WO2004039813A1

WO2004039813A1 - An improved process for the preparation of chloro methyl cephem derivatives

Info

Publication number: WO2004039813A1
Application number: PCT/IB2003/004721
Authority: WO
Inventors: Pandurang Balwant Deshpande; Palanisamy Senthilkumar Udayampalayam; Sanjay Nivrutti Karale; Padmanabhan Ramar
Original assignee: Orchid Chemicals & Pharmaceuticals Ltd
Priority date: 2002-11-01
Filing date: 2003-10-23
Publication date: 2004-05-13
Also published as: CN1315841C; JP2006507289A; AU2003269416A1; KR20050087791A; CN1708501A

Abstract

The present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I), wherein R1 represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-chlorobenzyl or benzyl group; R2 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy group.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF CHLORO METHYL CEPHEM DERIVATIVES

Field of the Invention

The present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I).

wherein R₁ represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2- methoxybenzyl, 2-chlorobenzyl or benzyl group; R₂ represents hydrogen, (Cι-C₄)aJLkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy.

The chloromethylcephem derivatives of the formula (I) prepared according to the process of the present invention are useful for the preparation of cephalosporin antibiotics of the formula (II)

wherein R₄ is carboxylate ion or COOR_d, where Ra represents hydrogen, esters or a counter ion which forms a salt; R₆ represents H, CH₃, CR^aR COOR^c where R^a and R^b independently represent hydrogen or methyl and R^c represents hydrogen or (Cι-C₆)alkyl; R₅ represents CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, or

The cephalosporin antibiotics of the formula (II) have wide range of biological activity. Specifically the cephalosporin antibiotics of the formula (LI) have very good antibiotic activity.

Background of the Invention In view of the importance of the 3-chlo romethylcephems of the formula (I), as

I key intermediates for the synthesis of a wide variety of cephalosporin drugs, various methods of preparation were reported (US Patent 4,853,468; US Patent 4,789,740). In most of the cases, sulfonyl azetidinone derivatives of the formula (III) were subjected to allylic/ene-type chlorination with various chlorinating agents like chlorine, chlorine oxide, etc., to obtain the chloro azetidinone of the formula (IN). The chloro azetidinone compounds of the formula (IN) were further cyclized at low temperature in the presence of a base to get chloromethylcephems of the formula (I)

where Ri and R₂ are as defined above; R₃ represents phenyl, (Cι-C )alkylphenyl, ( - C )alkoxyphenyl or a heteroaryl group.

The preparation of sulfonyl azetidinone intermediate, as per the reported process, is always accompanied by the formation of a major impurity, leading to low purity of sulfonyl azetidinone, which in turn end up with low yield of the chloromethyl cephem of the formula (I).

In addition, the side product formed during the preparation of sulfonyl azetidinone intermediate could not be removed completely with the existing method of acetone/water system; and if this side product is not removed in this step, it leads to more impurity formation during conversion to next step of chlorination & cyclization. Thus, there is a need to generate a process, which could take care of the removal of side product from sulfonyl azetidinone intermediate.

In addition, in the last step of cyclization with ammonia in DMF, we found that the impurity formation is high during the addition of base. This necessitates the development of an alternative process, which would offer better conversion and consequently the yield.

With our continued search and intense investigation, we finally achieved identifying a clean process, which can address all the limitations discussed above, and produce the chloromethyl cephem derivatives of the formula (I).

Objectives of the Invention

The main objective of the present invention is to provide a simple and efficient process for producing chloromethyl cephem derivatives of the formula (I) through 3- chloromethyl azetidinone compounds of the formula (Nil).

Another objective of the present invention is to provide a process for manufacturing chloromethyl azetidinone compounds of the formula (Nil), without employing the hazardous reagents, which are difficult-to-handle in manufacturing scales. Another objective of the present invention is to carry out the preparation of the sulfonyl azetidinone in a clean manner, by controlling the formation of the major impurity & also provide a methodology to remove the side product.

