Title of Invention	AN IMPROVED FOR THE PREPARATION OF CEFOXITIN
Abstract	The present invention relates to an improved process for the preparation of cefoxitin of formula(I).

Full Text

Field of the Invention The present invention relates to an improved process for the preparation of cefoxitin of formula (I). Background of the Invention US patent 4,297,488 discloses different processes for the preparation of cefoxitin, which uses ester protected cephem nucleus. These processes involve deprotection after carbamoylation because of the yield of the product is less. US patent 4,210,750 and 4,292,750 disclose a process for the preparation cefoxitin, which involve the usage of an isocyanate wherein the labile substituent is hydrocarbyl or substituted hydrocarbyl group. The above said prior art processes always yield the cefoxitin with poor quality, and color. We have now found an improved process for the preparation of the compound of formula (I), which process has advantages over the processes described in the above-mentioned prior art documents. Objectives of the Invention The main objective of the present invention is to provide a process for preparation of cefoxitin of the formula (I). Another objective of the present invention is to provide novel intermediates of formulae (III) and (IV) their use in the preparation of cefoxitin of the formula (I). Yet another objective of the present invention is to provide the process for the preparation of cefoxitin, which is easy to implement on commercial scales. Still another objective of the present invention is to provide a high-yielding method of producing cefoxitin of the formula (I). Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of cefoxitin of the formula (I), the said process comprising the steps of: (i) treating the compound of formula (II) with a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxides at a temperature in the range of-100 °C to 0°C, isolating the product formed as an organic amine salt of the formula (III), where M+ represents an organic counter ion (ii) treating the salt of formula (III) with a base in the presence of solvent at a temperature in the range of-75 to 10 °C, isolating the product formed as an organic amine salt of the formula (IV),where M^ represents an organic counter ion and (iii) carbamoylating the compound of formula (IV) with isocyanate of formula (V) wherein R is a labile group in the presence of a solvent at a temperature in the range of -60°C to 0°C, and isolating to get cefoxitin of the formula (I). The synthesis of cefoxitin sodium of the formula (I) is as shown in Scheme-I Detailed Description of the Invention In an embodiment of the present invention, the halogenting agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N-bromosuccinimide, bromine or chlorine. In another embodiment of the present invention, the organic solvent used in step (i) is selected from dichloromethane, methanol chloroform, THF or ethylene chloride and the like or mixtures thereof. In another embodiment of the present invention, the organic amine used in step (i) is selected from diethylamine, methylethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'- diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N- diisopropylethylamine, N,N-diisopropylamine, octylamine, and the like, more particularly cyclohexy amine salt. In yet another embodiment of the present invention the alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide, magnesium methoxide, and the like. In still another embodiment of the present invention, the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate and the like or mixtures thereof; and the base employed in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like, more particularly sodium hydroxide. In another embodiment of the present invention, the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, 1,4- dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine, more particularly benzathine salt (N,N'-dibenzylethylenediamine). In another embodiment of the present invention, the solvent employed in step (iii) is selected from THF, methanol dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof. In still another embodiment of the present invention, the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group. In yet another embodiment of the present invention, the starting material of formula (II) is prepared according to the procedures available in the prior art. The foregoing technique has been found to be markedly attractive, both from commercial point of view and affords good quality of cefoxitin of formula (I). The present invention is illustrated with the following examples, which should not be construed as limiting to the scope of the invention. Example I Step i: Preparation of 7-(2-thienyl)acetamidocephalosporanic acid sodium salt To mixture of orthophosphoric acid (32.5 ml), water (1300 ml), and 15% sodium hydroxide (230 ml) 7-ACA (100 gm) was charged at 15-20 °C. 15% sodium hydroxide (20 ml) was added till pH of reaction mass become 7.2. 