the present invention relates to an improved process for the preparation of l-[2-(dimethylamino)-l-(4-methoxypheny!) ethyl] cyclohexanol hydrochloride (Venlafaxine hydrochloride). The drug may be represented by the following formula (1):

Venlafaxine and its pharmaceutically acceptable salts are useful as pharmaceuticals, in
particular, as antidepressants.
Background of Invention
In accordance with the prior art, described in EP 0112669, method of preparation of l-[2-
(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride of formula (1) by a
2-step procedure, which comprises: -
a. reduction of l-[cyano(p-methoxyphenyl)methyl]cyclohexanol of formula (2) using
5% rhodium on alumina in a mixture of ammonia-ethanol (20% v/v).
b. i.) treatment of l-[2-amino-l-(p-methoxy phenyI)ethyl]cycIohexanol of formula (3)
obtained in step (a) with a mixture of formaldehyde and formic acid to yield
compound of formula (4).
ii.) subsequent isolation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)-ethyl cyclohexanol of formula (4) and its acidification to yield the desired compound of formula (1)

The process can schematically be represented as follows: -

It is noteworthy to mention that the procedure disclosed in EP 0112669 involves the use of
expensive and commercially less accessible rhodium on alumina in first step. Also
preparation of a mixture of ammonia-ethanol (20% v/v) for the same step, apart from
increasing the number of steps of synthesis, is commercially less viable in terms of storage
and reuse.
EP 0112669 also discloses the yield of compound of formula (4) that is Venlafaxine base
from compound of formula (2) as 34.4 %, which is relatively low.
Moreover, the synthetic procedure also embodies isolation of compound of formula (4)
employing chromatographic technique, which is also not commercially viable.

As the compound of formula (1) (Venlafaxine hydrochloride) is a useful anti-depressant, it
is important to have a cost effective, commercially viable and industrially scaleable process
for preparing this compound.
Therefore, the main objective of the present invention is to develop a process for preparing
the compound of formula (1), which is high yielding, cost effective, commercially viable
and easily scaleable.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of 1-
[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride (Venlafaxine
hydrochloride) of formula (1), which comprises:
a. reduction of 1-[cyano-(p-methoxy phenyl)methyl]cyclohexanol of formula (2) using
palladium on carbon in organic acid to yield compound of formula (3) as herein
described;
b. treatment of l-[2-amino-l-(p-methoxy phenyl)ethyl]cyclohexanol of formula (3) with a
mixture of formaldehyde, formic acid and water accompanied by basification,
extraction and subsequent acidification to obtain the desired compound of formula (1)
such as herein described.

The process can be schematically be represented as follows:

It is important to mention that the present invention provides a simple two-stage method for preparation of Venlafaxine hydrochloride of formula (I). The first step involves usage of commercially available and relatively less expensive palladium on carbon for reduction of compound of formula (2).
Further more, second stage incorporates direct conversion of compound of formula (3) to Venlafaxine hydrochloride of formula 1 without chromatographic isolation of Venlafaxine base of formula (4) as suggested in EP 0112669 or isolating the Venlafaxine base of formula (4) and further acidification to afford Venlafaxine hydrochloride of formula (1).

Venlafaxine base of formula (4) is optionally isolated as a solid by recrystallisation of crude base of formula (4) in cyclic/acyclic/alicyclic aliphatic hydrocarbon solvents having C5-C10 carbon atoms in straight or branched chain, preferably acyclic C6 alkane such as hexane or alicyclic C6 alkane cyclohexane. The base herein is isolated without chromatographic purification in a yield of 60%, which is higher than 34.4 % that disclosed inEP 0112669.
The Venlafaxine base of formula (4) may be converted to Venlafaxine hydrochloride of formula (1), which is obtained in 54% yield.
The process described herein is commercially viable and well suited for scale-up. The present invention is, hence, directed to a high yielding, industrially suited, commercially viable and cost friendly process. Detailed Description of the Invention
The present invention provides an improved process for the preparation of Venlafaxine hydrochloride in two steps, which comprises: -
A. Preparation of l-[2-amino-l-(p-methoxy phenyl)ethyl]cyclohexanol of formula (3) by a process which comprises :-
a. reduction of l-[cyano(p-methoxyphenyl)methyl)cyclohexanol of formula (2) with
palladium on charcoal in an organic acid selected from formic acid, acetic acid or
propionic acid, preferably acetic acid in an autoclave at a pressure of 5-25 kg/cm
preferably 10-15 kg/cm^ at a temperature in the range of 30-75°C, preferably at 50-
55°C.
b. isolating the compound of formula (3) from the organic layer, after completion of
reaction, by evaporation of solvent.