Another objective of the present invention is to provide a process for cyclization of chloromethyl azetidinone compounds of the formula (Nil) while minimizing the formation of the impurities and achieve maximum conversion.

Summary of the Invention

Accordingly, the present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I)

wherein Ri represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2- methoxybenzyl, 2-chlorobenzyl, or benzyl group; R represents hydrogen, (Cι-C )alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy, the said process comprising the steps of

(i) converting a compound of formula (V) to a compound of formula (VI) where R₈ represents substituted or unsubstituted (Cι-C₆)alkyl or aryl group using a metal salt of aryl sulfinic acid or (Cι-C )alkyl sulfinic acid, a base and a solvent at a temperature in the range of 25 °C to 40 °C, wherein the improvement consists of adding the metal salt of aryl sulfinic acid in the pH range of 4 to 8.0,

(ii) chlorinating the compound of formula (VI) using chlorinating agent in the presence of base and a solvent at a temperature in the range of 15 °C to 40 °C to produce a compound of formula (VII), where R₈ represents substituted or unsubstituted (Cι-C₆)alkyl or aryl group and all other symbols are as defined above, and (vi). cyclizmg the compound of formula (VQ) using a base in a solvent at a temperature in the range of -60 °C to +50 °C to produce chloromethylcephem derivatives of the formula (I). The process of synthesizing chloromethyl cephem derivatives of the formula (I) is shown in Scheme I.

Scheme-I

(i) (VII) where Ri and R₂ are as defined above.

Description of the Invention

In an embodiment of the present invention the heteroaryl group represented by R₇ is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole or 2-mercapto-5-methyltetrazole.

In yet another embodiment of the present invention the conversion in step (i) is carried out using metal salt of aryl sulfinic acid selected from copper (II) p- toluenesulfinate, copper (II) benzenesulfinate, silver (II) p-toluenesulfinate, silver (II) benzenesulfϊnate and the like in the presence of a solvent selected from acetone, THF, dioxane, diglyme, 2-butanone, acetonitrile, alcohols such as methanol, ethanol or iso- propanol, with or without water.

In yet another embidoment of the present invention, the step (i) is carried out while controlling the pH in the range 4-8, more preferably 5-7, by employing the base selected from ammonia, alkali/alkali earth metal carbonate/bicarbonate such as calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, or the organic bases such as diisopropylethylamine, triethylamine and the like.

In yet another embodiment of the present invention, chlorinating agent used in step (ii) is selected from chlorine gas, HOCl, Cl₂O, CH₃OCl and the like in the presence of a base.

In yet another embodiment of the present invention, chlorinating agent used in step (ii) is either used as gas or a solution in a solvent selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof.

In yet another embodiment of the present invention, the base used in step (ii) is selected from alkali/alkali earth metal carbonate/bicarbonate such as calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate and the like.

In yet another embodiment of the present invention the cyclization in step (iii) is carried out using a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like di-isopropylamine, ethylenediamine, diethylamine, methylamine, ethylamine and the like. In yet another embodiment of the present invention, the cyclization step (iii) is carried out in a solvent selected from DMF, acetonitrile, dimethylacetamide, ethyl acetate, 4-formylmorpholine, 4-acetylmorpholine, dioxane, dimethylsulfoxide, THF, 1- methylpyrrolidine-2-one (NMP), methylene dichloride and the like, or the mixtures thereof. In another embodiment of the present invention the starting material can be prepared from the literature known in the prior art.

The foregoing technique has been found to be attractive from commercial, technological and ecological views, and affords chloromethyl azetidinone derivatives of the formula (Nil).

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention within the scope of disclosure.

The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.

