Synthesis of ceftiofur intermediate

Abstract

The present invention provides an improved process for the preparation of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) by the condensation of 7-amino cephalosporanic acid (7-ACA) represented by formula (II) with furyl-2-carbonylthiol represented by formula (III) using borontrifluoride as condensing agent in an organic solvent at a temperature range of 20°-50°C.

We claim:  
     
         1 . A process for preparation of 3-[2-(furylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I),  
       
         
           
           
               
               
           
         
       
       the said process comprising the steps of condensing 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride at 20-50° C. in an organic solvent and isolating the compound of formula (I)  
       
         
           
           
               
               
           
         
       
     
     
         2 . A process as claimed in  claim 1 , wherein the condensation reaction is performed at a temperature range of 30°-35° C.  
     
     
         3 . A process as claimed in  claim 1 , wherein the reaction mixture of condensation is poured into ice cold water, adjusting the pH of the solution to 3-4 with a base to precipitate the solid.  
     
     
         4 . A process as claimed in  claim 3 , wherein the pH of the solution lies/is in the range of 3.45-3.55.  
     
     
         5 . A process as claimed in  claim 2 , wherein the solid obtained by precipitation is washed with a mixture of water and organic solvent, drying the solid at a temperature range of 40°-45° C. under vacuum.  
     
     
         6 . A process as claimed in  claim 1 , wherein furyl-2-carbonylthiol of formula (III) without isolating is used as its solution in an organic solvent selected from a group consisting of ethylacetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether,di-isopropyl ether and/or mixture thereof.  
     
     
         7 . A process as claimed in  claim 1 , wherein the organic solvent used in the condensation reaction is selected from a group consisting of ethylacetate, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, di-isopropyl ether, acetonitrile, acetic acid or mixture thereof, most preferably ethyl acetate.  
     
     
         8 . A process as claimed in  claim 1 , wherein the condensing agent borontrifluoride is used in a gaseous form or its solution in an organic solvent selected from ethyl acetate, acetonitrile, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether, di-isopropyl ether and/or mixture thereof, most preferably in gaseous form.  
     
     
         9 . A process as claimed in  claim 1 , wherein 3-8 moles of borontrifluoride is used with respect to 7-aminocephalosporanic acid, the preferred molar ratio being 4.5:1.  
     
     
         10 . A process as claimed in  claim 3 , wherein the base used is selected from a group consisting of ammonium hydroxide, sodium hydroxide, or sodium carbonate and most preferably ammonium hydroxide.  
     
     
         11 . A process as claimed in  claim 5 , wherein the organic solvent used for washing the final product is selected from a group consisting of acetonitrile, ethylacetate, acetone, methyl acetate, propyl acetate, dichloromethane, toluene, diethyl ether,di-isopropyl ether and/or mixture thereof.