Novel process for making 5-substituted pyrazoles

Abstract

This invention relates to a novel process of preparing selected 5-substituted pyrazoles useful as p38 kinase and COX-2 inhibitors.

1 . A process of making a compound, wherein: 
 the compound corresponds in structure to Formula Ia or Ib:                          R 1  is phenyl substituted with one or more substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOalkyl, SO 2 NHCOalkyl, alkenyl, and alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino, dialkylamino, and phenyl substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino, and dialkylamino;    R 3  is selected from the group consisting of hydrogen, alkyl, and phenyl, wherein the alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO 2 CH 3 , halo, alkyl, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ;    R 4  and R 5  taken together form piperazine substituted with one or two alkyl; and    the process comprises: 
 reacting an organometallic reagent of the formula R 2 CH 2 M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula Ic:  
                     
 treating the ketone of Formula Ic with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce a dithietane derivative of Formula Id:  
                     
 reacting the dithietane derivative of Formula Id with an amine of formula R 4 —NH—R 5  to produce a thioamide of Formula Ie, If, or Ig:  
                     
 condensing the thioamide of Formula Ie, If, or Ig with hydrazine or substituted hydrazine.  
   
     
     
         2 . The process of  claim 1 , wherein: 
 R 1  is phenyl substituted with one or more substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-3  alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOC 1-4  alkyl, SO 2 NHCOC 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C 1-6 , alkyl, and 6-membered heterocycle substituted with 1 to 2 substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, C 1-6  dialkylamino, phenyl substituted with one or two substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, and C 1-6  dialkylamino;    R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, and phenyl, wherein the C 1-6  alkyl and phenyl may be optionally substituted by one or more substituents selected from the group consisting of SO 2 CH 3 , halo, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ; and    R 4  and R 5  taken together form piperazine substituted with one or two methyl.    
     
     
         3 . The process of  claim 1 , wherein the dihalomethane is dibromomethane.  
     
     
         4 . The process of  claim 1 , wherein the dihalomethane is iodochloromethane.  
     
     
         5 . The process of  claim 1 , wherein the process comprises making a compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A process of making a compound, wherein: 
 the compound corresponds in structure to Formula IIa or IIb:                          R 1  is phenyl substituted with one or more substituents selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOalkyl, SO 2 NHCOalkyl, alkenyl, and alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents is selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino, dialkylamino, and phenyl, wherein the phenyl is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino 2  and dialkylamino;    R 3  is selected from the group consisting of hydrogen, alkyl, and phenyl wherein the alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO 2 CH 3 , halo, alkyl, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ;    R 6  is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, alkoxycarbonyl, acyl, halo, OH, NH 2 , NHR 3 , N(R 3 ) 2 , and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring; and    the process comprises: 
 reacting an organometallic reagent of the formula R 2 CH 2 M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula IIc:  
                     
 treating the ketone of Formula IIc with a mixture of carbon disulfide and dihalo methane such as dibromomethane or iodochloromethane in the presence of a base and a solvent to produce a dithietane derivative of Formula IId:  
                     
 reacting the dithietane derivative of Formula IId with NaOR 6  to produce a compound of Formula IIe:  
                     
 condensing the compound of Formula IIe with hydrazine or substituted hydrazine.  
   
     
     
         7 . The process of  claim 6 , wherein: 
 R 1  is phenyl substituted by one or more substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-3  alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOC 1-4  alkyl, SO 2 NHCOC 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C 1-6  alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, C 1-6  dialkylamino, and phenyl substituted with one or two substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, and C 1-6  dialkylamino;    R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, and phenyl, wherein the C 1-6  alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO 2 CH 3 , halo, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ; and    R 6  is, selected from the group consisting of hydrogen and C 1-6  alkyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, OH, NH 2 , NHR 3 , N(R 3 ) 2 , and cyano, C 3-7  cycloalkyl, C 3-7  heterocycloalkyl, and 3-7 membered heterocycle ring.    
     
     
         8 . The process of  claim 6 , wherein the dihalomethane is dibromomethane.  
     
     
         9 . The process of  claim 6 , wherein the dihalomethane isiodochloromethane.  
     
     
         10 . The process of  claim 6 , wherein the dithietane is added to a solution of sodium alkoxide.  
     
     
         11 . The process of  claim 6 , the process comprises making a compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A process of making compounds of a compound, wherein: 
 the compound corresponds in structure to Formula IIIa or IIIb:                          R 1  is phenyl substituted with one or more substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOalkyl, SO 2 NHCOalkyl, alkenyl, and alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino, dialkylamino, and phenyl, wherein the phenyl is substituted substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , alkyl, alkylamino, and dialkylamino;    R 3  is selected from the group consisting of hydrogen, alkyl, and phenyl, wherein the alkyl and phenyl may be optionally substituted by one or more of the group consisting of SO 2 CH 3 , halo, alkyl, alkoxy, alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ;    R 6  is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, alkoxycarbonyl, acyl, OH, NH 2 , NHR 3 , N(R 3 ) 2 , and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring; and    the process comprises: 
 reacting an organometallic reagent of the formula R 2 CH 2 M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula IIIc:  
                     
 treating the ketone of Formula IIIc with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce a dithietane derivative of Formula IIId:  
                     
 reacting the dithietane derivative of Formula IIId with R 3 NHNH 2  to produce a heterocycle of the formula IIIe or IIIf and their tautomers:  
                     
 reacting the heterocycle of the formula IIIe or IIIf with an activated form of R 6  in the presence of a base and a solvent.  
   
     
     
         13 . The process of  claim 12 , wherein: 
 R 1  is phenyl substituted with one or more substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-3  alkyl, SO 2 CH 3 , SO 2 NH 2 , SO 2 NHCOC 1-4  alkyl, SO 2 NHCOC 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl;    R 2  is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C 1-6  alkyl, 6-membered heterocycle, wherein the heterocycle is substituted with one or two substients selected from the group consisting of halo, C 1-6  alkoxy, C 1-6 alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, C 1-6  dialkylamino, and phenyl, wherein the phenyl is substituted with one or two substituents selected from the group consisting of halo, C 1-6  alkoxy, C 1-6  alkylthio, cyano, CF 3 , OCF 3 , C 1-6  alkyl, C 1-6  alkylamino, and C 1-6  dialkylamino;    R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl, and phenyl, wherein the C 1-6  alkyl and phenyl may be optionally substituted by one or more substituents selected from the group consisting of SO 2 CH 3 , halo, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylthio, cyano, CF 3 , OCF 3 , and SO 2 NH 2 ; and    R 6  is selected from the group consisting of hydrogen and C 1-6  alkyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, OH, NH 2 , NHR 3 , N(R 3 ) 2 , and cyano, C 1-7  cycloalkyl, C 1-7  heterocycloalkyl, and 3-7 membered heterocycle ring.    
     
     
         14 . The process of  claim 12 , wherein the dihalomethane is dibromomethane.  
     
     
         15 . The process of  claim 12 , wherein the dihalomethane is iodochloromethane.  
     
     
         16 . The process of  claim 12 , wherein the process comprising making a compound selected from the group consisting of: