FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL PROCESS FOR PREPARATION OF

VENLAFAXINE

HYDROCHLORIDE AND ITS

INTERMEDIATES
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT
ESTATE,OFF.S.V.ROAD,JOGESHWARI (W), MUMBAI 400 102.
MAHARASHTRA, INDIA

The following specification particularly describes the invention and the manner in which it is to be performed.





A NOVEL PROCESS FOR PREPARATION OF VENLAFAXINE HYDROCHLORIDE AND ITS INTERMEDIATES
THE FIELD OF INVENTION
The present invention relates to a process for the preparation of anti-depressant ;ompound l-[(2-dimethylamino)-l-(4-methoxyphenyl)ethyl]-cyclohexanol hydrochloride and its intermediates.
BACKGROUND OF THE INVENTION
Venlafaxine, (±)-1 -(2(dimethylamino)-1 -(4-methoxyphenyl)ethyl]cyclohexanol, having formula (IV), is an antidepressant. Venlafaxine acts by inhibiting re-uptake of nor epinephrine and serotonine, and is an alternative to the tricyclic anti-depressants and ^elective re-uptake inhibitors.

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PRIOR ART
The US patent 4,535,186 describes the preparation of l-cyano-[(4-methoxyphenyl)
methyljcyclohexanol, (II), using n-butyllithium catalyzed condensation of
4-methoxyphenyl acetonitrile (I) with cyclohexanone at -70 °C affording l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol, (II) in <50% yield. The drawback of the process is low yield and high cost to maintain such a low temperature of-70 °C. An article Tetrahedron Letters, 45, (2004), 7291-95 mention that 1-cyano- [(4-methoxyphenyl)methyl]cyclohexanol having formula (II), can be prepared by using polyethylene glycol-600 (PEG-600). But the yield reported is very low (73%) and the time taken for this conversion is 48 hours.
British patent 2,227,743 describes condensation of 4-methoxyphenyl acetonitrile (I) with cyclohexanone using a base such as lithium diisopropylamide in solvent e.g. n-hexane or toluene etc. to obtain l-cyano-[(z-methoxyphenyl)methyl]cyclohexanol, (II), in 79% yield.
US patent 6,504,044 describes the preparation of 1-cyano-[(4-methoxyphenyl)methyl] cyclohexanol (II) in 87%-97% yield using phase transfer catalyst (PTC) e.g.
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tertiary(alkyl) ammonium halides; pure compound (II). The recrystal

This process requires recrystallization to obtain the lization reduces the yield of the product.

Thus most of the procedures described in the literature for the preparation of l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II), are using organometallic reagents viz. n-butyllithium, lithium diisopropylamide and the reaction is carried out at very low temperature. This makes them of great inconvenience at large scale preparations. Further, the need for setting up plants for operating at such a low temperatures, and high cost of organometallic reagents, make these methods unattractive at industrial level.
US patent 4,535,186 describes the preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) by hydrogenation in presence of rhodium catalyst. PCT application 0250017 describes a process for the preparation of the compound l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) by the reduction of corresponding cyano compound, l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II), in the presence of a nickel or cobalt catalyst. The drawback of these processes is that the use of these catalyst under high-pressure is hazardous and unsafe which makes them inconvenient to use at the industrial scale. Moreover this reaction needs a specialized pressure reactor.
The article Tetrahedron Letters, 45, (2004), 7291-95 mention a one pot process for preparation of 2-[dimethylamino-(4-methoxyphenyl)ethyl]cyclohexanol (IV) starting from 1-cyano- [(4-methoxyphenyl|methyl]cyclohexanol, (II) using Raney nickel as the catalyst under hydrogen gas atmosphere in the presence of formalin,. But the yield obtained is only 30% whereas the 60% of the starting material is recovered and recycled. Thus there is a need to provide a process for the preparation of pure venlafaxine with high yield, which is simple, convenient, cost-effective and non hazardous. Surprisingly, we discovered a novel process, which is simple, convenient, cost-effective, and non hazardous at industrial scale.
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SUMMARY OF THE INVENTION
to a process for the preparation of venlafaxine
The present invention relates hydrochloride, which comprises:
a) preparation of l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol, of the formula (II), from 4-methoxyphenyl acetonitrile of the formula (I) using polyethylene glycol-400 (PEG-400) or Aliquate-336 as a phase transfer catalyst;
b) preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol, of the formula (III), from l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II), using the reducing reagent borane-dimethyl sulphide complex (BDMS) or AICI3-NaBH4, in refluxing tetrahydrofuran;
c) N,N-dimethylation of the amino compound, l-[2-amino-l-(4-metho xyphenyl)ethyl] cycle hexanol (III) by Eschweiler-Clarks procedure employing l,4-dioxane:water system, to obtain l-[(2-dimethyl amino)-1-(4-methoxyphenyl)ethyl]cyclchexanol, of the formula (IV), which was treated with isopropanolic-HCl to get venlafaxine hydrochloride.
One embodiment of the invention is to provide a simple, convenient and cost effective
process for the preparation of l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol, of the
formula (II), with high yield and laving purity more than 99.5% without involving any
purification.
Another embodiment of the invention is to provide a safe and non hazardous process for
the preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) without
using any high pressure reactor / any metal catalyst.
Yet another embodiment of the invention is to provide a one-pot process for the
preparation of venlafaxine hydrochloride starting from l-cyano-[(4-
methoxyphenyl)methyl]cyclohexanol (II) in high yield and high purity.
DETAILED DISCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for synthesizing compound l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II) using polyethylene glycol-400 (PEG-400) as a PTC. l-Cyano-[(4-methoxyphenyl)methyl]cyclohexanol is further subjected to reduction usins a novel process that uses borane-dimethyl sulphide
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complex to obtain the compound l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III), which was subjected to N,N-dimethylation by using Eschweiler-Clarks procedure , to obtain compound venlafaxine (IV). The venlafaxine hydrochloride (V) is finally obtained by preparing hydrochloride salt of the free base (IV), using isopropanol saturated with HC1 gas. The synthetic pathway can be depicted in the following scheme-1:

