FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESSES FOR PREPARING AMINE INTERMEDIATE USEFUL FOR THE PREPARATION OF VENLAFEXEVE HYDROCHLORIDE


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hail, Ahmedabad 380 009, Gujarat, India

The following specification particularly describes the invention:


PROCESSES FOR PREPARING AMINE INTERMEDIATE USEFUL FOR THE PREPARATION OF VENLAFEXINE HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of l-[2-amino-l-(4-
methoxyphenyl)ethyl]cycIohexanol (V), comprising reducing l-[cyano-(4-
methoxyphenyl)methyl]cyclohexanol of formula (IV ) in a solvent in presence of a Sodium borohydride and Iron salts which is suitable for bulk production. Present invention also relates to the use of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (V) for the preparation of Venlafaxine and its pharmaceutical I y acceptable salts
BACKGROUND OF THE INVENTION;
Venlafaxine, l-(2-(dimethylamino)- 1 -(4-methoxyphenyl)ethyl]cyclohexanoi, having formula (I), is an antidepressant. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonine, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors, which has the structural formula (I):
OMe

.HCI
(I)
Venlafaxine and their intermediates are well known from US patent 4535186.
U.S. Patent 4535186 discloses a process for manufacture of l-[2- amino-1-(p-methoxyphenyl) ethylicyclohexanol (free base of formula V), an intermediate produced during the preparation

of Venlafaxine in two stages by reacting 4-methoxyphenyl acetonitrile with cyclohexanone at -70°C affording l-cyano-[(4- methoxyphenyi)methyl]cyclohexanol in presence of n-butyl lithium, in <50% yield to form 1 -[cyano(p-methoxyphenyl) methyl] Cyclohexanol (IV). Further hydrogenation of l-[cyano(p-methoxyphenyl) methyl] Cyclohexanol (IV) in presence of rhodium catalyst form l-[2-amino-l-(4- methoxyphenyl)ethyl]cyclohexanol (V)..
The synthesis of some Venlafaxine derivatives has been described by Yardley, J. P. et al. J. Med. Chem. 33: 2899-2905 (1990), the disclosure of which is hereby incorporated by reference. This method, which may be adapted for the synthesis of the compounds of this invention, is shown in Scheme




(b)

W

wherein R is methoxy or hydroxy, R is hydrogen or methyl, and the reaction conditions are as follows:
(a) LDA in cycloalkanone at-78°C;
(b) Rh/A1203; and
(c) HCHO, HCOOH, H20, reflux.
The drawback of the process is low yield and high cost to maintain such a low temperature of-78°C. and reduction using very expensive materials and hence the catalyst has to be recovered.

US 6342533 discloses the synthesis of optically pure Venlafaxine derivatives. According to the method disclosed in said document, the l-[cyano (p-methoxyphenyl) methyl] Cyclohexanol (IV). is prepared by reacting cyclohexanone with 4-methoxyphenylacetonitrile in presence of the catalyst lithium diisopropylamide (LDA), in an aprotic solvent such as THF. The cyano group of the compound so obtained is subsequently reacted with the reductant CoCI2/NaBH4 in methanol to form l-[2-amino-l-(4- methoxyphenyl)ethyl]cyclohexanol (V). According to the method disclosed in US 6342533 the sodium borohydride is applied in large quantity.
WO200250017 describes a process for the preparation of the compound l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (V) by the reduction of corresponding cyano compound, 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (IV), in 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 and moreover the Rhodium catalyst is very expensive and hence the catalyst has to be recovered.
US Patent Publication No. 20050033088 describes a process for preparing phenyl ethyl amine derivative, an intermediate of Venlafaxine hydrochloride; said process comprising steps of reduction of compound of formula IV with palladium on charcoal in an organic acid selected from formic acid, acetic acid or propionic acid, preferably acetic acid in an autoclave at a pressure of 5 to 25 kg/cm2 preferably 10 to 15 kg/cm2 at a temperature in the range of 30 to 75°C, preferably at 50 to 55°C till the hydrogenation substantially complete, filtering the palladium catalyst and evaporating the filtrate. Extracting the filtrate with halogenated hydrocarbon solvent and purifying the same. The process also describes the preparation of Venlafaxine hydrochloride without isolation of free base.
PCT application WO2007094008 describes a process for the preparation of the compound l-[2-amino-l~(4-methoxyphenyl)ethyl]cyclohexanol (V) by the reduction of corresponding cyano compound, l-cyano-[(4-methoxyphenyl)rnethyl]cyclohexanol (IV), in presence of a Boran-dimethyl sulphide complex(BDMS) or AlC13-NaBH4 in refluxing tetrahydrofuran and insitu