c. suspending the isolated compound in non polar solvent selected from toluene or xylene
and subjecting to azeotropic distillation to remove traces of acetic acid.
d. suspending the compound obtained in step c) in C1-C4 alkyl acetates such as methyl ,
ethyl, propyl and butyl acetates preferably ethyl acetate accompanied by stirring and
filtration to yield the desired compound of formula (3).
B. Preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol
hydrochloride of formula (1) by a process which comprises: -
a. reacting the compound of formula (3) with solution of formic acid and formaldehyde
in water such that the mole ratio of formic acid and formaldehyde is in range of 2:8 to
8:2 at a temperature of 70-100°C preferably 90-95°C till the conversion is substantially
complete;
b. washing the reaction solution of step a) with halogenated solvent such as methylene
chloride or chloroform preferably chloroform;
c. cooling of aqueous layer below 25°C preferably below 5°C and more preferably
between 0-5°C accompanied by basification with alkali hydroxide selected fi-om
sodium hydroxide, potassium hydroxide or ammonium hydroxide;
d. extracting and isolating the aqueous alkaline layer in step c) with halogenated solvent
selected from chloroform or hydrocarbon solvent selected fi'om toluene, preferably
chloroform, accompanied by distillation of organic layer to yield oily residue;
e. optional crystallization of oily residue of step d) using cyclic/acyclic/alicyclic aliphatic
hydrocarbon solvents having C5-C10 carbon atoms in straight or branched chain,
preferably acyclic C6 alkane such as hexane or alicyclic C6 alkane cyclohexane;

f. acidifying the oily residue or solid of step d) or e) with alcoholic hydrochloride selected
from methanolic hydrochloride or isopropanolic hydrochloride to acidic pH;
g. isolating the separated solid (formula 1) by conventional methods.
The improved process of the present invention for preparation of Venlafaxine Hydrochloride is hence directed to a more industrially suited, commercially viable and cost effective process as:
1. The present invention provides a simple two-stage method for preparation of Venlafaxine hydrochloride of formula (1). The first stage involves usage of commercially available and relatively less expensive palladium on carbon for reduction of compound of formula (2). The reduction is exemplified using 10%Pd/C. Similar results are also obtained with 5%Pd/C, also provided by way of example, further adding to the cost effectiveness of the process.
2. The second stage incorporates direct conversion of compound of formula (3) to Venlafaxine hydrochloride of formula (1) without chromatographic isolation of Venlafaxine of formula (4) as suggested in EP 0112669 rendering the process industrially suited and commercially viable.
3. The yield of Venlafaxine base is about 60% compared to 34.4 % obtained in EP 0112669.

The present invention will be explained in more detail with reference to the foI]ov\'ing examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. ExampIe-1: Step-1: Method-1:
Preparation of l-[2-Amino-l-(p-methoxy phenyl)ethyl]cyclohexanol (Formula 3): A suspension of 1-[cyano-(p-methoxy phenyl)methyl]cyclohexanol (60 g) in acetic acid (360.0 ml) was hydrogenated in an autoclave at a pressure of 10-15 kg/cm' in presence of 10% palladium on charcoal (1.8 g) at a temperature of in the range of 50-55C. The same temperature and pressure was maintained till the hydrogenation was substantially complete, after which the catalyst was filtered accompanied by acetic acid (60.0 ml) wash. The filtrate washings were combined and evaporated under reduced pressure. To the residue obtained o-xylene (3x60.0 ml) was added and traces of acetic acid removed azeotropically. The resultant solid obtained was suspended in ethyl acetate (120.0 ml) and stirred for 30 min. at ambient temperature. Upon completion of this step, the suspension was filtered . accompanied by ethyl acetate wash (20.0 ml). The solid thus obtained was dried in o\en at 55-60C to afford the desired compound (Yield: 56.5 g). Method-2:
Preparation of l-12-Amino-l-(p-methoxy phenyl)ethyl]cyclohexanol (Formula 3): A suspension of l-[cyano-(p-methoxy phenyl)methyl]cyclohexanol (50 g) in acetic acid (350.0 ml) was hydrogenated in an autoclave at a pressure of 10-15 kg/cm" in presence of 5% palladium on charcoal (3.5 g) at a temperature of in the range of 50-55'C. The same

temperature and pressure was maintained till the hydrogenation was substantially complete, after which the catalyst was filtered accompanied by acetic acid (50.0 ml) wash. The filtrate washings were combined and evaporated under reduced pressure. To the residue obtained o-xylene (3x 50.0 ml) was added and traces of acetic acid removed azeotropically. The resultant solid obtained was suspended in ethyl acetate (100.0 ml) and stirred for 30 min. at ambient temperature. Upon completion of this step, the suspension was filtered accompanied by ethyl acetate wash (20.0 ml). The solid thus obtained was dried in o\-en at 55-60°C to afford the desired compound (Yield: 48.8 g). Step-2:
Preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyllcyclohexanoI
hydrochloride (Formula 1):
A stirred mixture of l-[2-amino-l-(p-methoxy phenyl)ethyl]cyclohexanol (55.0 g), formic acid (25.0 ml), 40% formaldehyde solution (92.0 ml) and water (275.0 ml) was healed at 90-98*^C for 19 hrs. The reaction mass was cooled and washed with chloroform (4x55.0 ml). The washings were discarded. The aqueous layer was then cooled to 5C and basified with 48% sodium hydroxide solution (25.0 ml). The product was extracted from the alkaline aqueous layer by chloroform (3x100.0 ml). The organic layer was then evaporated under reduced pressure to yield an oily residue, which was dissolved in isopropyl alcohol (225.0 ml). The resultant solution was acidified with isopropyl alcohol hydrochloride till pH of ~2 was achieved. The precipitated solid was filtered and washed with isopropyl alcohol (25.0 ml). It was then dried at 55-60°C to yield the desired compound of formula 1 (Yield: 44.0 g).

