THIS APPLICATION HAS BEEN DIVIDED OUT OF INDIAN
APPLICATION NO. 1843/KOLNP/2005
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of
phenethylamine derivatives by hydrogenation of phenylacetonitriles in the presence
of a nickel or cobalt catalyst.
BACKGROUND
The compounds of formula I are useful intermediates for preparing
pharmaceutically active substances, which have central nervous system anti-
depressant effects by inhibiting re-uptake of the neurotransmitters, norepinephrine
and serotonin. An example of such antidepressants is Venlafaxine (see Merck Index
Twelfth Edition 1996, No. 10079). As disclosed in U.S. Patent No. 4,535,186, the
compounds of formula I can be produced by coupling a cycloalkanone or a
cycloalkenone with an appropriately substituted phenylacetonitriles (step 1), and then
catalytic hydrogenation of the coupled phenylacetonitriles (step 2). The present
invention is related to an improvement of the second step reaction.
According to the preparation method disclosed in the '186 patent, the coupled
phenylacetonitrile is hydrogenated over rhodium on alumina catalyst. However, the
use of an Rh/Alumina catalyst is not desirable in terms of manufacturing costs, and
thus, Rh/Alumina catalyst is not considered practical for industrial scale synthesis.
PCT WO 02/50017 discloses a process for preparation of phenethylamine
derivatives by hydrogenation of phenylacetonitriles in the presence of a nickel or
cobalt catalyst. Exemplification of PCT WO 02/50017 teaches a hydrogenation

process carried out using a pretreated nickel or cobalt catalyst, for example, Raney
nickel or Raney cobalt, in an organic solvent, such as alcohol, in the presence of a
base, such as NH3, NH4OH, NaOH at a temperature of 27°C to 60 °C.
A process employing a nickel or cobalt catalyst is considered to meet
practical, economic considerations. However, some nickel or cobalt catalysts, for
example, Raneyl nickel or Raney cobalt, are alkaline in their manufactured forms,
and thus, require pretreatment with an acid, which is a cumbersome procedure.
Furthermore, hydrogenation of nitrile compounds is usually conducted in a basic
condition, such as an ammonia solution, because hydrogenation conducted in an
acidic condition generally produces more undesired secondary or tertiary amines
rather than desired primary amines as depicted in the scheme below, and the
reaction may proceed slowly. In light of this, the pretreatment of a nickel or cobalt
catalyst with an acid is not desirable.
It has been found that if hydrogenation of phenylacetonitriles in the presence
of a nickel or cobalt catalyst is conducted under a basic condition at above room
temperature such as those used in the process disclosed in PCT WO 02/50017, such
a hydrogenation reaction results in cracking of the starting nitrile compounds to
produce 4-methoxyphenylacetonitrile, which may be hydrogenated to produce 4-
methoxyphenethylamine impurities, as shown below.
-2-


The present invention is based in part on a finding that hydrogenation of
coupled phenylacetonitriles using a nickel or cobalt catalyst in a basic condition at a
higher temperature produces substantial amounts of phenalkylamine impurities. The
phenalkylamine impurities are very similar to the desired end products of primary
amines in terms of physical and chemical properties, and thus, it is very difficult to
separate them from the desired end products.
The improvement of reducing impurities, in particular, impurities that are
difficult to separate, is an advantage over previously known processes.
SUMMARY
Accordingly, one of the objects of the present invention is directed to an
improvement of a hydrogenation reaction using a nickel or cobalt catalyst to obtain
high yield and purity compounds of formula (I), with decreased production of
phenylalkylamine impurities such as 4-methoxyphenethylamine, by conducting the
reaction at temperatures between 5°C and 25°C.
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Another object of the present invention is to provide a simplified process, for
the preparation of compounds of formula I in high yields and purity, which does not
require pretreatment with an acid of a nickel or cobalt catalyst and is thus cost
effective on an industrial scale.
A further object of the present invention is to provide an improved process
for the preparation of phenethylamine compounds of formula (II) in high yields and
purity.
DETAILED DESCRIPTION
One aspect of the present invention is to provide a process for the
preparation of a compound of formula I,

