Title of Invention

A PROCESS TO PREPARE CEFEPIME

Abstract

A novel process is disclosed for the preparation of Cefepime, a cephalosporin antibiotic, using novel new intermediates of the general Formula, This process comprises the step of cyclizing the bromo or chloro intermediate with thiourea to produce Cefepime of high purity. A process to prepare bromo or chloro intermediate comprising the acylation of 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate with 4-halo-2-methoxyimino-3-oxobutyric acid halide is also described.

Full Text

FIELD OF THE INVENTION The present invention relates to a process for the preparation of Cefepime by using novel intermediates of the general Formula, BACKGROUND OF THE INVENTION Cefepime, also known as 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate is a useful broad spectrum antibiotic cephalosporin and has the chemical structure of Formula I Cefepime and its preparation has been first disclosed in US Patent 4,406,899. Two reaction schemes have been discussed in this patent to prepare Cefepime. Both of these schemes make use of the protecting groups that require additional blocking and deblocking steps. Furthermore, the exemplified process makes use of a chromatographic purification to obtain Cefepime zwitterion. US Patent 4,754,031 describes a process where 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid is activated by reacting with methanesulfonyl chloride to form an anhydride for acylation of 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate to obtain Cefepime. Although this process does not use protecting groups but it requires column chromatography as a purification method which is not practical in manufacturing. US Patent 5,594,129 describes preparation of Cefepime wherein acid chloride hydrochloride of the Formula, has been used for the 7V-acylation of 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate under anhydrous conditions. The use of the same acid chloride hydrochloride in aqueous conditions for N-acylation to prepare Cefepime has been demonstrated in the US Patent 5,594,130. In both of these US patents, the preparation of the desired acid chloride hydrochloride involves first the conversion of syn-2-(2-amino-4-thia2olyl)-2-methoxyiminoacetic acid to the corresponding hydrochloride salt which is then treated with chlorinating agent under specifically defined reaction conditions to obtain the syn-isomer of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride that contains less than about 5% of the undesirable anti-isomer which may affect the subsequent acylalion reaction to obtain the antibiotic. Cephalosporins have been prepared in literature through an alternate method in which the amino group in the cephem nucleus is first acylated with 4-halo-2-methoxyimino-3-oxobutyric acid and the thiazolyl ring formation is subsequently effected with thiourea. However, there is no such report yet to date for preparing Cefepime through this route. This procedure of preparing a cephalosporin compound is described in the present invention to obtain highly pure Cefepime. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 7-{4-halo-3-oxo-2-methoxyiminobutyrylamino)cephalosporin compounds of the general Formula II as well as its salts and hydrates, which comprises reacting the above compounds of Formula II with thiourea, and converting Cefepime of Formula I into a hydrate of the said salt. Accordingly, a process for the preparation of 7-[(Z)-2-(2-amino-4-thia2olyl)-2-(methoxyimino)acetamido]-3-[( 1-methyl-]-pyrrolidinium)methy]]-3-cephem-4-carboxylate. known as Cefepime of Formula 1 comprising the steps of i) N-acylation of 7-amino-3-[( 1-methyl-]-pyrrolidinium)methyl]-3-cephem-4-carboxylate or its salt, of Formula III, a compound prepared in a known manner, with halogenated carboxylic acid derivative of Formula IV, a compound prepared in a manner as herein described, where X represents bromine or chlorine atom Y represents hydroxy! or a halo group TO a suitable solvent(s), as herein described, preferably at one molar equivalent at a temperature ranging from -30°C to -10°C, to obtain a reaction mixture. ii) adding water to the above said reaction mixture to precipitate 7-(4-halo-3-oxo-2-methoxyiminobutyrylamino)cephalosporin derivative of Formula II where X represents bromine or chlorine atom iii) isolation of Formula II by filtration. iv) reacting the said Formula II with thiourea in a solvent or