2-Thiophene acetyl chloride (70.0 gm) in ethyl acetate (110 ml) was added dropwise over 15 minutes at 20 °C and maintained at the same temperature till completion of reaction. After completion of reaction, ethyl acetate (1060 ml) was added, pH was adjusted to 1.7 using 1:1 hydrochloric acid, and layer was separated. To ethyl acetate layer anhydrous sodium acetate (39.0 gm) in methanol (340 ml) was added at 15-20 °C, and stirred 30 minutes. The solid obtained was filtered, washed with ethyl acetate dried under reduced pressure to give title compound (139 gm). Step ii: Preparation of 7-oc-methoxy-7-(2-thienyl)acetamidocephaIosporanic acid cyclohexyl amine salt To dichloromethane (806 ml) and methanol (83.0 ml), 7-(2-thienyl) acetamidocephalosporanic acid sodium salt (100 gm) was added and cooled to -20 °C. Methane sulfonic acid (25.3 gm) was added and cooled to -90 °C. N-Chlorosuccinimide (60.8 gm) was added followed by sodium methoxide solution (337.3 gm) in methanol (160 ml) was added slowly at -90 °C. The reaction mass was stirred till completion of reaction, after completion of reaction sodium metabisulphite (20.6 gm), aqueous acetic acid (150 ml) and sodium chloride solution (189 gm in 1164 ml water) were added at -90 ""C. After addition, 1:1 HCl (23.5 ml) was added at 0 °C, then layer was separated, organic layer was washed with water and distilled of organic layer until final volume becomes (500 ml). To this mass cyclohexyl amine in acetone was added dropwise till pH becomes 6.5. IPE was added and stirred reaction mass for 2 hour at 0 °C. The solid obtained was filtered, washed with acetone and dried to get the title compound (101.0 gm). Step iii: Preparation of 3-hydroxymethyl-7-oc-niethoxy-7-[(2-thienyI)acetamido]-3-cephem-4-carboxylic acid N,N*-bis(phenylmethyl)-l,2-etlianediamine salt To a mixture of DM water (326 ml) and methanol (366 ml), 7-oc-methoxy cephalothin (100 gm) obtained from step (ii) was added at 1 °C and cooled to -45 °C. To the reaction mixture, sodium hydroxide solution (28 gm in 167 ml water) was added slowly at 5 °C and stirred at -45 °C till completion of reaction. After completion of reaction, pH was adjusted to 7.0 using aqueous acetic acid at -45 °C. The reaction mass temperature was raised to 28 °C and distilled approximately 400 ml reaction mass. Ethyl acetate (52 ml), benzathine diacetate (40 gm) were added and stirred reaction mixture for 2 hour at 20 °C. The reaction mass was cooled and the solid obtained was filtered, washed with water followed by ethyl acetate and dried to get the title compound (72 gm). Step iv; Preparation of 7-x-methoxy-7-[(2-thienyl)acetamido]-3-caramoyloxymethyl-3-cephem-4-carboxylic acid To THF (400 ml) decarbomoyl cefoxitin benzathine salt (50 gm) obtained from step (iii) was added, and cooled to -55 °C, followed by slow addition of precooled solution of chloro sulphonyl isocynate (35.0 gm) in THF (50 ml) at -55 °C. Reaction mass was stirred till completion of the reaction. After completion of the reaction, the reaction mass was added into cold DM water and stirred for 2 hours. Ethyl acetate (1277.0 ml) was added, the byproduct obtained was filtered and washed with ethyl acetate/water mixture. To the filtrate 10% sodium chloride solution (225 ml) was added, stirred 10 minutes then layer was separated. The organic layer was washed with 10% sodium chloride solution. The product was extracted with mixture of sodium bicarbonate solution and sodium chloride solution. The pH of aqueous solution was adjusted to 2.0 with 1:1 HCl and cooled to 10 °C. The solid obtained was filtered, washed, and dried. The dried solid was added DM water (462 ml) at 25 °C. pH of reaction mass was adjusted to 6.0 with sodium carbonate solution (83 ml) and degassed for 30 minutes. Acetic acid was added to adjust pH to 5.4-5.6, and activated carbon (3.5 gm) was added and stirred for 10 minutes. Carbon was filtered and washed the bed with water. To the filtrate ethyl acetate (9 ml) was added and pH of filtrate adjusted to 2.0 with 1:1 HCl (14 ml). The reaction mass cooled to 10 °C, the solid obtained was fihered, washed with water, and dried to title compound in pure form. We claim: 1) A process for the preparation of cefoxitin of formula (I) the said process comprising the steps of: (i) treating the compound of formula (II) with a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxide at a temperature in the range of-100 °C to 0°C, isolating the product formed as an organic amine salt of the formula (HI), where M^ represents an organic counter ion (ii) treating the salt of formula (III) with a base in the presence of solvent at a temperature in the range of-75 to 10 oC, isolating the product formed as an organic amine salt of the formula (IV), where M+ represents an organic counter ion and (iii) carbamoylating the compound of formula (IV) with isocyanate of formula (V) 2) The process as claimed in claim 1, wherein the halogenting agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N-bromosuccinimide, bromine or chlorine. 3) The process as claimed in claim 1, wherein the organic solvent used in step (i) is selected from dichloromethane, methanol chloroform, THF or ethylene chloride and the like or mixtures thereof. 4) The process as claimed in claim 1, wherein the organic amine used in step (i) is selected from diethylamine, methylethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1,8-diazabicyclo(5.4.0)undec-7"ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine or octylamine. 5) The process as claimed in claim 1, wherein alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide or magnesium methoxide. 6) The process as claimed in claim 1, wherein the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate or mixtures thereof. 7) The process as claimed in claim 1, wherein and the base employed in step (ii) is selected from sodium hydroxide, or potassium hydroxide. 8) The process as claimed in claim 1, wherein the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, 1,4- dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine. 9) The process as claimed in claim 1, wherein the the solvent employed in step (iii) is selected from THF, methanol dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof. 10) The process claimed in claim 1, wherein the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group.

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0236-che-2003 description (complete)-duplicate.pdf

0236-che-2003 form-13.pdf

236-che-2003-abstract.pdf

236-che-2003-claims.pdf

236-che-2003-correspondnece-others.pdf

236-che-2003-correspondnece-po.pdf

236-che-2003-description(complete).pdf

236-che-2003-form 1.pdf

236-che-2003-form 19.pdf

236-che-2003-form 3.pdf

236-che-2003-form 5.pdf

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