A PROCESS FOR THE PREPARATION OF l-[2-(DIMETHYLAMINO)-l-(4-METHOXYPHE]VV^L)ETHYL]CYCLOHEXANOL AND ITS ACID ADDITION SALTS THEREOF
Field of the invention
The present invention relates to a process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol, which is substantially free from 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)-undecane and its acid addition salts thereof. Particularly, the present invention relates to a process for the preparation of venlafaxine hydrochloride. Background and prior art
Venlafaxine is a useful pharmaceutical agent as an antidepressant and it is known by the chemical name l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride, which is represented by the Formula-V.

EP 112669 discloses a process for the preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol an intermediate produced during the preparation of venlafaxine in two stages by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n-butyl lithium to form l-[cyano(4-methoxyphenyl) methyljcyclohexanol.
The second stage is the conversion of compound l-[cyano (4-methoxyphenyl) methyl] cyclohexanol to l-[2-amino-l-(4-methoxyphenyl) ethyl]cyclohexanol by hydrogenating the compound l-[cyano (4-methoxyphenyl)methyl]cyclohexanol using rhodium on alumina.
The third stage in the process of preparing venlafaxine is methylating l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol with a mixture of formaldehyde (1.45V), formic acid (1.89V) and large excess of water (18V) resulting in 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)- undecane and low yield of the compound of Formula-II (30-32%).

The disadvantages of this process are using hazardous and costly chemical n-butyl lithium in the first step, rhodium catalyst in the second step, large volumes of water used for isolating free venlafaxine and low yield in the third step.
US 2005/0033088A1 (claims priority from Indian Patent Application NO.460/MAS/2003) discloses a process for the preparation of venlafaxine hydrochloride which comprises the reduction of l-[cyano(4-methoxyphenyl) methyljcyclohexanol with palladium on charcoal in an organic acid selected from formic acid, acetic acid or propionic acid, preferably acetic acid. In this process, acetic acid is evaporated and the resulting compound is neutralized and extracted with an organic solvent to obtain l-[cyano (4-methoxyphenyl) methyl]cyclohexanol, which is then converted to the acetate salt by the addition of acetic acid. When this process was tried to obtain the acetate salt, it resulted in an impure product in poor yield. As the amine acetate is heated to higher temperature to remove traces of acetic acid, the salt tends to decompose rapidly forming impurities, which affect the final conversion to venlafaxine hydrochloride. Removal of traces of acetic acid is very difficult and requires high vacuum and the conversion of acetate salt to pure amine by neutralization and isolation of the amine in the pure form is cumbersome and time consuming.
GB 2227743 discloses a process for the preparation of venlafaxine hydrochloride which comprises the condensation of arylacetonitriles with cyclohexanone using lithiumdiisopropylamide in hydrocarbon solvents like hexane, toluene or cyclohexane at ambient temperature thereby improving the yield to 79%. However, use of lithiumdiisopropylamide causes great inconvenience in large-scale preparation, since it is hazardous.
In our co-pending Indian patent application number 256/CHE/2006 we have disclosed a novel process for the preparation of 1 -[2-amino-1 -(4-methoxy phenyl)ethyl]cyclohexanol said process comprising; dissolving l-[cyano(4-methoxyphenyl)methyl]cyclohexanol in an alcohol and ammonium salt to obtain a reaction mixture, and treating the reaction mixture with hydrazine hydrate in the presence of a noble metal catalyst to obtain 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol, an important intermediate for the synthesis of Venlafaxine and its acid addition salts thereof

