FORM- 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
SECTION 10

TITLE

AN IMPROVED PROCESS FOR MANUFACTURE OF l-(CYANO (P-METHOXYPHENYL) METHYL ] CYCLOHEXANOL.

APPLICANT

ALEMBIC LIMITED, ALEMBIC ROAD, VADODARA-390003 GUJARAT, INDIA. AN INDIAN COMPANY.

The following Specification particularly describe and ascertains the nature of this invention and the manner in which it is to be performed.

Introduction-
The present relates to an improved process for the manufacture of l-[cyano (p-
methoxyphenyl) methyl] cyclohexanol which is an intermediate in the production of
Venlafaxine.
Background of Invention:
United States Patent 4,535,186 granted to Husbands et al is directed to
hydroxycycloalkanephenethyl amine anti depressant derivatives.
r
United States Patent 5043466 granted to Shepard et al is directed to the preparation of cyclohexanol derivatives and novel thioamide intermediates useful as antidepressants.
EP 0,112,669 teaches methods for the preparation of Venlafaxine and discloses the preparation of various 2-aryl-2-(l-hydroxycyclohexyl)ethylamine derivatives via a aryl-(X -(1-hydroxycyclohexyl) acetonitriles or (X-aryl-N,N-dimethyl- a -(1-hydroxycyclohexyl) acetamide as chemical intermediates. These chemical intermediates are prepared by condensing a -aryl-acetonitriles or a -aryl-N,N-dimethylacetamide with cyclohexanone. However, this known synthetic process tends to involve the use of hazardous, expensive and moisture sensitive reagents. In this process, very low reaction temperature (-50° C to -70°C) and reagent nBuLi is required and a hydrogenation step which uses expensive Rhodium on alumina catalyst. Materials in this process are not readily available, and the reaction conditions are harsh and difficult to work with, besides high demands on equipment along with high production costs.

GB 2,227,743 discloses yet another method for the preparation of 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol this time using Lithium diisopropyl amide (LDA) as the reagent for the condensation between p-methoxypohenylacetonitrile and cyclohexanone in better yields (79%) and at 10°C. However for making LDA they had to use nBuLi. The same patent discloses another route for Venlafaxine starting with N,N-dimethyl-p-methoxyphenylthioacetamide.
The process taught in GB 2,227,743 uses a ratio of 50:1 Raney nickel to thioamide in its desulfurisation step, and also requires the use of toxic solvents such as dioxane for the reduction of thioamide. These reagents and conditions make this process commercially unattractive. Zhou Jinpei et al. [Journal of China Pharmaceutical Uni. 1999,30(4)249-250] have reported the synthesis of Venlafaxine using methoxybenzene as a starting material. The route- involves 5 steps and gives 11% overall yield. In this route Anisole is treated with Chloroacetyl chloride under Friedel-Crafts acylation conditions followed by substitutions of ot-halo-p-methoxyacetophenone by dimethylamine which is reduced by potassium borohydride to give a p-hydroxydimethylamine derivative. This intermediate, on treatment with PBr3 followed by magnesium in tetrahydrofuran (THF), and subsequent treatment with cyclohexanone, yields Venlafaxine.

In this process ,the costly chemicals such as potassium borohydride and PBr3 are required as well as the purification of an important intermediate via distillation under high vacuum, which further adds to the cost.
EP0112669 discloses a process for preparing 1-[cyano (p-methoxyphenyl) methyl] cyclohexanol and 1-[2-amino-1-(p-methoxyphenyl) ethyl ] cyclohexanol. This process has been depicted hereinbelow-

The process necessitates the presence of extremely hazardous, expensive and highly moisture sensitive reagents such as n-Butyl lithium and expensive and rare catalyst Rhodium on alumina for reduction of cyano group to amino group.
It is therefore an objective of the present invention to provide an improved
method for the production of 1-[cyano (p-methoxyphenyl) methyl]
cyclohexanol and 1-[2-amino-1-(p-methoxyphenyl) ethyl ]
cyclohexanol or a pharmaceutical^ acceptable salt thereof which are the intermediates for Venlafaxine.