In one aspect the invention provides a process for the preparation of the compound 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II). The said process comprises:
a) reaction of cyclohexanone with the carbanion of an aryl acetonitrile viz. 4-methoxyphenyl acetonitrile (I) using a base and in the presence of a PTC at a
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temperature in the range from -5 to 35 °C, for time period in the range of 6 to 20 hours, b) isolating the pure compound (II), without any need for purification e.g. recrystallization etc; in high yields.
Accordingly, the carbanion of 4-methoxyphenyl acetonitrile (I) is reacted with cyclohexanone under PTC conditions using PEG-400 and a base. The PTC may be polyethylene glycol-400 (PEG-400) or Aliquate-336, more particularly PEG-400 in 0.01 equivalents to 1.0 equivalent, preferably 0.03 equivalents. The base used is alkali metal hydroxide preferably sodium hydroxide in the range of 0.25 mole equivalent to 1.0 equivalent, preferably 1.0 equivalent. Cyclohexanone and base sodium hydroxide, is added in two lots to obtain a better purity and higher yield. The obtained l-cyano-[(4-methoxyphenyl)methyl]cyclohexarjol (II) is highly pure (>99.5%) with more than 90% yield. Thus there is no need for further purification like recrystallization. Another advantage of this reaction is that the used PTC, PEG-400 is cheap, which makes it suitable for industrial scale. Yet another advantage of using PEG-400 is that it maintains the reaction mixture homogeneous.
Accordingly, the present invention provides an improved process for the preparation of compound l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) which comprises reduction of l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II) using borane-dimethyl sulphide complex or A C^-NaBHLt at ambient pressure and at the reflux temperature of tetrahydrofuran. This reduction procedure does not require specialized instruments like autoclave (high pressure reactor). This process avoids usages of handling of hazardous metal catalysts like Raney nickel, rhodium catalysts etc. The catalyst borane-dimethyl sulphide complex used is 1.44 equivalents to 3.0 equivalents, preferably 1.85 equivalents.
The obtained l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) is further subjected to N,N-dimethylation using Eschweiler-Clarks procedure to produce venlafaxine (IV). This is further treated with isopropanol saturated with HC1 gas to obtain venlafaxine hydrochloride (V).
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The invention can be illustrated purpose only and is not intended
by the following examples, which is for illustration to be limit the scope of the invention in any way.

Examples:
Example (A):
Preparation of l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II):
4-Methoxyphenyl acetonitrile (100 gm) was cooled to 0-5 °C and to this was added 10%
aqueous solution of sodium hydroxide (13.6 gm) followed by PEG-400 (7.3 ml). The
(49.1 ml) was added and reaction second lot of sodium hydroxide (1
reaction mixture was further stirred for 2 hours at 0-5 °C. Then first lot of cyclohexanone
mixture was further stirred for 1-1.5 hours. Then the 3.6 gm) and cyclohexanone (49.1 ml) was added to the
reaction mixture. Then the temperature of the reaction mixture was allowed to attain the ambient temperature and was stirred for 10-12 hours. The reaction progress was monitored by TLC. After the completion of the reaction (TLC), hexane (500 ml) was added to the reaction mixture and stirred for further 15 min. The reaction mixture was filtered and the collected solid was washed with n-hexane (200 ml) and water (200 ml).

