FIELD OF THE INVENTION
The field of the invention relates to highly 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 w-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 formalin, formic acid and a large excess of water. During methylation under said conditions appreciable amount of a by-product of formula II
(Formula removed)

is formed which should be reduced under more energetic conditions to lead to formation of venlafaxine and long reaction hours are required for the completion of
reaction. Further it is difficult to completely convert the compound of formula II to venlafaxine which leads to additional purification steps.
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, formaldehyde and formic acid. In this case also compound of formula II forms in appreciable amounts.
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 view of the above there is an urgent need to develop a process where the formation of compound of formula II is avoided and reaction moves smoothly to the preparation of venlafaxine.
Accordingly it is an object of the present invention to provide a simple and efficient process for preparation of highly pure venlafaxine from N,N.-didesmethyl venlafaxine of formula III,
(Formula removed)

or salt thereof in the presence of organic base wherein formation of compound of formula II is minimized and reaction time is reduced and hence impurity formation is very less leading to preparation of highly pure venlafaxine.
SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of highly pure venlafaxine or salt thereof which comprises:
adding organic base to N,N-didesmethyl venlafaxine or salt thereof, followed by formaldehyde and formic acid,
heating the reaction mixture at 95-105°C till complete conversion to venlafaxine,
treating the reaction mixture with base,
extracting compound with organic solvent,
distilling organic solvent completely 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 organic base is the inventive part of this invention. Generally methylation of N,N-didesmethyl venlafaxine or salt thereof is carried out in the presence of organic base using formaldehyde and formic
acid. 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. The organic base used is selected from trialkyl amines, tertiary alkyl amines, pyridine and the like. The trialkyl amines can be tributyl amine, triethyl amine or the like. Preferably triethyl amine is used.
It is advantageous to use excess of organic base in the ratio of 3-7 moles equivalent with respect to N,N-didesmethyl venlafaxine hydrochloride. Preferably 4-5 moles equivalent of base is used. The reaction is conducted at a temperature of 80-100° C and it takes 3-6 hours for completion of reaction. Specifically N,N-didesmethyl venlafaxine hydrochloride is treated with formic acid and formaldehyde in the presence of triethylamine at a temperature of 95-105° C. After completion of reaction, pH of reaction mass is adjusted to 10-11 using sodium hydroxide. Thereafter 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. Isopropanolic-hydrochloric acid is prepared by passing hydrochloric acid gas in isopropanol till concentration of hydrochloric acid in isopropanol reached the ratio of 20-22%. The hydrochloride formation 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 is 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.
Examples Example 1
PREPARATION OF l-[2-(DI-METHYLAMINO)-l-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDROCHLORIDE (Venlafaxine Hydrochloride)
Step I
Preparation of l-[2-Amino-l-(4-methoxy phenyl) ethyl]cyclohexanol hydrochloride
l-[Cyano-l-(4-methoxyphenyl)methyl]cyclohexanol (100.0 g) was dissolved in formic acid (800 ml; 98%) in an autoclave and cooled to 10-15°C. Palladium catalyst (Pd/C 15%, 15.0 gm: 50% wet) slurred in formic acid (45.0 ml) was added to the reaction mass and the reaction mass was stirred at 10 - 15°C under hydrogen pressure 3.5 - 4.0 kg/cm for 4.0 hrs.. After complete conversion of l-[cyano-l-(4-methoxyphenyl) methyl] cyclohexanol, the reaction mass was filtered and formic acid was recovered under vacuum at 40 - 45°C to obtain a viscous oily product. The oily product was dissolved in purified water (500 ml) and washed with ethyl acetate (3 x 100 ml). The aqueous layer was basified with 10% aqueous sodium hydroxide to pH 9.5 at 15 - 20°C. The reaction mixture was extracted with ethyl acetate (750 ml x3). The organic layer was combined and concentrated under vacuum at temperature 45 - 50°C. Ethyl acetate (450 ml) was added to the oil (115.0 gm) with stirring and pH was adjusted with ethyl acetate-hydrochloric acid at 20 - 30°C to pH 1 - 2. A thick white suspension was formed. The temperature of reaction mass was raised to 40 - 45°C and stirred for 2.0 hours at this temperature, cooled to 10 - 15°C and filtered. The wet product was slurred in ethyl acetate (200 ml) for 2.0 hours, filtered, washed with chilled ethyl acetate (100 ml) and dried under vacuum at 40 - 45°C for 8 - 10 hours to obtain 70.5 gm of title compound having purity 99.0% by HPLC.
Step II
Preparation of 1 - [2-(Di-methylamino)-1 -(4-methoxy phenvDethyll cyclohexanol hydrochloride (Venlafaxine hydrochloride)
