Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF CEFEPIME
Abstract	The present invention relates to a simple and efficient process for the preparation of highly pure Cefepime of Formula I which involves the acylation of amine compound of Formula n or its salts in aqueous acetone, with 2-mercaptobenzothiazolyl ester of Formula III in the presence of a base.

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FIELD OF THE INVENTION The present invention relates to a simple and efficient process for the preparation of highly pure Cefepime of Formula I BACKGROUND OF THE INVENTION Cefepime, also known as 7-[(Z)-2-(2-Amino-4-thiazolyl)-2- (methoxyimino)acetamido]-3-[(l -methyl-1 -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-aniino-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 IV has been used under anhydrous conditions for the N-acylation of silylated 7-amino-3-[(1-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate. The use of the same acid chloride hydrochloride in aqueous conditions for 7V-acylation to prepare Cefepime has been demonstrated in the US Patent 5,594,130. hi both of these US patents, the preparation of the desired acid chloride hydrochloride involves first the conversion of 5yn-2-(2-amino-4-thiazolyl)-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 acylation reaction to obtain the antibiotic. Acylating agents namely, 2-mercaptobenzothiazolylester of Formula III and 1-hydroxybenzotriazolyl ester of Formula V have been reported in literature to prepare Cefepime, Tetrahedron Letter vol. 31, pp 6481-6484, 1990. However, experimental details are not available in the references cited therein to prepare Cefepime using 2-mercaptobenzothiazolyl ester of Formula III. Preparation of Cefepime has been disclosed in Zhongguo Yaonu Hauxue Zazhi 2002, 12(6), 350-351, by acylation of compound of Formula n with 2-mercaptobenzothiazolyl ester of Formula III in methylene chloride. Methylene chloride is a widely employed solvent in the organic reaction because of its physical properties like low boiling point, and hence easy removal. However, the use of methylene chloride and other halogenated solvents has been criticized for years because of ecological hazards involved in using these solvents. Various pharmacopoeia commissions are considering the possibility of reducing methylene chloride residues in pharmaceuticals. In the process described in PCX Publication WO 04/037833 Al, reaction of compound of Formula II with 2-mercaptobenzothiazolylester of Formula in is effected in a mixture of tetrahydrofuran, dimethylacetamide and water to prepare Cefepime. To isolate the product, two further solvents have been employed namely, ethyl acetate and acetone, hi this process, the result is thus a mixture of solvents, the regeneration of which into pure individual components in an economical manner is difficult. hi view of above, there is a clear need to find an alternative industrially viable process for the production of Cefepime. Surprisingly we have found a new, substantially simple process for the production of highly pure Cefepime of Formula I without using ecologically hazardous methylene chloride or a complex mixture of solvents. SUMMARY OF THE INVENTION Accordingly, the present invention relates to a simple and an industrially advantageous process for the preparation of Cefepime of Formula I DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an industrial process for the preparation of Cefepime, wherein aqueous acetone has been used advantageously to carryout the acylation reaction and to isolate the product in high purity. The amine compound of Formula II is prepared by the prior art method reported in US Patent 5,294,131. Similarly, the compound of Formula III is prepared by the method described in US Patent 5,003,073. Specifically, the amine compoimd of Formula II or its salt is treated with 2-mercaptobenzothiazolyl ester of Formula III in aqueous acetone in the presence of a base. The base can be either a tertiary amine, e.g. a trialkylamine such as triethylamine, tributylamine, N-ethylpiperidine or iV-methylmorpholine, and preferably triethylamine, or an inorganic base such as sodium hydroxide, sodium hydrogen carbonate or sodium carbonate. The reaction is carried out suitably at a temperature varying fi-om 0°C to 40°C and it takes about 3-8 hours to complete the Cefepime formation which is monitored by HPLC analysis. Thereafter, the reaction mass can optionally be diluted with more acetone to directly isolate Cefepime or alternatively, it can be washed with ethyl acetate to remove 2-mercaptobenzothiazole by-product prior to isolation of Cefepime. During isolation of Cefepime, it is converted to hydrochloride using hydrochloric acid and the dihydrochloride monohydrate is then isolated in high yield having HPLC