FIELD OF THE INVENTION
The field of the invention relates to pure Venlafaxine or salt thereof and a process for preparing highly pure Venlafaxine of structural Formula I, or salt thereof.
(Formula removed)

BACKGROUND OF THE INVENTION
Venlafaxine of Formula-I is a useful antidepressant and is chemically known as (±)-l-[a-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol. Venlafaxine has been first disclosed in US patent 4,535,186. The process comprises the reaction of p-methoxy phenyl acetonitrile at -78°C, with cyclohexanone under the influence of n-butyl lithium, following available methods [Sauvetre et al. Tetrahedron 34 2135 (1978)] followed by reduction under high pressure using Rhodium on alumina as the catalyst. Symmetrical N-methylation is accomplished via modified Eschweiler-Clarkes procedure employing formaldehyde, formic acid and a large excess of water.
US patent application 2002/0143211 Al discloses a process for the preparation of essentially pure venlafaxine. The process comprises treating N,N-didesmethyl venlafaxine hydrochloride with sodium hydroxide and subsequently with formaldehyde and formic acid.
PCT patent application 2005/058796 Al discloses a process for the preparation of venlafaxine by treating N.N-didesmethyl venlafaxine hydrochloride, spiro compound in the presence of a salt of formic acid selected from the group of metal salt and an ammonium salt of formic acid.
In general, N-methylation of n, N-didesmethyl venlafaxine of formula II,
(Formula removed)

