Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFOXITIN SODIUM

Abstract

The present invention is directed to a new process of preparing highly pure Cefoxitin sodium of Formula I, an antibacterial agent. The invention is further directed to novel intermediates useful in making Cefoxitin sodium and processes of making these derivatives. Examples of such intermediates include amine salt of 3-acetyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate; amine salt of 3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate.

Full Text

FIELD OF THE INVENTION The present invention relates to a process for the preparation of Cephalosporin derivative. Specifically the Cephalosporin derivative is Cefoxitin sodium of Formula I and its intermediates with high purity starting from cephalothin derivatives of the Formula II. represents hydrogen or alkali metals such as sodium and potassium BACKGROUND OF THE INVENTION Cefoxitin sodium of Formula I, is a well known antibacterial agent useful in the treatment of anaerobic and mixed bacterial infections. It possesses high resistance to P-lactamase inactivation and is chemically known as sodium (6R,7S)-3-[(Carbamoyloxy)methyl]-7-methoxy-8-oxo-7-[[(thiophen-2-yl)acetyI]amino]-5-thia-1 -azabicyclo-[4,2,0]oct-2-ene-2-carboxylate Several processes for the preparation of Cefoxitin sodium and key intermediates have been disclosed by Merck in different US patents 3,780,031, 3,780,033, 3,780,037, 3,775,410, 4,297,888 which are herein incorporated by reference. US patent 4,297,888 is the basic product patent. This patent also describes different routes to prepare Cefoxitin sodium and intermediates starting from 7-aminocephalosporanic acid of Formula III. The major drawback to the processes disclosed in '888 is that all the processes consist of multi steps, and having low yields. Further, the chromatographic techniques are used to obtain the intermediates of desired quality. As chromatographic techniques are tedious, cumbersome and time consuming; therefore, various routes taught by the '888 patent are not viable on industrial scale. British Patent GB 1,350,772 teaches a process for the preparation of Cefoxitin acid and other intermediates. The Cefoxitin acid is prepared by the carbamoylation of potassium 3-hydroxymethyl-7-methoxy-7-(2-thienyl-acetamido)-3-cephem-4-carboxylate compound of Formula IV This hydroxyniethyl compound of Formula IV has been prepared by the enzymatic reduction of potassium 7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate compound of following Formula V. No yields are reported for this preparation. The compound of Formula V is prepared in seven steps starting from 7-aminocephalosporanic acid of Formula III in overall yield of 10-15% and purity of compounds is not reported. Most of known processes for the preparation of Cefoxitin are making use of chromatographic techniques to purify the product of desired quality and further yields are also very low. These processes are having multiple stages and operational complexities during commercial production and therefore not viable for commercial production. Hence, there is an urgent need to develop a cost-effective, efficient and commercially viable process to prepare Cefoxitin sodium, where the use of chromatographic techniques can be avoided. It is therefore an object of the present invention to provide an efficient and cost-effective industrially advantageous process to prepare highly pure Cefoxitin sodium in good yields without using chromatographic techniques. SUMMAR Y OF THE INVENTION: The present invention relates to an industrially advantageous process for the preparation of Cefoxitin sodium starting from Cephalothin and its alkali metal salts, which comprises: a) converting cephalothin sodium of formula II to the corresponding ester of formula VI using conventional methods, b) methoxylating the compound of formula VI to compound of formula VII using lithium methoxide and t-butyl hypochlorite in organic solvents at a temperature of-100°C to -40°C, c) converting the compound of formula Vn to the corresponding acid of formula Vni by deprotection of the ester group using