Method for preparing silodosin

Abstract

The present invention relates to a process for preparing silodosin with high optical purity up to 99.9% enantiomeric excess (e.e.) or above. The process makes use of a method step, in which the enantiomers contained in a racemic mixture of a compound represented by the general formula V: wherein * denotes the asymmetric center, R 1 is a protecting group, and R 2 is cyano or carbamoyl, are separated.

1 . A process for preparing silodosin of formula XXV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, which process comprises the method steps of:
 a) separating the enantiomers contained in a racemic mixture of a compound represented by the general formula V: 
 
       
         
           
           
               
               
           
         
         wherein * denotes the asymmetric center, 
         R 1  is a protecting group, and 
         R 2  is cyano or carbamoyl; 
         b) reacting the R-enantiomer of the compound of formula V (R-V) with a compound represented by formula XXII under reductive animation conditions, or with a compound represented by formula XXIII: 
       
       
         
           
           
               
               
           
         
       
       wherein X represents a leaving group, to obtain a compound represented by the general formula XXIV: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  have the same meaning as defined above; 
         c) deprotecting the compound of formula XXIV and, if R 2  is conducting a hydrolysis reaction to afford silodosin; and 
         d) optionally purifying the silodosin obtained in step (c) by crystallization from a solvent. 
       
     
     
         2 . The process according to  claim 1 , wherein the solvent in method step (d) contains a carboxylic acid ester. 
     
     
         3 . The process according to  claim 2 , wherein the carboxylic acid ester is a C 1-6 -alkyl acetate, preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixtures thereof. 
     
     
         4 . The process according to  claim 1 , wherein the separation of the compound of formula R-V in step (a) is conducted by
 i) dissolving the compound of formula V and an optically active acid in a solvent to obtain a solution of a diastereomeric mixture containing a compound represented by the general formula XXI:   
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  have the same meaning as defined in  claim 1 ,
 ii) separating the compound of formula XXI from the solution of the diasteriomeric mixture obtained in step (i) by crystallization, 
 iii) dissolving the compound of formula XXI and a base in water, and 
 iv) extracting the compound of formula R-V from the aqueous solution obtained in step (iii) using a water-immiscible solvent. 
 
     
     
         5 . The process according to  claim 4 , wherein the optically active acid is L-tartaric acid. 
     
     
         6 . The process according to  claim 4 , wherein the water-immiscible solvent contains a carboxylic acid ester. 
     
     
         7 . The process according to  claim 6 , wherein the carboxylic acid ester is a C 1-6 -alkyl acetate, preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixtures thereof. 
     
     
         8 . The process according to  claim 1 , wherein the compound represented by the general formula V: 
       
         
           
           
               
               
           
         
       
       is prepared by reducing a compound represented by the general formula XX: 
       
         
           
           
               
               
           
         
       
       wherein R 1  has the same meaning as defined in  claim 1 . 
     
     
         9 . The process according to  claim 8 , wherein the compound XX is subjected to catalytic hydrogenation using platinum on charcoal (e.g. 5% Pt/C) or platinum(IV) oxide as a catalyst. 
     
     
         10 . Use of a racemic mixture of a compound of formula V, 
       
         
           
           
               
               
           
         
         wherein * denotes the asymmetric center, 
         R 1  is a protecting group, and 
         R is cyano or carbamoyl, 
         for the preparation of silodosin or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The use of  claim 10 , wherein the racemic mixture is subjected to enantiomeric resolution procedure to obtain a compound of formula R-V: 
       
         
           
           
               
               
           
         
       
       with an optical purity of at least 85% enantiomeric excess 
     
     
         12 . The use of  claim 11 , wherein the silodosin or a pharmaceutically acceptable salt thereof having an optical purity of at least 85% e.e. is purified by crystallization from a solvent to obtain a silodosin or a pharmaceutically acceptable salt thereof with an optical purity of at least 95% e.e., preferably at least 98% e.e., more preferred at least 99% e.e., most preferred at least 99.9% e.e. 
     
     
         13 . The process according to  claim 12 , wherein the solvent contains a carboxylic acid ester. 
     
     
         14 . The process according to  claim 13 , wherein the carboxylic acid ester is a C 1-6 -alkyl acetate, preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixtures thereof.