The resulting solid was dried

at 55-60 °C. The dried product was l-cyano-[(4-

methoxyphenyl)methyl]cyclohexar.ol (II) (150 gm, 90%) in >99.5% purity.

'H (CDC13): 7.3 and 6.9 (q, 4H), 3.

8 (s, 3H), 3.75 (s, 1H), 1.55 (m, 10H)

Example (B.l):
followed by ethyl acetate (500 ml) was separated and the aqueous laye
Preparation of l-[2-amino-l-(4-me:hoxyphenyl)ethyl]cyclohexanol (III): 1-cyano [(4-methoxyphenyl)methyl]cyclohexanol (II) (100 gm) was charged in a three-necked flask, followed by THF (500 ml) and stirred for 5 min. To this solution borane-dimethyl sulphide complex (94%) solution (67.5 ml) was carefully added in 15 min. Reaction mixture was then re fluxed and the reaction progress was monitored by TLC. After the completion of the reaction (TLC), reaction mixture was cooled to ambient temperature and then quenched carefully with methanol (1500 ml). Solvents were then distilled under reduced pressure below 40 °C. To the residue water (500 ml) was added
and the mixture stirred for 10 min. The organic layer was further extracted with ethyl acetate (500 ml x 2).

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The combined organic layer were washed with sat. aqueous sodium bicarbonate solution (500 ml) followed by sat. aqueous sodium chloride solution (500 ml). The organic layer was then dried over anhydrous sodium sulphate and solvents were then distilled under the reduced pressure below 40 C, to obtain l-[2-amino-l-(4-methoxyphenyl)ethyl] cyclohexanol (III) (85.75 gm, 85%).
'H (CDC13): 7.20 and 6.85 (q, 4H), 3.80 (s, 3H), 3.20 (m, 2H), 2.70 (t, 3H), 2.35 (br s, 3H), 1.4 (m, 10H)

Example (B.2):
Preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III): 1-cyano [(4-methoxyphenyl)methyl]cyclohexanol (II) (100 gm) was charged in a three-necked flask, followed by THF (700 ml) and stirred for 5 min. To this solution aluminium chloride (217 gm) was carefully added over 30 min. at 25-27 C. Then sodium borohydride (62 gm) was added to it. Reaction mixture was then refluxed at 65 °C for 6-8 hours and the reaction progress was monitored by TLC. After the completion of the reaction (TLC), reaction mixture was quenched with water and then washed with hexane. The aqueous layer was basified with NaOH and then extracted with toluene. The toluene
layer was distilled below methoxyphenyl)ethyl]cyclohexanol
40° C to get compound l-[2-amino-l-(4-
(III) (71.7 gm, 70%) 'H (CDCI3): 7.20 and 6.85 (q,

4H), 3.80 (s, 3H), 3.20 (m, 2H), 2.70 (t, 3H), 2.35 (br s, 3H), 1.4 (m, 10H)
Example (C):
Preparation of l-[(2-dimethyl amino)-l-(4-methoxyphenyl)ethyl]cyclohexanol, of the
formula (IV):
l-[2-arnino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III), (100 gm) was charged in a
three-necked flask, followed by 1.4-dioxane (1280 ml) and stirred for 5 min. To this
solution formic acid (128.6 ml), 37%) aqueous formaldehyde solution (99.3 ml) and water
(1060 ml) were successively added. The reaction mixture was then stirred at 90-92 °C,
and the reaction progress was moritored by TLC. After the completion of the reaction
(TLC), reaction mixture was cooled to ambient temperature. The solvents were then
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distilled under the reduced pressure below 50 °C. The residue obtained was extracted with ethyl acetate (200 ml) and the ethyl acetate layer was discarded. The aqueous layer was then basified using solid potassium hydroxide (pH= 9-10). The aqueous layer was then extracted with toluene (500 ml x 3). The combined organic extracts were washed with sat. aqueous sodium chloride solution (200 ml) and then dried over anhydrous sodium sulphate. The solvent was then distilled under the reduced pressure below 50 °C, to obtain l-[(2-dimethyl amino)-l-(4-methoxyphenyl)ethyl]cyclohexanol, of the formula (IV)(100gm, 90%).
'H (CDC13): 7.05 and 6.80 (q, 4H{ 3.80 (s, 3H), 3.30 (t, 1H), 2.35 (s, 6H), 2.30 (dd, 1H), 1.30 (m, 10H),MS(277,M+)
Example (D): {one pot procedure}:
l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II) (10 gm) was charged in a 4 necked flask, followed by addition of 1,4-dioxane (50 ml) and stirred for 10 min. To this solution borane dimethyl sulphide complex (94%) solution (6.75 ml) added carefully in 10 min. and stirred for 15 min. at ambient temperature. The reaction mixture was then refluxed at 92 °C and the reaction progress was monitored by TLC. After the completion of the reaction (TLC), reaction mixture was cooled to ambient temperature. To this reaction mixture formic acid (13.0 ml), 37% aqueous formaldehyde solution (9.85 ml) and water (100 ml) were added successively. The reaction mixture was then stirred at 90-92 °C. and the reaction progress was monitored by TLC. After the completion of the reaction (TLC), reaction mixture was cooled to ambient temperature. The solvents were then distilled under the reduced pressure below 50 °C. The residue obtained was washed using ethyl acetate (20 ml) and the ethyl acetate layer was discarded. The aqueous layer was then basified using solid potassium hydroxide (pH= 9-10). The aqueous layer was then extracted with toluene (50 ml x 3). The combined organic extracts were washed with sat. aqueous sodium chloride solution (20 ml) and then dried over anhydrous sodium sulphate. The solvent was then distilled under the reduced pressure below 50 °C, to obtain l-[(2-dimefhyl amino)-l-(4-methoxyphenyl)ethyl]cyclohexanol, of the formula (IV) (7.34gm, 65% w. r. t. (II)).
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'H (CDCI3): 7.05 and 6.80 (q, 4H|), 3.80 (s, 3H), 3.30 (t, IH), 2.35 (s, 6H), 2.30 (dd, IH), 1.30 (m, 10H),MS(277,M+)