conventional methods and treating the acid with suitable organic amine in a suitable organic solvent such as C1-C4 alcohols, ethers, halogenated hydrocarbons, hydrocarbons, ketones, esters and the like or the mixtures thereof at a temperature of below 40°C and isolating the compound of formula VIII as amine salt, d) hydrolysing the compound of formula VIII with the base in alcoholic solvents and in their aqueous mixture thereof at a temperature of -60°C to -15°C, and treating the resulting compound with suitable amine and isolating compound of formula IX as amine salt, e) carbamoylating the compound of formula IX as obtained above using halosulfonyl isocyanate in organic solvent at a temperature of -70°C to 0°C and isolating the Cefoxitin acid of formula X and f) converting the Cefoxitin acid to the pharmaceutical acceptable salt by the conventional methods. The process is shown below: R represents hydrogen or alkali metals such as sodium and potassium. R represents benzyl, nitrobenzyl, alkoxy benzyl, alkylbenzyl alkoxyl alkyl benzyl, benzhydryl X represents organic amine group. DETAILED DESCRIPTION OF THE INVENTION The instant invention is directed to a new, efficient, cost-effective and industrially advantageous process for the preparation of highly pure Cefoxitin sodium of Formula I in good yields. The present invention is also directed to the new intermediate of Formula VIII The process of preparing the compound of Formula VIII involves three steps. In first step, Cephalothin sodium of Formula II, is protected with suitable carboxylic acid protecting groups such as benzyl, nitrobenzyl, alkoxybenzyl, alkyl benzyl, alkoxy alkyl benzyl, benzhydryl and the like, and most preferably with p-nitrobenzyl, in the presence of an inert organic solvent. The organic solvent can be selected from ethers such as tetrahydrofuran, dioxane, amides such as N,N-dimethylformamide, N,N-dimethylacetamide esters and the like or mixture thereof; preferably N,N-dimethylformamide is used. The most preferred technique to prepare carboxylic acid protected cephalothin is performed by treating the cephalothin sodium of Formula II, with 1-2.5 moles of /?-nitrobenzyl bromide in A'i/^-dimethylformamide at a temperature of 10-40°C and preferably at 20-25°C. In the second step, the resulting protected cephalothin compoimd is methoxylated. The methoxylation is achieved using lithium methoxide in the presence of t-butyl hypochlorite in any inert organic solvent. The organic solvent used can be selected from tetrahydrofuran, dichloromethane, acetone, toluene, ethyl acetate, N,Ndimethylformamide, N,N-dimethylacetamide, ethers and the like or mixtures thereof and preferably N,N-dimethylformamide, tetrahydrofuran and dichloromethane is used. The reaction is performed at a temperature of-100°C to -40°C and preferably at -95° to -80°C. After completion of methoxylation in the third step protecting group can be removed by the methods reported in the art. Specifically the p-nitrobenzyl group is removed by hydrogenolysis and more preferably using 5-10% palladium on carbon in methanol at a temperature of 25-50°C. After removal of the protecting group, the methoxylated cephalothin is isolated as an amine salt of Formula VIII The amine salt is prepared by the reaction of the methoxylated cephalothin with organic amines in a suitable organic solvent at a temperature of below 40°C. The organic amines can be selected from cyclohexylamine, dicyclohexylamine, N-methylmorpholine, piperazine, morpholine, N,N-dibenzylethylenediamine, N,N'-diphenylethylenediamine, N,N-di(4-methylbenzyl)ethylenediamine, N,N-diisopropylethylamine, N,N-diisopropylamine and the like. Preferably cyclohexylamine is used. The suitable organic solvent can be selected from C1-C4 alcohols e.g. methanol, ethanol; ethers e.g. diisopropyl ether, tetrahydrofuran; halogenated hydrocarbons e.g. dichloromethane, dichloroethane, chloroform, hydrocarbons e.g. toluene, benzene, cyclohexene, hexane, heptane; ketones e.g. acetone, methyl isobutyl ketone; esters e.g. ethyl acetate and the like or mixture thereof. The most preferred method to prepare amine salt of Formula VIII