Objects of the invention
A primary object of the present invention is to provide an economically viable method of preparing 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol and its acid addition salts thereof.
Another object of the present invention is to provide a process wherein formic acid and water are used in reduced volumes to yield l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol and its acid addition salts thereof.
Yet another object of the present invention is to provide an improved process for preparing l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride of Formula-I, in high yield and purity.
Still another object of the present invention is to provide a process for preparing l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol free from 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)-undecane. Summary of the invention
A process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, which is substantially free from a spiro compound 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)- undecane and acid addition salts thereof, said process comprising; dissolving an acid addition sah of I-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-IV in a solvent to obtain a corresponding solution; adding a base to said solution to obtain l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill; methylating said l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill with reduced volumes of formic acid, and water along with formaldehyde to obtain l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, which is substantially free from a spiro compound 5-(4-methoxyphenyl)-3-methyl-3-aza-I-oxaspiro(5.5)- undecane; and converting said I-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II by treating with an acid in lower alcohols to obtain an acid addition salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-I.
The present invention also provides a process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride of Formula V. Detailed description of the invention
Accordingly the present invention provides a process for the preparation of 1-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, which is

substantially free from a spiro compound 5-(4-methoxyphenyl)-3-methyl-3aza-l-oxaspiro(5.5)-undecane and acid addition salts thereof,

said process comprising;
a) dissolving an acid addition salt of l-[2-amino-l-(4-methoxyphenyl) ethyl]
cyclohexanol of Formula-IV
in a solvent to obtain a corresponding solution;
b) adding a base to said solution to obtain l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill;
c) methylating said l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill with reduced quantities of formic acid, and water along with formaldehyde to obtain l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, which is substantially free from a spiro compound 5-(4-methoxyphenyl)-3-methyl-3aza-l-oxaspiro(5.5)-undecane; and
d) converting said 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II by treating with an acid in lower alcohols to

obtain an acid addition salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-I.
In an embodiment of the present invention, the acid addition salt of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol of formula IV is selected from the group consisting of aliphatic sulphonates such as methane sulphonate, ethane sulphonate and the like, aryl sulphonates such as p-toluenesulphonate, benzene sulphonate, and the like and oxalate.
In another embodiment of the present invention wherein solvent is ester such as ethyl acetate, methyl acetate and the like and halogenated solvent such as methylenechloride, dichloroethylene, trichloroethylene, and the like, and mixtures thereof, preferably ethyl acetate.
In still another embodiment of the present invention, wherein the base is selected from the group consisting of alkali and alkaline metal hydroxides such as sodium hydroxide, potassium hydroxide, and the like, and magnesium hydroxide, calcium hydroxide, and the like, alkali and alkaline carbonates and bicarbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, and the like, aqueous ammonia, aliphatic amines such as methyl amine, ethyl amine, dimethylamine, and the like, and aromatic amines such as aniline, triphenylamine and the like, preferably aqueous ammonia.
It is also an embodiment of the present invention, wherein the reduced quantity of formic acid is in the range of 0.6 to 0.9V, preferably 0.8V.
In yet another embodiment of the present invention, wherein the reduced quantity water is the range 0.7 to 0.9V, preferably 0.83V.
In further another embodiment of the present invention, wherein the acid is hydrochloric acid.

In yet another another embodiment of the present invention, wherein the lower alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, or mixtures thereof, preferably isopropanol.
It is also an embodiment of the present invention wherein reduced volumes of formic acid and water is used resulting in high yield and purity of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula II and its acid addition salts thereof.
It is observed here that during the methylation of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill, by using a combination of reduced volumes of formic acid and water along with formaldehyde, the formation of a spiro compound 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)- undecane is prevented, which is normally an occurrence in known processes for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, thereby increasing the yield and purity of the end product.
The synthetic pathway for the preparation of I-[2-(dimethylamino)-I-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II and acid addition salts thereof can be depicted in the following scheme.

