Field of the invention
The present invention relates to an improved process for the preparation of Cefoxitin of Formula I

its pharmaceutically acceptable salts and intermediates with high purity starting from cephalothin derivatives of the Formula II

Background of the Invention
Cefoxitin and its pharmaceutical^ acceptable salts 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 (6i??7iS)-3-[(Carbamoyloxy)methyl]-7«methoxy-8-oxo-7-[[(thiophen-2-
yl)acetyl]amino-5-thia-l-azabicyclo-[4,2,0]oct-2-ene-2»carboxylate.
Several processes for the preparation of Cefoxitin sodium and its key intermediates have been disclosed by Merck in different US patents Viz US 3,780,031, US 3,780,033, US 3,780,037, US 3,775,410, US 4,297,888 some of which are herein incorporated by reference

US patent 4,297,888 is the basic product patent which describes different routes to prepare Cefoxitin sodium and intermediates starting from 7-aminocephalosporanic acid
Formula III
The major drawback of this patent is that all the processes described therein are 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 US '888 are not viable on industrial scale.
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-metoxy-7-(2-thienyl-acetamido)-3-cephem-4-carboxylate compound
Formula IV
This hydroxymethyl compound of Formula IV has been prepared by the enzymatic reduction of potassium 7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate
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 an overall yield of 10-15 % and purity of compounds is also not reported.
US 4,210,750 and US 4,292,427 disclose a process for the preparation of Cefoxitn, which involves the usage of an isocyanate wherein the labile substituent is hydrocarbyl or substituted hydrocarbyl group
US 2006/0252928 Al also discloses a process for the preparation of Cefoxitin as shown


This process overcomes some of the disadvantages of the prior-art. In this process novel intermediates are employed resulting in high yield and high purity.
Most of the known processes for the preparation of Cefoxitin make use of chromatographic techniques to purify the product of desired quality and further the yields obtained are also very low. These processes are having multiple stages and operational complexities during commercial production and therefore not viable for commercial production.
OBJECTIVES OF INVENTION
The main objective of the present invention is to provide a process for the preparation of Cefoxitin of Formula I
Another objective of the present invention is to provide a process for the preparation of Cefoxitin, which is easy to implement on commercial scale.



with a halogenating agent in the presence of alkali/alkaline earth metal methoxide in an organic solvent, isolating the product formed as an organic amine salt of Formula

wherein X represents organic amine ii) hydrolyzing the salt of compound of Formula VI with a base in an alcoholic solvent and treating the resulting compound with a suitable amine and isolating the

wherein X is as defined above iii) carbamoylating the compound of Formula VII using halosulfonyl isocyanate of Formula VIII,
RNCO Formula VIII
wherein R represents a labile group in an organic solvent to give Cefoxitin of Formula I.

DETAILED DESCRIPTION OF INVENTION
The present invention relates to a process for preparing Cefoxitin of Formula I.
The compound of Formula II is treated with halogenating agent in the presence of
alkali/alkaline earth methoxide in an organic solvent. The halogenating agent employed
can be selected from t-butyl hypochlorite, N-chlorosuccinimide, N-bromosuccinimide,
bromine or chlorine more preferably t-butylhypochlorite. The organic solvent is selected
from methanol, dichloromethane, acetone, toluene, ethyl acetate, N,N-
dimethylformamide, Af,Af-dimethylacetamide, ethers like diisopropyl ether,
tetrahydroflxran and the like or mixtures thereof and preferably mixture of N,N-
dimethylformamide, methanol and methylene chloride is used. The methoxylation is
achieved by using alkali/alkaline earth metal methoxides selected from lithium
methoxide, sodium methoxide, magnesium methoxide and the like, more preferably
sodium methoxide. The reaction is performed at a temperature of -100°C to -40°C and
preferably at -80° to -95 °C. After completion of the methoxylation, the reaction
mixture is acidified with hydrochloric acid, washed with water and the organic layer is
treated with a suitable organic amine and the product is isolated as an amine salt of
Formula VI. The organic amine is selected from diethylamine, methylethylamine,
triethylamine, cyclohexylamine, dicyclohexylamine, i^JV'-dibenzylethylenediamine,
7V;A/^'-di(4-methyl benzyl)ethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU),
1,5-diazabicyclo(4.3.0)non-5-ene, N,N -diphenylethylenediamine, 1,4-
diazabicyclo(2.2.2)octane, Af,JV-diisopropylethylamine, JV^-diisopropylamine, octylamine, and the like, more preferably cyclohexylamine. The suitable organic solvent can be selected from C1-C4 alcohol e.g methanol, ethanol, methylene chloride, chloroform, ethers e.g diisopropyl ether, hydrocarbons e.g toluene, benzene, esters like ethyl acetate and the like or mixture thereof.
In the most preferred embodiment, a solution of cyclohexylamine in dichloromethane ride was added to the above organic layer and pH adjusted to 6.3 at 10-20°C. Thereafter,

