Process for the preparation of beta-lactam derivatives

Abstract

A process for the preparation of Cefuroxime acid (1), which comprises the following steps: (1) Extraction of deacetyl 7-glutaryl ACA (II) aqueous solution at acid pH with organic solvents (for example according to the procedures disclosed in U.S. Pat. No. 5,801,241); (2) drying the resulting solution while preventing lactonization of the intermediate; (3) carbamoylation of the hydroxymethyl group at the 3-position by reaction with chlorosulfonyl isocyanate or similar products; (7) extraction of the carbamoyl derivative from step 3 with water at neutral pH; (8) enzymatic hydrolysis of the amide at the 7-position of the cephalosporanic ring with glutaryl acylase; (6) acylation of the amino group by condensation with 2-furanyl(sin-methoxyimino)acetic acid chloride or mixed anhydride.

1 . A process for the preparation of Cefuroxime acid (I)  
       
         
           
           
               
               
           
         
       
       starting from deacetyl 7-glutaryl ACA (II), which comprises the following steps: 
 a) extracting a deacetyl 7-glutaryl ACA (II) aqueous solution at pH 1-3 and at a temperature of 0-15° C. with an organic solvent, to obtain an organic phase containing deacetyl 7-glutaryl ACA (II)  
                     
 b) adjusting said organic phase to pH 6-8, then drying such phase by distillation under vacuum at a temperature below or equal to 25° C.;  
 c) reacting deacetyl 7-glutaryl ACA (II) with an activated isocyanate at temperatures ranging from −30° to 0° C., to obtain (6R,7R)-7-[(4-carboxy-1-oxobutyl)amino]-3-carbamoyloxymethyl-ceph-3-em-4-carboxylic acid (III)  
                     
 d) extracting said compound (III) from the reaction mixture with water at pH of 6-8 and at a temperature of 0-15° C.;  
 e) transforming compound (III) into (6R,7R)-7-amino-3-carbamoyloxymethyl-ceph-3-em-4-carboxylic acid (IV)  
                     
  by glutaryl acylase enzymatic hydrolysis, at pH 7-9 and at a temperature of 20-30° C.;  
 f) condensing compound (IV) with a 2-furanyl(sin-methoxyimino)acetic acid halide or anhydride, to obtain the desired Cefuroxime acid (I).  
 
     
     
         2 . A process as claimed in  claim 1 , in which said organic solvent is cyclohexanone.  
     
     
         3 . A process as claimed in  claim 2 , in which said deacetyl 7-glutaryl ACA (II) aqueous solution has a concentration of 1-20%.  
     
     
         4 . A process as claimed in any one of the above claims, in which in step b) the organic phase is dried to a water content below 0.5%.  
     
     
         5 . A process as claimed in any one of the above claims, in which said activated isocyanate is chlorosulfonyl isocyanate.  
     
     
         6 . A process as claimed in any one of the above claims, in which said glutaryl acylase is supported on a macroreticular resin.  
     
     
         7 . A process as claimed in  claim 6 , in which said resin is a polyacrylic epoxide resin.  
     
     
         8 . A process as claimed in  claim 7 , in which said glutaryl acylase is isolated from an  Escherichia Coli  culture.  
     
     
         9 . The compound of formula (III)  
       
         
           
           
               
               
           
         
       
       and the salts thereof.