(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date (10) International Publication Number

2 1 June 2007 (21.06.2007) PCT
(51) International Patent Classification:
C07C 213/02 (2006.01) C07C 217174 (2006.01)
(21) International Application Number:
PCT/IN2006/000474
(22) International Filing Date:
27 November 2006 (27.1 1.2006)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
1483/MUM/2005
30 November 2005 (30. 11.2005) IN
(71) Applicant (for all designated States except US): AARTI
HEALTHCARE LIMITED [IN/IN]; 71, Udyog Kshetra,
2nd Floor, Mulund Goregaon Link Road, Mulund (W),
Mumbai 400 080, Maharashtra (IN).
(72) Inventors; and
(75) Inventors/Applicants (for US only): DESAI PARI-
MAL HANSMUKH [IN/IN]; Aarti Healthcare Limited,
D-53/D-60, MIDC, Phase II, Kalyan Shil Road, Dombivli
(E), District Thane 421 204, Maharashtra (IN). SALVI,
Narendra Jagannath [IN/IN]; Aarti Healthcare L im
ited, D-53/D-60, MIDC, Phase II, Kalyan Shil Road,
Dombivli (E), District Thane 421 204, Maharashtra
(IN). PATRAVALE,Bharat Kumar Surendra [IN/IN];
Aarti Healthcare Limited, D-53/D-60, MIDC, Phase II,
Kalyan Shil Road, Dombivli (E), District Thane 421 204,
Maharashtra (IN). PATIL Sudhir Tulshiram [IN/IN];
Aarti Healthcare Limited, D-53/D-60, MIDC, Phase II,
Kalyan Shil Road, Dombivli (E), District Thane 421 204,
Maharashtra (IN).
WO 2007/069277 A2
(74) Agents: MADAN, Jose, A. et al; Khaitan & Co., Meher
Chambers, 4th & 5th Floors, R K Marg, Ballard Estate,
Mumbai 400 038, Maharashtra (IN).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT,
RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
GN, GQ, GW, ML, MR, NE, SN, TD, TG).
Declarations under Rule 4.17:
— as to applicant's entitlement to apply for and be granted a
patent (Rule 4.17(U))
— of inventor ship (Rule 4.17 (iv))
Published:
— without international search report and to be republished
upon receipt of that report
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ance Notes on Codes and Abbreviations" appearing at the beg in
ning of each regular issue of the PCT Gazette.

(54) Title: A PROCESS FOR THE PREPARATION OF VENLAFAXINE HYDROCHLORIDE

(57) Abstract: A process for preparing venlafaxine hydrochloride and also a process for preparing l-[2-amino- l-(4-methoxy
phenyl)ethyl]cyclohexanol hydrochloride, an intermediate of venlafaxine hydrochloride are disclosed. p-Methoxy phenyl
acetonitrile is condensed with cyclohexanone in the presence of a base selected from alkali metal alkoxides and solvent selected
from C4 alcohol at - 10 to - 5° C to obtain l-[cyano-l-(p-methoxy phenyl)m ethyl] cyclohexanol which is directly converted
it into the l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol without being isolated. The molar ratio of base to p-methoxy
phenyl acetonitrile or cyclohexanone used is 0.1 to 0.4:1. The l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol is converted
its hydrochloride salt and subsequently formylated to venlafaxine base. The venlafaxine base is further converted into its salt
namely venlafaxine hydrochloride. Both venlafaxine hydrochloride and l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol
hydrochloride are obtained in high yield with high purity.
 TITLE OF THE INVENTION
A process for the preparation of venlafaxine hydrochloride

Technical field of invention

The invention relates to a process for the preparation of venlafaxine hydrochloride.

The invention also relates to a process for the preparation of l-[2-amino-l-(4-methoxy

phenyl)ethyl]cyclohexanol hydrochloride, a key intermediate of venlafaxine hydrochloride.

Venlafaxine is a non-tricyclic antidepressant chemically named as (±)-l-[2-(dimethyl amino)- 1-

(4-methoxy phenyl)ethyl] cyclohexanol. It is widely used to treat depression and antisocial
disorders. It is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic
or other available antidepressant agents. The antidepressant action of venlafaxine in humans is
believed to be associated with its potentiation of neurotransmitter activity in the Central Nervous
System.

