Process of producing cycloalkylcarboxamido-indole compounds

Abstract

The present invention features processes for preparing compounds, such as (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1), useful for treating CFTR mediated diseases such as cystic fibrosis.

1 - 19 . (canceled) 
     
     
         20 . A method for preparing a compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence:
 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
 Hal is a halide; 
 R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
 R J  is hydrogen or C 1-6  aliphatic; 
 m is an integer from 0 to 3 inclusive; and 
 n is an integer from 1 to 4 inclusive; 
 
       comprising the steps of
 a) reacting a compound of formula IIA in a first organic solvent 
 
       
         
           
           
               
               
           
         
         wherein, independently for each occurrence: 
         ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
         R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
         R J  is hydrogen or C 1-6  aliphatic; 
         m is an integer from 0 to 3 inclusive; and 
         Hal is a halide; 
         with a compound of formula IIB: 
       
       
         
           
           
               
               
           
         
         wherein 
         X is CN or CO 2 R; 
         R is C 1-6  aliphatic or aryl; and 
         R J  is hydrogen or C 1-6  aliphatic, to form a compound of formula IIC: 
       
       
         
           
           
               
               
           
         
         wherein, independently for each occurrence: 
         ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
         R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
         R J  is hydrogen or C 1-6  aliphatic; 
         X is CN or CO 2 R; 
         R is C 1-6  aliphatic or aryl; and 
         m is an integer from 0 to 3 inclusive; 
         b) removing the —CO 2 R J  group from compound IIC in a second organic solvent to form a compound of formula I: 
       
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence:
 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
 R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
 R J  is hydrogen or C 1-6  aliphatic; 
 X is CN or CO 2 R; 
 R is C 1-6  aliphatic or aryl; and 
 m is an integer from 0 to 3 inclusive; 
 c) reacting a compound of formula I with a compound of formula IID in the presence of a base: 
 
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence:
 Hal is a halide; and 
 q is an integer from 0 to 3 inclusive; to produce a compound of formula IIE: 
 
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence:
 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
 R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
 R J  is hydrogen or C 1-6  aliphatic; 
 m is an integer from 0 to 3 inclusive; 
 X is CN or CO 2 R; 
 R is C 1-6  aliphatic or aryl; and 
 n is an integer from 1 to 4 inclusive; 
 d) sequentially reacting a compound of formula IIE with a hydroxide base and acid to form a compound of formula F: 
 
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence:
 ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; 
 R 1  is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ; 
 R J  is hydrogen or C 1-6  aliphatic; 
 m is an integer from 0 to 3 inclusive; and 
 n is an integer from 1 to 4 inclusive; and 
 e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II. 
 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 20 , wherein in step a), the first organic solvent is toluene. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The method of  claim 20 , wherein in step a), ring A is 
       
         
           
           
               
               
           
         
       
     
     
         26 - 28 . (canceled) 
     
     
         29 . The method of  claim 20 , wherein in formula IIC, ring A is 
       
         
           
           
               
               
           
         
       
       m is 0, X is CN, and R J  is Et. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 20 , wherein in step b), the second solvent is dimethylsulfoxide. 
     
     
         32 . The method of  claim 20 , wherein in formula I, ring A is 
       
         
           
           
               
               
           
         
       
       m is 0, and X is CN. 
     
     
         33 . The method of  claim 20 , wherein in step c), the base is an inorganic base. 
     
     
         34 . The method of  claim 20 , wherein in formula IID, one Hal is Cl and the other Hal is Br. 
     
     
         35 . The method of  claim 20 , wherein in step d), the base is NaOH. 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 20 , wherein in step d), reaction with a hydroxide base takes place at about 60° C. to 100° C. 
     
     
         38 . The method of  claim 20 , wherein in formula IIE, ring A is 
       
         
           
           
               
               
           
         
       
       m is 0, n is 1, and X is CN. 
     
     
         39 - 40 . (canceled) 
     
     
         41 . The method of  claim 20 , wherein in step e), the halogenating agent is SOCl 2 . 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 20 , wherein in formula IIF, ring A is 
       
         
           
           
               
               
           
         
       
       m is 0, and n is 1. 
     
     
         44 . The method of  claim 20 , wherein in formula II, ring A is 
       
         
           
           
               
               
           
         
       
       m is 0, n is 1, and Hal is Cl. 
     
     
         45 - 117 . (canceled)