Novel Process For Preparation of Cefprozil Intermediate

Abstract

The present invention relates to a process for preparing a key intermediate of cefprozil and use of this intermediate in the preparation of cefprozil thereby avoiding impurity-causing self-acylation. [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt is reacted with ethyl chloroformate to obtain mixed anhydride which is then silylated with N,O-bis(trimethylsilyl)acetamide. The silylated compound obtained is reacted with [7-trimethylsilylamino-3-(Z/E-propen-1-yl)-3-cephem-4-carboxylic acid]trimethylsilyl ester and deprotected with aqueous hydrochloric acid to give cefprozil.

1 . A process for preparing silylated mixed anhydride of formula II: 
       
         
           
           
               
               
           
         
       
       which comprises reacting the compound of formula III or a salt thereof: 
       
         
           
           
               
               
           
         
       
       with ethyl chloroformate of formula IV: 
       
         
           
           
               
               
           
         
       
       to obtain mixed anhydride of formula V: 
       
         
           
           
               
               
           
         
       
       then silylating the mixed anhydride of formula V obtained above with N,O-bis(trimethylsilyl)acetamide to obtain the compound of formula II. 
     
     
         2 . The process according to  claim 1 , wherein the mixed anhydride of formula V is prepared by reacting [R-(Z)]-[4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]]benzeneacetic acid, mono potassium salt (amoxydane salt) with ethyl chloroformate in a chlorinated solvent. 
     
     
         3 . The process according to  claim 2 , wherein the chlorinated solvent is methylene chloride. 
     
     
         4 . The process according to  claim 2 , wherein the reaction is carried out in the presence of dimethylformamide along with the said chlorinated solvent. 
     
     
         5 . The process according to  claim 2 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used. 
     
     
         6 . The process according to  claim 1 , wherein the reaction between the compound of formula III or salt thereof and ethyl chloroformate is carried out below about −20° C. 
     
     
         7 . The process according to  claim 6 , wherein the reaction is carried out below −40° C. 
     
     
         8 . The process according to  claim 1 , wherein the silylation of the mixed anhydride is carried out in a chlorinated solvent. 
     
     
         9 . The process according to  claim 8 , wherein the chlorinated solvent is methylene chloride. 
     
     
         10 . The process for preparing (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4-carboxylic acid of formula I (cefprozil) or hydrate; or a pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
         which comprises: 
         a) acylating the compound formula VI: 
       
       
         
           
           
               
               
           
         
       
       with the compound of formula II: 
       
         
           
           
               
               
           
         
         in a chlorinated solvent to obtain a compound of formula VII: 
       
       
         
           
           
               
               
           
         
         b) deprotecting the compound obtained above with an aqueous hydrochloric acid to give cefprozil of formula I; 
         c) precipitating cefprozil as dimethylformamide solvate from the reaction mass obtained in step (b) and 
         d) converting the solvate of step (c) into cefprozil or cefprozil hydrate; or 
         pharmaceutically acceptable salt. 
       
     
     
         11 . The process according to  claim 10 , wherein the chlorinated solvent is methylene chloride. 
     
     
         12 . The process according to  claim 10 , wherein the solvate is precipitated from the reaction mass at a pH of above 5.5 to 7.0 in the presence of dimethylformamide. 
     
     
         13 . The process according to  claim 10 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying. 
     
     
         14 . The process according to  claim 3 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used. 
     
     
         15 . The process according to  claim 4 , wherein the catalytic quantities of N-methyl morpholine and methanesulfonic acid are used. 
     
     
         16 . The process according to  claim 11 , wherein the solvate is precipitated from the reaction mass at a pH of above 5.5 to 7.0 in the presence of dimethylformamide. 
     
     
         17 . The process according to  claim 11 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying. 
     
     
         18 . The process according to  claim 12 , wherein cefprozil hydrate is prepared in step (d) by stirring dimethylformamide solvate in water, filtering the de-solvated cefprozil and drying.