7-aminocephem derivative compounds

Abstract

This disclosure provides methods of making certain 7-aminocephem derivatives useful in the manufacture of cephalosporin antibiotic compounds.

We claim: 
     
         1 . A method of making compound (II): 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         (a) forming a reaction mixture comprising phosphorous pentachloride (PCl 5 ) and pyridine; 
         (b) adding compound (IIa) to the reaction mixture: 
       
       
         
           
           
               
               
           
         
         (c) adding isobutyl alcohol; 
         (d) adding a solvent comprising water; 
         (e) adding ethyl acetate; and 
         (f) obtaining compound (II). 
       
     
     
         2 . The method of  claim 1 , wherein step (a) comprises:
 (1) combining PCl 5  and dichloromethane; and   (2) adding pyridine.   
     
     
         3 . The method of  claim 2 , wherein step (1) comprises:
 (i) combining 2.0 equivalents PCl 5  and 6.0 volumes dichloromethane while maintaining the temperature below 30° C.; and   (ii) adjusting the temperature to 10 to 30° C. and agitating.   
     
     
         4 . The method of  claim 2 , wherein step (2) comprises:
 (i) adjusting the temperature to −10 to −5° C.;   (ii) adding 2.0 equivalents of pyridine while maintaining the temperature at −10 to 5° C.; and   (iii) adjusting the temperature to −5 to 0° C. and agitating.   
     
     
         5 . The method of  claim 1 , wherein step (b) comprises:
 (1) adding 1.0 equivalent compound (IIa) to the reaction mixture of step (a) while maintaining the temperature of the mixture at −10 to 0° C.; and   (2) stirring the mixture at −10 to 0° C.   
     
     
         6 . The method of  claim 5 , wherein the mixture of step (2) comprises <5.0% compound (IIa) relative to compound (II) +compound (IIa). 
     
     
         7 . The method of  claim 1 , wherein step (c) comprises:
 (1) adjusting the temperature of the mixture to −20 to −10° C.;   (2) adding 2.0 volumes of isobutyl alcohol dropwise while maintaining the temperature of the mixture at -20 to 5° C.; and   (3) agitating the mixture at −10 to 0° C.   
     
     
         8 . The method of  claim 1 , wherein step (d) comprises:
 (1) adding a solvent comprising water to the mixture of step (c) while maintaining the temperature of the mixture at −10 to 5° C.;   (2) agitating the mixture at −5 to 5° C.; and   (3) separating a lower organic phase from the mixture and collecting the lower organic phase.   
     
     
         9 . The method of  claim 8 , wherein the solvent comprising water is a mixture of ethanol and water. 
     
     
         10 . The method of  claim 8 , further comprises:
 (4) adding dichloromethane to the mixture at −10 to 0° C.;   (5) agitating the mixture at −10 to 0° C.; and   (6) separating a lower organic phase from the mixture and collecting the lower organic phase.   
     
     
         11 . The method of  claim 1 , wherein step (e) comprises:
 (1) concentrating the organic phase to 4 to 5 volumes;   (2) adjusting the temperature to −10 to −5° C.;   (3) adding 2.1 volumes of ethyl acetate dropwise while maintaining the temperature of the mixture at −10 to −5° C.; and   (4) agitating the mixture at −10 to 5° C.   
     
     
         12 . The method of  claim 11 , wherein step (e) further comprises:
 (5) observing the formation of a precipitate;   (6) concentrating the organic phase to 4 to 5 volumes;   (7) adjusting the temperature of the mixture to −10 to −5° C.;   (8) adding 2.1 volumes of ethyl acetate while maintaining the temperature of the mixture at −10 to −8° C.; and   (9) agitating the mixture at −10 to −5° C.   
     
     
         13 . The method of  claim 1 , wherein step (f) comprises:
 (1) centrifuging the mixture to produce a cake; and   (2) collecting the cake.   
     
     
         14 . The method of  claim 13 , wherein step (f) further comprises:
 (3) adding 2.2 volumes of ethyl acetate;   (4) adjusting the temperature to −10 to −5° C.;   (5) agitating at −10 to −5° C.;   (6) centrifuging to produce a cake;   (7) collecting the cake; and   (8) drying the cake at 5 to 20° C.   
     
     
         15 . A composition comprising compound (II): 
       
         
           
           
               
               
           
         
       
       and compound (IIa): 
       
         
           
           
               
               
           
         
       
     
     
         16 . The composition of  claim 15 , further comprising compound (IIb): 
       
         
           
           
               
               
           
         
       
     
     
         17 . A composition comprising compound (II): 
       
         
           
           
               
               
           
         
       
       and compound (IIb):