a mixture of solvents such as herein described at a temperature ranging from 20°C to 40°C to obtain the desired compound, Cefepime; and v) isolating the said Cefepime in a known manner and converting into salt form by using conventional methods. According to the present invention, the intermediate compounds of Formula II are prepared by A^-acylation of 7-amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate of Formula III or its HX salt wherein HX is HCl. HI or H2SO4, with halogenated carboxylic acid of the general Formula IV where X represents bromine or chlorine atom Y represents hydroxyl or a halo group 4-(Bromo or Chloro)-2-methoxyimino-3-oxobutyric acid of Formula IV is prepared in high purity and good yield starting from tert-butyl acetoacetate as per the procedure described in the US Patent 5,095,149. tert-Butyl acetoacetate has been prepared from tert-butyl acetate as given in Organic Synthesis Coll. Vol. V, p-156. This is converted into the corresponding acid chloride of Formula IV where X represents bromine or chlorine atom Y represents chlorine atom by reacting with halogenating agents such as phosphorous oxychloride, phosphorous pentachloride, oxalyl chloride etc and the acid chloride thereby produced may be isolated prior to acylation with cephalosporin compound or may be generated in situ and used as such. The acid chloride formation is conducted in an inert organic solvent such as chloroform, methylene chloride, acetonitrile or the like and most preferably the reaction is carried out in methylene chloride at a temperature of-25°C to -I5°C. The cephalosporin compound of Formula III and its HX salt, which is substantially free from A -isomer, may be prepared by the general procedure described in the US Patent 5,594,131. The cephalosporin compound, 7-amino-3-[(l-methyl-l-pyrroIidinium)methyl]-3-cephem-4-carboxylate, which is preferably available as its hydrochloride salt, may advantageously be silylated in an inert organic solvent to form an in situ solution of the soluble silylated derivative. It is important to add sufficient silylating agent to solubilize the cephalosporin compound of Formula 111 before treating it with acid chloride of Formula V. Silylating agents which may be used are, for example, hexamethyldisilazane, trimethylchlorosilane, N,N-bis(trimethylsilyl)urea, N-(trimethylsilyl)acetamide,N,O-bis(trimethylsilyl)acetamide, tert-butyldimethylchlorosilane or the like and most preferably N-(trimethylsiIyl)acetamide may be used. Suitable solvents which may be used in the acylation process are all inert organic solvents in which the silylated derivative of cephalosporin compound of Formula III is soluble, for example, toluene, tetrahydrofuran, acetone, acetonitrile, methylene chloride, chloroform or the like and most preferably methylene chloride may be used. Soluble silylated derivative is then treated with the acid chloride of Formula V, preferably with one molar equivalent, and most preferably with a slight excess of the acid chloride. The silylation of cephalosporin compound of Formula III is completed at about 15°C to 30°C while the N-acylation is advantageously carried out at -30°C to -10°C. After N-acylation is complete, as ascertained by the known detection methods reported in the art, water is added to the reaction mixture to precipitate 7-(4-halo-3-oxo-2-methoxyiminobutyrylamino)cephalosporin compound of the general Formula II, which is isolated by filtration. The halo intermediates of Formula II and their preparation from Cephalosporin compound of Fonnula III constitutes the inventive part of the present invention to prepare Cefepime. The reaction of halo intermediates of Formula II with thiourea to prepare Cefepime, in accordance with the present invention is preferably carried out in a solvent such as ethanol, acetone, tetrahydrofuran, N,N-dimethylformamide, water and mixture thereof and preferably aqueous acetone is used. The reaction is generally carried out at a temperature range of 20°C to 40°C and preferably at room temperature. Thereafter, when it is desired to prepare Cefepime dihydrochloride monohydrate, the reaction mass after cyclization with thiourea is treated with sufficient amount of hydrochloric acid. The resulting reaction mixture is then diluted with water miscible appropriate solvent such as acetone to ensure the crystallization of the desired Cefepime dihydrochloride monohydrate form. The Cefepime dihydrochloride