Background and prior art

The hydrochloride salt of venlafaxine is convenient to be formulated into tablets, capsule,

lozenges, powders or the like for oral administration and is currently available under the trade
name Effexor as a racemic mixture of (+) and (-) enantiomers and is indicated for the treatment
of depression.

Processes for the preparation of Venlafaxine and it's acid addition salts and intermediates have
been reported in US 4,761,501 (hereinafter referred as '501), Drugs of Future 1988, 13(9), 839-
840, US 5,043,466 (hereinafter referred as '466), international publication WO 00/59851, US
6,506,941 (hereinafter referred as '941), US 6,350,912 (hereinafter referred as '912),
International publication WO 03/0500074, US 6,756,502 (hereinafter referred as '502), US
2004/0106818, US 2004/0181093, CN 1,225,356 and US 2005/0033088. The processes for the
preparation of venlafaxine hydrochloride of the formula (VI)
 Formula (VI)
generally comprise the following steps :
1. Condensation of p-methoxy phenyl acetonitrile of the formula (I)

Formula (I)
with cyclohexanone of the formula (II)

Formula (II)
to obtain l-[cyano-l-(p-methoxy phenyl)methyl] cyclohexanol of the formula (III);

Formula (III)
2. Hydrogenation of l-[cyano-l -(p-methoxy phenyl)methyl] cyclohexanol of the
formula (III) to obtain lr[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol of the
formula (IV);

Formula (IV)
 3 . Symmetrical N-methylation of l-[2-amino-l-(4-methoxy phenyl) ethyl ]
cyclohexanol of the formula (IV) in the presence of formic acid and formaldehyde
(Eschweiler-Clarke reaction) to obtain Venlafaxin base of the formula (V);

Formula (V)
and
4. Conversion of Venlafaxine base of the formula (V) into pharmaceutically acceptable
acid addition salts thereof.

In US '501 condensation is carried out in the presence of n-butyl lithium as a catalyst and
tetrahydrofuran as a solvent at temperature around -70 to -50°C. The n-butyl lithium is highly
sensitive to moisture and air and can cause fire hazards and is therefore unsafe besides being
expensive. The compound (III) is isolated in crystalline form and hydrogenated in a mixture of
20 % v/v ammonia-ethanol over 5 % Rhodium on alumina to obtain the compound (IV).
Rhodium catalyst is expensive and uneconomical especially on plant scale. In order to save cost,
the catalyst is recovered and recycled, thereby increasing the process steps. During recovery and
recycling of the catalyst, there is the possibility of the catalytic effect of the recycled catalyst
being reduced. The compound (IV) is treated with a mixture of formaldehyde, formic acid and
water at 100° C to obtain venlafaxin base (V) which is purified by column chromatography
using Mallinckrodt Silica CC7 silica gel as a stationary phase and ethanol: 2 N ammonia : ethyl
acetate : cyclohexane in a ratio of 45:8:100:100 v/v as a mobile phase and converted it into
venlafaxine hydrochloride (VI).

US '466 describes a process for the preparation of l-[cyano-l-(p-methoxy phenyl)methyl]

cyclohexanol (III), a key intermediate of venlafaxine. p-Methoxy phenyl acetonitrile is
condensed with cyclohexanone in the presence of lithium di-isopropylamide at a temperature
below 1O0C. Lithium di-isopropylamide is also highly sensitive to moisture and air and unsafe
besides being expensive.

CN1225356 describes a process for the preparation of l-[2-amino-l-(p-methoxyphenyl) ethyl]

cyclohexanol, which is an important intermediate of venlafaxin. The process uses sodium
methylate, sodium ethylate, sodamide or sodium hydride as a substitute for n-butyl lithium or
lithium diisopropylamide in the condensation step and borane as a substitute for catalyst
Rhodium-aluminium trioxide in the hydrogenation step. The reagents used in this process are
also sensitive to moisture and air and unsafe.

US '912 describes a process for the preparation of venlafaxine which comprises reduction of the
compound (III) with a formylating agent in the presence of protic solvent and Raney nickel
catalyst at a temperature in the range of 30 to 60° C and at the hydrogen pressure in the range of
100 to 400 psi for 6 to 16 hours followed by purification of the venlafaxine base (V). The yield
of venlafaxine is reported to be in the range of 15 to 30 %. Further the un-reacted nitrile is
required to be isolated from the reaction mixture.

US '502 describes a process for the preparation of venlafaxine hydrochloride from epoxy nitrile
intermediates. This process comprises additional steps to prepare the epoxy nitrile derivatives.