Formula II
or its salt is carried out using formaldehyde, formic acid and optionally in the presence of base in water. Formaldehyde is a toxic reagent, lachrymatory in nature and causes eye, skin and gastrointestinal tract burns.
In view of the above it is an object of the present invention to provide a simple and efficient process for preparation of highly pure venlafaxine without making use of toxic reagent like formaldehyde.
Accordingly present invention provides a simple and efficient process for preparation of highly pure venlafaxine from N,N-didesmethyl venlafaxine or salt thereof using hexamethylenetetramine, which is easy to handle and is not toxic.
SUMMARY OF THE INVENTION
The instant invention provides an improved process for preparation of highly pure venlafaxine hydrochloride thereof which comprises:
heating N, N-didesmethyl venlafaxine or salt with hexamethylenetetramine and formic acid in aqueous medium at temperature room temperature to reflux till complete methylation,
treating the reaction mixture with base,
extracting compound with organic solvent,
distilling of organic solvent to obtain venlafaxine as oil,
treating the above reaction mass in organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
isolating venlafaxine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The inventors have developed an efficient process for the preparation of highly pure venlafaxine hydrochloride. Preparation of N,N-didesmethyl venlafaxine or salt thereof is carried out by methods reported in prior art. The conversion of N,N-didesmethyl venlafaxine or salt thereof to venlafaxine in the presence of hexamethylenetetramine is the inventive part of this invention. Generally methylation of N,N-didesmethyl venlafaxine or salt thereof is carried out in the presence of hexamethylenetetramine and formic acid in aqueous medium. The salt can be any acid addition salt such as hydrochloride, formate, acetate, propionate, sulphate or the like. Specifically N,N-didesmethyl venlafaxine hydrochloride is converted to venlafaxine hydrochloride.
It is advantageous to use slight excess of hexamethylenetetramine in the ratio of 1.0-2.5 mole equivalent with respect toN,N-didesmethyl venlafaxine hydrochloride. Preferably 1.0- 1.5 equivalent of hexamethylenetetramine is used. The reaction is conducted at a temperature of 80-105° C and it takes 8-10 hours for completion of reaction. SpecificallyN,N-didesmethyl venlafaxine hydrochloride is treated with formic acid and hexamethylenetetramine in the presence of water at a temperature of 95-105° C. After completion of reaction, pH of reaction mass is adjusted to 10-11 using sodium hydroxide. Thereafter the product is extracted with organic solvent. Organic solvent can be selected from isopropyl ether, ethyl acetate and preferably
ethyl acetate is used. Organic layer is dried over sodium sulphate and solvent is concentrated to obtain oil. The crude oil can be dissolved in alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof. The hydrochloride formation is achieved using isopropanolic hydrochloric acid. The reaction is carried out at ambient temperature and pH is adjusted to 1-2. Venlafaxine hydrochloride is isolated by filtration and optionally purified by slurring at temperature of 25-50°C in a solvent selected from alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and are not intended to 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-1
PREPARATIONOFl-r2-(DI-METHYLAMINOVl-(4-METHOXYPHENYL) ETHYL1CYCLOHEXANOL HYDROCHLORIDE (Venlafaxine Hydrochloride)
To a solution of l-[2-Amino-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (25.0 gm; 87.56 mmol) in purified water (200 ml) was added hexamethylenetetramine (15.5 gm; 110.56 mmol), and formic acid ( 45.0 ml; 1193.47 mmol). The reaction mixture was stirred at room temperature for 15 min. then the temperature was raised to 98 - 102°C. The reaction mixture was stirred at 98 - 102°C till completion of methylation. After completion of reaction, the reaction mass was cooled to 15 - 20°C and pH was adjusted to 10 - 11 using sodium hydroxide solution (20%). The reaction mass was extracted with ethyl acetate. The organic layer was dried over sodium sulphate (13.0 gm) and ethyl acetate was
distilled out under vacuum. Isopropyl alcohol: ethyl acetate (4:1, 50.0 ml) was added to the residue with stirring and pH was adjusted to 1 -2 using isopropanolic-hydrochloric acid (20- 22%) yielded a thick white suspension. This was diluted with isopropyl alcohol: ethyl acetate (4:1, 62.5 ml) and the temperature of reaction mass was raised to 40 - 45°C and stirred at this temperature for 3.0 hours. The reaction mass was cooled to 0 - 5°C, stirred and filtered to afford crude venlafaxine hydrochloride. Crude material was slurred in isopropyl alcohol: ethyl acetate (4:1, 50.0 ml) at 40 - 45°C. Thereafter the reaction mixture was cooled to 0 - 5°C, filtered, washed with chilled isopropyl alcohol: ethyl acetate (4:1, 25 ml) and dried under vacuum at 45-50°C for 9 hours to obtain 19.1gm of l-[2-(dimethyl)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride having purity 99.7 9% by HPLC.
Example-2
PREPARATIONOFl-r2-(DI-METHYLAMINO)-l-(4-METHOXYPHENYL) ETHYL1CYCLOHEXANOL HYDROCHLORIDE (Venlafaxine Hydrochloride)
To a solution of l-[2-Amino-l-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride (10.0 gm; 35.02 mmol) in purified water (80 ml) was added hexamethylenetetramine (6.2 gm; 59.50 mmol), and formic acid ( 18.0 ml; 477.39 mmol). The reaction mixture was stirred at room temperature for 15 min. Thereafter temperature was raised to 98 - 102°C. The reaction mixture was stirred at 98 -102°C till completion of methylation. After completion of reaction, the reaction mass was cooled to 15 - 20°C and pH was adjusted to 10 - 11 using sodium hydroxide solution (20%). The reaction mass was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and ethyl acetate was distilled out under vacuum. Isopropyl alcohol: ethyl acetate (4:1, 20.0 ml) was added to the residue with stirring and pH was adjusted to 1 -2 using isopropanolic-hydrochloric acid (20- 22%) yielded a thick white suspension. This was diluted with isopropyl
alcohol: ethyl acetate (4:1, 25 ml) and the temperature of reaction mass was raised to 40 - 45°C and stirred at this temperature for 3.0 hours. The reaction mass was cooled to 0 - 5°C, stirred and filtered to afford crude venlafaxine hydrochloride. Crude material was slurred in isopropyl alcohol: ethyl acetate (4:1, 20.0 ml) at 40 -45°C. Thereafter the reaction mixture was cooled to 0 - 5°C, filtered, washed with chilled isopropyl alcohol: ethyl acetate (4:1, 10 ml) and dried under vacuum at 45-50°C for 8 - 10 h to obtain 6.8 gm of l-[2-(dimethyl)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride having purity 99.88% by HPLC.

WE CLAIM
1. A process for the preparation of highly pure venlafaxine or salt thereof which comprises:
a) heating N, N-didesmethyl venlafaxine or salt with hexamethylenetetramine and formic acid in aqueous medium at temperature from room temperature to reflux till completion of methylation,
b) treating the reaction mixture with base,
c) extracting compound with organic solvent,
d) distilling of organic solvent to obtain venlafaxine as an oil,
e) treating the above reaction mass in organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
f) isolating venlafaxine hydrochloride.
2. The process according to claim 1, wherein in step-1 N,N-didesmethyl venlafaxine is
used in the form of hydrochloride, formate or acetate salt.
3. The process according to claim 2, wherein in step-1 N,N-didesmethyl venlafaxine is used in the form of hydrochloride salt.
4. The process according to claim 1, wherein hexamethylenetetramine is used in molar
ratio of 1.0-2.5.
5. The process according to claim 4, wherein hexamethylenetetramine is used in molar
ratio of 1.0-1.5.
6. The process according to claim 1, wherein base used in step-b, is selected from
alkaline hydroxides.
7. The process according to claim 5, wherein base used in step-b is sodium hydroxide.
8. The process according to claim 1, wherein organic solvent used in step-c is selected from isopropyl ether and ethyl acetate.
9. The process according to claim 1, wherein organic solvent used in step-e is selected from alcohols such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof.