WO2004083216A1

WO2004083216A1 - A process for the preparation of cephalosporins

Info

Publication number: WO2004083216A1
Application number: PCT/IB2003/004942
Authority: WO
Inventors: Pandurang Balwant Deshpande; Parven Kumar Luthra; Ramakrishna Kamma; Sreedhar Gedi
Original assignee: Orchid Chemicals and Pharmaceuticals Ltd
Current assignee: Orchid Pharma Ltd
Priority date: 2003-03-20
Filing date: 2003-11-05
Publication date: 2004-09-30
Anticipated expiration: 2005-09-20

Abstract

The present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I)

Description

APROCESS FORTHE PREPARATIONOFCEPHALOSPORINS

Field of the Invention

wherein Ri represents hydrogen, trityl, CH₃, CR_aR COOR_c where R_a and R_b independently represent hydrogen or methyl and R_e represents hydrogen or ( - C₆)alkyl; R₂ represents CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,

.

of the Invention

EP 0030294 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 1 :

Scheme 1 wherein R represents hydrogen atom or a readily hydrolysable ester group and X represents one of the groups

EP patent 0 842 937 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 2 :

S

H₂N A N.H„

Scheme 2 wherein R is

WO 00/63214 discloses a process for the preparation of cephalosporins by condensation of carboxy ester intermediate with silylated thiourea.

/ OR 1. OR

wherein X and Ri are substituents useful in cephalosporin chemistry and R_E is hydrogen, a negative charge or together with the COO- group to which R_E is attached is an ester, Y is halogen; R is hydrogen or silyl and R" is silyl; R'_E is silyl or together with the COO- group to which R_E is attached is an ester. This patent publication discloses an alternate process, which involves the desilylation of compound of formula (II) and then condensation of desilylated compound with thiourea.

WO 02/083634 discloses a process for the preparation of cefpodoxime of formula (XII), as shown in scheme 3 below :

Scheme 3 wherein R is hydrogen or silyl group and R' is silyl group or COOR⁵ is a carboxylic acid salt; X is halogen. The process comprises reacting the compound of formula (DC) with compound of formula (III) and desilyating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce cefpodoxime acid of formula (XII).

Objectives of the Invention The primary objective of the invention is to provide a new method for the preparation of cephalosporin antibiotics of the formula (I), which would be easy to implement in commercial scales. Summary of the Invention

Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) or its esters, which form prodrug or a counter ion which forms salt

wherein Ri represents hydrogen, trityl, CH₃, CR_aR COOR_c where R_a and R_b independently represent hydrogen or methyl and R_e represents hydrogen or ( - C₆)alkyl; R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,

which comprises: (i) condensing the activated derivative of the formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of

7-amino cephalosporin of the formula (XIII) wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group in the presence of a solvent at a temperature in the range of -50 °C to 0 °C to produce a compound of formula (XIV), where R is as defined earlier,

(ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compound of the formula (XV) wherein R is as defined earlier,

(iii) deesterifymg the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0 °C to 60 °C to produce a compound of formula (I) and

(iv) converting the compound of formula (I)₅ to its pharmaceutically acceptable salt or its esters which form prodrug.

The process is shown in Scheme-4 below

Scheme-4 In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII)

which comprises ;

(i) reacting the 7-aminocephalosporin derivative of the formula (XVI) wherein R₃ represents hydrogen, (C C₄)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R₂ - X, wherein X represents halogen atom and R₂ is as defined earlier in the presence in an organic solvent and a base at a temperature in the range of 0 °C to 30 °C to produce 7- aminocephalosporin derivative of the formula (XVII),

(ii) deacylating the compound formula (XVII) using PCl₅/POCl₃/ρyridine,

PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and

(iii) isolating the compound of formula (XIII).

