Substantially pure O-desmethylvenlafaxine and processes for preparing it

Abstract

Methods for preparing substantially pure O-desmethylvenlafaxine are described.

1 - 7 . (canceled) 
   
   
       8 . A process for preparing a substantially pure O-desmethylvenlafaxine comprising:
 a) combining venlafaxine, an organic solvent and a reagent selected from the group consisting of thiophenol and a C 1 -C 8  alkyl thiolate, to form a mixture;   b) heating the mixture; and   c) recovering substantially pure O-desmethylvenlafaxine.   
   
   
       9 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 8 , wherein the organic solvent is selected from the group consisting of a C 3 -C 7  ketone, a C 3 -C 7  ester, a C 5 -C 8  aliphatic hydrocarbon, a C 6 -C 12  aromatic hydrocarbon, a high boiling point solvent, a C 2 -C 8  ether, a chlorinated hydrocarbon and a C 2 -C 8  alcohol. 
   
   
       10 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 9 , wherein the high boiling point solvent is selected from the group consisting of toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl-2-pyridone, N-methyl-2-pyrrolidone, 1-methyl-2-pyrolidinone (NMP) and dimethylacetamide (DMA). 
   
   
       11 . (canceled) 
   
   
       12 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 9 , wherein the organic solvent is selected from the group consisting of acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol. 
   
   
       13 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 12 , wherein NMP is the organic solvent and venlafaxine and NMP in the mixture are in a ratio of venlafaxine:NMP from 1:1 to 1:20 by volume. 
   
   
       14 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 12 , wherein the organic solvent is DMF or DMA and venlafaxine and the organic solvent are in a ratio of venlafaxine:organic solvent from 1:1 to 1:10 by volume. 
   
   
       15 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 8 , wherein when the reagent is thiophenol a catalyst is added to the mixture of step (a). 
   
   
       16 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 15 , wherein the catalyst is a base. 
   
   
       17 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 16 , wherein the base is an alkalimetal carbonate. 
   
   
       18 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 17 , wherein the alkalimetal carbonate is potassium carbonate. 
   
   
       19 . The process for preparing a substantially pure O-desmethylvenlafaxine according  claim 8 , wherein the mixture is heated in step (b) to a temperature of about 100° C. to about 210° C. for a period of about 1 to about 12 hours. 
   
   
       20 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 19 , wherein the mixture is heated to a temperature of about 110° C. to about 190° C. 
   
   
       21 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 19 , wherein the period is about 3 hours to about 10 hours. 
   
   
       22 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 8 , wherein venlafaxine, the organic solvent and the reagent are combined under reduced pressure, and the mixture is heated in step (b) at a temperature of about 30° C. to about 220° C. 
   
   
       23 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 22 , wherein the pressure is less than 1 atmosphere. 
   
   
       24 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 8 , wherein the recovering of O-desmethylvenlafaxine comprises crystallization. 
   
   
       25 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 24 , wherein the obtained crystalline O-desmethylvenlafaxine is characterized by a powder X-ray diffraction pattern having peak reflections at about 12.1, 13.2, 15.9, and 20.4 degrees two theta±0.2 degrees two theta. 
   
   
       26 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 8 , further comprising, before recovering the substantially pure O-desmethylvenlafaxine, slurrying the mixture in a solvent selected from the group consisting of water, a water/alcohol mixture and a water/acetonitrile mixture. 
   
   
       27 . The process of preparing a substantially pure O-desmethylvenlafaxine according to  claim 26 , wherein the water/IPA mixture is in a ratio of 15:25 to 80:20 (by volume). 
   
   
       28 . The process of preparing a substantially pure O-desmethylvenlafaxine according to  claim 27 , wherein the water/IPA mixture has a 80:20 ratio (by volume). 
   
   
       29 . The process of preparing a substantially pure O-desmethylvenlafaxine according to  claim 26 , wherein the slurrying is conducted at a temperature of about 20° C. to about 70° C. for a period of about 5 minutes to about 5 hours. 
   
   
       30 . The process of preparing a substantially pure O-desmethylvenlafaxine according to  claim 28 , wherein slurrying is conducted at about room temperature for a period of about 2 hours. 
   
   
       31 - 39 . (canceled) 
   
   
       40 . A process for preparing a substantially pure O-desmethylvenlafaxine, comprising:
 a) combining venlafaxine and thiophenol to form a mixture;   b) heating the mixture to a temperature of about 100° C. to about 210° C.; and   c) recovering substantially pure O-desmethylvenlafaxine.   
   
   
       41 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 40 , wherein a catalyst is added to the mixture of step (a). 
   
   
       42 . The process for preparing a substantially pure O-desmethylvenlafaxine according to  claim 41 , wherein the catalyst is a base. 
   
   
       43 .- 74 . (canceled)