Process for the preparation of l-[2-(dimethyIamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride of Formula V
The present invention provides a process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride of Formula-V,


said process comprising;
a) dissolving l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol
methanesulphonate of Formula-VI

in ethyl acetate to obtain a solution of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol methanesulphonate of Formula-VI;
b) adding aqueous ammonia to said solution of l-[2-amino-l-(4-
methoxyphenyl) ethyl] cyclohexanol methanesulphonate of Formula-VI to
obtain I-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-Ill;

c) methylating said l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of
Formula-Ill with formaldehyde, formic acid and water to yield l-[2-
(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II;
and


d) converting said l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl]
cyclohexanol of Formula-II by treating with isopropyl hydrochloride in
isopropanol to obtain 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl) ethyl]
cyclohexanol hydrochloride of Formula-V.
The synthetic pathway for the preparation of l-[2-(dimethylamino)-l-(4-
methoxyphenyl) ethyl] cyclohexanol hydrochloride of Formula-I can be depicted in the
following scheme.

The process steps of the present invention are described in the following examples, which are illustrative in nature only and should not be construed as limiting the scope of the invention in any manner.
Example 1 Preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyI]cyclohexanol hydrochloride of Formula-V
Ethyl acetate (690ml) is added to l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol methanesulphonate salt (69.3g) of Formula-VI

charged into R.B. flask and stirred the solution for 15 minutes at room temperature. The reaction mixture is basified with aqueous ammonia till pH 9 is achieved and stirred for 10 minutes at room temperature. The aqueous and organic layers are separated and the aqueous layer is extracted twice with ethyl acetate (60ml). The combined organic layer is washed twice with water and concentrated under vacuum at 50°C to yield 50g of crude l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol (yield 100%) of Formula-Ill.
42 ml of demineralised water is added to 50g of crude l-[2-amino-l-(4-
methoxyphenyl) ethyl] cyclohexanol of Formula-Ill charged in a round-bottomed flask
and stirred for 10 minutes at room temperature. The reaction mixture is acidified with
formic acid till pH 7 is achieved and then 0.67 V of formic acid is added (a total 0.8V
of formic acid is used). The reaction mixture is stirred for 10 minutes at room
temperature and I.IV of formaldehyde is added to the reaction mixture at room
temperature, stirred for 10 minutes and the temperature is raised to 60°C and the
temperature is maintained for 3-4 hours. The temperature of the reaction mixture is
raised to 95-lOO^C, and maintained the temperature till the completion of the reaction.
After completion of the reaction, the reaction mixture is cooled to 20*^C. The reaction
mixture is basified with 50% sodiumhydroxide solution and pH is adjusted to about 10-
13. The layers are separated and the alkaline aqueous layer is extracted thrice with ethyl
acetate (3 x 200ml), The organic layer is washed thrice with water (3 x 50ml), dried
over sodium sulphate, and ethyl acetate is completely distilled out under vacuum to
yield 55.5g of crude compound l-[2-(dimethylamino)-l-(4-
methoxyphenyl)ethyl]cyclohexanol (yield 100%) of Formula-II.
55.5g of crude l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of Formula-II and isopropanol (300ml) are charged into a round-bottomed flask and stirred for 10 minutes at room temperature. The resultant solution is acidified with isopropanol hydrochloride till pH 2 is achieved at 30-35*^C and maintained for 30 minutes. The solution is cooled to 10-20°C, maintained for 30 minutes, filtered and washed with ethylacetate (60ml). It is then dried under hot air oven at 50°C to yield 1-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (50g, 79.4%) of Formula-V with 99.8% HPLC purity.
Example 2 Preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride of Formula-V

