WO2006035457A1

WO2006035457A1 - A process for the manufacture of venlafaxine and intermediates thereof

Info

Publication number: WO2006035457A1
Application number: PCT/IN2005/000314
Authority: WO
Inventors: Uday Balkrishna Gokhale; Chandrashekar Parenky
Original assignee: Amoli Organics Ltd
Current assignee: Amoli Organics Ltd
Priority date: 2004-09-17
Filing date: 2005-09-16
Publication date: 2006-04-06
Anticipated expiration: 2007-03-17

Abstract

The present invention provides an improved process for the preparation of Venlafaxine and the intermediates thereof. The present invention provides a process for preparing compound of formula (IV), an intermediate for preparing Venlafaxine by hydrogenating a compound of formula (III): in the presence of toluene, water, and Raney nickel as catalyst with the process yield of 66% formula (IV) with 99% HPLC purity. The compound of formula (III) is prepared by drop wise addition of p-methoxyphenyl acetonitrile as a solution in tetrahydrofuran to the solution of butyl lithium in hexane the said process yields 89% of compound of formula (III) with 99.8% purity.

Description

TITLE

AN IMPROVED PROCESS FOR THE MANUFACTURE OF VENLAFAXINE AND INTERMEDIATES THEREOF.

TECHNICAL FIELD

The present invention relates to a process for manufacturing Venlafaxine hydrochloride and intermediates thereof.

BACKGROUND OF THE INVENTION

Venlafaxine is known by the chemical name 1-[2-dimethylamino-1-(4 methoxyphenyl ethyl Cyclohexanol hydrochloride and structure of formula (V).

(V)

Venlafaxine is a useful pharmaceutical agent as an antidepressant. Venlafaxine, the intermediates in the manufacture of Venlafaxine, the process of preparing said Venlafaxine and their intermediates are well known from US Patents 4,535,186, US Patent No. 6,350,912, and CN 1225356.

Further International Publication No. WO03/050074 discloses the manufacture of Venlafaxine Hydrochloride and crystalline polymorphs Form I, Form II, Form III and optically pure (R) and (S) enantiomers exhibiting different crystalline structures of Venlafaxine hydrochloride. The preparation of all the forms of Venlafaxine and their inter-conversion are also described in said WO03/0500074 publication. U.S. Patents 4535186, 4761501 disclose a process for manufacture of 1-[2- amino-i-(p-methoxyphenyl) ethyljcyclohexanol (free base of formula IV), an intermediate produced during the preparation of Venlafaxine in two stages by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n- butyl lithium (Stage 1) to form 1-[cyano(p-methoxyphenyl) methyl] Cyclohexanol of formula III

(111)

This process is commonly used for the preparation of formula III. The US Patent 4,535,186 produces a yield of about 30% based on p-methoxyphenyl acetonitrile.

WO/03/050074 suggests an alternate way of preparing compound of formula III without using butyl lithium i.e. by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of alkali metal hydroxide in a mixture of toluene and hexane. The publication WO/03/050074 also suggests a material yield of 74% based upon p-methoxyphenyl acetonitrile and purity.

The drop wise addition of butyl lithium to p-methoxyphenyl acetonitrile is hazardous and hence it requires skill and safety measures to be taken by the person skilled in the art for handling butyl lithium over the addition period to avoid any accidents during the preparation process.

The second stage i.e. conversion of compound of formula III to formula IV described in US patent US 4,535,186 is by hydrogenating compound of formula III using Rhodium on alumina. The catalyst Rhodium is recycled by filtering and washing the catalyst with ethanol and the combined filtrate evaporated and dried under vacuum yielding free base as an oil. However, the cost of Rhodium catalyst is very high and hence the catalyst has to be recovered.

WO/02/500017 suggests the use of a Nickel or cobalt catalyst for the hydrogenation, which is highly economical when compared with the Rhodium catalyst as suggested by US Patent No. 4,535,186. The International Publication WO/02/500017 teaches that the hydrogenation reaction of Stage Il may be carried out in the presence of an organic solvent preferably an alcohol. The international publication also suggests the pretreatment of the catalyst with ethanol.