wherein R1 and R2 are ortho or para substituents, independently selected from the
group consisting of hydrogen, hydroxyl, C1-C8 alkyl, C1-C6 alkoxy, C7-C9 aralkoxy,
C2-C7 alkanoyloxy, C1-C6 alkylmercapto, halo or trifluoromethyl; R3 is hydrogen or
C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl, formyl or C2-C7 alkanoyl; n is one of the
integers 0,1,2,3 or 4; and the dotted line represents optional olefinic unsaturation;
comprising hydrogenating a compound of formula III,
-4-


in the presence of a nickel or cobalt catalyst at a temperature of 5°C to 25°C.
Another aspect of the present invention is to provide a process for preparing a
compound of formula (II)

wherein R1, R2, R3, R4, n and the dotted line are as defined above; R5 is hydrogen or
C1-C6 alkyl and R6 is C1-C6 alkyl;
comprising hydrogenating a compound of formula (III) in the presence of a nickel or
cobalt catalyst at a temperature of 5°C to 25°C to produce a compound of formula (I)
and alkylating the compound of formula (I).
-5-

The alkylation of a compound of formula (I) to a compound of formula (II) can
be conducted by methods well known in the art. Such alkylation and the reaction
conditions to be used are described in U.S. Patent No. 4,535,186, incorporated by
reference herein in its entirety.
Preferably, R1 is hydrogen, hydroxy, C1-C3 alkoxy, chloro, bromo, trifluoro-
methyl or C1-C3 alkyl; R2 is C1-C3 alkyl, C1-C3 alkoxy, chloro, bromo, trifluoromethyl or
C2-C3 alkanoyloxy; R3 is hydrogen or C1-C3 alkyl; R4 is hydrogen; R5 is hydrogen or
C1-C3 alkyl and R6 is C1-C3 an alkyl.
More preferably, R1 is hydrogen, and R2 is other than hydrogen, R2 being in
a para position, and n is 2.
The most preferred compounds of formula I are 1-[2-amino-1-(4-methoxy-
phenyl)ethyl]cyclohexanol and 1-[2-amino-1-(4-hydroxy-phenyl)ethyl]cyclohexanol.
The most preferred compounds of formula II are venlafaxine, O-desmethyl-
venlafaxine, N-desmethylvenlafaxine, N.N-didesmethylvenlafaxine, N,O-didesmethyI-
venlafaxine and O-desmethyl-N,N-didesmethylvenlafaxine.
In accordance with the present invention is provided compounds of Formula I
substantially free of phenalkylamine impurities. In particular aspects of the invention
the impurity is 4-methoxyphenethylamine or 4-hydroxyphenethylamine. Substantially
free, as used herein, refers to greater than about 92% purity, more preferably greater
than 95% purity and most preferably greater than 98% purity. Purity as used herein,
-6-

refers to the absence of impurities, the majority of impurities, i.e. greater than 50%,
being phenalkylamine impurities.
Nickel or cobalt catalysts to be used in the present invention are well known
and commonly used in the art. Detailed information on nickel or cobalt catalysts are
provided in WO 02/50017 A1, which is incorporated by reference in this application.
The catalysts can be in supported or unsupported form. Typical support materials
include, for example, carbon, aluminum oxide, silicium dioxide, Cr2O3, titanium
dioxide, zirconium dioxide, zinc oxide, calcium oxide, magnesium oxide, barium
sulfate, calcium carbonate or aluminum phosphate. The nickel or cobalt catalyst can
be bound on the substrate in an amount of, for example, about 1.0 to about 20.0% by
weight.
The preferred catalysts are Raney-Ni and Raney cobalt catalysts. Such
catalysts are, for example, formed by mixing nickel and aluminum or cobalt and
aluminum and subsequently treating the respective mixtures with a suitable base,
such as sodium hydroxide to remove the aluminum, thus leaving a highly reactive
nickel or cobalt metal catalyst.
In all cases, nickel catalysts are preferred; and highly preferred are Raney-Ni
catalysts. Raney-Ni catalysts are commercially available from Grace, Degussa (for
example, product No. B111 W, B112 W, B2112 Z), PMC (for example, product No.
5200, 5020, 5800), and AMC (for example, Product No. A-5000).
-7-