is to treat the methoxylated compound with cyclohexylamine in a mixture of dichloromethane and acetone at a temperature of 20-25 °C and the highly pure compound, monocyclohexylamine-3-acetyloxymethyl-7-methoxy-7-(2-thienyl-acetamido)-3-cephem-4-carboxylate is isolated. The present process has the advantage of providing pure compounds of Formula VIII without making use of column chromatography. The present invention is further directed to a new process of converting compound of Formula VIII to the compound of Formula IX This conversion is achieved by treating the compound of Formula Vin with a base such as alkali metal hydroxides, trialkylamines and pyridine in suitable solvent and compound of Formula DC is isolated as amine salt. The amines can be selected from cyclohexylamine, dicyclohexylamine, A'-methyl morpholine, piperazine, morpholine, N,N-dibenzyl-ethylenediamine,N,N-diphenylethylene-diamine, N,N-di(4-methylbenzyl)ethylenediamine, N,N-diisopropylethylamine, N,N-diisopropylamine and the like. The bases used can be selected from potassium hydroxide, sodium hydroxide, triethylamine, tributylamine, pyridine or the like and most preferably sodium hydroxide is used. The suitable solvent can be selected from alcohols like ethanol, methanol and the like; water or mixtures thereof and most preferably methanol and water are used. Specifically the hydrolysis of compound of Formula VIII is carried out using aqueous sodium hydroxide solution in the mixtures of methanol and water at a temperature of-60°C to -15°C and preferably at -45°C to -40°C. The present invention has the advantage that reduction of compound of Formula VIII is performed chemically, whereas in the prior art, this reduction is reported enzymatically only. Furthermore, yields are improved, isolation facilitated and lactone formation is avoided by the formation of amine salts of Formula IX. This pure amine salt of Formula IX leads to the preparation of Cefoxitin sodium in high purity and good yields without using any column chromatography. The present invention is further directed to a new process of preparing a compound of Formula I from the above amine salt of formula IX. The compound of formula DC is then carbamoylated with halosulphonyl isocyanate in suitable organic solvent at a temperature of -70°C to 0°C and preferably at -60°C to -45^C. For carbamoylation the solvent can be selected from organic solvent like acetonitrile, dichloromethane, acetone, tetrahydrofuran and the like or mixture thereof, preferably tetrahydrofuran is used. Halosulphonyl isocyanate is selected from chlorosulphonyl isocyanate or bromosulphonyl isocyanate. Preferably the reaction is carried out using chlorosulfonyl isocyanate, since it is easily available. It is desirable to use an excess of halosulfonyl isocyanate in order to obtain maximum yields of the desired product, Cefoxitin acid. Further, Cefoxitin acid is purified in alcohol preferably in ethanol to obtain pure Cefoxitin acid having purity >99% by high performance liquid chromatography. Preferably, the Cefoxitin acid is converted to highly pure Cefoxitin sodium by treating the Cefoxitin acid with 2-ethylsodiumhexanoate or sodium acetate using conventional methods. The major advantages realized in the present process as compared to the prior art is the isolation of highly pure compound of Formula VIE and Formula IX without using any column chromatography leading to the preparation of highly pure Cefoxitin sodium in good yields and hence a commercially viable process to prepare Cefoxitin sodium is in place. The invention will now be more fully described with reference to the following examples, which are only illustrative and not to be construed as any limitation thereof Example-l PREPARATION OF SODIUM (6R,7S)-3'[(CARBAMOYLOXY)METHYL]-7- METHOXY-8-OXO'7-[[(THIOPHEN'2-YL)ACETYL]AMINO]-5'THIA-l' AZABICYCLO'f4,lOJOCT-2-ENE-2-CARBOXYLATE STEP-I PREPARA TION OF p-NITROBENZYL 3-ACETYLOXYMETHYL-7-(2-THIENYLA CETAMIDO)-3-CEPHEM-4-CARBOXYLA TE Sodium 3-acetyloxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (350 g; 0.837 mol) and p-nitrobenzyl bromide (397.89 g; 1.842 mol) were added to anhydrous N,N-dimethylformamide (1750 ml) at 20-25°C and stirred for 2 hours at the same temperature. After completion of reaction, the reaction mass was poured into a mixture of water (7000 ml) and toluene (2800 ml) at 0-5°C. The precipitated product was filtered and washed with toluene (350 ml). The wet product was slurried in toluene (1750 ml) and water (525 ml) at 25-30°C for 30 min. The product was filtered, washed with toluene (350 ml) and dried at 55-60°C under reduced pressure to obtain 412 g (92.66 %) of the title compound having purity 97.72% by HPLC. STEP-II PREPARATION OF CYCLOHEXYLAMINE 3'ACETYLOXY-METHYL-7-METHOXY- 7-(2' THIENYLA CETAMIDO)-3CEPHEM-4-CARBOXYLA TE p-Nitrobenzyl 3-acetyloxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (350 g; 0,659 mol) was added to the mixture of anhydrous N,N-dimethylformamide (612 ml) and tetrahydrofuran (1837 ml) under nitrogen atmosphere and reaction mixture was cooled to -90 to -95°C. Pre-cooled methanolic lithium methoxide solution (6.22% w/v; 442.60 ml; 0.725 mol) followed by pre-cooled solution of t-butyl hypochlorite (94.27 ml; 0.790 mol) in tetrahydrofuran (350 ml) were added to the reaction mixture at -80 to -95°C. The reaction mixture was maintained at -80 to -95°C till completion of the reaction. Thereafter, to the reaction mixture acetic acid (39.54 g; 0.564 mol) in methanol (40 ml) was added at -80 to -95°C followed by sodium metabisulfite (31.3 g; 0.164 mol) in water (93 ml) was added to the reaction mixture at -70 to -95°C and then heated to 20-25°C. The reaction mixture was concentrated to the residue under reduced pressure at below 45°C and treated with ethyl acetate (4200 ml) and water (2000 ml). The layers were separated and organic layer was washed with 10% aqueous sodium chloride solution (2x1500 ml). The ethyl acetate solution was concentrated and the resulting compound was dissolved in methanol (2800 ml). The methanolic solution and 10% palladium on carbon (43.75 g; 50% wet) were charged into hydrogenator at 25-30oC. The reaction mixture was hydrogenated at 40-45°C maintaining 7-10 Kg/Cm2 hydrogen gas pressure till completion of reduction. After completion of the reduction, the reaction mixture was filtered and washed with methanol (500 ml). Thereafter, the filtrate was concentrated to dryness at 40-45°C under reduced pressure. The residue was dissolved in a mixture of dichloromethane (1400 ml) and acetone (700 ml) and pH was adjusted to 7.0-7.2 with cyclohexylamine at 20-25°C. The reaction mass was cooled to 0-5 °C and precipitated the product with diisopropyl ether (1400 ml). Reaction mixture was maintained for 2 hours at 0-5°C, filtered the product, washed with acetone (350 ml) and dried the product at 55-60°C under reduced pressure to obtain 223.5 g of the title compound having 96.91% purity by HPLC. STEP-III PREPARA TION OF N,N'-DIBENZYLETHYLENEDIAMINE-BIS[3-HYDROXY-METHYL'7-METHOXY'7^2-THIENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLA TE] Cyclohexylamine 3-acetyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate (200 g; 0.380 mol) was added to a solution of methanol (750 ml) and water (677 ml) at 0-5°C and cooled to -45°C. To the reaction mass, 17% aqueous sodium hydroxide solution (328 ml; 1.394 mol) was added at -40 to -45°C and maintained at same temperature till completion of the reaction. After completion of reaction, pH of the reaction mixture was adjusted to 6.9-7.0 with acetic acid at -30 to -45°C. The reaction mass was heated to 20-25°C and methanol-water mixture was distilled approximately 780 ml under reduced pressure. A',A^-dibenzyl-ethylenediamine diacetate (96 g; 0.266 mol) and ethyl acetate (105 ml) were added and stirred for 2 hours at 15-20°C. The reaction mass was cooled to 7-10°C, filtered the product, washed with cold water (2x400 ml) followed by ethyl acetate (300 ml). The product was dried at 50-55°C under reduced pressure to obtain the title compound (150,5 g) having 96.06% purity by HPLC. STEP-IV PREPARATION OF 3-CARBAMOYLOXYMETHYL-7-METHOXY-7-(2' THIENYL-A CETAMIDO)-3-'CEPHEM-4'-CARBOXYLIC A CID The mixture of N,N-dibenzylethylenediamine