Novel thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds

Abstract

The present invention provides novel thioester derivatives of thiazolyl acetic acid of the general formula (I), also, the invention provides a method for preparation of the thioester derivatives and reaction of the thioester derivatives with cephem carboxylic acids to produce cephalosporin antibiotic compounds having general formula (II).

1 . A novel derivative of thiazolyl acetic acid represented by the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents H, trityl, CH 3 , CR a R b COOR 3  (R a  and R b  independently of one another represents hydrogen or methyl and R 3  represents H or C 1 -C 7  alkyl). 
 R 2  represents C 1 -C 4  alkyl or phenyl  
 
     
     
         2 . A process for preparing thiazolylacetic acid derivative represented by formula (I), said process comprises the step of reacting a thiazolylacetic acid represented by formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents H, trityl, CH 3 , CR a R b COOR 3  (R a  and R b  independently of one another represents hydrogen or methyl and R 3  represents H or C 1 -C 7  alkyl). 
 with thio-oxadiazole of formula (VI) in presence of an organic solvent base and a  
                     
 wherein, R 2  represents C 1 -C 4  alkyl or phenyl condensation agent at temperature being maintained in the range −10° C. to +30° C.  
 
     
     
         3 . The process of  claim 2  wherein the organic solvent is selected from the group comprising dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, acetone, carbon tetrachloride and mixture thereof.  
     
     
         4 . The process of  claim 2  wherein the organic base is selected from the group comprising triethylamine, diethylamine, tributylamine, pyridine, N-alkylanilines, 1,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine and mixtures thereof.  
     
     
         5 . The process of  claim 2  wherein the condensation agent selected is bis-(2-oxo-oxazolidinyl)phosphinic chloride.  
     
     
         6 . A process for preparing a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein, R 1  represents H, trityl, CH 3 , CR a R b COOR 3  (R a  and R b  independently of one another represents hydrogen or methyl and R 3  represents H or C 1 -C 7  alkyl). 
 R 4  is CH 3 , —CH═CH 2 , CH 2 OCH 3 , CH 2 OCOCH 3 ,  
                     
 or a standard cephalosporins substituent.  
 R 5 is H or a salt or a carboxylic protecting group.  
 R 6  is H or silyl  
 acylating a compound of formula (III)  
                     
 wherein, R 4 , R 5  and R 6  are defined as above with a compound of formula I. In the presence of an organic solvent, organic base and a silylating agent at a temperature in the range of −10° C. to +30° C.  
                     
 wherein, R 1  & R 2  are as defined above.  
 
     
     
         7 . The process of  claim 6  wherein R 5  is hydrogen or alkali metal salt.  
     
     
         8 . The process of  claim 6  wherein said compound of formula II is a syn isomer.  
     
     
         9 . The process of  claim 6  wherein R 6  is H, the acylation is done in the presence of water and an organic solvent selected from the group consisting of tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, and mixtures thereof.  
     
     
         10 . The process of  claim 6  wherein R 6  is silyl, the acylation is achieved by doing the reaction in aprotic organic solvent like halogenated hydrocarbon, toluene, alkyl ether preferably in dichloromethane.  
     
     
         11 . The process of  claim 6  wherein the organic base is selected from the group consisting of triethylamine, N-methylmorpholine, N-methylpyridines, N-methylanilines, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, and mixtures thereof.  
     
     
         12 . The process of  claim 6  wherein R 2  is methyl, R 4  is (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl, purification of this compound is achieved by dissolving the crude product in mixture of water and water miscible organic solvent selected from acetone, IPA, dioxane and mixture thereof.  
     
     
         13 . The process of  claim 6  wherein R 2  is methyl, R 4  is (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl, the colour impurities are separated at −10° C. to 0° C. and precipitation by water miscible organic solvent selected from acetone, IPA, dioxane and mixture thereof.