preparation of Venlafaxine from l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol (IV). This process has several drawbacks as mentioned below:
1. It uses high cost raw materials which end up as a by-product to be separated from reaction mass.
2. The use of high temperature (65° and above) also brings about some charring of material requiring special treatment to remove impurities formed during the manufacturing process.
3. Disclosed process for the preparation of l-[2-amino-l-(4-methoxyphenyI) ethyl] cyclohexanol (V) by employing AlCI3-NaBH4, yield is 71 %. However, when repeating the same experiment the inventor of the present invention obtained only 45-46% yield against 71% due to the formation of gelatinous mass & slow filtration rate. Process results in the formation of a stoichiometric amount of Aluminum hydroxide as a by-product during the work-up, which is immiscible with water and sticky in nature and its removal from the reaction mass is also cumbersome.
EP 1238965 to the Council of Scientific and Industrial Research and the article Tetrahedron Letters, 45, (2004), 7291-95 mention a one pot process for preparation of 2-[dimethylamino-(4-methoxyphenyl)ethyl]cyclohexanol (V) starting from 1 -cyano- [(4-methoxyphenyl)methyl]cycIohexanol (IV) using Raney nickel as the catalyst under hydrogen gas atmosphere in presence of formalin,. But the yield obtained is only 30% whereas the 60% of the starting material is recovered and recycled.
Thus most of the procedures described in the literature for the preparation of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (V) and l-cyano-[(4- methoxyphenyl)methyl]cyclohexanol (IV), are using organometallic reagents viz. n- butyllithium, lithium diisopropylamide and costly catalyst in high pressure or excess amount of borohydride used and the reaction is carried out at very low temperature. This makes them inconvenient 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.

According to the prior art, the one-step process is still at the experimental stage because the low yield makes it inapplicable to industrial production.
Thus there is a need to provide a process for the preparation of of I-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol (V), and its use to prepare Venlafaxine with high yield, which is simple, convenient, cost-effective and non hazardous and can be scaled up for commercial production.
Surprisingly, inventors of the present invention have found a novel process, which is simple, convenient, cost-effective, and non hazardous at industrial scale.
SUMMARY OF THE INVENTION:
In one embodiment, the present invention provides a process for the preparation of l-[2-amino-l-(4-methoxyphenyI) ethyl] cyclohexanol (V):

(V) Comprising, reducing 1 -cyano- [(4-methoxyphenyl) methyl] cyclohexanol (IV)
OMe

(IV)

with an Iron salt and sodium borohydride in presence of an inert solvent.
In another embodiment, the present invention provides a process for the preparation of I-(2-(dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol; having formula (I):
OMe


(i)

.HCI

comprising the steps of:
(i) reacting a 4-methoxyphenyl acetonitrile of formula (II)
OMe

(ll)
With Cyclohexanone of formula (III)
0

(III) to give 1-cyano- [(4-methoxyphenyl)methyl]cyclohexanoI (IV).
OMe

(IV) (ii) isolating 1-cyano- [(4-methoxyphenyl)rnethyl]cyclohexanol (IV) in solid form:

(iii) reducing I-cyano- [(4-methoxyphenyl)methyl]cyclohexanol (IV) with an Iron salt
and sodium borohydride in presence of an inert solvent to form l-[2-amino-l-(4-
methoxyphenyl) ethyl] cyclohexanol (V);
OMe

