Pure darifenacin hydrobromide substantially free of oxidized darifenacin and salts thereof and processes for the preparation thereof

Abstract

Provided are darifenacin hydrobromide free of oxidized darifenacin, and processes for the preparation thereof.

1 . A process for preparing darifenacin hydrobromide, comprising:
 a) combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate or the free base derivative of the following formula,   
       
         
           
           
               
               
           
         
         a compound of the following formula II, 
       
       
         
           
           
               
               
           
         
         having less than 0.25% of a compound of the following formula I, 
       
       
         
           
           
               
               
           
         
         a solvent selected from the group consisting of a C 6-9  aromatic hydrocarbon, a polar aprotic organic solvent, water, and mixtures thereof, and a base to form a mixture; and b) admixing HBr with the mixture to obtain darifenacin hydrobromide having less than 0.1% of oxidized Darifenacin and salts thereof, wherein Y is a leaving group selected from the group consisting of Cl, I, brosyloxy, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy. 
       
     
     
         2 . The process of  claim 1 , wherein the compound of formula II has less than 0.15% of the compound of formula I, and the obtained Darifenacin hydrobromide has less than 0.08% of oxidized Darifenacin and salts thereof. 
     
     
         3 . The process of  claim 1 , wherein the compound of formula II has less than 0.1% of the compound of formula I, and the obtained Darifenacin hydrobromide has less than 0.05% of oxidized Darifenacin and salts thereof. 
     
     
         4 . The process of  claim 3 , wherein Y is Cl. 
     
     
         5 . The process of  claim 1 , wherein the polar aprotic organic solvent is selected from the group consisting of an amide, a C 1-10  halogenated aliphatic hydrocarbon, a sulfoxide, an ester, a nitrile, and a ketone. 
     
     
         6 . The process of  claim 5 , wherein the amide is dimethylformamide. 
     
     
         7 . The process of  claim 5 , wherein the C 1-10  halogenated aliphatic hydrocarbon is C 1-5  halogenated aliphatic hydrocarbon. 
     
     
         8 . The process of  claim 7 , wherein the C 1-5  halogenated aliphatic hydrocarbon is dichloromethane. 
     
     
         9 . The process of  claim 5 , wherein the sulfoxide is a C 1-4  sulfoxide. 
     
     
         10 . The process of  claim 9 , wherein the C 1-4  sulfoxide is dimethylsulfoxide. 
     
     
         11 . The process of  claim 5 , wherein the ester is a C 2-5  ester. 
     
     
         12 . The process of  claim 11 , wherein the C 2-5  ester is ethyl acetate. 
     
     
         13 . The process of  claim 5 , wherein the ketone is a C 3-6  ketone. 
     
     
         14 . The process of  claim 13 , wherein the C 3-6  ketone is methyl ethyl ketone. 
     
     
         15 . The process of  claim 5 , wherein the nitrile is a C 2-4  nitrile. 
     
     
         16 . The process of  claim 15 , wherein the C 2-4  nitrile is acetonitrile. 
     
     
         17 . The process of  claim 1 , wherein the C 6-9  aromatic hydrocarbon is toluene or xylene. 
     
     
         18 . The process of  claim 17 , wherein the C 6-9  aromatic hydrocarbon is toluene. 
     
     
         19 . The process of  claim 5 , wherein the solvent is a mixture of toluene and water or of dichloromethane and water. 
     
     
         20 . The process of  claim 1 , wherein the solvent is water. 
     
     
         21 . The process of  claim 1 , wherein the base is an organic base. 
     
     
         22 . The process of  claim 21 , wherein the organic base is selected from the group consisting of aliphatic and aromatic amines. 
     
     
         23 . The process of  claim 22 , wherein the aliphatic amine is triethylamine, tributylamine, methylmorpholine, or N,N-diisopropylethyl amine. 
     
     
         24 . The process of  claim 22 , wherein the aromatic amine is pyridine. 
     
     
         25 . The process of  claim 1 , wherein the base is an inorganic base. 
     
     
         26 . The process of  claim 25 , wherein the inorganic base is either alkali carbonate or alkali bicarbonate. 
     
     
         27 . The process of  claim 26 , wherein the alkali carbonate is sodium carbonate or potassium carbonate. 
     
     
         28 . The process of  claim 26 , wherein the alkali bicarbonate is either sodium bicarbonate or potassium bicarbonate. 
     
     
         29 . The process of  claim 1 , wherein the base is potassium carbonate. 
     
     
         30 . The process of  claim 1 , wherein the mixture is heated to a temperature of about 50° C. to about reflux, prior to admixing with HBr. 
     
     
         31 . The process of  claim 1 , wherein the mixture is cooled to a temperature of about 35° C. to about 15° C. 
     
     
         32 . The process of  claim 31 , wherein after cooling, an organic solvent selected from the group consisting of dichloromethane, ethyl acetate, and butyl acetate is added to the mixture, to give a mixture having an aqueous phase and an organic phase. 
     
     
         33 . The process of  claim 32 , wherein the phases are then separated, and HBr is admixed with the organic phase. 
     
     
         34 . The process of  claim 33 , wherein an anhydride is added to the organic phase, after separating the phases. 
     
     
         35 . The process of  claim 34 , wherein the organic solvent is removed, and a C 2-5  alcohol and hydrobromic acid are added. 
     
     
         36 . The process of  claim 35 , wherein the C 2-5  alcohol is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, or isopropanol. 
     
     
         37 . The process of  claim 1 , further comprising recovering the darifenacin hydrobromide.