Example 1:

Step -1

Preparation of p-Methoxybenzyl 2-(2-benzothiazolvIdithio)-α-(l-methylethenylV4- oxo-3-phenacetamido-l-azetidineacetate (V) To dry toluene (500 ml) contained in a RB flask fitted with a Dean-Stark water separator, p-methoxybenzyl 6-phenacetamidopencillanate-l -oxide (25 gm) and 2- mercaptobenzothiazole (8.9 gm) were added at 27°C under nitrogen. The reaction mixture was heated under reflux over a period of 30 minutes and maintained at reflux temperature over 5 hours. After the reaction was over, the solvent was removed under vacuum to afford p-methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenyl)-4- oxo-3-phenacetamido-l-azetidineacetate, which was taken to next step.

Step -2

Preparation of p-Methoxybenzyl 2-(p-toIuenesulfonylthio)-α-(l-methylethenyl)-4- oxo-3-phenacetamido-l-azetidineacetate (VI)

To p-Methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate (obtained from 25 g of p-methoxybenzyl 6- phenacetamidopencillanate-1 -oxide), acetone (220 mL) was added under stirring to get a clear solution at 28-30 °C & cooled to 20-25 °C. Water (32 mL) was added under stirring at this temperature. The pH of the solution was adjusted to 6.0-7.0 using saturated sodium bicarbonate solution. To the stirred solution, copper (II) p- toluenesulfinate (13.0 g) was added over a period of 90-120 rnin at 20-25 °C in lots while maintaining the pH at 5.5-6.5 using saturated sodium bicarbonate solution. After the reaction was over, the reaction mixture was filtered through hyflo bed and the bed washed with acetone. The filtrate was concentrated under vacuum to remove the solvent in a rotary evaporator. To the residual mass, ethyl acetate (125 mL) and water (125 mL) were added, stirred for 5-10 min followed by sodium chloride addition. Organic layer was separated and washed two times with water. The organic layer was concentrated under vacuum at < 25 °C until a pasty mass was obtained. Methanol was added, stirred at 28-30 °C to get a slurry and cooled to 2-5 °C. The slurry was stirred for 1 h at this temperature, filtered and washed with cold methanol. The filtrate was concentrated under vacuum at < 25 °C to yield p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which is used in the next step with out any further purification. (Purity by HPLC 89-90%).

Step -3

Preparation of p-Methoxyb enzyl 2-(p-toluenesuIfonylthio)-α-(l- chloromethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (VIT)

1,4-Dioxane (150 ml) was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1₂/CC1₄ (12.5% w/v) (60 ml) added slowly. After the completion of the reaction, reaction mixture was filtered and washed with dichloromethane (150 ml). To the filterate, cold water (450 ml) was added, organic layer separated, and washed with a solution of sodium thiosulphate followed by water. The organic layer was treated with charcoal, concentrated and worked up as usual to get p- methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l-chloromethylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate, which was taken to next step without purification.

Step ^l Preparation of p-Methoxybenzyl 7-phenylacetamido-3-chloromethyI-3-cephem-4- carboxylate (I)

To p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l-chloromethylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate (obtained from 25.0 gm of p-methoxybenzyl 6- phenacetamido pencillanate-1 -oxide), l-methylpyrrolidin-2-one (125 mL) was added at 28-30 °C and stirred to get a clear solution. To the solution, dichloromethane (50 mL) was added and cooled to -50 to -40 °C. To the reaction mixture, aqueous ammonia solution (25%, 8.8 mL) in l-methylpyrrolidin-2-one (25 mL, 2-5 °C) was added at -50 °C over a period of 2-5 min and the temperature was allowed to raise to -40 °C. The reaction mixture was stirred at -A5 to -40 °C for 15-20 min. To the reaction mixture, cold dil. HCl (1 : 1; 27 mL; 2-5 °C) was added at -50 to -40 °C in drops over a period of 5 min. The reaction mixture was poured into cold water (900 mL) at 2-5 °C. Dichloromethane was added, stirred for 5-10 min and the organic layer was separated. The aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with cold water four times at 5-10 °C. The solvent was removed completely under vacuum at < 20 °C. To the residual mass, methanol (175 mL) was added at 28-30 °C, stirred to get a slurry over 10-15 min and cooled to 3-5 °C. The slurry was stirred at this temperature over 1 h, filtered and washed with cold methanol. The material thus obtained was dried under vacuum for 4-5 h to get p-methoxybenzyl 7- phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate, as colorless solid. (15.1 gm). Example 2:

