Process for preparing modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The present invention relates to processes for preparing solid state forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, including Compound 1 Form A, Compound 1 Form A-HCl, Compound 1 Form B, and Compound 1 Form B-HCl, any combination of these forms, pharmaceutical compositions thereof, and methods of treatment therewith.

What is claimed is: 
     
         1 - 21 . (canceled) 
     
     
         22 . A process for preparing Compound 3 
       
         
           
           
               
               
           
         
         comprising: 
         (a) reacting compound 7, wherein Hal is F, Cl, Br or I, with 7-azabicyclo[2.2.1]heptane 8, or a salt thereof, to generate compound 9 
       
       
         
           
           
               
               
           
         
       
       and
 (b) reducing the nitro moiety in compound 9 to provide aniline 3. 
 
       
         
           
           
               
               
           
         
       
     
     
         23 . The process of  claim 22 , wherein step (a) is performed in the presence of a base in a polar aprotic solvent. 
     
     
         24 . The process of  claim 23 , wherein the base is triethyl amine, or diisopropylethyl amine and the solvent is acetonitrile. 
     
     
         25 . The process of  claim 22 , wherein step (b) is performed using hydrogen gas and a transition metal catalyst in an alcoholic solvent. 
     
     
         26 . The process of  claim 25 , wherein the catalyst comprises a group 9 or group 10 transition metal selected from Pt, Pd, or Ni. 
     
     
         27 . The process of  claim 26 , wherein the catalyst comprises Pd. 
     
     
         28 . The process of  claim 23 , wherein the solvent comprises isopropanol, ethanol or methanol. 
     
     
         29 . The process of  claim 28 , wherein the solvent comprises ethanol. 
     
     
         30 . The process of  claim 22 , wherein compound 8 is in the salt form, Compound 8-HCl: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The process of  claim 22 , further comprising contacting Compound 3 with HCl to provide the hydrochloride salt 3-HCl: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The process of  claim 31 , wherein step (a) is performed in the presence of sodium carbonate and DMSO. 
     
     
         33 . The process of  claim 31 , wherein step (b) is performed using hydrogen gas and a transition metal catalyst in an alcoholic solvent. 
     
     
         34 . The process of  claim 33 , wherein the catalyst comprises a group 9 or group 10 transition metal catalyst derived from Pt, Pd, or Ni, and the solvent comprises isopropanol, ethanol or methanol. 
     
     
         35 . The process of  claim 34 , wherein the catalyst comprises Pd and the solvent comprises ethanol. 
     
     
         36 - 69 . (canceled)