Triethyl amine (121.96 gm; 1.20 mol) was added to a solution of 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (70.0 gm; 0.245 mol) in purified water (210 ml) followed by addition of formic acid (140 ml; 3.71 mol) and formaldehyde (101.5 ml; 1.25 mol). The reaction mixture was stirred at ambient temperature for 15 minutes and temperature was raised to 98 - 102°C. The reaction mixture was stirred at 98 - 102°C till complete conversion to venlafaxine (4.5 hours). After completion of reaction, the reaction mass was cooled to 15 - 20°C and pH was adjusted to 10 - 11 with sodium hydroxide solution (20%). The product was extracted with ethyl acetate (2000ml) and ethyl acetate was recovered under vacuum at temperature 45 - 50°C to obtain crude Venlafaxine as oil.
A mixture of isopropyl alcohol and ethyl acetate (4:1, 140 ml) was added to the oil with stirring and pH was adjusted to 1 - 2 with isopropanolic-hydrochloric acid (20 - 22%, 50 ml). A thick white suspension was formed. To this suspension isopropyl alcohol: ethyl acetate (4:1, 175 ml) was added and the temperature was raised to 40 - 45°C and stirred for 2.0 hours at the same temperature. The reaction mass was cooled to 0 - 5°C and stirred for 2.0 hours. The white suspension was filtered and wet product was slurred in isopropyl alcohol: ethyl acetate (4:1, 140 ml). The slurry was stirred for 1.0 hour at 40 - 45°C and for 1.0 hour at 0 - 5°C. The cooled suspension was filtered, washed with isopropyl alcohol: ethyl acetate (4:1) 70 ml and dried under vacuum at 45-50°C for 10 hours to obtain 53.4 gm of Venlafaxine hydrochloride having purity 99.89% by HPLC.
Example 2
PREPARATION OF l-[2-(DI-METHYLAMINO)-l-(4-METHOXYPHENYL) ETHYL] CYCLOHEXANOL HYDROCHLORIDE (Venlafaxine Hydrochloride)
Step I
Preparation of l-[2-Amino-l-(4-methoxy phenyl) ethyllcyclohexanol hydrochloride
l-[Cyano-l-(4-methoxyphenyl)methyl]cyclohexanol (100.0 gm) was dissolved in formic acid (800 ml; 98%) in an autoclave and cooled to 10-15°C. Palladium catalyst (Pd/C 15%, 15.0 gm: 50% wet) slurred in formic acid (45.0 ml) was added to the reaction mass and the reaction mass was stirred at 10 - 15°C under hydrogen pressure 3.5 - 4.0 kg/cm2 for 4.15 hrs.. After complete conversion of l-[cyano-l-(4-methoxyphenyl) methyl] cyclohexanol, the reaction mass was filtered and formic acid was recovered under vacuum at 40 - 45°C to obtain a viscous oily product. The oily product was dissolved in purified water (500 ml) and washed with ethyl acetate (3 x 100 ml). The aqueous layer was basified with 10% aqueous sodium hydroxide to pH 9.5 at 15 - 20°C. The reaction mixture was extracted with ethyl acetate (750 ml x3). The organic layer was combined and concentrated under vacuum at temperature 45 - 50°C. Ethyl acetate (450 ml) was added to the oil (115.0 gm) with stirring and pH was adjusted with ethyl acetate-hydrochloric acid at 20 - 30°C to pH 1 - 2. A thick white suspension was formed. The temperature of reaction mass was raised to 40 - 45°C and stirred for 2.0 hours at this temperature, cooled to 10 - 15°C and filtered. The wet product was slurred in ethyl acetate (200 ml) for 2.0 hours, filtered, washed with chilled ethyl acetate (100 ml) and dried under vacuum at 40 - 45°C for 8 - 10 hours to obtain 65.2 gm of title compound having purity 99.45 % by HPLC.
Step II
Preparation of l-[2-(Di-methvIamino)-l-(4-methoxyphenvI)ethvllcyclohexanol hydrochloride (Venlafaxine hydrochloride)
Triethyl amine (111.51 gm; 1.10 mol) was added to a solution of 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (64.0 gm; 0.224 mol) in purified water (192 ml) followed by addition of formic acid (128 ml; 3.39 mol) and formaldehyde (92.2ml; 1.13 mol). The reaction mixture was stirred at ambient temperature for 15 minutes and temperature was raised to 98 - 102°C. The reaction mixture was stirred at 98 - 102°C till complete conversion to venlafaxine (4 hours). After completion of reaction, the reaction mass was cooled to 15 - 20°C and pH was adjusted to 10.5 with sodium hydroxide solution (20%). The product was extracted with ethyl acetate (1800ml) and ethyl acetate was recovered under vacuum at temperature 45 - 50°C to obtain crude Venlafaxine as oil. A mixture of isopropyl alcohol and ethyl acetate (4:1, 120 ml) was added to the oil with stirring and pH was adjusted to 1 - 2 with isopropanolic-hydrochloric acid (20 - 22%, 45 ml). A thick white suspension was formed. To this suspension isopropyl alcohol: ethyl acetate (4:1,160 ml) was added and the temperature was raised to 40 - 45°C and stirred for 2.0 hours at the same temperature. The reaction mass was cooled to 0 - 5°C and stirred for 2.0 hours. The white suspension was filtered and wet product was slurred in isopropyl alcohol: ethyl acetate (4:1,128ml). The slurry was stirred for 1.0 hour at 40 - 45°C and for 1.0 hour at 0 - 5°C. The cooled suspension was filtered, washed with isopropyl alcohol: ethyl acetate (4:1) 64 ml and dried under vacuum at 45-50°C for 8 hours to obtain 53.7 gm of Venlafaxine hydrochloride having purity 99.90% by HPLC.

