Process for making modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The invention provides a process for the preparation of a compound of Formula 1, comprising coupling a carboxylic acid of Formula 2 with an aniline of Formula 3 in the presence of a coupling agent.

1 - 58 . (canceled) 
     
     
         59 . A process for the preparation of a compound of Formula 8 
       
         
           
           
               
               
           
         
       
       comprising nitrating a compound of Formula 7 using a mixture of sulfuric acid and nitric acid in the presence of dichloromethane 
       
         
           
           
               
               
           
         
       
       wherein PG is a protecting group and R 2  and R 4  are each tert-butyl, and wherein the nitro compound of Formula 8 is purified by crystallization. 
     
     
         60 . The process of  claim 59 , wherein PG is propoxy formyl, methanesulfonyl, 4-nitro-benzoyl, ethoxy formyl, butoxy formyl, t-butoxy formyl, i-propoxy formyl or methoxy formyl. 
     
     
         61 . The process of  claim 60 , wherein PG is methoxy formyl. 
     
     
         62 . The process of  claim 59 , further comprising producing a compound of formula 7 by reacting a compound of Formula 6 
       
         
           
           
               
               
           
         
       
       with a reagent capable of causing a protecting group to be attached to the phenolic oxygen of a compound of Formula 6 in the presence of a solvent. 
     
     
         63 . The process of  claim 62 , wherein the solvent is diethyl ether, or methylene chloride. 
     
     
         64 . The process of  claim 63 , wherein the solvent is methylene chloride. 
     
     
         65 . The process of  claim 59 , further comprising producing a compound of Formula 5 
       
         
           
           
               
               
           
         
       
       by reducing a compound of formula 8. 
     
     
         66 . A process for the preparation of Compound 31, comprising contacting Compound 30 with a mixture of nitric acid and sulfuric acid in the presence of dichloromethane 
       
         
           
           
               
               
           
         
       
     
     
         67 . The process of  claim 66 , wherein the reaction is quenched by adding the reaction mixture to cold water. 
     
     
         68 . The process of  claim 66 , wherein the aqueous layer is extracted with dichloromethane. 
     
     
         69 . The process of  claim 68 , wherein the dichloromethane is further washed with water. 
     
     
         70 . The process of  claim 66 , wherein the product is isolated by crystallization with hexane. 
     
     
         71 . The process of  claim 66 , further comprising contacting Compound 31 in the presence of hydrogen gas, palladium on carbon, and methanol to provide Compound 32