bis[3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate] (140 g; 0.1388 mol) and tetrahydrofuran (1120 ml) was cooled to -55 to -50°C. To the reaction mixture, chlorosulphonyl isocyanate (117.9 g; 0.833 mol) in cold tetrahydrofiiran (140 ml) was added slowly at -55 to -50°C and maintained till completion of the reaction. Thereafter, cold water (1680 ml) was added slowly at -55 to -30°C, the temperature of the reaction mass was raised to 20-25°C and maintained for 2 hours. Ethyl acetate (3360 ml) and 10% aqueous sodium chloride solution (700 ml) were added to the reaction mass. The reaction mass was filtered and washed the solid with a mixture of ethyl acetate (560 ml) and water (280 ml). The organic layer was separated and washed with 10% aqueous sodium chloride solution (2x700 ml). pH of the organic layer was adjusted to 6.4-6.6 with a mixture of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride solution. Aqueous layer was separated and pH was adjusted to 1.9-2.0 with about 15% w/w aqueous hydrochloric acid at 20-25°C, cooled to 7-10°C, filtered the crude product and washed with cold water (400 ml). The crude wet product was added to the water (1260 ml) at 20-25°C and pH is adjusted to 6,0-6.3 with 10% aqueous sodium carbonate solution and allowed for 30 min at 20-25°C. pH of the resulting solution was adjusted to 5.4-5.6 with acetic acid and decolourised with activated carbon (15 g) for 20 min, filtered and washed with water (300 ml). Ethyl acetate (30 ml) was added to the filtrate and pH was adjusted to 1.9-2.0 with about 15% w/w hydrochloric acid and cooled to 10°C. The product was filtered, washed with cold water (300 ml). The wet product was purified twice in 5 volumes of ethyl alcohol of each time and dried at 40-45°C under reduced pressure to obtain 79.46 g of the title compound having purity 99.3% by HPLC. STEP-V PREPARA TION OF SODIUM 3-CARBAMOYLOXYMETHYL-7-METHOXY-7-(2-TRIETHYL'ACETAMIDO)-3'CEPHEM-4-CARBOXYLATE 3-Carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (65 g; 0.1522 mol) was dissolved in a mixture of acetone (1200 ml) and methanol (552.5 ml) at 20-25°C under nitrogen atmosphere. 2-Ethylsodiumhexanoate in ethyl acetate (40.3% w/w; 62.7 g; 0.1522 mol) was added dropwise to the reaction mixture at 20-25°C and maintained for 1 hour. The reaction mass was cooled to 7-10°C and filtered the product, washed with acetone (400 ml) under nitrogen atmosphere. The wet product was dried at 35-40°C under reduced pressure to obtain the title compound (58.5 g) having purity 99.85% by HPLC. Example-2 PREPARATION OF SODIUM (6R,7S}'3-[(CARBAMOYLOXY)METHYLJ-7-METHOXY-8-OXO'7'[[(THIOPHEN-2'YL)ACETYL]AMINO]-S'THIA'l' AZABICYCLO'[4,2,0]OCT'2-ENE'2'CARBOXYLA TE STEP-I PREPARA TION OF p-NITROBENZYL 3-A CETYLOXYMETHYL- 7(2' THIENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLATE Sodium 3-acetyloxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (500g; 1.196 mol) and p-nitrobenzyl bromide (568.42 g; 2.631 mol) were added to anhydrous N,N-dimethylformamide (1500 ml) at 20-25°C and stirred for 4 hours at the same temperature. After completion of reaction, the reaction mass was poured into a mixture of water (6000 ml), toluene (4000 ml) at 0-5°C. The precipitated product was filtered and washed with toluene (500 ml). The wet product was slurried in toluene (2500 ml) and water (750 ml) at 20-25°C for 30 min. The product was filtered, washed with toluene (500 ml) and dried at 55-60°C under reduced pressure to obtain 592 g of the title compound having purity 98.26% by HPLC. STEP-II PREPARATION OF CYCLOHEXYLAMINE S-ACETYLOXY-METHYL-?