WO0059851 describes a process for the preparation of venlafaxin and its hydrochloride salt by
condensing p-methoxy phenyl acetonitrile with cyclohexanone in the presence of lithium
diisopropyl amide to obtain the compound (III) followed by hydrogenation in the presence of
cobalt chloride and sodium borohydride in methanol to obtain the compound (IV). The
compound (IV) is treated with formaldehyde and formic acid to give venlafaxine base (V),
which is converted into its hydrochloride salt (VI). The hydrogenation of the compound (III) in
the presence of cobalt chloride and sodium borohydride is also disclosed in WO0032556. The
reagents used in this process are very expensive.

WO0250017 describes hydrogenation of the compound (III) in the presence of pretreated nickel
or cobalt catalyst, alcohol and base such as NH 3, NH 4OH and NaOH. The nickel or cobalt
catalyst is pretreated with a carboxylic acid or a salt or an anhydride thereof or with an
ammonium salt or a vanadium-, a tungsten-, or a molybdenum compound. Pretreatment
procedure is cumbersome and time consuming. Further the hydrogenation reaction carried out
under basic conditions at above room temperature results in the cracking of the starting nitrile
compound to produce 4-methoxyphenyl acetontrile, which may undergo hydrogenation to
produce 4-methoxy phenethyl amine as an impurity. The phenethyl amine or phenalkyl amine
impurities are very similar to the end products of primary amines in terms of physical and
chemical properties. Therefore, it is very difficult to separate the desired end products from the
undesired ones.
WO 03050074 describes a process for the preparation of venlafaxine hydrochloride and its
polymorphs. P-methoxy phenyl acetonitrile is condensed with cylohexanone in the presence of
inorganic base like alkaline earth metal hydroxides selected from lithium hydroxide, sodium
hydroxide or potassium hydroxide to obtain l-[cyno-(4-methoxyphenyl)methyl]cyclohexanol
followed by hydrogenation of the l-[cyno-(4-methoxyphenyl)methyl]cyclohexanol in the
presence of Raney nickel catalyst at 60 psi under anhydrous ammonia in methanol at 30° C to
obtain l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol. The hydrogenated product is
formylated with formic acid and formaldehyde to yield venlafaxine, which is converted into its
hydrochloride salt. Handling of the alkaline earth metal hydroxide like sodium hydroxide with a
relatively strong base especially at industrial scale is very difficult.

US 20040181093 describes hydrogenation using a nickel or cobalt catalyst at temperature of

about 5° C to 25° C to obtain compound (IV). The yield of the compound (IV) is reported to be
about 70 % .

US 2004/0106818 describes a process for the preparation of venlafaxin hydrochloride by

carrying out the condensation in the presence of metal hydride followed by the reduction of the
compound (III) by the metal hydrides or by the Raney nickel catalyst and hydrogen and isolation
of venlafaxin base (IV). The product obtained by hydrogenation of the compound (III) is
purified by silica gel chromatography. The base is converted into its hydrochloride salt (V).

US2005/0033088 describes a process for the preparation of venlafaxine hydrochloride in which

reduction of the compound (III) is carried out in an organic acid selected from propionic acid,
acetic acid or formic acid and Pd/C as a hydrogenation catalyst under a pressure of 5 to 25
kg/cm2 and at 50-55° C temperature. The resulting acetate salt of the compound (IV) is
formylated with formic acid and formaldehyde to give the final product (V). The yield of the
acetate salt of the compound (IV) is reported to be about 45-55%.

The prior art processes use the base either in 1:0.5 to 3 mole with respect to p-methoxy phenyl
acetonitrile and cyclohexanone or in excess. Use of increased quantity of base leads to self-
condensation of two molecules of p-methoxy phenyl acetonitrile or cyclohexanone to form
undesired side products. This reduces the yield and purity of the compound (III) thereby
reducing yield of the final product and calling for purification of the final product using
expensive procedures and techniques.
Objects of the invention

An object of the invention is to provide a simple, efficient and economical process for preparing
venlafaxine hydrochloride in high yield with high purity.

Another object of the invention is to provide a process for preparing venlafaxine hydrochloride,
which reduces formation of undesired impurities.

Another object of the invention is to provide a process for the preparation of venlafaxine
hydrochloride, which eliminates elaborate work up and purification procedure like
chromatography.