Example 2:
Preparation of l-[2-(dimethyIaniino)-l-(4-methoxyphenyl) ethyll cyclohexanol
(Formula 4):
A stirred mixture of l-[2-amino-l-(p-methoxyphenyl)ethyl]cyclohexanol (30.0 g), formic acid (37.2 ml) and 40% formaldehyde solution (19.2 ml) was heated at 50-55°C for 4 hrs. The temperature was then raised to 91-97°C and maintained at the same temperature till the reaction was substantially complete. The reaction mass was cooled to 5°C and hexane (12.0 ml) was added, after which, the reaction mixture was basified with 40% solution of sodium hydroxide (50.0 ml). The precipitated solid was stirred at 10*^C for 30-45 min. where after, it was filtered. The wet solid obtained was dissolved in hexane (80.0 ml) and heated to reflux till clear solution is obtained followed by carbon treatment and filtration. The filtrate was evaporated under reduced pressure to half of its volume and subsequently cooled to ambient temperature. The suspension was filtered and solid obtained was dried at 25-40°C (Yield: 20.0 g).

We claim:
1. An improved process for the preparation of Venlafaxine Hydrochloride of formula (1), which comprises;

a. reduction of l-[cyano-(p-methoxy phenyl)methyl]cyclohexanol of formula (2) using
Palladium on carbon in organic acid to yield compound of formula (3) as herein
described;
b. treatment of l-[2-amino-l-(p-methoxy phenyl)ethyl]cyclohexanol of formula (3) with a
mixture of formaldehyde, formic acid and water accompanied by basification,

extraction, optional isolation of free base and subsequent acidification to obtain the desired compound of formula (1) such as herein described.
2. The process as claimed in claim la wherein reduction of l-[cyano-(p-methoxy
phenyl)methyl]cyclohexanol of formula (2) is carried by a process which comprises:
a. reduction of l-[cyano(p-methoxyphenyl)methyl)cyclohexanol of formula (2) with
palladium on charcoal in an organic acid selected from formic acid, acetic acid or
propionic acid, preferably acetic acid in an autoclave at a pressure of 10-40 kg/cm^
preferably 10-15 kg/cm^ at a temperature in the range of 40-75°C, preferably at 50-
55°C.
b. isolating the compound of formula (3) from the organic layer after completion of
reaction by evaporation of solvent.
c. suspending the isolated compound in non polar solvent selected from toluene or xylene
and subjecting to azeotropic distillation.
d. suspending the compound obtained in step c) in C1-C4 alkyl acetates such as methyl ,
ethyl, propyl and butyl acetates preferably ethyl acetate accompanied by stirring and
filtration to yield the desired compound of formula (3).
3. The process as claimed in claim lb involving preparation of l-[2-(dimethylamino)-l-
(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride of formula (1) by a process,
which comprises: -
a) reacting the compound of formula (3) with solution of formic acid and formaldehyde in water such that the mole ratio of formic acid and formaldehyde is in range of 2:8 to 8:2 at a temperature of 70-100°C preferably 90-95°C till the conversion is substantially complete;

b) washing the reaction solution of step a) with halogenated solvent such as methylene chloride or chloroform preferably chloroform;
c) cooling of aqueous layer below 25°C preferably below 5°C and more preferably between 0-5°C accompanied by basitication with alkali hydroxide selected from sodium hydroxide, potassium hydroxide or ammonium hydroxide;
d) extracting and isolating the aqueous alkaline layer in step c) with halogenated solvent selected from chloroform or hydrocarbon solvent selected from toluene, preferably chloroform, accompanied by distillation of organic layer to yield oily residue;
e) optional crystallization of oily residue of step d) using cyclic/acyclic/alicyclic aliphatic hydrocarbon solvents having C5-C10 carbon atoms in straight or branched chain, preferably acyclic C(, alkane such as hexane or alicyclic Ce alkane cyclohexane;
f) acidifying the oily residue or solid of step d) or e) with alcoholic hydrochloride selected from methanolic hydrochloride or isopropanolic hydrochloride to acidic pH;
g) isolating the separated solid (formula 1) by conventional methods.
4. A process according to claim 2 step (a), wherein the organic acid is acetic acid.
5. A process according to claim 2 of step (a), wherein the catalyst for reduction is either 10% Palladium on Carbon or 5% Palladium on Carbon.
6. A process according to claim 2 of step (a), wherein the pressure of the reaction is 10-15 kg/cml

7. A process according to claim 2 of step (a), wherein the reaction temperature is
50-55°C.
8. A process according to claim 3 of step (a), wherein mole ratio of formic acid to
formaldehyde is 2:8 to 8:2, more particularly 3:6.
9. A process according to claim 3 of step (a), wherein the reaction temperature is
90-95°C.
10. An improved process for the preparation of Venlafaxine hydrochloride as herein
described with particular reference to examples.