FORM 2
THE PATENT ACT 1970
(39 of 1970)&The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR PREPARATION OF VENLAFAXINE OR
SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an improved process for the preparation of
venlafaxine hydrochloride in high purity.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention relates to an improved process for the preparation of venlafaxine hydrochloride in high purity.
Venlafaxine is known as antidepressant. Chemically venlafaxine is (±)-1-[a-[(dimethylamino) methyl]-p-methoxybenzyl] cyclohexanol having structure as depicted in Formula I.

US patent, US 4,535,186 provides a process for preparation of venlafaxine or salt thereof which involves use of rhodium or n-Butyl lithium for reduction of 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol (hereinafter referred to as cyano intermediate) to corresponding 1-(2-amino-(4-methoxyphenyl)ethyl]cyclohexanol followed by isolation of the product using column chromatography.
US patent, US 6,350,912 provides a one-pot process for the preparation of venlafaxine wherein the cyano intermediate undergoes catalytic reductive methylation to form venlafaxine. Raney Nickel is used as catalyst. However, in the process almost 60-65% of the cyano intermediate remains unreacted and the yield of venlafaxine is only 15-30%.
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US patent, US 7,026,513 provides similar process for reduction of cyano intermediate using Raney Nickel Crom III catalyst. However, (4-methoxyphenyl) ethylamine impurity (hereinafter referred to as MPEA impurity) of Formula III is formed during this reduction and is present in about 10-65%.

US patent application US 04/106576 and US 04/180952 provide process for reduction of cyano intermediate using cobalt chloride and sodium borohydride.
Other methods of preparing venlafaxine or its pharmaceutical^ acceptable salts are disclosed in U.S. Pat. Nos. 5,043,466, 6,506,941, 6,620,960, 6,756,502 and PCT Patent application WO 05/049560, WO 05/587796 and WO 06/35457
The present inventors while working on the problem of removing the MPEA impurity of formula III have surprisingly found that when metal catalyst is used along with high capacity solvent to reduce cyano intermediate to amino intermediate, the starting material is completely reduced and MPEA impurity is formed less than 0.1% during the reduction. The process of present invention is cost-effective and easily scalable at commercial scale.
A first aspect of the present invention provides a process for preparation of venlafaxine or salt thereof wherein the said process comprises of
a) providing a solution of the cyano intermediate of formula IV in a high capacity solvent,

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b) combining the above solution with a metal hydrogenation catalyst
c) exposing the combination of solution of step b) to hydrogen gas to get compound of formula V

d) treating compound of Formula V with aqueous formic acid and
formaldehyde to get Venlafaxine base and its conversion to its salt thereof.
In another aspect of the invention the compound of formula V is converted to its hydrochloride salt of formula VI in alcoholic -hydrogen chloride mixture

A solution of cyano intermediate in high capacity solvent combined with a metal hydrogenation catalyst raney nickel kalcat 8030. The combination was exposed to hydrogen gas at 150-200 psi pressure. Typically, the catalyst quantity is 10% to 50% of cyano intermediate. The catalytic hydrogenation in a high capacity solvent was carried out between temperature 40°C and 100°C. The isolation includes the steps of separating catalyst from the solution after reduction, concentrating high capacity solvent under reduced pressure, adding organic solvent to the residue, basification and washing of the organic layer with water for the removal of traces of high capacity solvent and reduced amino product was separated by the removal of organic solvent. Amino intermediate thus obtained was treated with alcoholic - hydrogen chloride mixture to obtain amino
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hydrochloride intermediate of formula VI. Alcoholic-hydrogen chloride having hydrogen chloride contain less than 30% w/w. Precipitated product was separated from reaction mixture as hydrochloride salt and dried.
The amino hydrochloride intermediate was converted to freebase, methylated and converted to venlafaxine and its salt thereof by the method known in the art.
Non-limiting examples of the high capacity solvent includes from the group of formic acid, acetic acid, propionic acid and the like.
Non-limiting examples of organic solvent are toluene, dichloromethane, chloroform and solvent a like.
Non-limiting examples of alcohol includes from the group of C-1 to C-4 straight chain or branched chain alcohol such as ethanol, isopapanol and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Preparation of 1-[2- amino-(p-methoxy phenyl) ethyl] cyclohexanol hydrochloride of Formula VI
EXAMPLE 1a
Cyano intermediate (150 gm) was suspended in acetic acid (900 ml) and stirred under hydrogen pressure (150-200 psi) in presence Raney Nickel (75 gm) catalyst at room temperature till the disappearance of cyano intermediate. The reaction mass was filtered and washed with acetic acid. The acetic acid was distilled out under vacuum below 70° C. Resultant residue was diluted with water (150 ml) and dichloromethane (1.0 L), cool to 10° C and basified with aqueous
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ammonia to get pH of 10-10.5. Separate the lower organic layer and washed with water (150 ml). Distilled out dichloromethane below 60° C azeotropically and finally residual solvent was distilled out completely under reduced pressure to yield amino intermediate
Yield: 142 gm.
MPEA impurity: 0.06%
EXAMPLE 1b
Amino intermediate (142 gm) thus obtained from example 1a was taken in ethyl
acetate (900 ml) cool to 10° C and convert the free base to hydrochloride in
isopropyl alcohol-hydrogen chloride mixture (25-30%w/w, 87 gm). The separated
hydrochloride salt was filtered and dried under vacuum to get the title compound.
Yield: 98 gm
Assay: 99.20%
MPEA impurity: Not detected
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WE CLAIM:
1. A process for preparation of venlafaxine or salt thereof wherein the said process comprises of,
a) providing a solution of the cyno intermediate of formula IV in a high capacity solvent,

b) combining the above solution with a metal hydrogenation catalyst
c) exposing the combination of solution of step b) to hydrogen gas to get compound of formula V

d) treating compound of Formula V with aqueous formic acid and
formaldehyde to get Venlafaxine base and its conversion to its salt thereof.
2. A process of claim 1 wherein high capacity solvent is from the group of formic acid, acetic acid, propionic acid and the like.
3. A process of claim 1 wherein metal hydrogenation catalyst is Raney nickel.
4. A process of claim 1 wherein alcohol is isopropyl alcohol.
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5. A process of claim 1 wherein reduction is carried out about 200 psi hydrogen pressure.
6. A process of claim 1 wherein reduction is carried out at temperature 50°C.
7. A process of Claim 1 wherein MPEA impurity is not more than 0.1%.
8. A process for preparation of hydrochloride salt of formula VI,

Wherein, the said process comprises of treating compound of Formula V with alcoholic -hydrogen chloride.

9. A process according to claim 8 alcoholic-hydrogen chloride mixture is isoprapanol alcohol containing 25-30% hydrogen chloride gas.
10. A process according to claim 8 the intermediate VI is used for making venlafaxine and its salt thereof.

Dated this 23 th day of September, 2006

For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory

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