof. 4. The process according to claim 1 wherein R represents acetyl and R represents hydrogen, the acylation is carried out in the presence of an organic base such as triethylamine, N-methyl morpholine, N-alkylpiperdines, triethylamine, n- butylamine, and mixtures thereof, and aqueous organic solvent such as tetrahydrofuran, acetonitrile, acetone, dioxane, N,N-dimethylformamide. 5. The process according to claim 1 wherein R represents acetyl and trityl R" represents trialkylsilyl, the acylation is carried out in the presence of silylating agent such as hexamethyldisilazane, bis(trimethyl)silyl acetamide, mono(trimethyl)silyl acetamide, trimethylsilyl chloride or mixtures thereof, and aprotic organic solvent such as dichloromethane, toluene, acetonitrile alkyl ethers.

Documents:

0969-che-2004 abstract duplicate.pdf

0969-che-2004 abstract.pdf

0969-che-2004 claims duplicate.pdf

0969-che-2004 claims.pdf

0969-che-2004 correspondence others.pdf

0969-che-2004 correspondence po.pdf

0969-che-2004 description (complete) duplicate.pdf

0969-che-2004 description (complete).pdf

0969-che-2004 form-1.pdf

0969-che-2004 form-19.pdf

0969-che-2004 form-3.pdf

0969-che-2004 form-5.pdf

0969-che-2004 others.pdf

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