WE CLAIM
1. A process for the preparation of highly pure Venlafaxine of structural Formula I or salt thereof
(Formula removed)

which comprises:
a) adding organic base to N,N-didesmethyl venlafaxine of formula III or salt thereof,
(Formula removed)

followed by addition of formaldehyde and formic acid,
b) heating the reaction mixture at 95-105°C till complete conversion to venlafaxine,
c) treating the reaction mixture with base,
extracting compound with organic solvent,
distilling organic solvent completely to obtain venlafaxine as oil,
f) treating the above reaction mass in organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
g) isolating venlafaxine hydrochloride.
2. The process according to claim 1, wherein in step-a, N,N-didesmethyl venlafaxine is used in the form of its hydrochloride salt
The process according to claim 1, wherein in step-a, organic base used is selected from trialkyl amines, tertiary alkyl amines and pyridine.
The process according to claim 3, wherein organic base is triethylamine.
The process according to claim 1, wherein base used in step-c is selected from alkaline hydroxides.
The process according to claim 5, wherein base used in step-c is sodium hydroxide.
The process according to claim 1, wherein organic solvent used in step-d is selected from isopropyl ether and ethyl acetate.
The process according to claim 1, wherein organic solvent used in step-f is selected from alcohols such as , ethanol, isopropyl alcohol, ethyl acetate or mixture thereof.