Processes for preparing darifenacin hydrobromide

Abstract

The invention encompasses processes for the preparation of darifenacin hydrobromide.

1 . A process for preparing darifenacin hydrobromide comprising:
 a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C 6-9  aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,   
       
         
           
           
               
               
           
         
         b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a C 6-9  aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II; 
       
       
         
           
           
               
               
           
         
         c) reacting the (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III, 
       
       
         
           
           
               
               
           
         
       
       wherein the bromine acceptor is phenol only when the acid is HBr;
 d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III, a compound of the formula V, 
 
       
         
           
           
               
               
           
         
       
       a solvent selected from the group consisting of a C 6-9  aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to obtain a mixture;
 e) heating the mixture of step d; 
 f) admixing the mixture of step d with an acid to obtain a (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; and 
 
       
         
           
           
               
               
           
         
         g) admixing the (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV, an inorganic base and a protic solvent; and 
         h) reacting with hydrobromic acid to obtain darifenacin hydrobromide, wherein X is either C 1-10  alkyl or C 6-9  aryl, wherein Y is a leaving group selected from the group consisting of I, Cl, Br, mesyl, tosyl, brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z 1  and Z 2  are independently an acid. 
       
     
     
         2 . The process of  claim 1 , wherein X is C 6-9  aryl. 
     
     
         3 . The process of  claim 1 , wherein X is tolyl. 
     
     
         4 . The process of  claim 1 , wherein Y is Cl. 
     
     
         5 . The process of  claim 1 , wherein Z 1  and Z 2  are independently HBr or HCl. 
     
     
         6 . The process of  claim 1 , further comprising recovering the darifenacin hydrobromide.