The US Patent 4,535,186 describes the third stage in the process of preparing Venlafaxine i.e. conversion of compound of formula IV (free base) to compound V i.e. Venlafaxine by methylating the compound of formula IV (free base) with a mixture of formaldehyde and formic acid in water.

(IV)

US Patent Publication No. 2005/0033088 describes a process for preparing phenylethylamine derivative, an intermediate of Venlafaxine hydrochloride; said process comprising steps of reduction of compound of formula III 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 freebase.

The hydrogenation step in prior art use alcohols as a bulk solvent. Therefore, additional distillation operation is required prior to isolation of product salt and the recovery of solvent is an essential operation.

SUMMARY OF THE INVENTION

The object of the present invention is to provide an improved process for preparing compound of formula IV, that increases the purity and yield of said compound of formula - V.

(IV)

Another object of the present invention is to provide a safer industrial operation for easy handling of butyl lithium during coupling reaction for preparing compound of formula III, i.e. 1-[cyano-(4-methoxyphenyl) methyl ] cyclohexanol

(111) Another object of the present invention is to provide an improved process for manufacturing compound of formula III with high yield and purity.

Further object of the present invention is to provide an economically viable method of preparing Venlafaxine thereby reducing the cost of production.

Yet another object of the present invention is to reduce the number of steps in the preparation of venlafaxine.

The first aspect of the invention provides a process for preparing compound of formula IV an intermediate for preparing Venlafaxine using Raney Nickel as a catalyst in the presence of toluene and water. The process comprises the step of hydrogenating a compound of formula-Ill:

(III)

in the presence of toluene, water, and a catalyst wherein said process yields 66% formula (IV) with 99% HPLC purity. The catalyst used in the present invention is Raney Nickel. Raney nickel prepared from Nickel Aluminum alloy with Ni content of 90-92% and aluminum content of 8 - 10%. Particle size of the catalyst may vary from about 150 to about 250 mesh. The catalyst Raney Nickel is washed with water to make it alkali free. The use of the solvent toluene/ water produces a good yield of about 66% of the compound of formula IV with 99% HPLC purity. The process of the present invention uses water as a bulk solvent and toluene as a co-solvent. . Toluene is used as a co-solvent in the amounts of about 20% by volume. During the work-up of the reaction, reaction product is retained in toluene and acetate salt is isolated from this toluene extract. The second aspect of the invention provides a process for preparing a compound of formula III. An improved process for preparing a compound of formula

(III)

Comprising the steps of charging butyl lithium and tetrahydrofuran; cooling the reaction mixture to about -50°C to -75°C; adding drop wise p-methoxyphenyl acetonitrile in tetrahydrofuran; and reacting with cyclohexanone at a temperature below -50^°C wherein the said process yields 89% of compound of formula III with 99% purity.

The third aspect of the invention provides a process for preparing Venlafaxine a compound of formula V. The said process comprising steps of preparing compound of formula (III) according to Step 1 of present invention; preparing compound of formula ((IV) according to step Il of present invention; methylating the compound of formula (IV) by formaldehyde and formic acid mixture wherein the purity of compound (V) is 99.9% by HPLC with a yield of 84%.

The fourth aspect of the invention provides a process for preparing compound of formula IV by hydrogenating compound of formula III in the presence of Nickel catalyst and water

The improved process for preparing Venlafaxine and the intermediates thereof according to the present invention provides an economically viable process with 89% yield of the intermediate 1-[cyano-(4-methoxyphenyl) methyl] Cyclohexanol, with 66% molar yield of 1-[2-amino-1-(4-methoxyphenyl)ethyl cyclohexanol] acetate and with an overall molar yield of 50% of Venlafaxine of 99.9% HPLC purity. Use of water as a bulk solvent reduces the cost of manufacture of the Venlafaxine and its intermediates considerably with substantially good yield and purity as that of the prior art processes.

Venlafaxine produced by this procedure exhibits following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.

(The abbreviations in brackets mean : (vs) = Relative intensity above 80%; (s) = 30% - 80%; (m) = 15% - 30%; (w) = 8% to 15% and (vw) = below 8%.)