(V) and (iv) methylating the compound of formula (V) obtained from step (iii) using
formaldehyde and formic acid in inert solvent and isolating Venlafaxine in
hydrochloride form.
Another embodiment of the present invention provides a safe and cost effective process for the preparation of l-[2-amino-I-(4-methoxyphenyl) ethyl] cyclohexanol (V) without using any high pressure reactor / any metal catalyst.
In yet another embodiment, the present invention provides a one-pot process for the preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl]cyclohexanol (V) staring from 4-methoxyphenyl acetonitrile of formula (II) in high yield avoiding recycle of 1 -cyano- [(4-methoxyphenyl)methyl]cyclohexanol (IV)
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes",

"including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "Reduction", "reducing" as used herein means nucleophilic addition of hydride ion from the source of complex reducing agent (NaBH4-FeCI3) to the nitrile group to give a dianion, which is protonated by water to convert in primary amine.
The term "one-pot" as used herein means without isolating intermediate in solid form directly taken for reduction.
The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by

The present invention relates, in general, to an improved process for preparing l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol (V), which is the key intermediate for the preparation of Venlafaxine and its pharmaceutically acceptable salts, as well as its use for the preparation of Venlafaxine and its pharmaceutical ly acceptable salts.
In general, the present invention provides process of preparation of 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V) without isolating 1 -cyano- [(4-methoxyphenyl) methyl] cyclohexanol (IV) and reduction by Iron salts and sodium borohydride as illustrated in scheme.
Scheme


In step (i), condensation of formula (II) and formula (III) may be carried out by any means known to the skilled artisan, such as by method as disclosed in IN 194085 (78/CAL/2003) and US 4535186. The compound of formula (IV) is prepared according to present invention by reacting the 4-methoxy phenylacetonitile (II) with Cyclohexanone (III) using base such as metal hydroxide in an alcoholic solvent at temp range of-5° tol5°C. quench the reaction mass in water, adjusting pH at 5 to 6 and extracting material with water immiscible solvent followed by solvent distillation and adding fresh solvent or alternatively organic layer is directly used for next stage. The obtained reactive intermediate of formula (IV) is either isolated using known methods in art or else can be taken as it is for the further reaction i.e. without isolation.
In step (ii), the compound of formula (IV) as obtained in step (i) is reduced using Sodium borohydride and Iron salts at ambient pressure and at the reflux temperature using suitable solvent. Preferably, in present process, the reduction is carried out in an inert solvent. Inert

solvent is selected from the group comprising of lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, isobutanol, aromatic hydrocarbon such as toluene, xylene, chlorinated solvents such as dichloromethane, esters such as ethyl acetate, ethers, diethyl ether, tetrahydrofuran, dipolar aprotic solvents such as dimethylformamide, cyclohexane, ketones, acetone, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane. Most preferably the organic solvent is selected from Tetrahydrofuran and toluene. Most preferably Tetrahydrofuran is used, to obtain l-[2-amino-l-(4-methoxyphenyl) ethyl]cyclohexanol (V).
The reduction is expediently carried out at a temperature from -10 to 80° C and the conversion is accomplished over a time period of about 0.5 to about 20 hours, however the appropriate time and temperature will vary based on the other parameters, such as reagent choice, solvent etc. provided that the reducing borohydride agent complex of sodium borohydride and iorn salt is applied in the aforementioned relative amount. It may be preferable to adjust the temperature when combining or adding the respective ingredients, as can be determined by the skilled person. Most preferably the temperature of the reaction mixture is maintained within the range of 25-45°C once all reactants have been added and/or combined.
The iron salt is selected from the group consisting of ferric chloride, ferric sulfate, ferric bromide, ferric iodide, and ferric perchlorate; Most preferably ferric chloride is used.
Any suitable ratio of Iron salt and Sodium borohydride can be used for reduction, however in the present invention the preferred ratio is 1:3, more preferably 1:2 and most preferably 1:1.
Alternatively, it is also possible to carry out the procedure in the absence of solvent or using a mixture with an inert solvent. At the end of the reaction, the solid may be separated by simple filtration or any other equivalent means.
Another embodiment of the present invention includes the use of Compound (V) as obtained according to the present invention for producing Venlafaxine and its pharmaceutically acceptable salts by method known in the art.

