BACKGROUND The compounds of formula I are useful intermediates for preparing pharmaceutical 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 merci Index Twelfth Edition 1996, No. 10079). As disclosed in U. S. Patent No. 4, 535, 186, the compounds of formula) 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, NH40H, 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. CN acid Me0 CN NaOH/40°CN Con Me0 k MeO Me0 acidic/H2 amine

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.

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 1, (1) wherein Ri and R2 are ortho or para substituents, independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, Ci-Ce alkoxy, C7-Cg aralkoxy, C2-C7 alkanoyloxy, C1-C6 alkylmercapto, halo or trifluoromethyl ; R3 is hydrogen or Ci-Ce alkyl ; R4 is hydrogen, Ci-Ce alkyl, formyl or C2-C7 alkanol ; 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 5°C to 25°C.

Another aspect of the present invention is to provide a process for preparing a compound of formula (11)

(II) wherein Ri, R2, R3, R4, n and the dotted line are as defined above; R5 is hydrogen or Ci-Ce 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).

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, Ri is hydrogen, hydroxy, Cl-C3 alkoxy, chloro, bromo, trifluor- methyl or Cl-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 Cl-C3 an alkyl.

More preferably, Ri 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 11 are venlafaxine, 0-desmethyl- venlafaxine, N-desmethylvenlafaxine, N, N-didesmethylvenlafaxine, N, O-didesmethyl- 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,

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, Cr203, 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).

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 Ill.

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 111.

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.

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 650mut : CH3CN 350ml : H3PO4 1 ml Detector: UV 220nm Flow rate : 1 ml/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

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 400moi 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 lR (KEr pellet) : 3494 cm~1, 3069, 2930, 2184, 1635, 1612, 1539 1H NiViR Analysis (DMSO-de) : 8 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). 1- [cyano (4- Ex. methoxyphenyl)-Raney Ammonia Reaction Reaction Purity Yield No. methyl] cyclo- Ni (g) Solution temperature Time (%) (%) hexanol (g) (ml) (°C) (hr) 2 7.0 3.5 3.5 r.t. 23 93. 9 61 3 14. 0 7. 0 7. 0 r. t. 21 97. 1 73 4 14.0 7.0 7.0 r.t. 21 98. 3 75 5 14.0 2.8 7.0 r.t. 22 99. 5 60 6 7.0 1.4 7.0 r.t. 24 99. 1 62 7 50.0 15 25 r.t. 22 98. 6 63 8 50. 0 15 25 r. t. 22 98. 6 60 9 50. 0 15 25 r. t. 23 98. 6 61 10 50. 0 15 25 r. t. 24 99. 0 60

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

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 acid, 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-methoxy-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. 1- [cyano (4- No. methoxyphenyl)-Raney Ammonia Reaction Reaction Purity* Major methyl] cyclo- Ni (g) Solution Temperature Time (%) impurity** hexanol (g) (ml) (°C) (hr) (%) Com. 7. 0 0. 7 3. 5 30 22 55. 05 44. 19 Ex. 1 Com. 7.0 3.5 3.5 25 22 52.07 39.04 Ex. 2 Com. 21.0 10.5 10.5 5 45 92.91 3.13 Ex. 3 Reaction not completed * Purity (%): content of 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol ** Major impurity (%): content of 4-methoxyphenethylamine

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.