Processes for preparing darifenacin hydrobromide

Abstract

The invention encompasses processes for the preparation of darifenacin hydrobromide.

1 . A process for preparing darifenacin hydrobromide, comprising converting N-protected-3-(S)-pyrrolidinol of the formula 
     
       
         
         
             
             
         
       
     
     into darifenacin hydrobromide, wherein X is S, SO 2 , Si, or CO, and R is phenyl, tolyl, ortho, meta, or para-xylyl, linear or branched C 1-10  alkyl, H, or CF 3 . 
   
   
       2 . The process according to  claim 1 , wherein the conversion comprises preparing 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I 
     
       
         
         
             
             
         
       
     
     in a process comprising combining 3-(S)-(+)-hydroxypyrrolidine, a sulfonyl halide, a base, and a solvent selected from the group consisting of a C 6-9  aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, wherein X is either C 1-10  alkyl or C 6-9  aryl. 
   
   
       3 . The process of  claim 2 , wherein X is tolyl. 
   
   
       4 . The process of  claim 2 , wherein the solvent is selected from a group consisting of C 6-9  aromatic hydrocarbon, C 1-10  halogenated aliphatic hydrocarbon, amide, sulfoxide, and mixtures thereof. 
   
   
       5 . The process of  claim 4 , wherein the solvent is selected from a group consisting of toluene, o-xylene, m-xylene, p-xylene, dichloromethane, 1,2-dichloroethane, dichloropentane, dimethylformamidem Dimethylacetamide, dimethylsulfoxide, and mixtures thereof. 
   
   
       6 . The process of  claim 2 , wherein the process, further comprises a phase transfer catalyst. 
   
   
       7 . The process of  claim 6 , wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tributylmethylammonium chloride, tetrabutylammonium sulfate, and dimethylsulfoxide. 
   
   
       8 . The process of  claim 2 , wherein the halide moiety of the sulfonyl halide is selected from chloride, bromide, and iodide. 
   
   
       9 . The process of  claim 8 , wherein the sulfonyl halide is tosylchloride, mesylchloride, or brosylchloride. 
   
   
       10 . The process of  claim 2 , wherein the base is an organic base. 
   
   
       11 . The process of  claim 10 , wherein the organic base is selected from the group consisting of aliphatic and aromatic amines. 
   
   
       12 . The process of  claim 11 , wherein the organic base is selected from a group consisting of triethylamine, methylmorpholine, N,N-diisopropylethyl amine, pyridine and mixtures thereof. 
   
   
       13 . The process of  claim 2 , wherein the base is an inorganic base. 
   
   
       14 . The process of  claim 13 , wherein the inorganic base is an alkali base. 
   
   
       15 . The process of  claim 14 , wherein the alkali base is sodium hydroxide or potassium hydroxide. 
   
   
       16 . The process of  claim 2 , further comprising recovering the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine. 
   
   
       17 . The process according to  claim 1 , wherein the conversion comprises preparing (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile of formula II 
     
       
         
         
             
             
         
       
     
     in a process comprising combining 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, and an inorganic base to obtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile, wherein X is either C 1-10  alkyl or C 6-9  aryl. 
   
   
       18 . The process of  claim 17 , wherein X is tolyl. 
   
   
       19 . The process of  claim 17 , wherein the solvent is selected from a group consisting of C 6-9  aromatic hydrocarbon, amide, and sulfoxide. 
   
   
       20 . The process of  claim 19 , wherein the solvent is selected from a group consisting of C 1-2  amide, dimethylformamide, dimethylacetamide, C 1-4  sulfoxide, dimethylsulfoxide and mixtures thereof. 
   
   
       21 . The process of  claim 17 , wherein the inorganic base is a metal alkoxide or an alkali hydroxide. 
   
   
       22 . The process of  claim 21 , wherein the inorganic base is selected from a group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide. 
   
   
       23 . The process of  claim 17 , further comprising recovering the (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile. 
   
   
       24 . The process according to  claim 1 , wherein the conversion comprises preparing 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI 
     
       
         
         
             
             
         
       
     
     in a process comprising:
 a. combining (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III, 
 
     
       
         
         
             
             
         
       
     
     a solvent selected from the group consisting of a water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof, and an inorganic base to form a mixture;
 b. acidifying the mixture; 
 c. heating the mixture; 
 d. basifying the mixture; and 
 e. combining the mixture with a C 1-4  alcohol and L-tartaric acid to obtain 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate, 
 wherein Z1 is an acid. 
 
   
   
       25 . The process of  claim 24 , wherein Z 1  is HBr or HCl. 
   
   
       26 . The process of  claim 24 , wherein the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III is converted into the free base of formula XI 
     
       
         
         
             
             
         
       
     
     prior to step b). 
   
   
       27 . The process of  claim 26 , wherein the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III is converted into the free base of formula XI by combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III a solvent selected from the group consisting of water immiscible organic solvents, a polar aprotic organic solvent, water, and mixtures thereof, and an inorganic base. 
   
   
       28 . The process of  claim 24 , wherein the solvent is selected from a group consisting of C 6-9  aromatic hydrocarbon, water, C 1-10  halogenated aliphatic hydrocarbon, ester, and mixtures thereof. 
   
   
       29 . The process of  claim 28 , wherein the solvent is selected from a group consisting of toluene, xylenes, isopropylbenzene, styrene, water, dichloromethane, 2-dichloroethane, 1,1,-dichloroethane, 1,5-dichloropentane, ethyl acetate and mixtures thereof. 
   
   
       30 . The process of  claim 28 , wherein the solvent is a mixture of a C 1-10  halogenated aliphatic hydrocarbon and water. 
   
   
       31 . The process of  claim 30 , wherein the C 1-10  halogenated aliphatic hydrocarbon is dichloromethane. 
   
   
       32 . The process of  claim 24 , wherein the acidifying comprises adding an acid to the mixture and heating the mixture. 
   
   
       33 . The process of  claim 32 , wherein the strong mineral acid is sulphuric acid or phosphoric acid. 
   
   
       34 . The process of  claim 32 , wherein the mixture is heated to a temperature of about 80° C. to about 110° C. 
   
   
       35 . The process of  claim 24 , wherein the mixture is basified to a pH of about 10 to about 13. 
   
   
       36 . The process of  claim 24 , wherein the mixture is basified by adding an inorganic base. 
   
   
       37 . The process of  claim 36 , wherein the inorganic base is an aqueous solution of an alkali base. 
   
   
       38 . The process of  claim 37 , wherein the alkali base is selected from a group consisting of sodium hydroxide, potassium hydroxide sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof. 
   
   
       39 . The process of  claim 24 , wherein the C 1-4  alcohol is methanol, ethanol, isopropanol, or n-butanol. 
   
   
       40 . The process of  claim 24 , further comprising recovering the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI. 
   
   
       41 . 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 with 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 with 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 and an inorganic base with a solvent selected from the group consisting of water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof to form a mixture; 
 e) acidifying the mixture; 
 f) heating the mixture 
 g) basifying the mixture; 
 h) combining the mixture with a C 1-4  alcohol and L-tartaric acid to obtain 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI; 
 
     
       
         
         
             
             
         
       
       i) converting 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI to Darifenacin hydrobromide.