Process for preparing amine-substituted benzofurans

Abstract

The present invention relates to processes for preparing amine substituted benzofurans, and more particularly 4-(2{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile, and salts thereof. Compounds prepared by the processes of the invention have demonstrated activity as histamine-3 receptor ligands.

1 . A process for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein 
 A is heterocycle selected from pyrrolidinyl or piperidinyl, wherein the heterocycle is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl; and  
 R 1  is 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl of 4-cyanophenyl, the aryl, or the heteroaryl is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl;  
 the process comprising the steps of:  
 (1a) treating a compound of formula (II),  
                     
 wherein R A  is selected from the group consisting of bromo, chloro, 4-cyanophenyl, aryl, and heteroaryl, and the phenyl portion of the 4-cyanophenyl, the aryl, and the heteroaryl are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl, with a halogenating reagent selected from the group consisting of N-bromosuccinimide, N-iodosuccinimide, N-iodoacetamide, N-bromoacetamide, N-iodophthalimide, N-bromopthalimide, iodine, bromine, ICl, IBr, and BrCl, to provide a compound of formula (III),  
                     
 wherein X is Br or I;  
 (1b) treating the compound of formula (III) with 3-butyn-1-ol to provide a compound of formula (IV),  
                     
 (1c) treating the compound of formula (IV) with a sulfonating reagent to provide a compound of formula (V),  
                     
 wherein R B  is toluenesulfonate, methanesulfonate, or trifluoromethansulfonate, and  
 (1d) treating the compound of formula (V) with an amine reagent, selected from the group consisting of pyrrolidinyl and piperidinyl, wherein the pyrrolidinyl or piperidinyl is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl, to provide the compound of formula (VI),  
                     
 wherein A is as defined above for a compound of formula (I), and  
 (1e) further treating the compound of formula (V), wherein R A  is bromo or chloro, with a compound of formula (VIII),  
   (HO) 2 B—R 1    (VIII),  
 or a compound of formula (VIII-a),  
   (R e O)(R f O)B—R 1    (VIII-a),  
 wherein R 1  is 4-cyanophenyl, aryl, or heteroaryl, wherein the phenyl of 4-cyanophenyl, the aryl, or the heteroaryl is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl; and R e  and R f  are each independently alkyl or R e  and R f  are taken together to form a ring, wherein the ring is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl or aryl.  
 
     
     
         2 . The process according to  claim 1  wherein R 1  is 4-cyanophenyl.  
     
     
         3 . The process according to  claim 2  wherein the halogenating reagent in step (1a) is N-bromosuccinimide or N-iodosuccinimide.  
     
     
         4 . The process according to  claim 1  wherein A is (2R)-2-methylpyrrolidinyl.  
     
     
         5 . The process according to  claim 1  wherein R B  in a compound of formula (V) represents a toluenesulfonate group.  
     
     
         6 . A process for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein 
 A is heterocyclic group selected from pyrrolidinyl or piperidinyl, wherein the heterocycle is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl; and  
 R 1  is 4-cyanophenyl;  
 the process comprising the steps of:  
 (6a) treating a compound of formula (III-a),  
                     
 wherein R A1  is selected from the group consisting of bromo, chloro, 4-cyanophenyl; with a compound of formula (VII),  
                     
 wherein A is a heterocylic group selected from the group consisting of pyrrolidinyl and piperidinyl, said heterocyclic group substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl, to provide a compound of formula (VI-a),  
                     
 wherein R A1  and A are as defined above; and  
 (6b) further treating the compound of formula (VI-a), wherein R A1  is bromo or chloro, with a compound of formula (VIII),  
   (HO) 2 B—R,   (VIII),  
 or a compound of formula (VIII-a),  
   (R e O)(R f O)B—R 1    (VIII-a),  
 wherein R 1  is 4-cyanophenyl; and R e  and R f  are each independently alkyl or R e  and R f  are taken together to form a ring, wherein the ring is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl or aryl.  
 
     
     
         7 . The process according to  claim 6  wherein the compound of formula (III-a) in step 6a is reacted with the compound of formula (VII) and a palladium catalyst, metal halide, and base, wherein the palladium catalyst is selected from the group consisting of tetrakis(triphenylphosphine)palladium, (dibenzylideneacetate)palladium, (tris(dibenzylideneacetate)dipalladium, bis(tricyclohexylphosphine)palladium, (2-(diphenylphosphino)ethyl)palladium, (1,1′-bis(diphenylphosphino)ferrocene)palladium, bis(triphenylphosphine)dichloropalladium, bis(1,1′-bis(diphenylphosphino)ferrocene)palladium, bis(2-(diphenylphosphino)ethyl)dichloropalladium, and PdCl 2 (CH 3 CN) 2 .  
     
     
         8 . The process according to  claim 7  wherein the palladium catalyst is bis(triphenylphosphine)dichloropalladium (PdCl 2 (Ph 3 P) 2 ).  
     
     
         9 . The process according to  claim 7  wherein the metal halide is copper(I) iodide and the base is diisopropylamine.  
     
     
         10 . The process according to  claim 6  wherein A is (2R)-2-methylpyrrolidinyl.  
     
     
         11 . A process for preparing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is bromo or iodo and R A  is selected from the group consisting of bromo, chloro, 4-cyanophenyl, aryl, and heteroaryl, wherein the phenyl portion of 4-cyanophenyl, the aryl, or the heteroaryl group is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl, comprising the step of treating a compound of the formula (II),  
       
         
           
           
               
               
           
         
       
       wherein R A  is as previously defined, with a halogenating reagent of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is bromo or iodo to provide a compound of the formula (III).  
     
     
         12 . The process according to  claim 11  further comprising the step for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein 
 A is heterocyclic group selected from pyrrolidinyl or piperidinyl, wherein the heterocycle is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkyl and fluoroalkyl; and  
 R 1  is 4-cyanophenyl wherein the phenyl of 4-cyanophenyl is substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylthio, alkylthioalkyl, cyano, haloalkoxy, halogen, and haloalkyl; by chemically processing a compound of formula (III).  
 
     
     
         13 . The process according to  claim 11  wherein the halogenating reagent is N-iodosuccinimide.  
     
     
         14 . Compounds prepared according to the processes of claims  1 ,  6 , and  11 .  
     
     
         15 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is bromo or iodo and R c  is 4-cyanophenyl.