monohydrate thus obtained is substantially free from anti-isomer and N-isomer. The present process provides control of the stereochemical configuration of methoxyimino isomer and the N-double bond of cephalosporin nucleus without the need to separate undesirable cephalosporin by-product by chromatography. Another advantage of present invention is the use of acid chloride of Formula V wherein the simple chloride ion is the leaving group and thus avoids unusual and sometimes complex leaving groups described in the art. The examples below illustrate our invention without limiting the scope of the invention. The examples are described as two stage processes where the first stage forms the preparation of the inventive intermediates, and the second stage is their conversion to Cefepime dihydrochloride monohydrate. Example -1 STAGE-1: STEP'A: SILYLATION OF 7-AMINO'3-l(I'METHYL'I-PYRROLIDINIUM)METHYL/-3'CEPHEM-4' CARBOXYLATEHYDROCHLORIDE (SOLUTIONA) To a suspension of 7-amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (10 g, 0.03 mol) in methylene chloride (100 ml) at 20-25°C, N-trimethylsilylacetamide solution (containing 26.72 g A^-trimethylsilylacetamide, 0.20 mol) was added and stirred for 1 hour to obtain a clear solution. This solution was cooled to -25°C to-20'C until use. STEP-B: PREPARATJON OF4-BROMO-2'METHOXYIMINO-3-OXOBUTYRYLCHLORIDE (SOLUTION B) To a suspension of phosphorous pentachloride (7.5 g; 0.036 mol) in methylene chloride (62 ml), 4-bromo-2-methoxyimino-3-oxobutyric acid (7.73 g, 0.035 mol) was added in small lots over a period of 10 minutes, while maintaining the temperature between -25°C and -20°C. The reaction mass was stirred at -25°C to -20°C until the starting materiars absence was noted with TLC (30 minutes). The reaction mass was then washed with water (23 ml) to remove inorganic impurities and by-products. This solution was used as such in the next step. STEP'C: PREPARA TION OF 7'(4-BROMO-2-METHOXYIMINO-3-OXOBUTYRAMJDO)-3'{(I' METHYL-I-PYRROLIDimUM)METHYLJ'3-CEPHEM-4'CARBOXYLATE (BROMO INTERMEDIATE) Solution B was added to solution A, while maintaining the temperature between -25°C and -20°C over a period of about 10 minutes and the reaction mass was stirred for 1 hour at this temperature. Thereafter cold water (50 ml, 5°C) was added and the reaction mass was stirred at 2-5°C for 1 hour. The product thus obtained was filtered, washed with methylene chloride (20 ml) and dried to obtain the bromo intermediate as its hydrochloride salt (13.2 g). The structure of this compound was confirmed by spectroscopic data. 'H NMR (300 MHz) {DMS0'd6) S : 2.11 (m, 4H), 2.94 (5, 3H), 3.45 {m, IH), 3.59 (w, 3H), 3.66 & 4.05 {2d, each IH), 4.05 (5, 3H), 4.30 & 4.61 {2d, each IH), 4,86 (.y, 2H), 5.33 (5, IH), 5.91 {dd, IH), 9.55 (J, IH). IR(KBr)cin"' : 1785, 1714, 1678, 1610 MASS (Positive ion Mode) : 503, 505 [M+1]; 525, 527 [M+Na] corresponding to Br and Br isotopes. STAGE-Il: PREPARA TION OF CEFEPIME DIHYDROCHLORIDE MONOHYDRA TE Thiourea (0.31 g, 0.0040 mol) was added to a suspension of bromo intermediate (2.0 g, 0.0037 mol, as obtained above) in a mixture of acetone (20 ml) and water (10 ml) at 20-25°C. The reaction mass was stirred at 20-25°C for 2 hours. The pH was adjusted to 6.7 using triethylamine (1 ml) and the reaction mass was stirred for 10 minutes. Thereafter, reaction mass was cooled and concentrated hydrochloric acid (2.8 ml) was added at 5-8°C followed by acetone (60 ml) The resulting slurry was cooled and stirred at 0-5^C for 1 hour. The product thus obtained was filtered, washed with acetone (2x5 ml) and dried to obtain 1.47 g of Cefepime dihydrochloride monohydrate having HPLC purity 99,42%. 1H NMR (300 MHz) (DMSO'd6) S : 2.10 (m, 4H), 2.94 {s, 3H), 3.45 (m, IH), 3.59 (w, 3H), 3.66 & 4.04 {2d, each IH), 3.93(5, 3H), 4.31 &4.6I (2^, each IH), 5.33 {d, IH), 5.89 {dd. IH), 6.88 {s, IH), 8.51 (Z?, 2H), 9.83 (^, IH). IR(KBr)cm-1 : 1773, 1730, 1658, 1634 MASS (Positive ion Mode) : 481 [M+1]+ 503 [M+Na]+ Example - 2 STAGE-1: PREPARATION OF 7'(4-CHLORO-2-^METHOXY!MINO-3-OXOBUTYRAMIDO)-3-l(l-METHYL]~ PYRR0L1DINIVM)METHYLI-3'CEPHEM'4'CARB0XYLA TE (CHLORO INTERMEDIATE) 4-Chloro-2-inethoxyimino-3-oxobutyric acid (6.2 g, 0.0345 mol) was added to a suspension of phosphorous pentachloride (7.5 g, 0.0360 mol) in methylene chloride (62 ml) in small lots over a period of 10 minutes while maintaining temperature between -25°C and -20°C. The reaction mass was stirred at -25°C to -20°C until completion of the reaction (-1 hour) and then washed with cold water (23 ml, 5°C). The resulting acid chloride is reacted with silyalted 7-amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxy late hydrochloride as per the procedure given in Example - 1 to obtain the chloro intermediate as its hydrochloride salt. The structure of this compound was confirmed by spectroscopic data. -1 1H NMR (300 MHz) (DMSO-ds) S IR (KBr) cm MASS (Positive ion Mode) 2.11 (m, 4H), 2.94 (s, 3H), 3.45 {m, IH), 3.60 (m, 3H), 3.68 & 4.06 {2cl, each IH), 4.05 {s, 3H), 4.34 & 4.60 (2c/, each IH), 4.86 (s, 2H), 5.33 (5, IH), 5.90 (dd, IH). 