Ethyl acetate (15ml) is added to 1 -[2-amino-1 -(4-methoxyphenyl) ethyl]eyelohexanol oxalate sah (1.5g) charged into R.B. flask and stirred the solution for 15 minutes at room temperature. The reaction mixture is basified with aqueous ammonia till pH 9 is achieved and stirred for 10 minutes at room temperature. The aqueous and organic layers are separated and the aqueous layer is extracted twice with ethyl acetate (2ml), The combined organic layer is washed twice with water and concentrated under vacuum at 50°C to yield l.lg of crude l-[2-amino-l-(4-methoxyphenyl) ethyljcyclohexanol (yield 100%) of Formula-Ill.
1.3 ml of demineralised water is added to l.lg of crude 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol of FormuIa-III charged in a round-bottomed flask and stirred for 10 minutes at room temperature. The reaction mixture is acidified with formic acid till pH 7 is achieved and then 0.67 V of formic acid is added (a total 0.87V of formic acid is used). The reaction mixture is stirred for 10 minutes at room temperature and I.IV of formaldehyde is added to the reaction mixture at room temperature, stirred for 10 minutes and the temperature is raised to 60°C and the temperature is maintained for 3-4 hours. The temperature of the reaction mixture is raised to 95-100°C, and maintained the temperature till the completion of the reaction. After completion of the reaction, the reaction mixture is cooled to 20°C. The reaction mixture is basified with 50% sodiumhydroxide solution and pH is adjusted to about 10-13. The layers are separated and the alkaline aqueous layer is extracted thrice with ethyl acetate (3 x 7ml). The organic layer is washed thrice with water (3 x 1ml), dried over sodium sulphate, and ethyl acetate is completely distilled out under vacuum to yield Ig of crude compound l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol (yield 100%) of Formula-II.
1 g of crude l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol of Formula-II and isopropanol (300ml) are charged into a round-bottomed flask and stirred for 10 minutes at room temperature. The resultant solution is acidified with isopropanol hydrochloride till pH 2 is achieved at 30-35°C and maintained for 30 minutes. The solution is cooled to 10-20°C, maintained for 30 minutes, filtered and washed with isopropyl alcohol (10ml). It is then dried under hot air oven at 50°C to yield 1 -[2-(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (0.95g, 68.84%) of Formula-V with 99.52% HPLC purity.

Advantages of the present invention:
The process of the present invention consumes reduced volume of formic acid (0.8V) and water (0.83V) resulting in high yield and purity of Venlafaxine.
The present invention provides a process for preparing l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol which is free from 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)- undecane.

We Claim:
1. A process for the preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II, which is substantially free from a spiro compound 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5.5)- undecane and acid addition salts thereof,
said process comprising;
a) dissolving an acid addition salt of l-[2-amino-l-(4-methoxyphenyl) ethyl]
cyclohexanol of Formula-IV
in a solvent to obtain a corresponding solution;
b) adding a base to said solution to obtain l-[2-amino-l-(4-methoxyphenyl)
ethyl] cyclohexanol of Formula-Ill;

c) methylating said l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of
Formula-Ill with reduced volumes of formic acid, and water along with
formaldehyde to obtain l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl]
cyclohexanol of Formula-II, which is substantially free from a spiro

compound 5-(4-methoxyphenyl)-3-methyl-3-aza-l-oxaspiro(5,5)- undecane; and d) converting said l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-II by treating with an acid in lower alcohols to obtain an acid addition salt of l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol of Formula-I.

2. The process as claimed in claim 1, wherein the acid addition salt of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol of formula IV is selected from the group consisting of aliphatic sulphonates, aryl sulphonates and oxalate.
3. The process as claimed in claim 2, wherein the aliphatic sulphonate is methane sulphonate.
4. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of an ester, a halogenated solvent and mixtures thereof.
5. The process as claimed in claim 4, wherein the ester is ethyl acetate, methyl acetate or mixtures thereof, preferably ethyl acetate and the halogenated solvent is methylenechloride, dichloroethylene, trichloroethylene or mixtures thereof.
6. The process as claimed in claim 1, wherein the base is selected from the group consisting of alkali and alkaline metal hydroxides, carbonates, and bicarbonates, aqueous ammonia, aliphatic and aromatic amines, preferably aqueous ammonia.
7. The process as claimed in claim 1, wherein the reduced volume of formic acid is in the range of 0.6 to 0.9V, preferably 0.8V.
8. The process as claimed in claim 1, wherein the reduced volume of water is in the range 0.7 to 0.9V, preferably 0.83V.
9. The process as claimed in claim 1, wherein the acid is hydrochloric acid.

10. The process as claimed in claim 1, wherein the lower alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, or mixtures thereof, preferably isopropanol.