The amount of a nickel or cobalt catalyst to be used is not specifically limited
and may be in the range from about 10% to about 50% by weight or more. Higher
amounts of catalysts may be preferable in terms of activity and selectivity. However,
reasonable amounts of catalysts are usually used in view of cost considerations.
Catalyst is used in an amount of about 30% to 50% by weight, based on the amount
of a compound of formula III.
The hydrogenation reaction of the present invention is preferably conducted
in an organic solvent. An alcohol, such as MeOH, EtOH or isopropyl alcohol, is
preferably used, MeOH is most preferable.
In the present invention, a basic compound such as ammonia may optionally
be added to a reaction solution, which is advantageous to prevent production of
impurities, such as secondary or tertiary amines, during the reduction process.
Preferably, the amount of ammonia used is from 0.5 to about 1.5 equivalent,
preferably from about 0.9 to about 1.1 equivalent, based on the weight of a
compound of formula III.
In the present invention, the reaction temperature for the hydrogenation
reaction is in the range of 5°C to 25°C, preferably in the range of 10°C to 25°C, and
more preferably in the range of 15°C to 20°C. If the temperature is more than 25°C,
the production of impurities is increased. If the temperature is less than 5°C, the
reaction rate becomes too slow.
-8-

A compound of formula (II) can be converted to a pharmaceutically
acceptable salt. Said salts are prepared in accordance with procedures known to the
art and may be formed conventionally by reaction of the free base with an equivalent
amount of any acid which forms a non-toxic salt. Pharmaceutically acceptable
inorganic or organic salts, include, but are not limited to, hydrochloric, hydrobromic,
fumaric, maleic, succinic, tartarate, sulfuric, phosphoric, tartaric, acetic, and citric.
The present invention will now be described in detail with reference to the
following examples, which are not intended to limit the scope of the present
invention.
HPLC analysis was carried out under the following conditions:
Column: YMC Pack ODS AQ 4.6 x 250mm
Mobile phase: 5mM KH2PO4 650ml: CH3CN 350ml: H3PO4 1ml
Detector: UV 220nm
Flow rate: 1ml/min
Sample concentration: 0.01g/1ml Eluent
Run time: 50 min
Example 1
The reactor was charged with 25.0g of Raney-Ni (Kawaken, Grace 2400,
2724, Degussa B111W, 112W), and 250 ml of MeOH and 25 ml of an ammonia
solution (25% NH3) were added. To the mixture was added 50g of 1-[cyano(4-
methoxyphenyl) methyl] cyclohexanol, followed by 250 ml of MeOH. The reactor was
settled and purged with N2 gas two or three times. After fully purged with N2, the
reactor was purged with H2 gas two or three times. Internal pressure of the reactor
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was adjusted to 60 psi and the reaction mixture was stirred. After 20 to 30 hours of
reaction at room temperature (about 10 to 20°C), in-process analysis of a sample of
mixture was made. After the reaction was completed, Ra-Ni was removed by
filtration with a celite pad. The filtrate was distilled under reduced pressure until all of
the solvent was evaporated, and 200ml of isopropyl alcohol and 400ml of ethyl
acetate were added to the residue oil to dissolve the resulting product to give a clear
or a little hazy solution. To the solution was added 10ml of acetic acid dropwise, and
an exothermic reaction began with some fumes given off. After about 10 to 20
minutes of adding all of the acetic acid, a solid began to form. The solution was
stirred for about one hour, filtered and washed with ethyl acetate to give the desired
product, 1-[2-amino-1-(4-methoxyphenyl) ethyl] -cyclohexanol, 44.2g (yield 70%,
purity 99%).
HPLC analysis: desired product: 3.5min; starting material: 35min, 4-methoxy-
phenethylamine: 2.8 min, dehydrated compound: 8.5min
IR (KBr pellet): 3494 cm-1, 3069,2930,2184,1635,1612, 1539
1H NMR Analysis (DMSO-d6):  1.0-1.71 (m, 10H, cyclohexane), 1.818(s,
3H, acetic acid), 2.72(dd, 1H), 2.97(t,1H), 3.27(dd, 1H). 3.73 (3H, s, OCH3), 6.85 (d,
2H, aromatic), 7.15(d, 2H, aromatic)
Examples 2 to 10
The tests were carried in the same manner as in Example 1, except the
amounts of starting material, Raney-Ni and ammonia solution, the reaction
temperature, and the reaction time as shown in the table below, and purities and
yields of desired products were also shown in the end column of the table (r.t.=room
temperature of about 10 to 20°C).
-10-


