Process for the preparation of cephalosporins

Abstract

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

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 R 1  represents hydrogen, trityl, CH 3 , CR a R b COOR c  where R a  and R b  independently represent hydrogen or methyl and R c  represents hydrogen or (C 1 -C 6 )alkyl; R 2  represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 , CH 2 OCONH 2 ,  
       
         
           
           
               
               
           
         
       
       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 R 2  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),  
                     
 where R 1  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) deesterifying 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, (C 1 -C 3 )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 R 3  represents hydrogen, (C 1 -C 4 )alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R 2 —X, wherein X represents halogen atom and R 2  represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 , CH 2 OCONH 2 ,  
                     
 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 PCl 5 /POCl 3 /pyridine, PCl 5 /pyridine, triphenyl phosphite/Cl 2  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, (C 1 -C 3 )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), 1,5-diaza-bicyclo[4,3,0]-non-5-ene (DBN), 1,8-diazabicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.  
     
     
         11 . A process for the preparation of compound of formula (XIII)  
       
         
           
           
               
               
           
         
       
       wherein R 2  represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 , CH 2 OCONH 2 ,  
       
         
           
           
               
               
           
         
       
       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 PCl 5 /POCl 3 /pyridine, PCl 5 /pyridine, triphenyl phosphite/Cl 2  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).  
 
     
     
         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, (C 1 -C 3 )alcohol or mixtures thereof.  
     
     
         16 . A process for the preparation of compound of formula (XIII)  
       
         
           
           
               
               
           
         
       
       wherein R 2  represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 , CH 2 OCONH 2 ,  
       
         
           
           
               
               
           
         
       
       comprising esterifying the compound of the formula (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, (C 1 -C 3 )alcohol or mixtures thereof.  
     
     
         18 . The process as claimed in  claim 16 , wherein the base used is selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-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)  
       
         
           
           
               
               
           
         
       
       wherein X represents halogen atom such as chlorine or bromine; R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R 2  represents hydrogen, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 , CH 2 OCONH 2 ,