It is further objective of the present invention to provide a method that avoids use of extremely hazardous, expensive and highly moisture sensitive reagents such as n-Butyl lithium.
It is a still further objective of the invention to provide a method which results in higher yields of the desired product. For instance in the prior art, 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol was prepared in a yield of about 30% [EP 0,112,669] which was increased to 79% [GB 2227743] in comparison to the yield of 90% by employing the process of the present invention.
It is still a further objective of the present invention to provide a process that does not involve tedious purification processes such as high vacuum distillation of the intermediates.
It is still a further objective of the present invention to provide a process which does not use the reagents - such as Dioxane and Raney Ni - in exorbitant ratio thereby making the process of the present invention not only user friendly but also eco-friendly and economical.
It is still a further objective of the present invention to provide a process which avoids the usage of expensive and rare catalyst Rhodium on alumina for reduction of cyano group to amino group.

In accordance with the present invention relates to a novel process for manufacture of l-(cyano (p-methoxyphenyi) methyl ] cyclohexanol of the structural formula given in Figure 1 which comprises reaction of 4-methoxyphenylacetonitrile with cyclohexanone characterized in that of 4-methoxyphenylacetonitrile is reacted with cyclohexanone in the presence of alkali metal hydroxide or carbonate in acqueous medium under phase transfer catalysis.

Summary of Invention:
The present invention provides an improved process for manufacture of l-[cyano(p-methoxyphenyl) methyl ] cyclohexanol which is one of the intermediates for production of Venlafaxine in an operationally simple and economically advantageous manner as depicted below.

l-[cyano(p-methoxyphenyl) methyl] cyclohexanol can further be reduced to produce 1-
[2-amino-l-(p'methoxyphenyl) ethyl ] cyclohexanol or a pharmaceutically acceptable
salt thereof.
Detailed description of the best mode for carrying out the Invention:
The inventors of the present invention conducted extensive research to achieve the
foregoing object and found that the preparation of l-[cyano (p-methoxy phenyl) methyl]
cyclohexanol in high yield can be carried out by reaction of p-
methoxyphenylacetonitrile and cyclohexanone using alkali metal hydroxide or
carbonate as a base in aqueous medium with at least one phase transfer catalyst.

Preferably the alkali metal hydroxide is sodium hydroxide.
More preferably the alkali metal hydroxide is potassium hydroxide.
Preferably the alkali metal carbonate is sodium carbonate.
More preferably the alkali metal carbonate is potassium carbonate.
Preferably the reaction is carried out at a temprature of 10 °C to 80 °C. More preferably the reaction is carried out a temprature of between 10 °C to 40 °C.
Preferably the catalyst is selected from the group comprising tetra butyl ammonium hydroxide, tetra butyl ammonium bromide, phenyl trimethyl ammonium chloride, cetrimide.
1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol is reduced by catalytic hydrogenation using a hydrogenation catalyst to 1-[2-amino-1-(p-methoxyphenyl) ethyl ] cyclohexanol in a suitable solvent.
Preferably hydrogenation catalyst is selected from the group comprising Raney Ni and Platinum dioxide.

Preferably the said solvent is an alcoholic solvent such as methanol, ethanol, propanol or butanol.
More preferably the solvent is ammoniacal alcohol when Raney Ni is used.
More preferably the solvent is acidic methanol when PtC>2 is used.
Still more preferably the acid is hydrochloric acid.
1-[2-amino-1-(p-methoxyphenyl) ethyl ] cyclohexanol or a pharmaceutical^ acceptable salt thereof so produced by the process of the invention can be converted in to Venlafaxine Hydrochloride by known process reported in EP 0112699.
The process of the invention will now be described in greater detail making reference to the following examples. The illustrated examples, however should not be construed to limit the scope of the invention:
Example :1 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol
In a 3 litre 3 necked flask equipped with an overhead stirrer, thermometer and dropping funnel were placed 60 g (1.5 mole) of sodium hydroxide dissolved in 600 ml of water and tetrabutyl ammonium bromide(2.0 g ).To the mixture was added drop wise 147 g (1.0 mole) of p-methoxyphenylacetonitrile at 10-15°C