The process is shown in Scheme-5 below

(XVI)

Step-2

Scheme-5 In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII)

which comprises ; (i) acylating the 7-aminocephalosporin derivative of the formula (XVIII) phenyl acetyl chloride to produce compound of formula (XIX) in the presence of an organic solvent at a temperature in the range of -20 °C to 30 °C, (ii) esterifying the compound of formula (XIX) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25 °C to 50 °C to produce a compound of formula (XX)

(iii) deacylating the compound of formula (XX) using PCl₅/POCl₃/pyridine, PCl₅/pyridine- triphenyl phosphite/Cl₂ complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and (iv) isolating the compound of formula (XIII). The process is shown in Scheme-6 below

Scheme-6 In still another embodiment of the present invention the compound of formula (XIII), can be prepared by a process, which comprises esterifying the compound of the formula (XVIII) using an esterifying agent in the presence of a solvent and base. The process is as shown in Scheme-7 below

Scheme-7 wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group and R² is as defined above. In another embodiment of the present invention, there is provided a new intermediate of the formula (XIV)

/

wherein X represents halogen atom such as chlorine or bromine; R represents p- methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R₂ represents hydrogen, CH_3s CH₂OCH₃, CH₂OCOCH₃, CE-=CH₂, CH₂OCONH₂,

Detailed Description of the Invention

In yet another embodiment of the present invention, the condensation of compound of formula (III) with (XIII) is performed by using the activated derivative of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.

The compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, active amides. The acid halides are acid chlorides or acid bromides. The mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate.

In yet another embodiment of the present invention, the silylation of 7- amino cephalosporin of the formula (XIII) is carried out using silylating agent selected from hexamethyldisilazane (HMDS), trimethylchlorosilane(TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O- bistrimethylsilyltrifiuoroacetamide (BSTFA), methyldichlorosilane, dimethyldichlorosilane, diphenyldichlorosilane, N-methylsilylacetamide (MSA), bistrimethylsilylurea and the like.

In yet another embodiment of the present invention, the cyclisation of compound of (XIV) is carried out using solvents selected from water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, (Cι-C₃)alcohol and the like or mixtures thereof.

In still another embodiment of the present invention the deesterifϊcation of compound of formula (XV) is carried out using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the absence or presence of dichloromethane, dichloroethane as a solvent. In another embodiment of the present invention, the pharmaceutically acceptable salt is sodium or hydrochloride.

In yet another embodiment of the present invention the prodrug ester is proxetil, axetil, hexetil, pivoxil and the like.

In another embodiment of the present invention, the solvent used for reacting the compound of formula (XVI) in step (i) of scheme-5 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, (Cι-C₃)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4- diazabicyclo-[2,2,2]-octane (DABCO), l,5-diazabicyclo[4,3,0]-non-5-ene (DBN), l,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate. In another embodiment of the present invention, the acylation of compound of formula (XVIII) in step (i) of scheme-6 is carried out in the presence of solvent selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like. In another embodiment of the present invention, the esterification of compound of formula (XIX) in step (ii) of scheme -6 is carried out using esterifying agents such as diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride and a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulf oxide N,N-dimethylacetamide, dioxane, (Cι-C₃)alcohol or mixtures thereof, in the presence of catalytic quantities of iodine. The reaction is carried out in the presence of base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In another embodiment of the present invention, the solvent used for reaction in scheme-7 is selected from tetrahydrofuran, acetone, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, dioxane, (Cι-C₃)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, l,4-diazabicyclo-[2,2,2]-octane (DABCO), l,5-diazabicyclo[4,3,0]-non-5-ene (DBN), l,8-diaza-bicyclo[5,4,0]-undec-7- ene(DBU), pyridine or sodium carbonate.

The substituent on R₃ in Scheme-5 is selected from methyl, methoxy, nitro or halogen atom.

In yet another embodiment of the present invention, the product obtained in any of the reactions may be used in next step without isolation. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

EXAMPLE-1 Step I

Preparation of 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid

7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) (100 gm) was reacted with N,0-Bis silyl acetamide (103.9 gm) in presence of methylene dichloride (300 mL) at RT for 1 hour under nitrogen atmosphere. The silylated mass was cooled to -10 to -15°C. To this phenyl acetyl chloride (95 gm) was added over 30 minutes, and stirred for 1 hour. After completion of the reaction, chilled water (1000 mL) was added at -10 to -15°C, distilled off methylene chloride under vacuum at 10-12°C for 30 minutes. Filtered the product and washed with isopropyl ether (1000 mL) and dried under vacuum 40-45 °C till to get the title compound (123 g, purity 95%).

