WO2008059525A2

WO2008059525A2 - An improved process for the preparation of venlafaxine and its analogs

Info

Publication number: WO2008059525A2
Application number: PCT/IN2007/000462
Authority: WO
Inventors: Bansi Lal; Vitthal Genbhau Gund
Original assignee: Calyx Chemicals and Pharmaceuticals Ltd
Current assignee: Calyx Chemicals and Pharmaceuticals Ltd
Priority date: 2006-09-29
Filing date: 2007-10-01
Publication date: 2008-05-22
Anticipated expiration: 2009-03-29
Also published as: WO2008059525A3

Abstract

A novel single step process for the synthesis of venlafaxine of formula I and N-desmethylvenlafaxine of formula II from 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile [cyano-intermediate] of formula V V comprising reacting 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF VENLAFAXINE AND ITS ANALOGS

FIELD OF INVENTION

The present invention relates to a novel process for the synthesis of l-[2-dimethylamino-l- (4-methoxyphenyl)ethyl]cyclohexanol, commonly known as venlafaxine, and its analog l-[2- methylammo-l-(4-methoxyphenyl)ethyl]cyclohexanol, known as N-desmethylvenlafaxine from 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile intermediate.

BACKGROUND OF THE INVENTION

A number of nontricyclic antidepressants have been developed that diminish the cardiovascular & anticholinergic liability characteristic of tricyclic antidepressants. The nontricyclic compound venlafaxine, chemically known as (±)-l-[2-(dimethylamino-l-(4- methoxyphenyl)ethyl] cyclohexanol is described in U.S. Patent No. 4,761,501 & in Drugs of the future 1988, 13(9), 839-840. Venlafaxine represented by formula I and its pharmaceutically acceptable salts developed by Wyeth-Ayerst & Company in 1983 are new generation antidepression drugs, which are quite different from other antidepressants, having a unique structure and morphological effects. (Zhou Jinpei, et.al. J. China Pharm University 1999, 30(4), 249-250). The formulation containing racemic venlafaxine hydrochloride salt is currently commercially available under the trade name Effexor.

Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin. It has been reported that its (-) enantiomer is a more potent inhibitor of norepinephrine synaptosomal uptake while its (+) enantiomer is more selective in inhibiting serotonin uptake (J. Med. Chem. 1990, 33(10), 2899-2905) In humans, venlafaxine is transformed by a metabolic pathway into two minor metabolites, N-desmethylvenlafaxine of formula II, N,O-di- desmethylvenlafaxine of formula IV and one major metabolite, O-desmethylvenlafaxine of formula III.

formula I formula II

formula III formula IV

In the literature there are several processes reported for the synthesis of venlafaxine of formula I and venlafaxine hydrochloride of formula Ia.

formula Ia

The synthesis of venlafaxine from 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (hereinafter called as cyano-intermediate and represented by formula V) involving two step synthesis is known in the prior art.

formula V

US 4,535,186 discloses the preparation of venlafaxine of formula I by the reaction of p- methoxyphenylacetonitrile with cyclohexanone at -78 ⁰C in the presence of n-butyllithium as a base which yields 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V. Reduction of the cyano-intermediate under hydrogen pressure with rhodium on alumina catalyst gives l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol. N-Methylation of the amino compound is accomplished employing formaldehyde and formic acid (Eschweiler- Clarke reaction) to give venlafaxine of formula I.

The reaction is as shown in the Scheme- 1.

Reduction

Scheme-1

Another prior art reference, Zhou Jinpei et.al, J. China Pharm. University, 1999, 30(4), 249- 50) discloses the preparation of venlafaxine starting from anisole. Anisole is acylated to the chloroacetyl derivative, which is then animated using N,N-dirnethylamine. The carbonyl group of this compound is reduced to the alcohol using KBH₄ and is converted to the bromo- derivative using PBr₃ which in turn when reacted with Mg and cyclohexanone undergoes a Grignard reaction to provide venlafaxine of formula I.

The reaction is as shown in the Scheme-2.

Scheme-2

US 2005033088 discloses a two step process for venlafaxine starting from the cyano- intermediate. The cyano-intermediate is reduced in the presence of palladium on charcoal in acetic acid at a hydrogen pressure of 5-25 kg/cm² at a temperature in the range of 30-75 ⁰C. The product of step 1 is N-methylated using formic acid, formaldehyde solution at a temperature of 90-98 ⁰C for 19 hrs to yield venlafaxine, which is then converted to its hydrochloride salt.

WO2006035457 also discloses a process of making venlafaxine and its intermediates. The process comprises the step of hydrogenating the cyano-intermediate in the presence of toluene, water, and Raney nickel where in the said process yields 66% of an intermediate with 99% HPLC purity. This reaction is carried out at 10-12 ⁰C and at 4-5 kg/cm² of hydrogen pressure for 2 hrs and further at 50 ⁰C at 7-8 kg/cm² for 7-8 hrs. This intermediate is N-methylated using formaldehyde and formic acid mixture to form venlafaxine, which is treated with IPA/HC1 to get venlafaxine hydrochloride.

US 6,350,912 discloses a one pot process for the preparation of venlafaxine in 15-28 % yield from the cyano-intermediate. In the said patent venlafaxine has been prepared by the reduction of cyano-intermediate in the presence of Raney nickel and without isolation of intermediate l-[2-amino-l-(4-methoxyphenyl) ethyl] cyclohexanol

CN 1850781 discloses a process for the preparation of venlafaxine by following steps: (1) carrying out condensation of 4-methoxyphenylacetonitrile and cyclohexanone in presence of base to obtain 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile, (2) reacting 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with cuprous chloride and dimethylamine to obtain 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)-N,N- dimethylacetimidamide, and (3) reacting 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)- N,N-dimethylacetimidamide with KBH₄ to obtain 1 - [2-dimethylamino)- 1 -(4-methoxyphenyl) ethyl)cyclohexanol (venlafaxine).

The reaction is as shown in the Scheme-3.

Scheme-3

The processes disclosed in the prior art have many disadvantages. Most of the prior art processes employ formaldehyde as a reactant for N-methylation step which is known to be a carcinogen. Acute exposure of the same is highly irritating to the eyes, nose and throat. Ingestion of formaldehyde is fatal and long term exposure causes respiratory problems and skin irritation.

Another disadvantage is the formation of an impurity (represented by formula VI), which is formed during N-methylation step using formaldehyde as a reagent.

formula VI

As may be appreciated, all the above well-known processes share the same strategy of synthesis, consisting of two steps for the synthesis of venlafaxine from cyano-intermediate or are prepared in one pot with poor yield.

Yet another drawback of the processes disclosed in the prior art is the use of expensive catalysts like rhodium on alumina and use OfBF₃ etherate which is highly corrosive.

Hence there is a need to develop an alternative process for the synthesis of venlafaxine and its analogs which is simple and cost effective, and avoids use of harmful chemicals.

Keeping in view the difficulties of above mentioned processes for the large scale preparation of venlafaxine of formula I and N-desmethylvenlafaxine of formula II, the present inventors aimed to develop a novel single step process for the preparation of venlafaxine and N- desmethy lvenlafaxine .

The present inventors have surprisingly found that venlafaxine of formula I and N- desmethylvenlafaxine of formula II can be prepared in single step by reacting the cyano- intermediate of formula V with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere. Another advantage of the present invention is that, the process avoids the use of formaldehyde reagent during the methylation step and hence absolutely avoids the formation of impurity of formula VI, which is otherwise difficult to separate.

The prior art references disclose the synthesis of alkoxyphenylethyldimethylamine from alkoxyphenylacetonitrile using excess dimethylamine and palladium catalyst in methanol solution which is firstly reported by Kindler and Hensse. (1. Kindler and Hesse; Arch. Pharm., 1933, 271, 439. 2. Johannes S. Buck, Richard Baltzly and Walter S. Ide; J. Am. Chem. Soc. 1938, 60(8), 1789-1792; 3. Albert J. Schuster and Eugene R. Wagner; J. Labelled Compounds and Radiopharmaceuticals 1992, XXXIII(3), 213-217).

The reaction is as shown in the Scheme-5.

Scheme-5

The above-mentioned conversion has so far not been reported on molecules of the formula V bearing a tertiary alcohol group. Inventors are the first to use this method for preparation of venlafaxine and and its analogs.

OBJECTIVES OF THE INVENTION

Accordingly, the main objective of the present invention is to provide a novel single step process for the synthesis of venlafaxine and N-desmethylvenlafaxine from 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile intermediate. Another objective of the present invention is to provide a better yielding process for the synthesis of venlafaxine and N-desmethylvenlafaxine with better purity.

Still another objective of the present invention is to provide a novel process for the synthesis , of venlafaxine and N-desmethylvenlafaxine that avoids the high temperature condition like in Eschweiler-Clarke reaction.

Yet another objective of the present invention is to provide a simple and economically viable process for the synthesis of venlafaxine and N-desmethylvenlafaxine

Further objective of the present invention is to provide an environmentally safe process for the synthesis of venlafaxine and N-desmethylvenlafaxine avoiding use of hazardous reagents like formaldehyde

SUMMARY OF THE INVENTION

According to an aspect of the invention there is provided a novel single step process for the synthesis of venlafaxine of formula I and N-desmethylvenlafaxine of formula II from 2-(l- hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V comprising reaction of 2- (l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere.

formula I formula II formula V DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a single step process for venlafaxine and its analog starting from the cyano-intermediate. The present invention circumvents the difficulties encountered in the prior art and is an economically viable process.

The present invention particularly relates to a single step synthesis of venlafaxine of formula I, and N-desmethylvenlafaxine of formula II from the cyano-intermediate of formula V.

The reaction of the present invention is as shown in Scheme-4:

formula V formula L R = CH₃ (Venlafaxine) formula II. R = H (N-desmethylvenlafaxine)

formula Ia. R = CH₃, X = Cl formula Ha. R = H, X = Cl

Scheme-4 The present inventors have found out that venlafaxine of formula I and N- desmethylvenlafaxine of formula II can be prepared in a single step by reacting the cyano- intermediate of formula V with an alkylamine and/or its salt in a solvent in the presence of transition metal catalysts, under hydrogen atmosphere. The reaction is carried out in an organic solvent or in mixture of organic solvent and water.

The cyano intermediate of formula V is prepared by the reaction of cyclohexanone with arylacetonitrile in the presence of base using the processes as described in the prior art.

The pharmaceutically acceptable salts of Venlafaxine of formula I and N- desmethylvenlafaxine of formula II is also prepared, as shown in scheme-4, in accordance with the procedures known to the art or conventionally by reaction of the free base of Formula I & II with an equivalent amount of any acid (HX) which forms non-toxic salts. Pharmaceutically acceptable inorganic or organic salts include, but are not limited to hydrochloric, hydrobromic, fumaric, maleic, succinic, tartarate, sulfuric, phosphoric, tartaric, acetic and citric.

In an embodiment of the present invention the alkylamine used is in the form of a free base solution in a solvent such as alcohol or in the form of its salt or as the combination of free base solution in alcohol and its salt.

In another embodiment of the present invention the alkylamine is selected from monoalkylamine or dialkylamine or their salts.

In further embodiment of the present invention the monoalkylamine is preferably methylamine, more preferably methylamine hydrochloride

In yet another embodiment of the present invention the dialkylamine is preferably dimethylamine, more preferably diniethylamine hydrochloride The molar ratio of the cyano-intermediate to the alkylamine and/or its salt is from 1:1 to 1:10, more preferably from 1:1 to 1:5.

The transition metal catalyst is selected from palladium, platinum, rhodium, or nickel. The catalyst is supported or unsupported. Preferably the catalyst is selected from palladium oxide, palladium hydroxide or 5-20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate, more preferably it is selected from 5-20% palladium supported on carbon and alumina.

The catalyst concentration with reference to the cyano-intermediate is from 5-100 wt %, preferably the catalyst concentration is 20-50 wt % .

The organic solvent is a polar organic selected from C₁-C₄ alcohol, water, N, N- dimethylformamide, esters, ethers, halogenated solvents or hydrocarbons. The preferred polar organic solvent of the present invention is C₁-C₄ alcohol, preferably C₁-C₂ alcohol, more preferably methanol.

The concentration of cyano-intermediate in the reaction mixture is in the range of 2-20% with reference to the solvent.

The hydrogen pressure is 1 to 10 atmosphere, more preferably 1 to 5 atmosphere and most preferably 1 atmosphere.

The reaction time varies from 5 to 40 hours, preferably between 10 to 22 hours.

The reaction is carried out at temperature of 0 to 50 °C, preferably at 15 to 35 °C, more preferably at 20 to 25 °C. The reaction conditions like time, temperature, hydrogen pressure and the ratio of reagents like cyano-intermediate, alkylamine and/or its salt and catalyst, are to a large extent interchangeable, as will be recognized by the skilled practitioner.

Depending upon the ratio of reagents like cyano-intermediate, alkylamine and/or its salt and catalyst and reaction conditions like time, solvent and hydrogen pressure, the HPLC conversion of cyano intermediate of formula V to venlafaxine of formula I varies from 30- 81%.

Synthesis of venlafaxine of formula I by reacting cyano-intermediate of formula V (1.0 equiv.) with dimethylamine hydrochloride (3-5 equiv.) using different palladium catalysts (10-50 wt %) in the presence of methanol and hydrogen pressure gave 30-89% conversion to venlafaxine. Similarly synthesis of N-desmethylvenlafaxine of formula II was accomplished by replacing dimethylamine hydrochloride with monomethylamine hydrochloride in the above process. The best results for the said conversion were obtained with 10% palladium on carbon and with 5% palladium on alumina catalysts. The experiments were performed using the general procedure as described in Example- 1.

The process of the present invention (Scheme-4) is described in more detail with reference to the following examples which are provided way of illustration only and should not be construed as limit to the scope of the reaction in any manner.

Example-1:

General procedure for synthesis of venlafaxine and N-desmethylvenlafaxine To the, stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (1.0 equiv.) in methanol (10-20 volumes), alkylamine (3-5 equiv.) was added and the mixture was stirred for 5-10 minutes to get a clear solution. Palladium catalyst (10-50 wt %) was added under nitrogen atmosphere to the above reaction mixture. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 5 to 40 hrs. The progress of the reaction was monitored by TLC and HPLC. After completion of the reaction, the catalyst was filtered through celite and washed with methanol. The combined filtrate was concentrated to dryness under reduced pressure and the residue was poured in water. The aqueous layer was basifϊed with 10% aq. NaOH to pH 8-10 and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were washed with brine and dried over sodium sulphate. Ethyl acetate was evaporated under vacuum to obtain the title compound.

Example-2: Venlafaxine

To the stirred solution of 2-(l-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (460.0 ml), dimethylamine hydrochloride (26.6 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 20 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.Og) which was directly converted to its hydrochloride salt using IPA/HC1. HPLC purity of the crude reaction mixture (18.Og) = 81.64%.

Venlafaxine-free base:

¹H NMR in CDCl₃ (300 MHz): δ 7.05 (d, 2H), 6.81 (d, 2H), 3.79 (s, 3H), 3.27 (t, IH), 2.94 , (dd, IH), 2.31 (s, 6H), 2.28 (dd, IH), 1.71-0.94 (m, 10H). 1³C NMR in CDCl₃: δ 158.16,' 132.65, 130.01, 113.20, 74.14, 61.14, 55.05, 51.52, 45.37, 37.99, 31.07, 25.91, 21.52, 21.23.

IR (KBr): 3152, 2980, 2941, 2895, 1728, 1607, 1512, 1462, 1439, 1358, 1279, 1204, 1186, 1177, 1146, 1103, 1040, 1011, 968, 851 cm^"1. HPLC Purity: 99.37 % (area %). GC-MS: 178 (M+H⁺).

Venlafaxine hydrochloride salt:

¹H NMR in D₂O (300 MHz): δ 7.23 (d, 2H), 6.91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 6H), 1.41-1.0 (m, 10H).

¹³C NMR in D₂O: δ 158.52, 130.86, 128.16, 114.25, 73.23, 58.26, 55.25, 50.38, 44.87, 41.41, 35.07, 33.34, 24.76, 21.08, 20.86.

IR (KBr): 3321, 2941, 2928, 2675, 2644, 2623, 2611, 2587, 2521, 2482, 2359, 2330, 1512, 1441, 1242, 1179, 1038, 829 cm^"1. HPLC Purity: 99.64 % (area %). GC-MS: 178 (M+H⁺).

Example-3: N-Desmethyl venlafaxine To the stirred solution of 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile (20.0 g, 1 equiv.) in methanol (350.0 ml), monomethylamine hydrochloride (27.7 g, 4 equiv.) was added and the mixture was stirred for 5-10 minutes at room temperature to obtain a clear solution. 5% Palladium on alumina (4.0 g, 20 wt %) was added under nitrogen to the above clear solution. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atmospheric pressure.) at room temperature for 24 hrs. After completion of the reaction product was isolated by the procedure as described in Example- 1 above to obtain light yellow viscous liquid (18.5g) which was directly converted to its hydrochloride salt using IPA/HCl.

HPLC conversion to N-desmethylvenlafaxine (in the crude reaction mixture = 18.5g): 35.46%. N-Desmethyl venlafaxine-free base:

¹H NMR in CDCl₃ (300 MHz): δ 7.23 (d, 2H), £91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd, IH), 2.97 (dd, IH), 2.69 (s, 3H), 1.41-1.0 (m, 10H)

Claims

1. A novel single step process for the synthesis of venlafaxine of formula I and its analogue N-desmethyl venlafaxine of formula II,

formula I formula II

comprising reacting 2-(l -hydroxy cyclohexyl)-2-(4-methoxyphenyl)acetonitrile of formula V,

formula V

with an alkylamine or its salt in a suitable solvent in the presence of a transition metal catalyst, under hydrogen pressure.

2. The process as claimed in claim 1, wherein alkylamine is selected from monoalkylamine, dialkylamine and their salts.

3. The process as claimed in claim 1 or 2, wherein the monoalkylamine is methylamine, preferably methylamine hydrochloride

4. The process as claimed in claim 1 or 2, wherein the dialkylamine is dimethylamine, preferably dimethylamine hydrochloride.

5. The process as claimed in claim 1, wherein solvent is a polar organic solvent selected from C₁-C₄ alcohol, water, N, N-dimethylformamide, esters, ethers, halogenated solvents, and hydrocarbons, preferably C₁-C₄ alcohol, more preferably methanol.

6. The process as claimed in claim 1, wherein the transition metal catalyst is selected from palladium, platinum, rhodium, or nickel, the catalyst is may be supported or unsupported,preferably selected from palladium oxide, palladium hydroxide or 5-

20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate, more preferably selected from 5-20% palladium supported on carbon and alumina.

7. The process as claimed in claim 1, wherein the molar ratio of the cyano-intermediate of formula V to the alkylamine or its salt is from 1:1 to 1:10, preferably from 1:1 to

1:5.

8. The process as claimed in claim 1, wherein the catalyst concentration with reference to the cyano-intermediate of formula V is from 5-100 wt %, preferably 20-50%.

9. The process as claimed in claim 1, wherein the concentration of cyano-intermediate of formula V in the reaction mixture with reference to the solvent is in the range of 2- 20%, preferably 10-20%.

10. The process as claimed in claim 1, wherein the hydrogen pressure in the reaction is between 1 to 15 atmosphere, preferably between 1 to 5 atmosphere.

11. The process as claimed in claim 1, wherein the reaction period varies from 5 to 40 hrs, preferably from 10 to 24 hrs.

12. The process as claimed in claim 1, wherein the reaction is carried out at temperature of 0 to 50 ⁰C, preferably at 15 to 35 °C, more preferably at 20 to 25 °C, most preferably at ambient temperature.