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Process for the synthesis of O-desmethylvenlafaxine

a technology of odesmethylvenlafaxine and synthesis process, which is applied in the field of synthesis of odesmethylvenlafaxine, can solve the problems of long operation time, complex operation, and inability to meet industrial scale manufacturing requirements

Inactive Publication Date: 2008-07-31
TEVA PHARM USA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a process for preparing hydroxyphenyl dimethylamide (OBA) and its protected derivatives, as well as a process for converting OBA to ODV. These processes involve combining specific starting materials with a catalyst and an acid activating agent to obtain activated acid, which is then combined with a dimethylamine to obtain OBA. The OBA can be further converted to ODV using various methods known in the art. The invention also provides a process for preparing ODV from COBA. These processes provide efficient and reliable methods for producing hydroxyphenyl dimethylamide and its derivatives."

Problems solved by technology

Hence, the process isn't suitable for industrial scale manufacture.
This operation is very complicated because the mixture containing the salt is highly viscous, hence the operation necessitate long time even under high vacuum.
When the reaction is performed in-situ via removal of methanol in situ, this operation is still tedious and only partially successful, since it is difficult to reach the high temperature that the reaction necessitate to advance.

Method used

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  • Process for the synthesis of O-desmethylvenlafaxine
  • Process for the synthesis of O-desmethylvenlafaxine
  • Process for the synthesis of O-desmethylvenlafaxine

Examples

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Effect test

example 1

[0081]A 500 ml three-neck flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBcarboxy (10 g, 65.72 mmol), DMF (1 ml) and CH2Cl2 (50 ml). The reaction mixture was stirred at 0° C. and SOCl2 was added dropwise.

[0082]The reaction was stirred at ambient temperature for 2 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (50 ml) and dimethylamine-HCl (100 g, 1.22 mol) was added. Then diisopropylethylamine (150 ml, 0.882 mol) was added dropwise. The mixture was stirred at ambient temperature overnight and then washed with a saturated solution of NaHCO3; a precipitate appeared. The precipitate was filtered under reduced pressure and washed with methylene chloride. The solid so-obtained was dried in a vacuum oven at room temperature to get 5.55 g of OBA (purity 99.45%).

[0083]The organic layer was washed with brine and evaporated to dryness yielding crystals 5.84 g OBA (purity 96.57%). Total yield=97.85...

example 2

[0084]A 100 ml three-neck flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBA (2.4 g, 13.39 mmol) TBDMS-Cl (4.5 g, 29.9 mmol), imidazole (5.5 g, 80.78 mmol) and CH2Cl2 (20 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was quenched with brine and a 10% aqueous solution of citric acid The organic phase was then washed with brine and dried over Na2SO4. After filtration the solvent was evaporated under reduced pressure to get 3.82 g OBA-P (purity: 99.34%, yield: 97.45%).

example 3

[0085]In a 50 ml flask equipped with a mechanical stirrer, OBA (1.45 g, 8.09 mmol) was dissolved at room temperature in DHP (8 ml) under nitrogen. Pyridinium p-toluene sulfonate (PPTS, catalytic amount) was added and the reaction mixture was heated to 55° C. for 5 hours. The reaction was monitored by HPLC. EtOAc was added and the organic layer was washed with brine, dried over MgSO4 and filtered under reduced pressure to get OBA-DHP.

Preparation of Protected COBA (PCOBA)

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Abstract

Provided are processes and intermediates for the synthesis of O-desmethylvenlafaxine.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit of the following U.S. Provisional Patent Application Nos. 60 / 833,616, filed Jul. 26, 2006; 60 / 837,879, filed Aug. 14, 2006; 60 / 849,216, filed Oct. 3, 2006; 60 / 843,998, filed Sep. 11, 2006; 60 / 849,255, filed Oct. 3, 2006; 60 / 906,639, filed Mar. 12, 2007; and 60 / 906,879, filed Mar. 13, 2007. The contents of these applications are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention encompasses a process for the synthesis of O-desmethylvenlafaxine.BACKGROUND OF THE INVENTION[0003]Venlafaxine, (±)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol, of the following formula,is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors.[0004]O-desmethylvenlafaxine, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, of th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C211/27C07C215/46
CPCC07C2101/14C07C235/34C07C2601/14A61P25/24C07C233/29C07C231/00
Inventor NIDDAM-HILDESHEIM, VALERIENIDAM, TAMAR
Owner TEVA PHARM USA INC
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