Step -1

Preparation of p-Methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenylV4- oxo-3-phenacetamido-l-azetidineacetate (V)

To dry toluene (500 ml) contained in a RB flask fitted with a Dean-Stark water separator, p-methoxybenzyl 6-phenacetamidopencillanate-l -oxide (25 gm) and 2- mercaptobenzothiazole (8.9 gm) were added at 27°C under nitrogen. The reaction mixture was heated under reflux over a period of 30 minutes and maintained at reflux temperature over 5 hours (The reaction may also be carried out in dioxane as a solvent). After the reaction was over, the solvent was removed under vacuum to afford p- methoxybenzyl 2-(2-benzothiazolyldithio)-α-( 1 -methylethenyl)-4-oxo-3-phenacetamido- 1-azetidineacetate, which was taken to next step.

Step -2

Preparation of p-Methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l-methylethenyl)-4- oxo-3-phenacetamido-l-azetidineacetate

To p-Methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate (obtained from 25 g of p-methoxybenzyl 6- phenacetamidopencillanate-1 -oxide), acetone (220 mL) was added under stirring to get a clear solution at 28-30 °C & cooled to 20-25 °C. Water (32 mL) was added under stirring at this temperature. The pH of the solution was adjusted to 6.0-7.0 using saturated sodium bicarbonate solution. To the stirred solution, copper (II) p- toluenesulfinate (13.0 g) was added over a period of 90-120 min at 20-25 °C in lots while maintaining the pH at 5.5-6.5 using saturated sodium bicarbonate solution. After the reaction was over, the reaction mixture was filtered through hyflo bed and the bed washed with acetone. The filtrate was concentrated under vacuum to remove the solvent in a rotary evaporator. To the residual mass, ethyl acetate (125 mL) and water (125 mL) were added, stirred for 5-10 min followed by sodium chloride addition. Organic layer was separated and washed two times with water. The organic layer was concentrated under vacuum at < 25 °C until a pasty mass was obtained. Methanol was added, stirred at 28-30 °C to get a slurry and cooled to 2-5 °C. The slurry was stirred for 1 h at this temperature, filtered and washed with cold methanol. The filtrate was concentrated under vacuum at < 25 °C to yield p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which is used in the next step with out any further purification. (Purity by HPLC 89-90%).

Step-3

Preparation of p-Methoxyb enzyl 2-(p-toluenesulfonylthio)-α-(l- chloromethyIethenyI)-4-oxo-3-phenacetamido-l-azetidineacetate

1,4-Dioxane (150 ml) was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1₂/CC1₄ (12.5% w/v) (60 ml) added slowly. After the completion of the reaction, reaction mixture was filtered and washed with dichloromethane (150 ml). To the filterate, cold water (450 ml) was added, organic layer separated, and washed with a solution of sodium thiosulphate followed by water. The organic layer was concentrated and worked up as usual to get p-methoxybenzyl 2-(p- toluenesulfonylthio)-α-(l-chloromethylethenyl)-4-oxo-3-phenacetamido-l- azetidineacetate, which was taken to next step without purification.

Step-4 Preparation of p-Methoxybenzyl 7-phenyIacetamido-3-chloromethyl-3-cephem-4- carboxylate p-Methoxybenzyl 2-(2-toluenesulfonylthio)-α-(l-chloromethylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate (obtained from 25.0 gm of p-methoxybenzyl 6- phenacetamido pencillanate-1 -oxide), obtained according to step-3 of example- 1 above, was added to DMF (125 ml) and cooled to -40 °C. A solution of ammonia (11.5 ml) in DMF was added and maintained at the same temperature until the reaction was completed. The reaction mixture was acidified with dil. HCl, filtered. The solid obtained was extracted with DMF: methanol (2:9) with charcoal, concentrated and treated with cold methanol to get p-methoxybenzyl 7-phenacetamido-3-chloromethyl-3-cephem-4- carboxylate. (13.6 gm).