It has surprisingly been found that the presence of an iro" complex with sodium borohydride catalyst will improve initial catalytic activity of the catalyst for the catalytic reduction of nitriles to produce amine.
The following examples are for illustrative purposes only ^ are not intended, nor should they be interpreted to, limit the scope of the invention.
Example-1:

4-methoxyphenylacetonitrile (50gm, 0.34mo!e) in Methanol (25ml) was cooled to 0-5°C . 160 ml of an Methanolic sodium hydroxide solution (16gm NaOH in 160ml of Methanol) was

above solution in 5 min The temperature was maintained at °-5°c for 9 to 10 hrs. Completion of the reaction was confirmed by thin layer chromatography (TLC). The reaction mass was quench in 200ml water. Charge Methylene chloride stir ar^ separate layer, Methylene chloride layer was with water and distilled out solvent under vacuum oily material obtained strip out the oily product with Isopropyl alcohol, isolate l-(cyano [4-rfiethoxyphenyl] methyl cyclohexanol (IV) from IPA. (71gm, 85%) Purity is >99%.
Example-2:

1-cyano [(4-methoxyphenyl) methyl] cyclohexanol (IV) (71 gm, 029 mole) was charged in three neck flask, followed by THF (568 ml) and stirred for 5 min. To this solution Ferric chloride (141 gm, 0.87 mole) was carefully added over 30 min. at below20°C. Then sodium borohydride (32 gm, 0.87 mole) was added to it. Reaction mixture was then refluxed at 40-45°C. for 12-18 hours and the reaction progress was mon'tored by TLC. After the completion of the reaction (TLC), distilled out THF, add water in the reaction mass and adjust pH not less than 11 using sodium hydroxide solutions at below 15°C. and then extracted with toluene. The

toluene layer was distilled below 40°C to get compound l-[2-amino-l-(4- methoxyphenyl) ethyl] cyciohexanol (V) (56 gm, 77.61% ) purity is > 90%.
Example-3:
{one pot procedure} Preparation of l-(2-amino-l-[4-methoxyphenyl] ethyl) cyciohexanol
(V)
4-methoxyphenylacetonitrile (50gm, 0.34mole) in Methanol (25ml) was cooled to 0-5°C . 160 ml of an Methanolic sodium hydroxide solution (I6gm NaOH in 160ml of Methanol) was added at 0-5°C in 10 min. followed by, cyclohexanone (49gm, 0.5 mole) was added to the above solution in 5 min The temperature was maintained at 0-5°C for 9 to 10 hrs. Completion of the reaction was confirmed by thin layer chromatography (TLC). The reaction mass was quench in 200ml water. Stir and adjust pH of reaction was 5-6 using 10% HCl solution. Charge Methylene chloride stir and separate layer, Methylene chloride layer was with water and distilled out solvent under vacuum oily material obtained strip out the oily product with THF . Fresh THF (800 ml) was charged and stirred for 5 min. To this solution Ferric chloride (141 gm, 0.87 mole) was carefully added over 30 min. at below20°C. Then sodium borohydride (32 gm, 0.87 mole) was added to it. Reaction mixture was then refluxed at 40-45°C. for 12-18 hours and the reaction progress was monitored by TLC. After the completion of the reaction (TLC), distilled out THF, add water (1000ml) in the reaction mass and adjust pH not less than 11 using sodium hydroxide solutions at below 15°C. and then extracted with toluene. The toluene layer was distilled below 40°C to get compound l-[2-amino-l-(4- methoxyphenyl) ethyl] cyciohexanol (V) (64 gm, 76% ) purity is > 90%.
Example-4:
Preparation of l-(2-dimethylamino-l-[4-methoxyphenyl] ethyl) cyciohexanol
hydrochloride (I)
l-[2-ammo-l-(4-methoxyphenyI)ethyl]cyclohexanol (V), (64gm, 0.257 mole) was charged in a three-necked flask, To this formic acid (lOOgm, 2.18 mole), 30% aqueous formaldehyde solution (78.4gm, 0.78 mole) and water (600 ml) were successively added. The reaction mixture was then stirred at 90-95°C for 24-28 hr, and the reaction progress was monitored by