An object of the invention is to provide a simple, efficient and economical process for preparing
l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride in high yield with high
purity.

Another object of the invention is to provide a process for preparing l-[2-amino-l-(4-methoxy

phenyl)ethyl]cyclohexanol hydrochloride, which reduces formation of undesired impurities.

Detailed Description

According to the invention there is provided a process for the preparation of venlafaxine
hydrochloride of the formula (VI):

Formula (VI)
the process comprising
a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone of
the formula (II)
 Formula (I) Formula (II)
in the presence of a base selected from the group consisting of alkali metal alkoxides
and a solvent selected from C4 alcohol at - 10 to 5° C in the molar ratio of the base to
p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1, acidifying the
reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5 to 5° C followed
by addition of water and separation of the organic layer containing l-[cyano-l-(p-
methoxy phenyl)methyl] cyclohexanol of the formula (III):

Formula (III)
b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel and
ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling off the
solvent to obtain a residue containing l-[2-amino-l-(4-methoxy
phenyl)ethyl] cyclohexanol of the formula (IV):

Formula (IV)
c . converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy
phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII):

Formula (VII)
 by dissolving the residue in an organic solvent at temperature of 0 to 5° C followed
by adding hydrogen chloride solution in an organic solvent to adjust pH of the
solution to 1 to 1.5 at the same temperature, adding anti-solvent to precipitate the
compound (VII) while maintaining the same temperature and filtering out and drying
the compound (VII);
d. dissolving the compound (VII) in methanol followed by adjusting the pH of the
solution to 9 to 9.5 by adding methanolic sodium hydroxide solution at 0 to 5° C,
distilling out the solvent from the solution to obtain residue followed by formylating
it with formaldehyde and formic acid at 95 to 100° C to obtain l-[2-dimethyl amino-
1-(4-methoxy phenyl)-ethyl] cyclohexanol of the formula (V) :

Formula (V)
and converting it into venlafaxine hydrochloride (VI) by adding hydrochloric acid in
isopropanol to adjust the pH of the reaction mixture to 1 to 1.5 followed by isolating
it by filtration.

According to the invention there is also provided a process for the preparation of l-[2-amino-l-
(4-methoxy phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII):

Formula (VII)
the process comprising
a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone of
the formula (II):
 Formula (I) Formula (II)

in the presence of a base selected from the group consisting of alkali metal alkoxides
and a solvent selected from C4 alcohol at - 10 to 5° C in the molar ratio of the base to
p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1, acidifying the
reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5 to 5° C followed
by addition of water and separation of the organic layer containing l-[cyano-l-(p-
methoxy phenyl)methyl] cyclohexanol of the formula (III):

Formula (III)
b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel and
ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling off the
solvent to obtain a residue containing l-[2-amino-l-(4-methoxy
phenyl)ethyl] cyclohexanol of the formula (IV);

Formula (IV)
and
b. converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy
phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII)
 Formula (VII)
by dissolving the residue in an organic solvent at temperature of 0 to 5° C followed
by adding alcoholic solution of hydrogen chloride to adjust pH of the solution to 1 to
1.5 at the same temperature, adding anti-solvent to precipitate the compound (VII)
while maintaining the same temperature and filtering out and drying the compound
(VII).

Preferably, the alkali metal oxide used in step (a) is selected from sodium n-butoxide, potassium
n-butoxide, sodium t-butoxide, potassium t-butoxide. Preferably the alkali metal alkoxide used
in the condensation step (a) is sodium butoxide and is used in the molar ratio of 0.1: 1 with
respect to p-methoxy phenyl acetonitrile or cyclohexanone. Preferably the C4 alcohol used in
step (a) is selected from n-butanol, isobutanol or tert-butanol. Preferably the condensation step
(a) is carried out at a temperature in the range of- 10 to -5° C . Preferably the hydrogenation step
(b) is carried out at the pressure of 120psi. On completion of hydrogenation the catalyst is
filtered and solvent is removed by distillation under vacuum to obtain residue. The organic
solvent used to dissolve the residue in step (c) is ethyl acetate, di-isopropyl ether or n-butanol.
Preferably, the hydrogen chloride solution in an organic solvent used to adjust the pH of the
solution in step (c) is hydrogen chloride solution in isopropyl alcohol, di-isopropyl ether or n-
butanol. Preferably, the anti-solvent used to precipitate the compound (IV) in step (c) is n-
pentane, n-hexane or n-heptane, acetone or ethyl methyl ketone.