Reference Example 3: Step -1

Preparation of p-Methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenyl)-4- oxo-3-phenacetamido-l-azetidineacetate (V)

To dry toluene (500 ml) contained in a RB flask fitted with a Dean-Stark water separator, p-methoxybenzyl 6-phenacetamidopencillanate-l -oxide (25 gm) and 2- mercaptobenzothiazole (8.9 gm) were added at 27°C under nitrogen. The reaction mixture was heated under reflux over a period of 30 minutes and maintained at reflux temperature over 5 hours (The reaction may also be carried out in dioxane as a solvent). After the reaction was over, the solvent was removed under vacuum to- afford p- methoxybenzyl 2-(2-benzothiazolyldithio)-α-(l-methylethenyl)-4-oxo-3-phenacetamido- 1-azetidineacetate, which was taken to next step. Step -2

Preparation of p-Methoxybenzyl 2-(p-toluenesulfonylthioVα-(l-methylethenyl)-4- oxo-3-phenacetamido-l-azetidineacetate (VD To p-Methoxybenzyl 2-(2-benzothiazolyldithio)-α-( 1 -methylethenyl)-4-oxo-3 - phenacetamido- 1-azetidineacetate (obtained from 25 g of p-methoxybenzyl 6- phenacetamidopencillanate-1 -oxide), acetone (220 mL) was added under stirring to get a clear solution at 28-30 °C & cooled to 20-25 °C. Water (32 mL) was added under stirring at this temperature. To the stirred solution, copper (II) p-toluenesulfinate (12.8 g) was added over a period of 90-120 min at 20-25 °C in lots. After the reaction was over, the reaction mixture was filtered through hyflo bed and the bed washed with acetone. The filtrate was concentrated under vacuum to remove the solvent in a rotary evaporator. To the residual mass, ethyl acetate (125 mL) and water (125 mL) were added, stirred for 5-10 min followed by sodium chloride addition. Organic layer was separated and washed two times with water. The organic layer was concentrated under vacuum at < 25 °C until a pasty mass was obtained. Methanol was added, stirred at 28- 30 °C to get a slurry and cooled to 2-5 °C. The slurry was stirred for 1 h at this temperature, filtered and washed with cold methanol. The filtrate was concentrated under vacuum at < 25 °C to yield p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate, which is used in the next step with out any further purification. (HPLC purity 75-80%)

Step -3 Preparation of p-Methoxyb enz yl 2-(p-toluenesulfonyIthio -α-(l- chIoromethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (VID

1,4-Dioxane (150 ml) was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)-α-(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1₂/CC1₄ (12.5% w/v) (60 ml) added slowly. After the completion of the reaction, reaction mixture was filtered and washed with dichloromethane (150 ml). To the filterate, cold water (450 ml) was added, organic layer separated, and washed with a solution of sodium thiosulphate followed by water. The organic layer was treated with charcoal, concentrated and worked up as usual to get p- methoxybenzyl 2-(p-toluenesulfonylthio)-α-( 1 -chloromethylethenyl)-4-oxo-3 - phenacetamido- 1-azetidineacetate, which was taken to next step without purification. Ste -4

Preparation of p-methoxybenzyl 7-phenacetamido-3-chloromethyl-3-cephem-4- carboxylate p-Methoxybenzyl 2-(2-toluenesulfonylthio)-α-(l-chloromethylethenyl)-4-oxo-3- phenacetamido- 1-azetidineacetate (obtained from 25.0 gm of p-methoxybenzyl 6- phenacetamido pencillanate-1 -oxide), obtained according to step-3 of example- 1 above, was added to DMF (125 ml) and cooled to -40 °C. A solution of ammonia (11.5 ml) in DMF was added and maintained at the same temperature until the reaction was completed. The reaction mixture was acidified with dil. HCl, filtered. The solid obtained was extracted with DMF: methanol (2:9) with charcoal, concentrated and treated with cold methanol to get p-methoxybenzyl 7-phenacetamido-3-chloromethyl-3-cephem-4- carboxylate. (11.4 gm)

