Process for the preparation of alkyl 3-difluoromethyl-1-methyl-1h-pyrazole-4-carboxylate and its analogs

Abstract

The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using Na 2 CO 3 and/or K 2 CO 3 to promote the ring-closure reaction to produce the alkyl 3-di-fluoromethyl-1-methyl-1H-pyrazole-4- carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoro methyl-2-methyl-1H-pyrazole-4-carboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

1 - 2 . (canceled) 
     
     
         3 . A process reacting a compound of Formula XVIII with methyl hydrazine hydrate (H 3 CNHNH 2 .H 2 O) or methyl hydrazine in the presence of a base weaker than KOH or NaOH to provide a compound of Formula XII 
       
         
           
           
               
               
           
         
         R 1  is CF 2 H, CFH 2 , CF 3 , CCl 2 H, CClH 2 , or CCl 3 ; 
         R 2  is C 1 -C 6  alkyl; 
         R 3  is methyl or ethyl; and 
         M is sodium, potassium, or lithium. 
       
     
     
         4 . The process of  claim 3 , additionally comprising basic hydrolysis of the compound of Formula XII followed by acidification with a strong acid 
       
         
           
           
               
               
           
         
         to provide a compound of Formula I. 
       
     
     
         5 - 10 . (canceled) 
     
     
         11 . The process of  claim 3 , wherein the reaction of the compound of Formula XVIII with methyl hydrazine hydrate occurs in a two-phase solvent. 
     
     
         12 . The process of  claim 11 , wherein the two phase solvent contains an organic phase and an aqueous phase and the organic phase contains a water-immiscible organic solvent, a low water-miscible organic solvent, or a mixture of a water-immiscible organic solvent and a low water-miscible organic solvent. 
     
     
         13 . The process of  claim 3 , wherein the base is Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , CaCO 3  MgCO 3 , or a combination of any of the foregoing. 
     
     
         14 . The process of  claim 3 , wherein the reaction of the compound of Formula XVIII with methyl hydrazine hydrate is conducted between about −20° C. and about 50° C. 
     
     
         15 . The process of  claim 3 , wherein the compound of Formula XII is purified by precipitation in a solvent mixture. 
     
     
         16 . The process of  claim 15  wherein the solvent mixture system is selected from the group consisting of toluene/petroleum ether, toluene/hexane, toluene/pentane, toluene/heptane, toluene/cyclohexane, toluene/ethyl acetate, toluene/isopropyl acetate, toluene/butyl acetate and toluene/MTBE. 
     
     
         17 . The process of  claim 15 , wherein the precipitation occurs between about 0° C. and about 25° C. 
     
     
         18 . The process of  claim 3 , wherein R 1  is CF 2 H or CF 3 , R 2  is ethyl, R 3  is ethyl, M is sodium, and R 4  is ethyl. 
     
     
         19 . The process of  claim 17 , wherein R 1  is CF 2 H. 
     
     
         20 . The process of  12 , wherein the organic phase comprises toluene.