-METHOXY- 7-(2'THIENYLA CETAMIDO)-3-CEPHEM-4-CARBOXYLA TE P-Nitrobenzyl 3-acetyloxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (570 g; 1.073 mol) was added to the mixture of anhydrous N,N-dimethyl-formamide (997.5 ml) and dichloromethane (2992.5 ml) under nitrogen atmosphere and reaction mixture was cooled to -90 to -95°C. Pre-cooled methanolic lithium methoxide solution (7.10% w/w; 631.47 ml; 1.180 mol) followed by pre-cooled solution of r-butyl hypochlorite (139.69 ml; 1.28 mol) in dichloromethane (570 ml) were added to the reaction mixture at -80 to -95°C. The reaction mixture was maintained at -80 to -95°C till completion of the reaction. Thereafter, to the reaction mixture acetic acid (64.38 g; 0.564 mol) in dichloromethane (65 ml) was added at -80 to -95°C followed by sodium metabisulfite (50.96 g; 0.268 mol) in water (153 ml) was added to the reaction mixture at -70 to -95 °C and then cold water (330 ml) was added. The layers were separated and organic layer was washed with water (1500 ml) followed by 10% aqueous sodium chloride solution (1500 mi). The organic layer was concentrated and the resulting compound was dissolved in methanol (4560 ml). The methanolic solution and 5% palladium on carbon (142.50 g; 50% wet) were charged into hydrogenator at 25-30'°C. The reaction mixture was hydrogenated at 30-40°C maintaining 3-5 Kg/Cm hydrogen gas pressure till completion of reduction. After completion of the reduction, the reaction mixture was filtered and washed with methanol (570 ml). Thereafter, the filtrate was concentrated to dryness at 3 0-3 5 ^C under reduced pressure. The residue was dissolved in a mixture of dichloromethane (2280 ml) and acetone (1140 ml) and pH was adjusted to 7.0-7.1 with cyclohexylamine at 20-25°C. The reaction mass was cooled to 0-5°C and precipitated the product with diisopropyl ether (2280 ml). Reaction mixture was maintained for 2 hours at 0-5 °C, filtered the product, washed with acetone (350 ml) and dried the product at 55-60°C under reduced pressure to obtain 349.10 g of the title compound having 97.55% purity by HPLC. STEP-III PREPARA TION OF N,N'DIBENZYLETHYLENEDIAMINE-BIS[3' HYDROXY-METHYL-7'METHOXY-7-(2-THIENYLACETAMIDO)-3-CEPHEM-4CARBOXYLA TE] Cyclohexylamine 3-acetyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate (300 g; 0.571 mol) was added to a solution of methanol (1125 ml) and water (1614 ml) at 0-5°C and cooled to -45°C. To the reaction mass, 17% aqueous sodium hydroxide solution (492 ml; 2.08 mol) was added at -40 to -45°C and maintained till completion of the reaction. After completion of reaction, pH of the reaction mixture was adjusted to 6.9-7.0 with acetic acid at -30 to -45°C. The reaction mass was heated to 20-25°C and methanol-water mixture was distilled approximately 130 ml under reduced pressure.N,N-Dibenzyl-ethylenediamine diacetate (139.8 g; 0.388 mol) and ethyl acetate (158 ml) were added and stirred for 2 hours at 15-20°C. The reaction mass was cooled to 7-10oC, filtered the product, washed with cold water (600 ml) followed by ethyl acetate (570 ml). The product was dried at 50-55°C under reduced pressure to obtain the title compound (228.7 g). STEP-IV PREPARA TION OF 3-CARBAMOYLOXYMETHYL-7-METHOXY-7'(2-THIENYL-ACETAMIDO)-3-CEPHEM-4'CARBOXYLICACID The mixture of .N,N-dibenzylethylenediamine bis[3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate] (140 g; 0.1388 mol) and tetrahydrofuran (1120 ml) was cooled to -55 to -50°C. To the reaction mixture, chlorosulphonyl isocyanate (117.9 g; 0.833 mol) in cold tetrahydrofuran (140 ml) was added slowly at -60 to -55°C and maintained till completion of the reaction. Thereafter, cold water (1680 ml) was added slowly at -55 to -30°C, the temperature of the reaction mass was raised to 20-25oC and maintained for 2 hours. Ethyl acetate (3360 ml) and 10% aqueous sodium chloride solution (700 ml) were added to the reaction mass. The reaction mass was filtered and washed the solid with a mixture of ethyl acetate (560 ml) and water (280 ml). The organic layer was separated and washed with 10% aqueous sodium chloride solution (2x700 ml). pH of the organic layer was adjusted to the 6.4-6.6 with a mixture of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride solution. Aqueous layer was separated and pH was adjusted to 1.9-2.0 with about 15% w/w aqueous hydrochloric acid at 20-25°C, cooled to 7-10°C, filtered the crude product and washed with cold water (300 ml). The crude wet product was added to the water (1260 ml) at 20-25°C and pH is adjusted to 6.0-6.3 with 10% aqueous sodium carbonate solution and allowed for 30 min at 20-25°C. pH of the resulting solution was adjusted to 5.4-5.6 with acetic acid and decolourised with