Step II Preparation of 7-pheny_acetamido-3-methoxymethyl-3-cephem-4-carboxyIic acid p-methoxy benzyl ester p-Methoxy benzyl chloride (66 g) was stirred with sodium iodide (41.4 g) in presence of dimethyl sulfoxide (200 mL) for 1 hour at 25-30°C. To this 7- phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid (100 gm) obtained in step I and sodium bicarbonate (35.3 g) was added and stirred for 25- 30°C for 5-7 hours. After completion of the reaction, the reaction mass was cooled to 20°C and added DM water (2.5 L) containing sodium thiosulphate (10 gm). The reaction mixture was stirred for 30 min. at 25-30°C, filtered the product and washed with DM water (500 mL). Finally stirred the product with methanol (600 mL) at -5°C and filtered, dried the product under vacuum 40-45°C till moisture less than 2% to get the title compound (120 gm, purity 96%).

Step III

Preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid p- methoxy benzyl ester To a suspension of PC1₅ (6.5 gm) in MDC (100 mL), pyridine (2.5 gm) was added under ice cooling and the resulting suspension was stirred at this temperature for 30 minutes. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step II was added at below 0°C. After stirring at 0°C for 90-120 min, the reaction mixture was cooled to -40°C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) was added below -10°C for 30 minutes. After being stirred at 0°C for 30 minutes, the mixture was concentrated at 45°C to get residue. This residue was triturated with water (10 mL), EtOAc (40 mL) and isopropyl ether (IPE) (40 mL). The resulting precipitate was collected by filtration, washed with IPE and dried to get the title compound (6.5 gm, >98%).

Step IV

Preparation of 7-[(2-(syn)methoxyimmo-3-oxo-4-chlorobutyrylamino]-3- methoxymethyl- 3-cephem-4-carboxylic acid p-methoxy benzyl ester To a suspension of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid p- methoxy benzyl ester (10 g), in MDC (50 mL, 5 volumes) obtained in step III, BSA (10 g) was added at 30°C for 30 minutes. After stirring at 30°C for 50-60 minutes solution was cooled to -30°C.

Meanwhile in another flask to a suspension of PC1₅ (7.89 g) in MDC (50 mL, 5 volumes), 4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid chloride (6.759) was added in four lots at 0 to -10°C. The resulting clear solution was added to the above silylated solution at -30 to -20°C for 10-15 minutes time. After being stirred for another 15 minutes at same temperature, chilled water (100 ml, 5 volumes) was added for 5 minutes time. Concentrated the separated organic layer at 40-45 °C to get residue, which is triturated, with IPE (100 mL) to get the title compound (9.0 gm, 90%).

Step V

Preparation of 7-[2-(2-aminothia__ol-4-yl)-2-methos iminoacetamido]-3 methoxymethyl- 3-eephem-4-carbo__ylic acid p-methoxy ben__yl ester To a mixture of THF (50 mL) and water (50 mL), 7-[(2-(syn)methoxyimino-3- oxo-4-chlorobutyrylamino] -3 -methoxymethyl-3 -cephem-4-carboxylic acid p- methoxy benzyl ester (10 g) obtained in step IV was added at 30°C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30°C was added and the resulting solution was stirred at 30°C for 8-10 hours. After extracting the mixture with methylene dichloride (MDC) (100 mL), the resulting MDC layer was concentrated at 40°C to get residue. This residue was crystallized with MDC-IPE (1:5) mixture to get the title compound (9.5 g, 90%).