TLC. After the completion of the reaction (TLC), reaction mixture was cooled to ambient temperature. Add DCM (504 ml) in reaction mass. The aqueous layer was then basified using solid sodium hydroxide (pH= 9-11). The aqueous layer was then extracted with DCM (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 30-35°C. . to obtain l-[(2-dimethyl amino)- l-(4-methoxyphenyl)ethyl]cyclohexanol and its hydrochloride salt in isopropyl alcohol by using IPA.HC1, of the formula (I) and recrystallized in isopropyl alcohol to get pure Venlafaxine Hydrochloride (53gm, 89%).purity > 99 %

We Claim:
1. A process for the preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol (V):
OMe

(V) Comprising, reducing 1 -cyano- [(4-methoxyphenyl) methyl] cyclohexanol (IV)
OMe

(IV) with an Iron salt and sodium borohydride in presence of an inert solvent.
2. The process as claimed in claim 1, wherein the Iron salt is selected from the group consisting of ferric chloride, ferric sulfate, ferric bromide, ferric iodide, and ferric perchlorate.
3. A process for the preparation of l-(2-(dimethylamino)-l-(4-methoxyphenyl)ethyl] cyclo hexanol hydrochloride, having formula (I):

OMe

comprising the steps of:
(v) reacting a 4-methoxyphenyl acetonitrile of formula (II)
OMe

(II)
With Cyclohexanone of formula (III)

to give 1-cyano- [(4-methoxyphenyl)methyl]cyclohexanol (IV).
OMe

(IV) (vi) isolating 1-cyano- [(4-methoxyphenyl)methyl]cyclohexanol (IV) in solid form: (vii) reducing 1-cyano- [(4-methoxyphenyl)methyl]cyclohexanol (IV) with an Iron salt
and sodium borohydride in presence of an inert solvent to form l-[2-amino-l-(4-
methoxyphenyl) ethyl] cyclohexanol (V) ;


anu
(viii) methylating the compound of formula (V) obtained from step (iii) using
formaldehyde and formic acid in inert solvent and isolating Venlafaxine in
hydrochloride form.
4. The process as claimed in claim 3, wherein Iron salt and sodium borohydride is used in a
ration of 1:3 preferably in a ratio of 1:2 and more preferably in a ration of 1:1.
5. The process as claimed in above claims 1 to 4, wherein inert solvent is selected from the
group comprising of lower aliphatic alcohols such as methanol, ethanol, propanol,
isopropanol, butanol, sec-butanol, tert-butanol, isobutanol, aromatic hydrocarbon such as
toluene, xylene, chlorinated solvents such as dichloromethane, esters such as ethyl acetate,
ethers, diethyl ether, tetrahydrofuran, dipolar aprotic solvents such as dimethylformamide,
cyclohexane, ketones, acetone, cyclic or acyclic alkanes such as hexane, heptane,
methylcyclohexane.
6. The process as claimed in above claims, wherein inert solvent is selected from
tetrahydrofuran and toluene.
7. A one-pot process for the preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl]
cyclohexanol (V) comprises:
(i) reacting 4-methoxyphenyl acetonitrile of formula (II) with Cyclohexanone formula (III) to give l-cyano-[(4-methoxyphenyl)methyl]cyclohexanol(IV),
(ii) reducing I-cyano-[(4-methoxyphenyl) methyljcyclohexanol (IV) to 1 -[2-amino- 1 -(4- methoxyphenyi)ethyl]cyclohexanol (V) using Iron salt and sodium borohydride at 40-

45°C. B ., The process as claimed in claim 7, wherein the Iron salt is selected from the group consisting of ferric chloride, ferric sulfate, ferric bromide, ferric iodide, and ferric perch 1 orate.
^m The process as claimed in claim 8, wherein the Iron salt is ferric chloride.
tQ. Process for the preparation of l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol (V) as herein described, particularly with reference to the foregoing examples.