diisopropyl ether was added and stirred for 2.5 hr at 0°C. The product was filtered, washed with mixture of dichloromethane and diisopropylether and dried to yield the amine salt of Formula VI. The present process has the advantage of providing pure compounds of Formula VI without making use of column chromatography.
The compound of Formula VI is hydrolyzed to compound of Formula VII. This conversion is achieved by treating the compound of Formula VI with a base such as alkali metal hydroxides, trialkylamines and pyridine in suitable solvent and compound of Formula VII is isolated as again an amine salt. The amine can be selected from cyclohexylamine, dicyclohexylamine, iV-methylmorpholine, piperazine, morpholine iV,JV'-dibenzylethylenediamine, AT,iV-di(4-Methylbenzyl)ethylenediamine, NtNL diphenylethylenediamine, AT,JV'-diisopropylethylamine, AT,i\T-diisopropylamine and the like. The base used is 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 of mixtures thereof and most preferably methanol and water is used. Specifically the hydrolysis of compound of Formula VI is carried out using aqueous sodium hydroxide solution in the mixture of methanol and water at a temperature of -60°C to -15°C and preferably at -45°C to -40°C. This pure amine salt of Formula VII is used in the preparation of Cefoxitin thus facilitating the production of Cefoxitin API in enhanced purity and yield.
The compound of Formula VII is then carbamoylated with halosulphonyl isocyanate of compound of Formula VIII in suitable organic solvent at a temperature of -70°C to 0°C and preferably at -60°C to -45°C. In the above mentioned carbamoylation, the solvent can be selected from acetonitrile, dichloromethane, acetone, tetrahydrofuran and the like or mixture thereof, preferably tetrahydrofuran is used. Halosulphonyl isocyanate is selected from chlorosulphonyl isocyanate or bromosulphonyl isocyanate. The reaction is preferably carried out using chlorosulfonyl isocyanate which is used in excess in order to obtain maximum yields of the desired product i.e Cefoxitin acid of Formula I.

Further, cefoxitin acid of Formula I is purified in a mixture of alcohol, preferably in ethanol to obtain pure Cefoxitin acid having a purity of > 98.5 % by HPLC.
Preferably, the Cefoxitin acid is converted to highly pure Cefoxitin sodium by treating the Cefoxitin acid with sodium 2-ethylhexanoate or sodium acetate using conventional methods.
The invention will now be more fully described with reference to the following examples, which are only illustrative and not be construed as any limitation thereof.
EXPERIMENTAL Example 1
Preparation of 3-Acetyloxymethyl-7-a-methoxy-7-[(2-thienyl)acetamido]-3-cephem-4-carboxylic acid cyclohexylamine salt
Cephalothin acid (300 g; 0.7576 mol) was dissolved in a mixture of dichloromethane (4.5 1) and Ar,Ar-dimethylformamide (0.3 1) and cooled to -90 to -95°C under nitrogen atmosphere. To the reaction mass, cold solution of sodium methoxide (163.68 gm) in methanol (1.086 1) was added followed by cold solution off-butyl hypochlorite (87.21 gm) in methylene chloride (300 ml) at -80 to -95°C. The reaction mixture was stirred at -80 to -95°C till completion of the reaction. Thereafter, the reaction mixture was acidified with hydrochloric acid (294 ml) and then added 15%w/w aqueous sodium metabisulfite solution (240 ml) at -75 to -95°C. After addition, 5%w/w aqueous sodium chloride solution (3.6 1) was added, separated the organic layer and washed with 5%w/w aqueous sodium chloride solution (2.4 1) at 5-15°C. The organic layer was dried over anhydrous sodium sulfate and distilled the solvent from the organic layer to 1.25 1 under reduced pressure. Solution of cyclohexylamine (75 gm) in dichloromethane (300 ml) was added gradually to the concentrated reaction mass and pH was adjusted to 6.3 at 10-20°C. Thereafter, diisopropyl ether (300 ml) was added and stirred for 2.5h at 0°C. The product was filtered, washed with a mixture of dichloromethane (168 ml) and

