Substantially pure o-desmethylvenlafaxine and processes for preparing it

A kind of methyl text, methyl technology, applied in the field of O-desmethyl venlafaxine, can solve problems such as unreachable

Inactive Publication Date: 2009-04-29
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

API does not need to be absolutely pure, because absolute purity is an ideal state in theory, but it cannot be achieved in practice

Method used

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  • Substantially pure o-desmethylvenlafaxine and processes for preparing it
  • Substantially pure o-desmethylvenlafaxine and processes for preparing it
  • Substantially pure o-desmethylvenlafaxine and processes for preparing it

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1: Preparation of O-desmethylvenlafaxine in NMP

[0131] Add venlafaxine (50 g, 180 mmol), thiophenol (20 ml, 195 mmol), K 2 CO 3 (1 g, 6 mmol) and NMP (90 ml). The mixture was heated to 190°C. After 5 hours at 190°C the heat bath was removed. (less than 1.5% VNL). IPA (300 mL) was added at 80°C. The solution was cooled to 0-5°C overnight. The solid was filtered under reduced pressure and washed with IPA and water. The solid was then vacuum dried overnight at 50°C to yield pure ODV base. The purity of the obtained ODV was 97%, and the assayed purity was 93.5%.

Embodiment 2

[0132] Example 2: Preparation of O-desmethylvenlafaxine in NMP

[0133] To a single-necked flask equipped with a magnetic stirrer, a Dean Stark apparatus, a condenser, and a thermometer, was added VNL (5 g, 18.2 mmol), hydrated Na 2 S (1.58 g, 12 mmol, assay purity >60%) and NMP (12 mL). The reaction mixture was heated to 150°C over 1 hour and maintained at this temperature for 7.5 hours. The reaction mixture was then cooled to room temperature where it was stirred overnight. Then add hydrated Na 2 S (0.71 g, 5.4 mmol, assay >60%). The mixture was heated to 165°C over 1 hour and maintained at this temperature for 5 hours. Thereafter, the reaction solution was cooled to 40° C., and IPA (30 mL) and 10% aqueous citric acid (20 mL) were slowly added through the dropping funnel until slight precipitation (pH 10) was observed. The suspension was stirred at room temperature over weekend and the solid was filtered under reduced pressure, washing with IPA (20 mL). The solid was d...

Embodiment 3

[0134] 5 g of VNL (0.0182 mol), 3.81 g of sodium ethanethiolate (0.0458 mol, 2.5 eq) and NMP (10 mL) were added to a 250 mL autoclave. The reaction mixture was stirred for 4 hours at 30°C to 220°C and a pressure of 1 to 20 bar. The mixture was then cooled to room temperature. IPA (10 mL) and water (10 mL) were added at ambient temperature. To this mixture was added 10% aqueous citric acid to bring the pH to about 12. A solid started to precipitate out and was stirred at room temperature for 2.5 hours. The solid was then filtered under reduced pressure and washed with solvent. The wet cake was dried in a vacuum oven at 50°C to obtain pure ODV.

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Abstract

Methods for preparing crystalline forms of O-desmethylvenlafaxine a described.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the following U.S. provisional patent applications: 60 / 792,801, filed April 17, 2006; 60 / 796,739, filed May 1, 2006; 60 / 899,166, filed February 1, 2007; 60 / 902,418, filed February 20, 2007; 60 / 872,955, filed December 4, 2006; 60 / 903,988, filed February 27, 2007. The contents of these applications are incorporated herein by reference. field of invention [0003] The present invention relates to substantially pure O-desmethylvenlafaxine. Background of the invention [0004] Venlafaxine, or (±)-1-[2-(dimethylamino)-1-(4-ethoxyphenyl)ethyl]cyclohexanol, is the first in a class of antidepressants kind. The role of venlafaxine is to inhibit the reuptake of norepinephrine and serotonin, which can replace tricyclic antidepressants and selective reuptake inhibitors. Venlafaxine has the chemical formula shown in the following formula I: [0005] [0006] Formula I [0007] O-desmet...

Claims

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Application Information

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IPC IPC(8): C07C215/64C07C217/74
Inventor V·尼达姆－希尔德谢姆
Owner TEVA PHARMA IND LTD
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