FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATIO

(See section 10 and rule13)
TITLE OF THE INVENTION:
A PROCESS FOR THE PREPARATION OF l-[CYANO-(4-METHOXYPHENYL) METHYL] CYCLOHEXANOL, AN USEFUL INTERMEDIATE IN THE 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 a process for the preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol, an useful intermediate in the preparation of venlafaxine or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to a process for the preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol, an useful intermediate in the preparation of venlafaxine or salt thereof.
Venlafaxine hydrochloride of the formula I is chemically known as (±)-1-[o> [(dimethylamino) methyl]-p-methoxybenzyl] cyclohexanol hydrochloride. Venlafaxine is indicated in the treatment of major depressive disorder.

FORMULA I
U.S. Patent number 4,535,186 disclosed a venlafaxine hydrochloride and its process for the preparation. The process involves preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol from the reaction of p-methoxyphenylacetonitrile with cyclohexanone in tetrahydrofuran solvent which is then converted to venlafaxine or salt thereof.
US Patent number 6,350,912 provides a one-pot process for the preparation of venlafaxine wherein the cyano intermediate undergoes catalytic reductive methylation to form venlafaxine.
Other methods of preparing venlafaxine or its pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 5,043,466; 6,506,941; 6,620,960; 6,756,502; 7,141,697 and PCT Patent application No. WO 06/35457.
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U.S. Patent Nos. 6,906,087, 7,045,661, 6,924,393, 7,030,164, U.S. patent application 2004/220278, 2006/074131, PCT patent application WO 2002/046140; WO 2003/042161; WO 2003/050074 and WO 2005/058796 discloses different polymorphic forms and the processes of preparation thereof.
The present inventors have developed a simple cost effective process for the preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol (hereafter referred as cyano intermediate) , an useful intermediate in the preparation of venlafaxine or salt thereof. It involves the reaction of p-methoxyphenylacetonitrile with cyclohexanone in water. The process of present invention avoids use of organic solvent for the reaction. The present inventors further found that cyano intermediate obtained by this process is highly pure.
In the aspect of the present invention there is provided a process for the preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol, an useful intermediate for the preparation of venlafaxine or salt thereof. The process includes step of:
a) reacting p-methoxyphenylacetonitrile with cyclohexanone in presence of water
b) isolating 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol from the reaction mixture thereof.
The process of present invention involves adding p-methoxyphenylacetonitrile and cyclohexanone in water. The reaction mixture was stirred at room temperature and then added with aqueous sodium hydroxide solution. During the addition of sodium hydroxide solution, a catalyst was added and the reaction mixture was further stirred. The cyano intermediate was then isolated from the reaction mixture thereof. The so obtained cyano intermediate has purity of 99.0 % or more.
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The 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol was then converted to venlafaxine or salt thereof by methods known in the art.
The catalyst includes phase transfer catalysts such as Tetra Butyl Ammonium Bromide, Tetra Propyl Ammonium Bromide, Tri butyl Benzyl Ammonium Chloride, Tetra Ethyl Ammonium Bromide, Tetra Octyl Ammonium Bromide, Tetra Butyl Ammonium Hydrogen Sulphate, Benzyl Trimethyl Ammonium Chloride, Benzyl Triethyl Ammonium Chloride, Tetra Butyl Ammonium Acetate, Tetra Butyl Ammonium Iodide and Ethyl Triphenyl Phosphonium Bromide and the like.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.
EXAMPLE
Preparation of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol
p-Methoxy phenyl acetonitrile (118.7 gm), cyclohexanone (110.8 gm) was added in water (970.00 ml) and stirred at 25-30°C. To this reaction mixture was added sodium hydroxide solution (48.40 gm sodium hydroxide dissolved in 322.00 ml water) in 25-30 minutes. During addition of sodium hydroxide solution to reaction mixture was charged tetra butyl ammonium bromide (1.0 gm) and the reaction mixture then further stirred for about 14-15 hours. The mixture was filtered and 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol was then isolated from the reaction mass. The so obtained 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol was then crystallized in toluene (522.0 ml) and pure title compound isolated from the mixture thereof.
Yield : 169 gm.
Purity : 99.95 % by HPLC.
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WE CLAIM:
1. A process for the preparation of 1-[cyano-(4-methoxyphenyl) methyl]
cyclohexanol, an useful intermediate for the preparation of venlafaxine or salt
thereof. The process includes step of:
a) reacting p-methoxyphenylacetonitrile with cyclohexanone in presence of water
b) isolating 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol from the reaction mixture thereof.

2. A process of claim 1, wherein the reaction of p-methoxyphenylacetonitrile with cyclohexanone was carried out in presence of catalyst.
3. A process of claim 2, wherein the catalyst includes from the group of Tetra Butyl Ammonium Bromide, Tetra Propyl Ammonium Bromide, Tri butyl Benzyl Ammonium Chloride, Tetra Ethyl Ammonium Bromide, Tetra Octyl Ammonium Bromide, Tetra Butyl Ammonium Hydrogen Sulphate, Benzyl Trimethyl Ammonium Chloride, Benzyl Triethyl Ammonium Chloride, Tetra Butyl Ammonium Acetate, Tetra Butyl Ammonium Iodide and Ethyl Triphenyl Phosphonium Bromide and the like..
4. A process of claim 1, wherein the purity of 1-[cyano-(4-methoxyphenyl) methyl] cyclohexanol is 99.0 % or more.

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