activated carbon (15 g) for 20 min, filtered and washed with water (100 ml). Ethyl acetate (30 ml) was added to the filtrate and pH was adjusted to 1.9-2.0 with about 15% w/w hydrochloric acid and cooled to 10°C. The product was filtered, washed with cold water (300 ml). The wet product was purified twice in 5 volumes of ethyl alcohol of each time and dried at 40-45oC under reduced pressure to obtain 73.80 g of the title compound having purity 99.71% by HPLC. STEP-V PREPARA TION OF SODIUM 3-CARBAMOYLOXYMETHYL-7'METHOXY-7'(2TRIETHYL-ACETAMIDO)-3'CEPHEM'4-CARBOXYLATE 3-Carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (60 g; 0.1405 mol) was dissolved in a mixture of acetone (1680 ml) methanol (400 ml) and water (40 ml) at 20-25°C under nitrogen atmosphere and cooled to 15-20°C. Sodium acetate solution (11.52 g; 0.1405 mol) in methanol (80 ml) and water (20 m) was added dropwise to the reaction mixture at 15-20°C and maintained for 1 hour. The reaction mass was cooled to 10-12°C and filtered the product, washed with acetone (100 ml) under nitrogen atmosphere. The wet product was slurried in acetone (600 ml) for 30 min at 20-25°C under nitrogen atmosphere and filtered the product, washed with acetone (100 ml). The wet product was dried at 35-40°C under reduced pressure to obtain title compound (52.1 g) having purity 99.88% by HPLC. Example-3 STEP-III PREPARATION OF N,N'-DI(4'METHYLBENZYL)ETHYLENEDIAMINE-BIS[3-HYDROXYMETHYL-7-METHOXY'7-(2'THIENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLA TE] Cyclohexylamine 3-acetyloxymethyl-7-methoxy-7-(2-thienyIacetamido)-3-cephem-4-carboxylate (10 g; 0.019 mol) was added to a solution of methanol (37.5 ml) and water (33.5 ml) at 0-5°C and cooled to -45oC. To the reaction mass, 17% aqueous sodium hydroxide solution (16.3 ml; 0.0693 mol) was added at -40 to -45°C and maintained till completion of the reaction. After completion of reaction, pH of the reaction mixture was adjusted to 6.9-7.0 with acetic acid at -30 to -45°C. The reaction mass was heated to 25-30°C and methanol-water mixture was distilled approximately 37 ml under reduced pressure. To the reaction mass .N,N--di(4-methylbenzyl)ethylenediamine diacetate (5.16 g; 0.0133 mol) and ethyl acetate (5.2 ml) were added and stirred for 2 hours at 20-25°C. The reaction mass was cooled to 10-15°C, filtered the product, washed with cooled water (40 ml) followed by ethyl acetate (40 ml). The product was dried at 55-60°C under reduced pressure to obtain the title compound (6.25 g). STEP-IV PREPARA TION OF 3-CARBAMOYLOXYMETHYL- V-METHOXY- 7'(2-THIENYL-A CETAMIDO)-3-CEPHEM-4-CARBOXYLIC A CID The mixture of .N,N--di(4-methylbenzyl)ethylenediamine bis[3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate] (5.13 g; 0.005 mol) and tetrahydrofuran (40 ml) was cooled to -60 to -55°C. To the reaction mixture, chlorosulphonyl isocyanate (3.5 g; 0.0248 mol) in cold tetrahydrofiiran (10 ml) was added slowly at -60 to -55°C and maintained till completion of the reaction. Thereafter, cold water (60 ml) was added slowly at -60 to -30°C, the temperature of the reaction mass was raised to 20-25°C and maintained for 2 hours. Ethyl acetate (128 ml) and 10% aqueous sodium chloride solution (25 ml) were added to the reaction mass. The reaction mass was filtered and washed the solid with a mixture of ethyl acetate (20 ml) and water (10 ml). The organic layer was separated and washed with 10% aqueous sodium chloride solution (2x25 ml). pH of the organic layer was adjusted to the 6.4-6.6 with a mixture of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride solution. Aqueous layer was separated and pH wa adjusted to 1.9-2.0 with about 15% w/w aqueous hydrochloric acid at 20-25°C, cooled to 7-10°C, filtered the crude product and washed with cold water (2x25 ml). The crude wet product was added to the water (50 ml) at 20-25°C and pH is adjusted to 6.0-6.3 with 10% aqueous sodium carbonate solution and allowed for 30 min at 20-25°C. pH of the resulting solution was adjusted to 5.4-5.6 with acetic acid and decolorized with activated carbon (0.5 g) for 20 min, filtered and washed with water (5 ml). Ethyl acetate (1.0 ml) was added to the filtrate and pH is adjusted to 1.9-2.0 with about 15% w/w hydrochloric acid and cooled to 10°C. The product was filtered, washed with cold water 50 ml). The wet product was purified in ethyl alcohol and dried at 40-45°C under reduced pressure to obtain 3.5 g of the title compound having purity 99.14% by HPLC. WE CLAIM: _ 1. A process for the preparation of Cefoxitin sodium of formula I using lithium methoxide and t-butyl hypochlorite in organic solvent(s) at a temperature of-100°C to -40°C and preferably at -95°C to 80°C, c) converting the compound of formula VII to the corresponding acid by deprotection of the ester group using conventional methods and treating the acid with suitable amine in a suitable organic solvent, at a temperature below 40°C and isolating the compound of formula VIII as amine salt, d) hydrolyzing the compound of formula VIE with the base in alcoholic solvents and in their aqueous mixture thereof at a temperature of-60°C to -15°C, and treating the resulting compound with suitable amine and isolating compound of formula IX as amine salt, e) carbamoylating the compound of formula IX as obtained above using halosulfonyl isocyanate in organic solvent at a temperature of -70°C to 0°C preferably at -60°C to -45°C and isolating the Cefoxitin acid of formula X and f) converting the Cefoxitin acid to the pharmaceutical acceptable salt by the conventional methods. 2. The process according to claim 1, wherein the solvent(s) used in step (b) is selected from .N,N--dimethylformamide, .N,N--dimethylacetamide, tetrahydrofuran, acetone, toluene, ethyl acetate, dichloromethane and mixture thereof. 3. The process according to claim 1, wherein the suitable amine used in step (c) is selected from cyclohexylamine, dicyclohexylamine, .N--methyl morpholine, piperazine, morpholine, .N,N-'-dibenzylethylenediamine, .N,N-'-diphenyl-ethylenediamine, .N,N--di(4-methylbenzyl)ethylenediamine, N,N-'-diisopropyl- ethylamine, . N,N--diisopropylamine. 4. The process according to claim 3, preferably cyclohexylamine is used. 5. The process according to claim 1, wherein the suitable organic solvent used in step (c) is selected from C1-C4 alcohols, ethers halogenated hydrocarbons, hydrocarbons, ketones, esters and mixtures thereof 6. The process to claim 5, wherein the organic solvent is selected from methanol, ethanol, diisopropyl ether, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, toluene, benzene, cyclohexene, hexane, heptane, acetone, methyl isobutyl ketone and ethyl acetate. 7. The process according to claim 1, wherein base used in Step (d) is selected from alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide; trialkylamines such as triethylamine, tributylamine and pyridine and most preferably aqueous sodium hydroxide is used. 8. The process according to claim 1, wherein the suitable amine used in step (d) is selected from cyclohexylamine, dicyclohexylamine, .N--methyl morpholine, piperazine, morpholine, .N,N-'-dibenzylethylenediamine, .N,N-'-diphenyl- ethylenediamine, .N,N-'-di(4-methylbenzyl)ethylenediamine, .N,N--diisopropyl- ethylamine, .N,N--diisopropylamine. 9. The process according to claim 1, wherein solvent used in step (d) is selected from C1-C4 alcohols and their aqueous mixtures thereof. 10. The process according to claim 1, wherein halosulfonyl isocyanate used in Step (e) is selected from chlorosulfonyl isocyanate and bromosulfonyl isocyanate and most preferably chlorosulfonyl isocyanate is used, 11. The process according to claim 1, wherein the organic solvent used in step (e) is selected from acetonitrile, dichloromethane, acetone, tetrahydrofuran and mixture thereof Dated this the 29th day of March 2004

Documents:

0303-che-2004 abstract-duplicate.jpg

0303-che-2004 abstract-duplicate.pdf

0303-che-2004 claims-duplicate.pdf

0303-che-2004 description (complete)-duplicate.pdf

303-che-2004-abstract.pdf

303-che-2004-claims.pdf

303-che-2004-correspondnece-others.pdf

303-che-2004-correspondnece-po.pdf

303-che-2004-description(complete).pdf

303-che-2004-form 1.pdf

303-che-2004-form 19.pdf

303-che-2004-form 3.pdf

303-che-2004-form 5.pdf