According to the invention the condensation step (a) is carried out with reduced amount of the
base (0.1 to 0.4 mole of the base with respect to 1 mole of p-methoxy phenyl acetonitrile or
cyclohexanone). 0.1 to 0.4 mole of the base is found to be sufficient to activate 1 mole of p-
methoxy phenyl acetonitrile. As the amount of the base is reduced, self condensation of two
molecules cyclohexanone and p-methoxy phenyl acetonitrile is eliminated and formation of
undesired side products is reduced. The venlafaxine hydrochloride is obtained in high yield of
94 to 95 % with high purity of 99.2 to 99.9 % . The l-[2-amino-l-(4-methoxy
phenyl)ethyl]cyclohexanol hydrochloride (VII) is also obtained in high yield of 88 to 90 % and
purity of 94 to 95 % The process of the invention does not isolate the intermediate (III) and thus
reduces the number of process step and process duration. The venlafaxine hydrochloride
obtained is a white crystalline solid and does not require any purification. The process is also
simple, easy and convenient to carry out, efficient and economical.

The following experimental examples are illustrative of the invention but not limitative of the

scope thereof.

EXAMPLE 1:

a) Preparation of 1-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII)

10 gm of p-methoxy phenyl acetonitrile, 6.85 gm of cyclohexanone, 25 ml of n-butanol
were mixed slowly with stirring while maintaining the temperature in the range of - 10 to
- 5° C for 15 to 20 mins. 20% solution of sodium butoxide was added to the reaction
mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in
the range of -10 to - 5 0C. The reaction mixture was stirred for 120 minutes while
maintaining the same temperature. The reaction mixture was acidified (pH about 5.5)
with glacial acetic acid while maintaining the temperature in the range of -5 to 50C. 30
ml of water was added to the reaction mixture and was stirred for 10 minutes. The
biphasic reaction mixture was allowed to settle and the organic layer was separated. To
this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical butanol (100 ml)
were added. The reaction mixture was transferred to autoclave vessel. H2 gas was flushed
to increase the pressure to 120psi. The mixture was slowly heated at temperature of 10 to
12 0C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of the
reaction was monitored with thin layer chromatography. After completion of reaction,
the catalyst was filtered off and the solvent was distilled off to obtain residue. The
residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 0C . 20 % solution of
hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust
the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of
n-hexane was added to the solution with stirring. Further the reaction mixture was stirred
for 3 hours at 0 to 50C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol
hydrochloride (VII) was filtered and dried at 50 to 52 0C.
% Yield : 90 %
% Purity : 95 %
b) Preparation of venlafaxine hydrochloride (VI)
13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 50G. To
this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to
9 to 9.5 and stirred it for 30 minutes at 0 to 50C. The reaction mixture was filtered and
solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid,
and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 0C.
The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95 to
1000C . The reaction was monitored with thin layer chromatography. The pH of reaction
mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of
20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4 O0C
for 30 minutes while stirring and the organic layer was separated out. The solvent was
distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml
of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 %
hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The
precipitated product was filtered and dried at 50-55 0C

% Yield : 95 %
% Purity : 99.9% .

EXAMPLE 2:
a) Preparation of l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII)

10 gm of p-methoxy phenyl acetonitrile, 6.85 gm of cyclohexanone, 25 ml of isobutanol

were mixed slowly with stirring while maintaining the temperature in the range of -10 to
-5° C for 15 to 20 mins. 20% solution of sodium isobutoxide was added to the reaction
mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in
the range of -10 to -5 0C. The reaction mixture was stirred for 120 minutes while
maintaining the same temperature. The reaction mixture was acidified (pH about 5.5)
with glacial acetic acid while maintaining the temperature in the range of -5 to 5°C. 30
ml of water was added to the reaction mixture and was stirred for 10 minutes. The
biphasic reaction mixture was allowed to settle and the organic layer was separated. To
this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical isobutanol (100 ml)
were added. The reaction mixture was transferred to autoclave vessel. H 2 gas was flushed
to increase the pressure to 120psi. The mixture was slowly heated at temperature of 10 to
12 0C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of the
reaction was monitored with thin layer chromatography. After completion of reaction,
 the catalyst was filtered off and the solvent was distilled off to obtain residue. The
residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 0C. 20 % solution of
hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust
the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of
n-hexane was added to the solution with stirring. Further the reaction mixture was stirred
for 3 hours at 0 to 50C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol
hydrochloride (VII) was filtered and dried at 50 to 52 0C.
% Yield : 89.1 %
% Purity : 94.5 %

b) Preparation of venlafaxine hydrochloride (VI)

13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 50C. To

this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to
9 to 9.5 and stirred it for 30 minutes at 0 to 50C. The reaction mixture was filtered and
solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid,
and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 0C.
The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95-
100 0C. The reaction was monitored with thin layer chromatography. The pH of reaction
mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of
20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4 O0C
for 30 minutes while stirring and the organic layer was separated out. The solvent was
distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml
of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 %
hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The
precipitated product was filtered and dried at 50-55 0C

% Yield : 94.5 %
% Purity : 99.5 % .

EXAMPLE 3:
a) Preparation of 1-[2-amino- 1-(4-methoxy phenyl)ethyl] cyclohexanol hydrochloride (VII)

10 gm of p-methoxy phenyl acetonitrile, 6.8 gm of cyclohexanone, 25 ml of tert-butanol

were mixed slowly with stirring while maintaining the temperature in the range of -10 to
-5° C for 15 to 20 mins. 20% solution of sodium tert-butoxide was added to the reaction
mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in
the range of -10 to -5 0C . The reaction mixture is stirred for 120 minutes while
maintaining the same temperature. The reaction mixture was acidified (pH about 5.5)
with glacial acetic acid while maintaining the temperature in the range of -5 to 50C. 30
ml of water was added to the reaction mixture and was stirred for 10 minutes. The
biphasic reaction mixture was allowed to settle and the organic layer was separated. To
this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical tert-butanol (100
ml) were added. The reaction mixture was transferred to autoclave vessel. H2 gas was
flushed to increase the pressure to 120psi. The mixture was slowly heated at temperature
of 10 to 12 0C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of
the reaction was monitored with thin layer chromatography. After completion of
reaction, the catalyst was filtered off and the solvent was distilled off to obtain residue.
The residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 0C. 20 % solution of
hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust
the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of
n-hexane was added to the solution with stirring. Further the reaction mixture was stirred
for 3 hours at 0 to 50C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol
hydrochloride (VII) was filtered and dried at 50 to 520C.
% Yield : 88.5 %
% Purity : 94.1 %

Preparation of venlafaxine hydrochloride (VI)

13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 50C. To

this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to
9 to 9.5 and stirred it for 30 minutes at 0 to 50C. The reaction mixture was filtered and
solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid,
and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 0C.
The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95-
100 0C. The reaction was monitored with thin layer chromatography. The pH of reaction
mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of
20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4 O0C
for 30 minutes while stirring and the organic layer was separated out. The solvent was
distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml
of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 %
hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The
precipitated product was filtered and dried at 50-55 0C
% Yield : 94.1 %
% Purity : 99.2 % .
0,
CLAIMS :

1. A process for the preparation of venlafaxine hydrochloride of the formula (VI) :

Formula (VI)
the process comprising
a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone
of the formula (II):

Formula (I) Formula (II)

in the presence of a base selected from the group consisting of alkali metal
alkoxides and a solvent selected from C4 alcohol at - 10 to 5° C in the molar ratio
of the base to p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1,
acidifying the reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5
to 5° C followed by addition of water and separation of the organic layer
containing l-[cyano-l-(p-methoxy phenyl)methyl] cyclohexanol of the formula
(III):

Formula (III)
b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel
and ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling
off the solvent to obtain a residue containing l-[2-amino-l-(4-methoxy
phenyl)ethyl]cyclohexanol of the formula (IV):

Formula (IV)
a. converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy
phenyl)ethyl]cyclohexanol hydrochloride of the formula (VII):

Formula (VII)
by dissolving the residue in an organic solvent at temperature of 0 to 5° C
followed by adding hydrogen chloride solution in an organic solvent to adjust pH
of the solution to 1 to 1.5 at the same temperature, adding anti-solvent to
precipitate the compound (VII) while maintaining the same temperature and
filtering out and drying the compound (VII);
b. dissolving the compound (VII) in methanol followed by adjusting the pH of the
solution to 9 to 9.5 by adding methanolic sodium hydroxide solution at 0 to 5° C,
distilling out the solvent to obtain residue followed by formylating it with
formaldehyde and formic acid at 95-100° C to obtain l-[2-dimethyl amino-1-
(4-methoxy phenyl)-ethyl]cyclohexanol of the formula (V):

Formula (V)
 and converting it into venlafaxin hydrochloride of formula (VI) by adding
hydrochloric acid in isopropanol to adjust the pH of the reaction mixture to 1 to
1.5 and isolating it by filtration.

2 . The process as claimed in claim 1, wherein the alkali metal alkoxide used in step (a) is
selected from sodium n-butoxide, potassium n-butoxide, sodium t-butoxide or potassium
t-butoxide.

3. The process as claimed in claim I 5 wherein the alkali metal alkoxide used in step (a) is
sodium butoxide and is used in the molar ratio of 0.1 : 1 with respect to p-methoxy
phenyl acetonitrile or cyclohexanone.

4 . The process as claimed in claim 1, wherein the C4 alcohol used in step (a) is selected
from n-butanol, isobutanol or tert-butanol.

5. The process as claimed in claim 1, wherein the condensation step (a) is carried out at - 10
to - 5° C .

6 . The process as claimed in claim 1, wherein the hydrogenation step (b) is carried out at
the pressure of 120 psi.

7. The process as claimed in claim 1, wherein the organic solvent used to dissolve the
residue in step (c) is ethyl acetate, di-isopropyl ether or n-butanol.

8. The process as claimed in claim 1, wherein the hydrogen chloride solution in an organic
solvent used to adjust the pH of the solution in step (c) is hydrogen chloride solution in
isopropyl alcohol, di-isopropyl ether or n-butanol.

9 . The process as claimed in claim 1, wherein the anti-solvent used to precipitate the
compound (IV) from the solution in step (c) is n-pentane, n-hexane, n-heptane, acetone
or ethyl methyl ketone.

10. A process for the preparation of l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol

hydrochloride of the formula (VII):
 Formula (VII)
the process comprising
a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone
of the formula (II):

Formula (I) Formula (II)

in the presence of a base selected from the group consisting of alkali metal
alkoxides and a solvent selected from C4 alcohol at - 10 to 5° C in the molar ratio
of the base to p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1,
acidifying the reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5
to 5° C followed by addition of water and separation of the organic layer
containing l-[cyano-l-(p-methoxy phenyl)methyl] cyclohexanol of the formula
(III):

Formula (III)
b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel
and ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling
off the solvent to obtain a residue containing l-[2-amino-l-(4-methoxy
phenyl)ethyl] cyclohexanol of the formula (IV):
 Formula (IV)
and
c. converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy
phenyl)ethyl]cyclohexanol hydrochloride of the formula (VII):

Formula (VII)
by dissolving the residue in an organic solvent at temperature of 0 to 5° C
followed by adding hydrogen chloride solution in an organic solvent to adjust pH
of the solution to 1 to 1.5 at the same temperature, adding anti-solvent to
precipitate the compound (VII) while maintaining the same temperature and
filtering out and drying the compound (VII).

11. The process as claimed in claim 10, wherein the alkali metal alkoxide used in step (a) is
selected from sodium n-butoxide, potassium n-butoxide, sodium t-butoxide or potassium
t-butoxide.

12. The process as claimed in claim 10, wherein the alkali metal alkoxide used in step (a) is
sodium butoxide and is used in the molar ratio of 0.1 : 1 with respect to p-methoxy
phenyl acetonitrile or cyclohexanone.

13. The process as claimed in claim 10, wherein the C4 alcohol used in step (a) is selected
from n-butanol, isobutanol or tert-butanol.

14. The process as claimed in claim 10, wherein the condensation step (a) is carried out at -
10 to - 5° C.
15. The process as claimed in claim 10, wherein the hydrogenation step (b) is carried out at
the pressure of 120 psi.

16. The process as claimed in claim 10, wherein the organic solvent used to dissolve the
residue in step (c) is ethyl acetate, di-isopropyl ether or n-butanol.

17. The process as claimed in claim 10, wherein the hydrogen chloride solution in an organic
solvent used to adjust the pH of the solution in step (c) is hydrogen chloride solution in
isopropyl alcohol, di-isopropyl ether or n-butanol.

18. The process as claimed in claim 10, wherein the anti-solvent used to precipitate the
compound (IV) from the solution in step (c) is n-pentane, n-hexane, n-heptane, acetone
or ethyl methyl ketone.