diisopropyl ether (57 ml) and dried to yield the product (336 gm) having 94.34% of HPLC purity.
Example 2
Preparation of Bis[3-hydroxymethyl-7-a-methoxy-7-[(2-thienyl)acetamido]-3-cephem-4-carboxyIaic acid iV9iV,-bis(phenyImethyl)-l92-ethanediamine salt
3-Acetyloxymethyl-7-a-methoxy-7-[(2-thienyl)acetamido]-3-cephem-4-carboxylic acid cyclohexylamine salt (300 g5 0.5714 mol) was added to a 1:1 mixture of water and methanol (3.216 1) and cooled the solution to -45°C. To the cold reaction mass, 17%w/v aqueous sodium hydroxide solution (495 ml) was added at -40 to -45°C and stirred till completion of the reaction. The reaction mixture was treated with acetic acid (134 gm) at -30 to -45°C. Thereafter, the reaction mass was warmed to 25°C, concentrated to the volume of 1.15 litres under reduced pressure and diluted with water (900 ml). The reaction mass was cooled to 10-15°C and then added ethyl acetate (150 ml) followed by AT,Af'-bis(phenylmethyl)-l,2-ethanediamine diacetate (127.64 gm). The resulting mixture was stirred for 2.5h at 10-15°C, cooled to 0-5°C, filtered the product, washed successively with water and by ethyl acetate and taken to dryness under reduced pressure to obtain the title compound (235.6 gm) having HPLC purity of 95.46%.
Example-3
Preparation of N,N'-di(4-methylbenzyl)ethylenediamine-bis[3-hydroxymethyI-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylate]
3-Acetyloxymethyl-7-a-methoxy-7"[(2-thienyl)acetamido]-3-cephem-4-carboxylic acid cyclohexylamine salt (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 -45°C. 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 concentrated to 50 ml under reduced pressure. To the reaction mass A^A/"'-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).
Example 4
Preparation of 3-Carbamoyloxymethyl-7-a-methoxy-7-[(2-thienyI)acetamido]-3-cephem-4-carboxylic acid (Cefoxitin acid)
Bis[3-hydroxymethyl-7-a-methoxy-7-[(2-thienyl)acetamido]-3-cephem-4-carboxylic acid A^-dibenzylethylenediamine salt (200g, 0.1984 mol) was added to tetrahydrofuran (1,6 1) and cooled to -55 to -60°C under nitrogen atmosphere. To the reaction mixture, chlorosulphonyl isocyanate (182.5 gm) in cold tetrahydrofuran (200 mi) was added at -55 to -60°C and stirred till completion of the reaction. Thereafter, the reaction mixture was added to the mixture of water (2.4 1), hydrochloric acid (107 ml) and ethyl acetate (4 1) at 0-5°C. After addition, the reaction mass was warmed to 10°C and stirred for 1 h. The reaction mass was filtered and the filtrate was washed with 10%w/w aqueous sodium chloride solution. The organic layer was separated and pH adjusted to 6.3 with 1:1 mixture of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride solution. Aqueous layer was separated, pH adjusted to 5.5 with 10% v/v aqueous acetic acid, treated with activated carbon (25 gm) at 10°C and filtered. pH of the filtrate was adjusted to 2.3 with 7% w/v aqueous hydrochloric acid at 0-5°C The crystallized product was filtered, washed with cold water and dried till moisture content is 4-5%w/w to yield crude Cefoxitin acid (137.3 gm). The crude Cefoxitin acid was added to ethanol (685 ml), stirred for lh at 20-30°C, cooled to 0-5°C, filtered, washed with ethanol and dried to yield Cefoxitin acid (119.4 gm) having HPLC purity of 98.87%.

