Methods for Preparing O-Desmethylvenlafaxine

Abstract

The present invention provides an efficient method of making O-desmethyl-venlafaxine.

1 . A method of preparing O-desmethylvenlafaxine which comprises reacting venlafaxine with a high molecular weight alkane or arene thiolate anion in an alcohol, ethylene glycol, ether of ethylene glycol, or mixture thereof, to provide O-desmethylvenlafaxine. 
     
     
         2 . The method of  claim 1  wherein the reaction is performed at about 150° C. to about 220° C. 
     
     
         3 . The method of  claim 1  wherein the reaction is carried out for about 2 to about 5 hours. 
     
     
         4 . The method of  claim 1  wherein the thiolate anion is a straight or branched chain alkane thiolate anion having 8 to 20 carbon atoms. 
     
     
         5 . The method of  claim 1  wherein the thiol is an arene thiolate anion having from 6 to 10 carbon atoms. 
     
     
         6 . The method of  claim 4  wherein the alkane thiolate anion is dodecanethiolate. 
     
     
         7 . The method of  claim 5  wherein the arene thiolate anion is benzenethiolate. 
     
     
         8 . The method of  claim 1  wherein the thiolate anion is generated in the presence of an alkoxide. 
     
     
         9 . The method of  claim 8  wherein the alkoxide is methoxide. 
     
     
         10 . The method of  claim 2  wherein the reaction is performed at from about 170° C. to about 220° C. 
     
     
         11 . The method of  claim 2  wherein the reaction is performed at from about 180° C. to about 200° C. 
     
     
         12 . The method of  claim 1  further comprising neutralizing the product to the isoelectric point in the presence of an alcohol comprising a straight or branched chain alkyl group of from 1 to 6 carbon atoms. 
     
     
         13 . The method of  claim 12  wherein the alcohol is isopropanol. 
     
     
         14 . The method of  claim 12  wherein the isoelectric point is about pH9.5 to about pH10. 
     
     
         15 . A method of preparing O-desmethylvenlafaxine which comprises the steps of demethylating venlafaxine with dodecyl thiolate and polyethylene glycol 400 in the presence of sodium methylate in methanol at about 180° C. to about 200° C. for about 2 to about 5 hours; and neutralizing the product to about pH 9.5 in the presence of isopropanol.