Advantages: Comparison of examples

From the table it can be concluded, pH adjustment during step (ii) increases the purity of 2-(p-toluenesulfonylthio)-α- ( 1 -methylethenyl)-4-oxo-3 -phenacetamido- 1 -azetidineacetate. The use of NMP at cyclization step gives more yields when compared to DMF.

Claims

We Claim:

1. An improved process to produce the chloromethylcephem derivatives of the formula (I)

wherein Ri represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2- methoxybenzyl, 2-chlorobenzyl or benzyl group; R₂ represents hydrogen, (Cι-C₄)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy, the said process comprising the steps of

(i) converting a compound of formula (V)

to a compound of formula (VI)

(VI) where R₈ represents substituted or unsubstituted (Cι-C₆)alkyl or aryl group using a metal salt of aryl sulfinic acid or (C₁-C )alkyl sulfinic acid, a base and a solvent at a temperature in the range of 25 °C to 40 °C, wherein the improvement consists of adding the metal salt of aryl sulfinic acid in the pH range of 4.0 to 8.0, (ii) chlorinating the compound of formula (VI) using chlorinating agent in the presence of base and a solvent at a temperature in the range of 15 °C to 40 °C to produce a compound of formula (VII),

(VII) where R₈ represents substituted or unsubstituted (Cι-C₆)alkyl or aryl group and all other symbols are as defined above, and

(iii) cyclizing the compound of formula (VTI) using a base in a solvent at a temperature in the range of —60 °C to +50 °C to produce chloromethylcephem derivatives of the formula (I).

2. The process according to claim 1, wherein the metal salt of aryl sulfinic acid used in step (i) is selected from copper (II) p-toluenesulfinate, copper (II) benzenesulfinate, sodium toluenesulfinate, silver (II) p-toluenesulfinate or silver (II) benzenesulfinate.

3. The process according to claim 1, wherein the solvent used in step (i) is selected from acetone, THF, dioxane, acetonitrile, alcohols such as methanol, ethanol or isopropanol, with or without water.

4. The process according to claim 1, wherein the addition of metal salt of aryl sulfinic acid or (C₁-C₆)alkyl sulfinic acid in step (i) is carried out preferably in the pH range of 5-7.

5. The process according to claim 1, wherein the base used in step (i) is selected from ammonia, calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, diisopropylethylamine, or triethylamine.

5. The process according to claim 1, wherein the chlorinating agent used in step (ii) is selected from chlorine gas, HOCl, Cl₂O or CH₃Ocl in the presence or absence of a solvent.

6. The process according to claim 5, wherein chlorinating agent is dissolved in dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof.

7. The process according to claim 1, wherein the solvent used in step (ii) is selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof.

8. The process according to claim 1, wherein the cyclization in step (iii) is carried out using a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like N,N-diisopropylamine, N,N-diethylamine, methylamine or triethylamine..

9. The process according to claim 1, wherein the solvent used in step (iii) is selected from l-methylρyrrolidine-2-one (NMP), DMF, acetonitrile, N,N-dimethylacetamide, ethyl acetate, dioxane, THF, methylene dichloride.

10. A compound of formula (I) according to claim 1, is useful in the preparation of compound of formula (II).

wherein j is carboxylate ion or COOR_d, where R_d represents hydrogen, esters or a counter ion which forms a salt; R₆ represents H, CH₃, CR^aR^bCOOR^c where R^a and R independently represent hydrogen or methyl and R^c represents hydrogen or (Cι-C₆)alkyl; R₅ represents CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, or