2.23 (VW), 2.29(VW), 2.32(VW), 2.35(VW), 2.38(VW), 2.43(VW), 2.46(VW), 2.48(VW), 2.55(M), 2.64(W), 2.69(W), 2.73(VW), 2.8(W), 2.83(W), 2.88(W), 2.93(VW), 3.09(VW), 3.12(M), 3.26(VM), 3.31 (VW), 3.38(W), 3.45(VW), 3.5(VW), 3.55(M), 3.69(VW), 3.87(VW), 3.99(VW), 4.07(M), 4.18(S), 4.35(VS), 4.48(VW), 4.68(M), 5.1(VW), 5.27(W), 5.42(VW), 5.55(VW), 5.63(M), 5.68(M), 5.76(VW), 6.5(S), 6.95(VS), 8.65(VW), 10.56(M), 13.06(M).

DESCRIPTION OF THE INVENTION

The route of synthesis for Venlafaxine (formula V) and intermediate of Venlafaxine (formula IV) is depicted in the following scheme:

Step -I

(I) (II) (III) Step-ll

(III) (IV)

Step-ll I

(IV) (V)

Accordingly, the present invention relates to an improved process for the preparation of compound of formula IV

(IV)

comprising the step of hydrogenating a compound of formula

(Hi)

in the presence of toluene, water, and a catalyst wherein the said process yields 66% formula (IV) with 99% HPLC purity.

The compound of formula IV is further methylated using formaldehyde and formic acid mixture to form Venlafaxine (formula V) followed by the treatment with HCL gas dissolved in Isopropanol.

(IV) (V)

2.23 (VW), 2.29(VW), 2.32 (VW), 2.35(VW), 2.38(VW), 2.43(VW), 2.46(VW), 2.48(VW), 2.55(M), 2.64(W), 2.69(W), 2.73(VW), 2.8(W), 2.83(W), 2.88(W), 2.93(VW), 3.09(VW), 3.12(M), 3.26(VM), 3.31 (VM), 3.38(W), 3.45(VW), 3.5(VW), 3.55(M), 3.69(VW), 3.87(VW), 3.99(VW), 4.07(M), 4.18(S), 4.35(VS), 4.48(VW), 4.68(M), 5.1 (VW), 5.27(W), 5.42(VW), 5.55(VW), 5.63(M), 5.68(M), 5.76(VW), 6.5(S), 6.95(VS), 8.65(VW), 10.56(M), 13.06(M). The present invention uses a novel solvent toluene / water for the preparation of compound of formula IV. The use of the solvent toluene /water produces a good yield of 66% of compound of formula IV with 99% HPLC purity. The process of the present invention uses water as a bulk solvent and toluene as a co-solvent. . Toluene is used as a co-solvent in the amounts of about 20% by volume. During the work-up of the reaction, reaction product is retained in toluene and acetate salt is isolated from this toluene extract. Further, the use of water as a bulk solvent reduces the cost of manufacture of the Venlafaxine and its intermediates considerably with substantially good yield and purity as that of the prior art processes.

According to the preferred embodiment of the present invention, nickel catalyst, preferably Raney nickel catalyst is used. The catalyst is washed in water to remove the alkali. No pretreatment of the nickel catalyst is required.

(HI) (IV)

According to another embodiment of the present invention, compound of formula IV is prepared by hydrogenating compound of formula III in the presence of Raney Nickel and water. According to another embodiment of the present invention, compound of formula III is prepared by charging p-methoxyphenyl acetonitrile into butyl lithium at -70 to -75°C and tetrahydrofuran; cooling the reaction mixture to about -50°C to -75⁰C; adding cyclohexanone at a temperature below -50⁰C quenching with ice and saturated ammonium chloride solution below 0^°C; and stirring and filtering the product of formula (III) wherein the said process yields 89% of compound of formula III with 99.8% purity. The reaction scheme is depicted as follows:

(I) (H) (III)

The dropwise addition of p-methoxy-phenyl acetonitrile to butyl lithium already charged in the reaction vessel reduces the risk of handling butyl lithium in the above coupling reaction. Moreover the reverse mode of addition also provides better yield of compound III of about 89%.

The process of the present invention will be explained in more detail with reference to the following examples, which is provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner.

Example 1 :

Preparation of 1-[cyano-(4-methoxyphenyl) methyl Icvclohexanol.

