Processes for preparing darifenacin hydrobromide

Abstract

The invention encompasses processes for the preparation of darifenacin hydrobromide.

1 . A process for preparing a compound of formula V, 
       
         
           
           
               
               
           
         
       
       comprising:
 a) combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid, a C 1-4  alcohol, and a catalyst to obtain 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester; 
 b) combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a reducing agent and a C 4-6  alcohol to obtain 2(2,3-dihydrobenzofura-5-yl)-ethanol; and 
 c) combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from the group consisting of a C 1-2  halogenated hydrocarbon, C 3-6  ester, and C 6-9  aromatic hydrocarbon, and a substance containing a leaving group Y, wherein Y is selected from the group consisting of Cl, Br, mesyl, brosyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl, to obtain the compound of formula V. 
 
     
     
         2 . The process of  claim 1 , wherein Y is Cl. 
     
     
         3 . The process of  claim 1 , wherein the C 1-4  alcohol is selected from the group consisting of methanol, ethanol, propanol, and butanol. 
     
     
         4 . The process of  claim 1 , wherein the C 1-4  alcohol is methanol. 
     
     
         5 . The process of  claim 1 , wherein the C 1-4  alcohol is admixed with toluene. 
     
     
         6 . The process of  claim 1 , wherein the catalyst is an acid. 
     
     
         7 . The process of  claim 6 , wherein the acid is an organic acid. 
     
     
         8 . The process of  claim 7 , wherein the organic acid is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid. 
     
     
         9 . The process of  claim 6 , wherein the acid is an inorganic acid. 
     
     
         10 . The process of  claim 9 , wherein the inorganic acid is selected from a group consisting of: HCl, HClO 4 , and H 3 PO 4 . 
     
     
         11 . The process of  claim 6 , wherein the acid is sulphuric acid. 
     
     
         12 . The process of  claim 1 , wherein step a) further comprises heating. 
     
     
         13 . The process of  claim 12 , wherein the heating is to a temperature of about 60° C. to about 70° C. 
     
     
         14 . The process of  claim 12 , wherein the heating is to a temperature of about 65° C. to about 70° C. 
     
     
         15 . The process of  claim 1 , wherein the C 4-6  alcohol is t-butanol. 
     
     
         16 . The process of  claim 1 , wherein the C 4-6  alcohol is admixed with a C 1-4  alcohol. 
     
     
         17 . The process of  claim 16 , wherein the C 4-6  alcohol is t-butanol and the C 1-4  alcohol is methanol. 
     
     
         18 . The process of  claim 1 , wherein the reducing agent is a metal hydride. 
     
     
         19 . The process of  claim 1 , wherein the reducing agent is selected from the group consisting of NaBH 4 , LiAlH 4 , and sodium dihydro-bis-(2-methoxyethoxy) aluminate. 
     
     
         20 . The process of  claim 1 , wherein the reducing agent is NaBH 4 . 
     
     
         21 . The process of  claim 1 , wherein step b) further comprises heating. 
     
     
         22 . The process of  claim 21 , wherein the heating is to a temperature of about 65° C. to about 75° C. 
     
     
         23 . The process of  claim 1 , wherein the heating is to a temperature of about 70° C. to 75° C. 
     
     
         24 . The process of  claim 1 , wherein the C 1-2  halogenated hydrocarbon is dichloromethane. 
     
     
         25 . The process of  claim 1 , wherein the C 3-6  ester is ethyl acetate, isopropyl acetate, butyl acetate, or isobutylacetate. 
     
     
         26 . The process of  claim 1 , wherein the C 3-6  ester is ethyl acetate. 
     
     
         27 . The process of  claim 1 , wherein the C 6-9  aromatic hydrocarbon is toluene, xylenes, isopropylbenzene, or styrene. 
     
     
         28 . The process of  claim 1 , wherein the solvent is toluene. 
     
     
         29 . The process of  claim 1 , wherein the substance containing a leaving group is selected from the group consisting of SOCl 2 , PCl 3 , PCl 5 , POCl 3 , tosylchloride, mesylchloride, brosylchloride, trifluoroacetyl chloride, and trifluoromethansulfonyl chloride. 
     
     
         30 . The process of  claim 1 , wherein the substance containing a leaving group is selected from the group consisting of SOCl 2 , PCl 3 , PCl 5 , and POCl 3    
     
     
         31 . The process of  claim 1 , wherein the substance containing a leaving group is SOCl 2 . 
     
     
         32 . The process of  claim 1 , wherein the substance containing a leaving group is selected from the group consisting of tosylchloride, mesylchloride, brosylchloride, trifluoroacetyl chloride, and trifluoromethansulfonyl chloride. 
     
     
         33 . The process of  claim 32 , wherein the process further comprises adding a base. 
     
     
         34 . The process of  claim 33 , wherein the base is an organic base. 
     
     
         35 . The process of  claim 34 , wherein the organic base is an aliphatic or aromatic amine. 
     
     
         36 . The process of  claim 35 , wherein the aliphatic amine is triethylamine, ethyldiisopropylamine, or N-methylmorpholine. 
     
     
         37 . The process of  claim 35 , wherein the aromatic amine is pyridine. 
     
     
         38 . The process of  claim 33 , wherein the base is an inorganic base. 
     
     
         39 . The process of  claim 38 , wherein the inorganic base is an alkali metal hydroxide or an alkali metal carbonate. 
     
     
         40 . The process of  claim 39 , wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or cesium hydroxide. 
     
     
         41 . The process of  claim 39 , wherein the alkali carbonate is sodium carbonate, potassium carbonate, or cesium carbonate. 
     
     
         42 . The process of  claim 33 , wherein the base is triethylamine. 
     
     
         43 . The process of  claim 1 , wherein step c) further comprises heating. 
     
     
         44 . The process of  claim 43 , wherein the heating is to a temperature of about 60° C. to about 80° C. 
     
     
         45 . The process of  claim 43 , wherein the heating is to a temperature of about 60° C. to about 70° C. 
     
     
         46 . The process of  claim 1 , further comprising recovering the compound of formula V. 
     
     
         47 . A process for preparing darifenacin hydrobromide comprising: a) preparing a compound of the following formula V, 
       
         
           
           
               
               
           
         
       
       by the process of  claim 1 ; and b) converting the compound of formula V into darifenacin hydrobromide, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyl, Br, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl.