International Bureau: (19) World Intellectual Property Organization
International Bureau: (19) World Intellectual Property Organization
International Bureau: (19) World Intellectual Property Organization
(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
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 '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.
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.
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:
% Yield : 95 %
% Purity : 99.9% .
EXAMPLE 2:
a) Preparation of l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII)
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)
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 :
Formula (VI)
the process comprising
a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone
of the 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.
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.