Process for preparing cephalosporins with salified intermediate

Abstract

Cephalosporins may be conveniently prepared by a process in which 7-ACA is silylated, acylated, desilylated and then salified to give an intermediate which is eventually cyclized with thiourea.

1 . A process for preparing a cephalosporin of formula (I)  
       
         
           
           
               
               
           
         
       
       in which R 1  is H or Na and R 2  is chosen from the group consisting of H, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2 ,  
       
         
           
           
               
               
           
         
       
       according to which a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       in which R 2  has the aforestated meanings is silylated at the carboxyl to give the corresponding trialkylsilyl-ester which is reacted with a compound of formula (III)  
       
         
           
           
               
               
           
         
       
       in which X is Cl or Br and Y is Cl, or  
         O—CH═N + (CH 3 ) 2  Cl −   
       to give a cephalosporin of formula (IV)  
       
         
           
           
               
               
           
         
       
       in which X and R 2  have the aforestated meanings, and R 3  is trialkylsilyl, which is hydrolyzed at pH 7÷7.5 and then treated in a partly aqueous solution with benzathine or a salt thereof, to obtain crystallization of a new cephalosporin of formula (V)  
       
         
           
           
               
               
           
         
       
       where Z is benzathine, in which the carboxyl is salified by the benzathine, this salt being filtered off, washed with water and reacted in a partly aqueous solvent with thiourea, to lead to the formation of the 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain and give a solution of the compound of general formula (I) in which R 2  has the aforestated meanings and R 1  is H, the compound of formula (I) being crystallized from this solution in the form of the sodium salt, of the salt of a pharmaceutically acceptable inorganic acid or of an internal salt.  
     
     
         2 . A process according to  claim 1 , wherein simultaneously with the formation of the 2-(2-aminothiazol-4-yl)-2-methoxyyminoacetic chain, there is the precipitation of benzathine hydrochloride which is filtered off and removed to leave a very pure solution of the compound of general formula (I).  
     
     
         3 . A process as claimed in  claim 1 , wherein a product of formula (I) is obtained in which R 1  is H or Na and R 2  is chosen from the group consisting of H, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2   
       
         
           
           
               
               
           
         
       
     
     
         4 . A process as claimed in  claim 2 , wherein a product of formula (I) is obtained in which R 1  is H or Na and R 2  is chosen from the group consisting of H, CH 3 , CH 2 OCH 3 , CH 2 OCOCH 3 , CH═CH 2   
       
         
           
           
               
               
           
         
       
     
     
         5 . The benzathine salt of a cephalosporin of formula (V)  
       
         
           
           
               
               
           
         
       
       where Z, X and R are as specified in  claim 1 .  
     
     
         6 . A process for preparing the benzathine salt of a cephalosporin of formula (V) of  claim 5 , according to which a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       in which R 2  has the aforestated meanings, is silylated at the carboxyl to give the corresponding trialkylsilyl-ester which is reacted with a compound of formula (III)  
       
         
           
           
               
               
           
         
       
       in which X is Cl or Br and Y is Cl, or  
         O—CH═N + (CH 3 ) 2  Cl −   
       to give a cephalosporin of formula (IV)  
       
         
           
           
               
               
           
         
       
       in which X and R 2  are as specified in  claim 1 , and R 3  is trialkylsilyl, which is hydrolyzed at pH 7÷7.5 and then treated in a partly aqueous solution with benzathine or a salt thereof, thus obtaining crystallization of a cephalosporin of formula (V) in which the carboxyl is salified by the benzathine, this salt being filtered off and washed with water.