Step VI Preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- methoxymethyl-3-cephem-4-carboxylic acid (cefpodoxime acid) Addition of trifluoro acetic acid (20.75 g) to a stirred solution of phenol (125 mL) and 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl- 3- cephem-4-carboxylic acid p-methoxy benzyl ester obtained in step V (50 gm) at 40°C over 20-30 minutes. The reaction mixture was maintained at 40-45 °C for 2- 4 hours. Monitored the reaction by HPLC. After completion of the reaction, the reaction mixture was cooled to 25-30°C and chilled water (250 mL), ethyl acetate (250 mL) was added and adjusted the pH to 7.3-7.5 with 25% Na₂CO₃ solution (90 mL) at 20°C. Stirred and separated the layers and extracted the aqueous layer with ethyl acetate (250 mL) and separated the layers. Adjusted the pH to 5.8 with 10% H₂S0 solution and charged carbon (10 gm), sodium dithionite (0.35 gm), and stirred the reaction mixture for 1 hour. Filtered and washed with water (50 mL). Adjusted the pH to 2.8 with 10% H₂S0₄ solution at 20-25°C and stirred the reaction mixture at 5°C for 3 hours. Filtered the product and washed with chilled acetone (-5 to -10°C, 100 mL) and suck dried to get the title compound (20 gm, purity >98%).

EXAMPLE-2

Step I

Preparation of 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylammo]-3- methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester

To a suspension of PC1₅ (6.5 gm) in MDC (100 mL), pyridine (2.5 gm) was added under ice cooling and the resulting suspension was stirred at this temperature for 30 minutes. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in step II was added at below 0°C. After stirring at 0°C for 90-120 min, the reaction mixture was cooled to -40°C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) was added below -10°C for 30 minutes. After being stirred at 0°C for 60 minutes, the mixture temperature was taken to -20°C and charged 20ml of water below -10°C. The pH of the mass is adjusted to 4-4.5 by adding 25% of sodium carbonate solution (40ml) keeping the temperature below -5°C. The temperature of the reaction mass is raised to 30°C in 30-40 min. The layers were separated and to the organic layer was added Bis -(trimethylsilyl)urea (BSU) 8.5g. The mass was stirred for 2-3 Hrs at 30°C .

The mixture was cooled to -30°C. Meanwhile in another flask to a suspension of PC1₅ (6.5 g) in MDC (50 mL, 5 volumes), 4-chloro-2(Z)- methoxyimino-3-oxo-butyric acid (5.6g) was added in four lots at 0 to -10°C. The resulting clear solution was added to the above silylated solution at -30 to - 20°C for 10-15 minutes time. After being stirred for another 15 minutes at same temperature, chilled water (100 m, 10 volumes) was added in 5 -10 minutes. The temperature of the mass was raised to 30°C over a period of 30-40min. The layers were separated and the organic layer was treated with sodium carbonate solution to bring its pH to 5.8-6.2. Again the layers were separated and the organic layer was concentrated at 40-45°C under vacuum to get residue, which is triturated, with IPE (100 mL) to get the title compound (8.0 gm, purity >85%)

Step II

Preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- methoxymethyl-3-cephem-4-carboxylic acid (cefpodoxime acid)

To a mixture of THF (50 mL) and water (50 mL), 7-[(2-(syn)methoxyimino-3- oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic acid p- methoxy benzyl ester (10 g) obtained in step III was added at 30°C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30°C was added and the resulting solution was stirred at 30°C for 8-10 hours. After extracting the mixture with methylene dichloride (MDC) (100 mL), the resulting MDC layer was concentrated at 40°C to get residue. To this residue was added phenol (25 mL) at 40-45°C. Trifluoro acetic acid (4.2 g) was added to the above mixture in 20- 25min at 40-45°C . The reaction mass was stirred for 4-5Hrs and finally poured into a mixture of ethyl acetate (50ml) and water(50ml). The pH of the reaction mass was adjusted to 8.5with 25% sodium carbonate solution at 30 C. The layers were separated. The aqueous layer was again washed with 50ml of ethyl acetate. Finally the aqueous layer is treated with charcoal (l.Og), charcoal is filtered off and to the clear filtrate dilute sulfuric acid is added to bring the pH to 2.6-2.8. The mixture was cooled to 5°C and product was collected by filtration and washed with acetone (3.0 g, purity > 98%).

Claims

Claims :

1. A process for the preparation of cephalosporin antibiotics of the formula

(I) or its esters, which form prodrug or a counter ion which forms salt

wherein Ri represents hydrogen, trityl, CH₃, CR_aR_bCOOR_c where R_a and R independently represent hydrogen or methyl and R_e represents hydrogen or ( - C₆)alkyl; R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,

which comprises:

(i) condensing the activated derivative of the formula (III)

where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII)

wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group and R² is as defined above in the presence of a solvent at a temperature in the range of -50 °C to 0 °C to produce a compound of formula

(XIV),

OR.

