Process for the Preparation of O-Desmethyl Venlafaxine and Intermediate for Use Therein

Abstract

The present invention relates to a compound of formula A, wherein R is alkyl. Compound A may be used as an intermediate in the preparation of O-desmethyl venlafaxine or a salt thereof, and the present invention provides such a preparation, as well as a process for preparing the compound of formula A.

What is claimed is: 
     
         1 . A process for preparing a compound of formula A, 
       
         
           
           
               
               
           
         
       
       wherein R is an alkyl group, the process comprising:
 a) esterifying (4-benzyloxy-phenyl)-acetic acid of formula I 
 
       
         
           
           
               
               
           
         
       
       to form a (4-benzyloxy-phenyl)-acetic acid alkyl ester of formula II; 
       
         
           
           
               
               
           
         
         b) reacting the (4-benzyloxy-phenyl)-acetic acid alkyl ester of formula II with paraformaldehyde in the presence of an inorganic base and a phase transfer catalyst to form a 2-(4-benzyloxy-phenyl)-acrylic acid alkyl ester of formula III; and 
       
       
         
           
           
               
               
           
         
         c) reacting the 2-(4-benzyloxy-phenyl)-acrylic acid alkyl ester of formula III with dimethylamine in the presence of a Lewis acid catalyst to form the compound of formula A. 
       
     
     
         2 . The process according to  claim 1 , wherein R is a C1-10 alkyl group. 
     
     
         3 . The process according to  claim 1 , wherein R is methyl or ethyl. 
     
     
         4 . The process according to  claim 1 , wherein esterification comprises reacting the acid of formula I with an alcoholic acid solution. 
     
     
         5 . The process according to  claim 1 , wherein esterification comprises reacting (4-benzyloxy-phenyl)-acetic acid with a mixture of an alcohol and thionyl chloride or potassium carbonate and dimethyl sulfate. 
     
     
         6 . The process according to  claim 4 , wherein the alcohol is methanol. 
     
     
         7 . The process according to  claim 1 , wherein the inorganic base used in step b) is selected from: an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide; and an alkali metal carbonate, preferably potassium carbonate, sodium carbonate or cesium carbonate. 
     
     
         8 . The process according to  claim 7 , wherein the inorganic base is an alkali metal carbonate, preferably potassium carbonate. 
     
     
         9 . The process according to  claim 1 , wherein the phase transfer catalyst in step b) is selected from: tetrabutyl ammonium hydrogen sulfate; an ammonium halide, preferably triethyl benzyl ammonium chloride; an alkyl ammonium halide, preferably tetrabutyl ammonium bromide or tetrabutyl ammonium iodide, most preferably tetrabutyl ammonium iodide. 
     
     
         10 . The process according to  claim 1 , wherein step b) is carried out in the presence of an organic solvent selected from toluene, chlorobenzene and o-xylene; preferably toluene. 
     
     
         11 . The process according to  claim 1 , wherein the source of dimethyl amine in step c) is dimethyl amine gas or an alcoholic solution of dimethyl amine. 
     
     
         12 . The process according to  claim 11 , wherein the alcohol is methanol. 
     
     
         13 . The process according to  claim 1 , wherein the Lewis acid catalyst used in step c) is selected from zinc chloride, ferric chloride, aluminium chloride, lithium perchlorate and stannic chloride; preferably from ferric chloride and lithium perchlorate. 
     
     
         14 . The process according to  claim 1 , wherein steps b) and c) are carried out without isolation of the 2-(4-benzyloxy-phenyl)-acrylic acid alkyl ester of formula III 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of formula A 
       
         
           
           
               
               
           
         
       
       wherein R is an alkyl group. 
     
     
         16 . The compound according to  claim 15 , wherein R is a C1-10 alkyl group. 
     
     
         17 . The compound according to  claim 15 , wherein R is methyl or ethyl. 
     
     
         18 . O-desmethyl venlafaxine (ODV) of formula V 
       
         
           
           
               
               
           
         
       
       prepared by a process comprising converting a compound of formula A 
       
         
           
           
               
               
           
         
       
       to ODV, wherein R is an alkyl group, wherein converting the compound of formula A to ODV comprises:
 d) reacting compound A with a Grignard reagent in the presence of a cyclic or acyclic ether as a solvent to form 1-[1-(4-benzyloxy-phenyl)-2-dimethylamino-ethyl]-cyclohexanol of formula IV; 
 
       
         
           
           
               
               
           
         
       
       and
 e) deprotecting 1-[1-(4-benzyloxy-phenyl)-2-dimethylamino-ethyl]-cyclohexanol to form ODV. 
 
     
     
         19 . A pharmaceutical composition comprising ODV according to  claim 18 , together with one or more pharmaceutically acceptable excipients. 
     
     
         20 . The method of treating depression comprising administering to a patient in need thereof ODV or a salt thereof according to  claim 18 .