We claim:
1. A process for the preparation of compound l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (II), which comprises:
a) reaction of cyclohexanone with the carbanion of 4-methoxyphenyl acetonitrile (I) using PTC and a base at a temperature in the range from -5 to 35 °C, for time period in the range of 6 to 20 hours
2. A process as claimed in claim preferably PEG-400 in 0.01 to
3. A process as claimed in claim
4. A process as claimed in claim taken in lots
5. A process for the preparation
b) isolating the pure compound (II), without any need for purification
1, wherein the PTC used is PEG-400 or Aliquate-336 1.0 equivalent preferably 0.03equivalent.
, wherein the base is sodium hydroxide taken in lots. '.., wherein the cyclohexanone in the reaction mixture is
of compound l-[2-amino-l -(4-methoxyphenyl) ethyl]

cyclohexanol (III), which comprises reduction of the compound l-cyano-[(4- methoxyphenyl)methyl]cyclohexanol (II), using borane-dimethyl sulphide complex or AlCl3-NaBH4 in tetrahydrofuran .
6. A process as claimed in claim 5, wherein the reaction is carried out at ambient
pressure and reflux temperature
7. A process as claimed in claim 5
NaBH4 used is 1.44 equivalents
of tetrahydrofuran.
wherein borane dimethyl sulphide complex or AICI3-to 3.0 equivalents, preferably 1.85 equivalents
8. A process for the preparation of venlafaxine hydrochloride comprising
a) l-cyano-[(4-methoxyphenyl)methyl] cyclohexanol (II) prepared according to claim 1, 2, 3, or 4; or
b) l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (III) prepared according to claim 5, 6, or 7.
9. A one-pot process for the preparation of venlafaxine hydrochloride from
1 -cyano-[(4-methoxyphenyl)methyl]cyclohexanol(II),where 1 -cyano-[(4-
methoxyphenyl)methyl]cyclohexanol (II) is reduced to l-[2-amino-l-(4-

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methoxyphenyl)ethyl]cyclohexanol (III) using borane-dimethyl sulphide complex in 1,4-dioxane at 60° C which is further refluxed in presence of aqueous solution of formaldehyde and formic acid in the same reaction pot.

Date 14/02/2006


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ABSTRACT:
A process for the preparation of l-cyano-[(4-methoxyphenyl)methyl] cyclohexanol by reacting cyclohexanone with the carbanion of 4-methoxyphenyl acetonitrile in the presence of polyethylene glycol-400 (PEG-400) or Aliquate-336, as a phase transfer catalyst (PTC). The present invertion also relates to an novel process for the preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol, using borane-dimethyl sulphide complex (BDMS) or AlCl3-NaBHL4, in refluxing tetrahydrofuran. l-[2-Amino-l-(4-methoxyphenyl)ethyl]cyclohexanol thus obtained was subjected to N,N-dimethylation using formic acid-formaldehyde in boiling l,4-dioxane:water mixture to obtain l-[2-(dimethylamino)-l-(4-methoxyphonyl)ethyl]cyclohexanol in high purity, which was treated with isopropanol saturated with HCl gas to get venlafaxine hydrochloride in high purity and high yield.
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