FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
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 efficient 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.
4. DESCRIPTION
The present invention relates to an industrial scale efficient process for the
preparation of venlafaxine hydrochloride of high purity.

FORMULA I
1
Venlafaxine is structurally novel antidepressant. Chemically venlafaxine is (±)-1-[a-[(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol having structure as depicted in Formula 1.

US Patent number 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 (hereinafter referred to as amine intermediate) followed by isolation of the product using column chromatography.
US Patent number 4,761,501 provides a similar process for preparation of venlafaxine wherein the amine intermediate is N-di-methylated in presence of formic acid and formaldehyde in water to get venlafaxine base. However the product is contaminated with a spiro-impurity of Formula 2. The percentage of this spiro-impurity in the final product even after column chromatography is about 15-22% w/w. The removal of this spiro-impurity from venlafaxine is very difficult and results in significant loss of the yield.

FORMULA 2
2
The present inventors while working on the problem of removing the spiro-impurity of Formula 2 have surprisingly found that after extended reflux during N-di-methylation of the amino intermediate using formic acid and formaldehyde under aqueous conditions the spiro impurity is reduced significantly. The resultant venlafaxine has less than 0.1% of the spiro-impurity at crude stage.

A first aspect of the present invention provides a process for preparation of venlafaxine or salt thereof wherein the said process comprises of
a) heating amino intermediate of Formula 3 with formic acid and a source of
formaldehyde in presence of water for 6 hours or more at a temperature of
80°C and above,

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FORMULA 3
b) isolating venlafaxine from the reaction mass thereof.
Amine intermediate of Formula 3 is heated under reflux for more than 6 hours with aqueous formic acid and formaldehyde mixture. The term "formaldehyde" referred in this specification means formaldehyde or an equivalent source such as paraformaldehyde and the like. After ensuring the completion of reaction and spiro-impurity absence, the resultant mass is cooled to about 10°C and basified. The aqueous layer is extracted with ethyl acetate and the organic extracts are washed with water and concentrated to remove residual water. The resultant organic layer free of water can be concentrated to dryness to get the free base of venlafaxine or can be treated with appropriate acid to get the acid addition salt.
A second aspect of the present invention provides venlafaxine or salt thereof having less than 0.1% of spiro-impurity.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those
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skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Preparation of venlafaxine hydrochloride
To amino intermediate (427 gm) was added a mixture of formaldehyde (500ml), formic acid (300 ml) and water (1.5 L) and the resultant mass is heated to reflux for about 9 hours. The resultant mass is cooled to about 10-15°C and basified using aqueous sodium hydroxide (about 325 ml, 25% w/v) to get a pH of 10-11. The resultant mixture is extracted with ethyl acetate (3 x 175L) at 40-45°C. The organic extracts were washed with water (2 x 500 ml) and the organic extracts were concentrated to remove water completely. To the resultant extract was added hydrogen chloride (25-30% w/w isopropanol solution, 200 gm) at a temperature of about 5-10°C. The separated solids were filtered to get the title compound.
Yield: 480 gm
Sprio-impurity: Not detectable
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WE CLAIM:
1. A process for preparation of venlafaxine or salt thereof wherein the said
process comprises of
a) heating amino intermediate of Formula 3 with formic acid and a source of formaldehyde in presence of water for 6 hours or more at a temperature of 80°C and above,
b) isolating venlafaxine or salt thereof from the reaction mass thereof.

2. A process of claim 1 wherein source of formaldehyde comprises of formaldehyde, paraformaldehyde or suitable equivalent thereof.
3. A process of claim 1 wherein the reaction mixture is refluxed.
4. A process of claim 1 wherein the reaction mixture is heated for about 9 hours.
5. A process of claim 1 wherein venlafaxine hydrochloride is isolated from reaction mass.
6. A process of claim 1 wherein isolation comprises of basification of reaction mass.
7. A process of claim 6 further comprising extracting the basic aqueous solution with ethyl acetate.
8. Venlafaxine or salt thereof having less than 0.1% w/w of spiro-impurity.
9. Venlafaxine or salt thereof of claim 8 having no detectable spiro-impurity.
10. Venlafaxine hydrochloride having less than 0.1% w/w of spiro-impurity.
Dated this 28TH day of February, 2006.

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