Example 11
After 40ml of H2O was added to a mass cylinder, the mass cylinder was
placed on a balance. The balance was then zeroed. Raney-Ni was added to the
mass cylinder and the increased volume of water was taken away while maintaining
the total volume at 40 ml, until the total weight indicated by the balance was 12 g.
H2O was removed and 40 g of fresh H2O was added in order to wash the catalyst.
After washing, the H2O was removed. The reactor was charged with Raney-Ni while
flushing with 20ml of H2O and 600 ml of MeOH. To the mixture was added 40g of 1-
[cyano(4-methoxyphenyl)methyl]cyclohexanol, followed by 20ml of an ammonia
solution. The reactor was settled, then purged with N2 gas two or three times. After
fully purged with N2, the reactor was purged with hydrogen gas two or three times.
The internal pressure of the reactor was adjusted to 60 psi, and then stirring was
initiated. After 20 to 30 hours of reaction at room temperature, in-process analysis of
-11-

a sample of mixture was made. After the reaction was completed, Ra-Ni was
removed by filtration with a celite pad. The filtrate was distilled under a reduced
pressure until all of the solvent was evaporated, and 160 ml of isopropyl alcohol and
320 ml of ethyl acetate were added to the residue oil and dissolved to give a clear or
little hazy solution. To the solution was added 12 ml of acetic acid drop-wise. An
exothermic reaction with some fumes began. After about 10 to 20 minutes of adding
all of the acetic add, a solid began to be produced. ' The solution was stirred for
about one hour, filtered and washed with ethyl acetate to give the clear product, 1-[2-
amino-1-(4-rnethoxy-phenyl)ethyl]cyclohexanol, 35.3g (yield 70%, purity 99%).
Comparative Examples 1 to 3
These comparative examples were carried in the same manner as those of
Example 1, except the amounts of starting material, Raney-Ni and ammonia solution,
the reaction temperature, and the reaction time as shown in the table below, and the
purities and yields of the desired products are shown in the end column of the table.

* Purity(%): content of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol
** Major impurity(%): content of 4-methoxyphenethylamine
-12-

While the present invention has been described with respect to the particular
examples, it will be apparent to those skilled in the art that many changes and
modifications may be made without departing from the scope of the invention as
defined in the appended claims.
-13-

WE CLAIM:
1. A process for the preparation of a compound of formula I,

wherein R1 and R2 are ortho or para substituents, independently selected from the
group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C9 alkoxy, C7-C9 aralkoxy,
C2-C7 alkanoyloxy, C1-C8 alkylmercapto, halo and trifluoromethyl; R3 is hydrogen or
C1-C6 alkyl ; R4 is hydrogen, C1-C6 alkyl, formyl or C2-C7 alkanoyl; n is one of the
integers 0,1,2,3 or 4; and the dotted line represents optional olefinic unsaturation;
comprising, hydrogenating a compound of formula III,

wherein R1, R2, R3, R4, n and the dotted line have the meanings same meanings as
those in formula (I) in the presence of a nickel or cobalt catalyst at a temperature of
5°C to 25°C.
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2. The process according to Claim 1 wherein the catalyst is Raney-Ni.
3. The process according to Claim 1 or 2 wherein the reaction temperature is
from10°C to 25°C.
4. The process according to any one of Claims 1 to 3 wherein the reaction
temperature is from 15°C to 20°C.
5. The process according to any one of Claims 1 to 4 wherein hydrogenation is
carried out in the presence of methanol, ethanol or isopropyl alcohol.

6. The process according to any one of Claims 1 to 5 wherein the amount of
catalyst is from 10 to 50% by weight based on the amount of the compound of
formula III.
7. The process according to any one of Claims 1 to 6 wherein the amount of
catalyst is from 30 to 50% by weight based on the amount of the compound of
formula III.
8. The process according to any one of Claims 1 to 7 wherein R1 is hydrogen,
hydroxyl, C1-C3 alkoxy, chloro, bromo, trifluoromethyl or C1-C3 alkyl; R2 is C1-C3 alkyl,
C1-C3 alkoxy, chloro, bromo, trifluoromethyl or C2-C3 alkanoyloxy; R3 is hydrogen or
C1-C6 alkyl; and R4 is hydrogen.
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9. The process according to any one of Claims 1 to 8 wherein R1 is hydrogen,
R2 is other than hydrogen, R2 is in a para position, and n is 2..
10. The process according to any one of Claims 1 to 9 wherein the compound of
Formula I is 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyc!ohexanol.
11. The process according to any one of Claims 1 to 9 wherein the compound of
Formula I is 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol.
12. The process of Claim 1 further comprising alkylating the compound of formula
(I) to provide compound of Formula (II)

wherein R1, R2, R3, R4, n and the dotted line are as defined in Claim 1, ; R5 is
hydrogen or C1-C6 alkyl; R6 is C1-C8 alkyl.
13. The process according to Claim 12, further comprising conversion of the
compound of formula (II) to a pharmaceutically acceptable salt.
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14. The process according to Claim 12 or 13, wherein the compound of formula II
is venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, N,N-didesmethyl-
venlafaxine, N,O-didesmethylvenlafaxine or O-desmethyl-N,N-didesmethylvenlafaxine,
or a pharmaceutically acceptable salt thereof.
15. A composition of formula (I) prepared according to the process of Claim 1,

wherein R1 and R2 are ortho or para substituents, independently selected from the
group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C7-C9 aralkoxy, C2-C7
alkanoyloxy, C1-C6 alkylmercapto, halo and trifluoromethyl; R3 is hydrogen or C1-C6
alkyl ; R4 is hydrogen, C1-C8 alkyl, formyl or C2-C7 alkanoyl; R5 is hydrogen or C1-C6
alkyl; R6 is C1-Ca alkyl; n is one of the integers 0, 1, 2, 3 or 4; and the dotted line
represent optional olefinic unsaturation, substantially free of phenylalkylamine
impurities.
16. A composition of Claim 15 wherein the compound is 1-[2-amino-1-(4-methoxy-
phenyl)ethyl]cyclohexanol or 1-[2-amino-1 -(4-hydroxyphenyl)ethyl]cyclohexanol.
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17. A composition of formula (II) prepared according to the process of Claim 13,

wherein R1 and R2 are ortho or para substituents, Independently selected from the
group consisting of hydrogen, hydroxyl, C1-C9 alkyl, C1-C8 alkoxy, C7-C9 aralkoxy,
C2-C7 alkanoyloxy, C1-C6 alkylmercapto, halo and trifluoromethyl; R3 is hydrogen or
C1-C6 alkyl; R4 is hydrogen, C1-C8 alkyl, formyl or C2-C7 alkanoyl; R5 is hydrogen or
C1-C6 alkyl; R6 is C1-C8 alkyl; n is one of the integers 0,1, 2, 3 or 4; and the dotted line
represents optional olefinic unsaturation, or a pharmaceutically acceptable salt, thereof,
said composition being substantially free of phenylalkylamine impurities.
18. The composition of Claim 17 wherein the compound is venlafaxine, N-des-
methylvenlafaxine, N,N-didesmethylvenlafaxine, or a pharmaceutically acceptable salt
thereof, substantially free of 4-methoxyphenethylamine impurities.
19. The composition of Claim 17 wherein the compound is O-desmethyl-
venlafaxine, N, O-didesmethylvenlafaxine, O-desmethyl-N,N-didesmethylvenlafaxine,
or a pharmaceutically acceptable salt thereof, substantially free of 4-methoxy-
phenethylamine impurities.
20. A process for the preparation of a compound of formula 1 substantially as herein
described.
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A process for the preparation of a compound of formula (I), wherein R1, and R2 are ortho or para substituents, independently
selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C7-C9 aralkoxy, C2-C7 alkanoyloxy,
C1-C6 alkylmercapto, halo and trifluoromethyl; R3 is hydrogen or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl, formyl or C2-C7 alkanoyl;
n is one of the integers 0, 1, 2, 3 or 4; and the dotted line represents optional olefinic unsaturation; comprising hydrogenating
a compound of formula (III), in the presence of a nickel or cobalt catalyst at a temperature of about 5°C to 25°C.