over a period of one hour .followed by stirring for 15 minutes. Gyclohexanone 132.3 g (1.35 mole) was added dropwise below 15°C.over a period of two hours. After stirring for six hours 870 ml of water was added and stirred for one hour. The crude 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol was filtered and washed with water (200 ml) and recrystallized from toluene to give 220.5 g of pure product. The yield of the obtained compound based on p-methoxyphenyl acetonitrile was 90%. M. P. 127-129°C
1H NMR (CDCI3): 5 7.32, 6.95 (4H 2-ds, p substituted aromatic); 3.8 (3H, s, O-CH3); 3.76 (1H,s,CH-CN); 1.56 (10 H, m, aliphatic cyclohexyl) ppm . MS :246(M+1);228[(M+1)-18].
Example : 2
In a 3 litre 3 necked flask equipped with an overhead stirrer, thermometer and dropping funnel were placed 60 g (1.5 mole) of sodium hydroxide dissolved in 600 ml of water and cetrimide (2.0 g ).To the mixture was added dropwise 147 g (1.0 mole) of p-methoxyphenylacetonitrile at 10-15°C over a period of one hour .followed by stirring for 15 minutes. Cyclohexanone 132.3 gm (1.35 mole) was added dropwise below 15°C.over a period of two hours. After stirring for six hours 870 ml of water was added and stirred for one hour. The crude 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol was filtered and washed with water (200 ml) and recrystallized from toluene to give 215 g of pure product. The yield

of the obtained compound based on p-methoxyphenylacetonitrile was 87.7% Melting point 127-129°C
Example : 3
In a 3 litre 3 necked flask equipped with an overhead stirrer, thermometer and dropping funnel were placed 98.8 g (1.5 mole) of potassium hydroxide dissolved in 600 ml of water and tetrabutyl ammonium bromide(2.0 g ).To the mixture was added dropwise 147 g (1.0 mole) of p-methoxyphenylacetonitrile at 10-15°C over a period of one hour .followed by stirring for 15 minutes. Cyclohexanone 132.3 g (1.35 mole) was added dropwise below 15°C.over a period of two hours. After stirring for six hours 870 ml of water was added and stirred for one hour. The crude 1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol was filtered and washed with water (200 ml) and recrystallized from toluene to give210 g of pure product. The yield of the obtained compound based on p-methoxyphenylacetonitrile was 85.8% Melting point 127-129°C
Example : 4 1 -[2-amino-1 -(p-methoxyphenyl) ethyl ] cyclohexanol using Raney Ni catalyst.
1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol (100g ) was dissolved in' ammoniacal methanol (1000 ml) and hydrogenated in an autoclave over Raney Ni (60 g ) at 10-12 kg pressure of hydrogen for 10 hours at room temperature

The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under reduced pressure yielding 1-[2amino-1-(p-methoxyphenyl) ethyl ] cyclohexanol as an oil. (82 gm) which can be used in the next step without purification for conversion to Venlafaxine. MS : 249 ( M+)
Example : 5 1-[2-amino-1-(p-methoxyphenyl) ethyl ] cyclohexanol using Pt02 catalyst.
1-[cyano (p-methoxyphenyl) methyl ] cyclohexanol (100g ) was dissolved in methanol (1000 ml) containing Hydrochloric acid( 50ml) and hydrogenated in an autoclave over Pt02 (6.0 g ) at 3-4 kg pressure of hydrogen for 24 hours at 50-60°C.The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under vacuum to give residue which was dissolved in water(400 ml), basified with 50% sodium hydroxide and extracted with ethylacetate (200ml x 2). The organic phase was dried over sodium sulfate and distilled out under reduced pressure yielding 1-[2-amino-1 -(p.methoxyphenyl) ethyl ] cyclohexanol as an oil. (79 g ) which can be used in the next step without purification for conversion to Venlafaxine.

We claim-
1. An improved process for manufacture of l-[cyano (p-methoxyphenyl) methyl ] cyclohexanol of the structural formula given in Figure 1 which comprises reaction of 4-methoxyphenylacetonitrile with cyclohexanone characterized in that 4-methoxyphenylacetonitrile is reacted with cyclohexanone in the presence of alkali metal hydroxide or carbonate in aqueous medium under phase transfer catalysis.

Fig 1.
2. A process as claimed in claim 1 wherein alkali metal hydroxide is sodium hydroxide.
3. A process as claimed in claim 1 wherein alkali metal hydroxide is potassium hydroxide.
4. A process as claimed in claim 1 wherein alkali metal carbonate is sodium carbonate.
5. A process as claimed in claim 1 wherein alkali metal carbonate is potassium carbonate.

6. A process as claimed in claim 1 wherein during phase transfer catalysis the
catalyst employed is selected from the group comprising tetra butyl ammonium
bromide, cetrimide or tetra butyl ammonium iodide.
7. A process for the manufacture of 1-[cyano-(p-
methoxyphenyl)methyl]cyclohexanol substantially as herein described with
reference to the foregoing description and the accompanying examples 1 and 3