Example 5
Preparation of sodium (6R,7S)-3-[(carbamoyIoxy)methyI]-7-methoxy-8-oxo-7-[J(thiophen-2yl)acetyl]amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylate (Cefoxitin sodium)
Cefoxitin acid (100 gm) was dissolved in a mixture of acetone (700 ml) and methanol (200 ml), treated with activated carbon at 25-35°C and filtered. To the filtrate, sodium acetate (22.07 gm) in methanol (200 ml) was added at 15-20°C. The reaction mass was cooled to 10°C and stirred for 30 min. The product was filtered, washed with acetone and dried under reduced pressure to yield Cefoxitin sodium (95 gm) having HPLC purity of 99.34%.

WE CLAIM

wherein X represents organic amine ii) hydrolyzing the salt of compound of Formula VI with a base in an alcoholic solvent and treating the resulting compound with a suitable amine, isolating the compound of Formula VII as amine salt,


wherein X is as defined above iii) carbamoylating the compound of Formula VII using halosulfonyl isocyanate of Formula VIII,
RNCO Formula VIII
wherein R represents a labile group in an organic solvent to give cefoxitin of Formula I.
2) The process according to claim 1, wherein the halogenating agent used in step(i) is t-butylhypochlorite, N-chlorosuccinimide, N-bromosuccinimide, bromine or chlorine.
3) The process according to claim 1, wherein the alkali/alkaline earth methoxide used in step(i) is selected from lithium methoxide, sodium methoxide, potassium hydroxide, magnesium methoxide, more preferably sodium methoxide.
4) The process according to claim 1, wherein the solvents used in step(i) is selected from iV,N-dimethylformamide, 7V,W-dimethylacetamide, tetrahydrofiiran, acetone, toluene, ethyl acetate, dichloromethane, methanol, diisopropyl ether or mixture thereof.
5) The process according to claim 1, wherein the amine used in step(i) is selected from diethylamine, methyethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, Af-methylmorpholine, piperazine, morpholine, N,N-dibenzylethylenediamine, Af,#-diphenylethylenediamine, N,N-di(4-methylbenzyl)ethylenediamine, N,iV-diisopropylehylamine, iV^iV-diisopropylamine, octylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane.

6) The process according to claim 1, wherein the base used in step (ii) is selected from alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide, such as triethylamine, tributylamine and pyridine and most preferably aqueous sodium hydroxide is used.
7) The process according to claim 1, wherein the amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, A^AT'diphenylethylenediamine, N,N-dibenzylethylenediamine, Ar,7V-di(4-methylbenzyl)ethylenediamine, N,N-diisopropylethylamine, JV,JV-diisopropylamine, morpholine, iV-methyl morpholine, piperazine and their salts.
8) The process according to claim 1, wherein the solvent used in step(ii) is selected from alcohols like ethanol, methanol or mixtures thereof.
9) The process according to claim 1, wherein halosulfonyl isocyanate used in step (iii) is selected from chlorosulfonyl isocyanate and bromosulfonyl isocyanate, more preferably chlorosulfonyl isocyanate.
10) The process according to claim 1, wherein the organic solvent used in step (Hi) is selected from acetonitrile, dichloromethane, acetone, tetrahydrofuran or mixtures thereof.