/ ¹

where R¹ is as defined above,

(ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compound of the formula (XV)

wherein all symbols are as defined above, (iii) deesterifymg the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0 °C to 60 °C to produce a compound of formula (I) and (iv) converting the compound of formula (I) to its pharmaceutically acceptable salt or its esters which form prodrug.

2. The process as claimed in claim 1, wherein the solvent used for condensation is selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N- dimethylformamide, dialkylethers, water or mixtures thereof.

3. The process as claimed in claim 1, wherein the activated derivative of the compound of formula (III) is an acid halide, a mixed anhydride, an active ester or an active amide

4. The process as claimed in claim 1, wherein solvent used for cyclisation in step (ii) is selected from water, tetrahydrofuran, acetone, acetonitrile, N,N- dimethylformamide, N,N-dimethylacetamide, dioxane, (C₁-C₃)alcohol or mixtures thereof.

5. The process as claimed in claim 1, wherein the solvent used for deesterification in step (iii) is selected from dichloromethane or dichloroethane.

6. The process as claimed in claim 1, wherein the pharmaceutically acceptable salt is sodium or hydrochloride.

7. The process as claimed in claim 1, wherein the prodrug ester is proxetil, axetil, hexetil or pivoxil.

8. A process for the preparation of compound of formula (XIII)

which comprises ;

(i) reacting the 7-aminocephalosporin derivative of the formula (XVI)

wherein R₃ represents hydrogen, (Cι-C₄)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R₂ - X, wherein X represents halogen atom and R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,

in the presence in an organic solvent and a base at a temperature in the range of 0

°C to 30 °C to produce 7-aminocephalosporin derivative of the formula (XVII),

(ii) deacylating the compound formula (XVII) using PCVPOCVpyridine, PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and (iii) isolating the compound of formula (XIII).

9. The process as claimed in claim 8, wherein the solvent used in step (i) is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (Cι-C₃)alcohol or mixtures thereof

10. The process as claimed in claim 8, wherein the base used in step (i) is selected from sodium acetate, potassium carbonate, triethylamine, 1,4- diazabicyclo-[2,2,2]-octane (DABCO), l,5-diazabicyclo[4,3,0]-non-5-ene (DBN), l,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.

11. A process for the preparation of compound of formula (XIII)

wherein R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,

which comprises ;

(i) acylating the 7-aminocephalosporin derivative of the formula (XVIII)

phenyl acetyl chloride to produce compound of formula (XIX)

in the presence of an organic solvent at a temperature in the range of -20 °C to 30 °C, (ii) esterifying the compound of formula (XIX) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25 °C to 50

°C to produce a compound of formula (XX)

(iii) deacylating the compound of formula (XX) using PCl₅/POCl₃/pyridine, PCls/pyridine, triphenyl phosphite/Cl₂ complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and

(iii) isolating the compound of formula (XIII).

12. The process as claimed in claim 11, wherein the solvent used in step (i) is selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like.

13. The process as claimed in claim 11, wherein the base used in step (ii) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

14. The process as claimed in claim 11, wherein the esterifying agent is selected from diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p- nitrobenzyl chloride.

15. The process as claimed in claim 11, wherein the solvent used for esterification is selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide N,N-dimethylacetamide, dioxane, (Cι-C₃)alcohol or mixtures thereof.

16. A process for the preparation of compound of formula (XIII)

comprising esterifying the compound of the formula (XVIII)

(XVIII)

using an esterifying agent in the presence of a solvent and base.

17. The process as claimed in claim 16, wherein the solvent used is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, (Ci -C₃)alcohol or mixtures thereof.

18. The process as claimed in claim 1 , wherein the base used is selected from sodium acetate, potassium carbonate, triethylamine, l,4-diazabicyclo-[2,2,2]- octane (DABCO), l,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza- bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.

19. An intermediate of the formula (XIV) OR.

/

wherein X represents halogen atom such as chlorine or bromine; R represents p- methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH=CH₂, CH₂OCONH₂,