9.58 (^, IH) 1785, 1717, 1682, 1609 459, 461 [M+1] corresponding to 'CI and - CI isotopes. STAGE'II: PREPARATION OF CEFEPIME DIHYDROCHLORIDE MONOHYDRATE Thiourea (0.92 g, 0.012 mol) was added to a suspension of chloro intermediate (4.0 g. 0.008 mol, as obtained above) in a mixture of acetone (40 ml) and water (20 ml). The reaction mass was stirred at 23-30°C till completion of reaction (--6 hours). Thereafter, reaction mass was cooled and concentrated hydrochloric acid (1.2 ml) was added at 5-8°C followed by addition of acetone (92 ml). The product thus obtained was filtered, washed with acetone (2x10 ml) and dried to obtain 3.4 g of Cefepime dihydrochloride monohydrate having HPLC purity 99.19%. WE CLAIM: 1. A process for the preparation of 7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate, known as Cefepime of Formula I comprising the steps of i) N-acylation of 7-amino-3-[( 1-methyl-l-pyrrolidinium)methyI]-3-cephem-4-carboxylate or its salt, of Formula III, with halogenated carboxylic acid derivative of Formula IV, where X represents bromine or chlorine atom Y represents hydroxyl or a halo group in suitable solvent(s), as herein described, preferably at one molar equivalent at a temperature ranging from -30°C to -10°C followed by addition of water to precipitate 7-(4-halo-3-oxo-2-methoxyiminobutyrylamino)cephalosporin derivative of Formula 11, where X represents bromine or chlorine atom ii) isolation of Formula 11 by filtration, iii) reacting the said Formnula II with thiourea in a solvent or a mixture of solvents such as herein described at a temperature ranging from 20°C to 40°C to obtain the desired compound, Cefepime and iv) isolating the said Cefepime in a known manner. 2. The process as claimed in claim 1, wherein the Cephalosporin derivative of Formula III or its salt is substantially free from -isomer. 3. The process as claimed in the preceding claims, wherein the Cephalosporin derivative of Formula III is optionally silylated in an inert organic solvent to form an in situ solution of the soluble silylated derivative. 4. The process as claimed in claim 3, wherein the silylating agent is selected from hexamethyldisilazane, trimethylchlorosilane, N,N-bis(trimethylsilyl)urea, N-(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)acetamide, tert-butyldimethyl-chlorosilane or a mixture thereof. 5. The process as claimed in claim 4, the most preferable silylating agent is N-(trimethylsilyl)acetamide. 6. The process as claimed in Step (iv) of claim 1, wherein the solvent used is ethanol, acetone, tetrahydrofuran, N,N-dimethylformamide, water or a mixture thereof. 7. The process as claimed in claim 6, wherein the solvent is aqueous acetone. 8. The process as claimed in Step (iv) of claim 1. wherein the reaction is carried out at room temperature. 9. The process as claimed in claim 1, wherein the Cefepime is optionally converted into a salt form in a known manner. 10. The process as claimed in claim 9, wherein the reaction mixture after cyclization with thiourea is treated i) with sufficient amount of an acid, ii) diluting with water miscible appropriate solvent such as acetone to ensure the crystallization of the Cefepime salt and iii) isolating the said salt in a known manner. 11. The process as claimed in claim 10, wherein the Cefepime salt is Cefepime dihydrochloride monohydrate. 12. The process as claimed in claims 10 and 11, wherein Cefepime dihydrochloride monohydrate is substantially free from anti isomer and Δ 2-isomer. 13. The process as claimed in any of the preceding claims, wherein stereochemical configuration of methoxyimino isomer is controlled. 14. A process for the preparation of Cefepime and or its'salt is substantially, as herein described and exemplified.

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