purity of greater than 99.5%. Major advantages realized in the instant invention as compared to the prior art are: - no chlorinated hydrocarbon is used - no silylation step is necessary and also - no mixture of solvents is required. In the process according to the present invention, apart from water the only solvent which is used is the ecologically substantially acceptable acetone. No mother liquors are obtained which are made of many solvents and are thus difficult to regenerate. The process is very simple and the desired Cefepime dihydrochloride monohydrate is obtained directly from the reaction mixture in high yield and in pure form. The process according to the invention thus offers great ecological and econonical advantages, since acylation reaction, including product isolation, and regeneration of the acetone from mother liquor is very simple. The process is suitable for industrial scale. Now the examples below illustrate our invention without limiting the scope of the invention: EXAMPLE 1 PREPARATION OF CEFEPIME 7-Amino-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate hydrochloride (lOg, 0.03 moles) was suspended in a mixture of DM water (80 ml) and acetone (100 ml) at 8-10°C. To this mixture, 2-mercaptobenzothiazolyl (Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (13.64 g, 0.039 moles) was added at 8-10°C followed by slow addition of triethylamine at 8-10°C to adjust the pH to 7.5-7.8. The reaction mass was stirred at 25-28°C for 6 hours and thereafter, diluted with ethyl acetate (100 ml) and stirred for further 15 min. Thereafter, the layers were separated and to the aqueous layer, concentrated hydrochloric acid (14 ml) was added at 0-5° followed by addition of acetone (500 ml) at 5-10°C to crystalhze the product. The resulting slurry was stirred at 5-10° C for 1 hour. The separated solid was filtered, washed with acetone and dried to obtain 12.2 g of the title compound as dihydrochloride monohydrate having purity of 99.86% by HPLC. EXAMPLE! PREPARATION OF CEFEPIME 7-Amino-3-[( 1 -methyl-1 -pyrrolidino)methyl]ceph-3-em-4-carboxylate monohydrochloride (20 g, 0.06 moles) was suspended in a mixture of DM water (160 ml) and acetone (300 ml) at 12-15°C. To this slurry, 2-mercaptobenzothiazolyl (2)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (27.2 g) was added at 12-15°C. Thereafter, pH was adjusted to 7.5-7.8 with triethylamine (-10 ml) and temperature raised to 25-30°C. Stirring was continued at 25-30°C by maintaining the pH 7.0-7.5 by dropping triethylamine (-2.5 ml) for 3 hours. Thereafter, reaction mass was cooled to 10-15°C and hydrochloric acid (28 ml, 32% w/w) was added. The solution was treated with activated carbon (2 g) for 30 min at 10-15°C. Carbon was separated through hyflo and the residue was washed with a 1:1 mixture of acetone and water (20 ml). The filtrate was cooled to 10-12°C, acetone (100 ml) was added in 30 min at 10-12°C and continued stirring for 60 min. Solid was filtered, washed with acetone (50 ml) and dried at 45°C under reduced pressure to obtain 26 g of Cefepime dihydrochloride monohydrate as off-white crystalline powder (yield: 76%, HPLC purity. 99.68%). This above material (10 g) was further purified by dissolving in methanol (45 ml) at 25-30°C. Activated carbon (1 g) was added and stirred for 30 min at 25-30°C. Carbon was separated and washed the residue with methanol (10 ml). The filtrate was cooled to 10-12°C and acetone (300 ml) was added. Crystals were filtered and washed with acetone (50 ml) to obtain Cefepime dihydrochloride monohydrate as white crystalline material (yield: 9 g, HPLC purity: 100%). WE CLAIM: 1. A process for the preparation of Cefepime of the Formula I as well as its salts and hydrates, which comprises, i) acylation of the amine compound of Formula 11 or its salts in aqueous acetone, - with 2-mercaptobenzothiazolyl ester of Formula III in the presence of a base at a temperature of 0-40°C, ii) isolating Cefepime by adding solvent to the reaction mixture and separating the layers. iii) treating the aqueous phase containing Cefepime with hydrochloric acid followed by addition of second organic solvent to crystallize Cefepime. 2. The process according to claim I, wherein the base is either a tertiary amine, e.g. a trialkylamine such as triethylamine, tributylamine, N-ethyipiperidine or N-methylmorpholine, and preferably triethylamine, or an inorganic base such as sodium hydroxide, sodium hydrogen carbonate or sodium carbonate. 3. The process according to claim 1, wherein acylation is carried out preferably at 5-30°C. 4. The process according to claim 1, wherein solvent used in isolation step is selected from ethylacetate. 5. The process according to claim 1, wherein second organic solvent is selected from acetone.

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