Process for total synthesis of venlafaxine

Patent metadata

Field	Value
Publication number	US-9527800-B2
Application number	US-201415033506-A
Country	US
Kind code	B2
Filing date	Oct 29, 2014
Priority date	Oct 29, 2013
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

There is a need for short, resolution free asymmetric process for synthesis of one isomer of venlafaxine, (−)-venlafaxine. The invention provides a novel, short process of synthesis of (−)-venlafaxine, with yield greater than 50% and ee>99%. This process can be used for racemic synthesis of venlafaxine with overall yield 65%.

First claim

We claim:

1. A process for the synthesis of venlafaxine of formula 1 or its enantiomer,

wherein the process comprising the steps:
a. homologating carbonyl of cyclohexanone with two carbon Wittig ylide with heating at 50° C. to 140° C. in toluene to obtain α, β-unsaturated ester;
b. subjecting the ester of step (a) to selective ester reduction by Red-Al to give allyl alcohol;
c. subjecting allyl alcohol of step (b) for epoxidation reaction to afford epoxide;
d. treating the epoxide of step (c) with methane sulphonyl chloride and triethyl amine to obtain crude mesylate, which on subsequently subjecting for amination in 40% aqueous dimethyl amine solution at room temperature to affords the epoxy amine; and
e. treating epoxy amine of step (d) with p-methoxyphenyl magnesium bromide in presence of catalytic copper iodide to furnish venlafaxine.

2. The process according to claim 1 wherein the epoxidation in step (c) is carried out by the method selected from a group consisting of Sharpless epoxidation or by mCPBA in presence of NaHCO 3 to produce chiral or racemic epoxide respectively.

3. The process according to claim 1 , step (a), wherein the temperature is ranging between 50-140° C. and reflux time is ranging between 20-24 h.

4. The process according to claim 1 , step (b), wherein the temperature is 0° C. and stirring time is 10 to 30 mins.

5. The process according to claim 1 , step (c), wherein the temperature is in the range of 20 to 35° C. and stirring time is 6-8 h.

6. The process according to claim 1 , step (d), wherein the epoxidation is carried out at temperature in the range of 0° C. to 60° C. and stirring time is ranging between 10-12 h.

7. The process according to claim 1 wherein Sharpless asymmetric epoxidation for synthesis of asymmetric venlafaxine is carried out at a temperature ranging between −20 to −50° C. to obtain chiral epoxide.

8. The process according to claim 1 , step (e), wherein the temperature is −30-to-40° C. and stirring for a period ranging between 4-5 h.

9. The process according to claim 1 , wherein the yield is preferably 53% with ee>99%.

10. The process according to claim 1 , wherein the yield is preferably >64% for racemic venlafaxine ((±)-venlafaxine).

Assignees

• Council Scient Ind Res

Inventors

• Chavan Subhash Prataprao
• Pawar Kailash Pralhad

Classifications

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C67/42

  by oxidation of secondary alcohols or ketones · CPC title

• C07C29/147

  of carboxylic acids or derivatives thereof · CPC title

• C07C2101/14

  Chemistry & Metallurgy · mapped topic

• C07C213/00 Primary

  Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton · CPC title