In a 2 ltr 4 necked round bottom flask equipped with a overhead stirrer, thermometer and dropping funnel, 100 ml dry THF followed by 210 ml Butylithium (1.6 M solution in Hexane) was charged. The reaction mixture was cooled to - 70⁰C. Added gradually a solution of 50 gm p-methoxyphenyl acetonitrile dissolved in 50 ml dry THF at -70 to -75°C. After 30 min, added solution of 33.1 gm Cyclohexanone in 50 ml THF. After the addition, maintained at -65 to -70⁰C and monitored by TLC. After 4 hrs, reaction mixture was gradually added over mixture of ice and 150 ml saturated ammonium chloride solution below 0°C and adjusted pH to 7 with dilute Hydrochloric acid. Stirred for 1 hr and filtered the product. Washed the product with 200 ml hexane and dried to obtain 74.3 gm. (The yield based on p-methoxyphenyl acetonitrile 89%, Melting range 123- 125°C, HPLC purity of 99.8%).

Example 2:

Preparation of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate

In an autoclave are charged 100 gm 1-[cyano(4- methoxyphenyl)ethyl]cyclohexanol, 100 ml toluene and 400 ml water at RT. Stirred and cooled to 10°C. Charged 20 gm Raney Nickel (which was prewashed with water to make it free of Alkali) and 100 ml liquor ammonia (20%). Then pressurized the autoclave with hydrogen to 4 - 5 kg pressure and maintained for 120 minutes below 12⁰C. Then the reaction temperature slowly raised to bout 50⁰C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 - 50°C for 8 hr. After the completion of the reaction, cooled the reaction to RT, released the hydrogen pressure and charged 400 ml toluene. Filtered the catalyst and washed bed with 100 ml toluene. Separated the organic layer from the filtrate. The organic layer was washed with 10% Sodium chloride solution. To the organic layer was added 40 ml methanol followed by 10 ml acetic acid. Stirred for 15 minutes and then again charged 10 ml acetic acid. Then heated to 75-8O⁰C and maintained for 15 minutes. Cooled to 0 - 5⁰C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 83.5 gm (Yield 66%, Melting range 164-166°C, HPLC purity 99%).

Example 3:

Preparation of H2-dimethylamino-1-(4-methoxyphenyl) ethvH Cyclohexanol Hydrochloride

To a stirred solution of 100 gm of 1-[2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate in 300 ml water was added 117 gm of formic acid (88%) and 91 gm of formaldehyde (40% solution). The solution was heated to 98°C and maintained for 20 hrs. Reaction mixture was cooled to about 10⁰C and added 500 ml ethyl acetate. The pH was adjusted to about 7 with sodium hydroxide solution and further to 10 - 10.5 with ammonium hydroxide solution. Layers were separated. Aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with water. Combined organic extract was stirred with activated carbon (5 gm) and filtered. Filtrate was concentrated in vacuum to completely remove ethyl acetate. Residue was dissolved in isopropanol (300 ml) and acidified at 30⁰C (pH 1-1.5) with the solution of HCI in isopropanol. Temperature was then raised to 60⁰C and maintained for 60 to 90 min. The reaction mass was cooled under agitation to 10°C and maintained under agitation at 10°C for 60 min. Product was isolated by filtration. Finally it was washed with isopropanol and dried at 60°C.

Dry wt. : 85 gm (84% yield, HPLC 99.9% purity with all individual impurities below 0.1% concentration). This material exhibited following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.

(The abbreviations in brackets mean : (vs) = Relative intensity above 80%; (s) = 30% - 80%; (m) = 15% - 30%; (w) = 8% to 15% and (vw) = below 8%.) 2.23 (VW), 2.29(VW), 2.32 (VW)₁ 2.35(VW), 2.38(VW), 2.43(VW), 2.46(VW), -2.48(VW)₁ 2.55(M), 2.64(W), 2.69(W), 2.73(VW), 2.8(W), 2.83(W), 2.88(W), 2.93(VW), 3.09(VW), 3.12(M), 3.26(VM), 3.31(VM), 3.38(W), 3.45(VW), 3.5(VW), 3.55(M), 3.69(VW), 3.87(VW), 3.99(VW), 4.07(M), 4.18(S), 4.35(VS), 4.48(VW), 4.68(M), 5.1 (VW), 5.27(W), 5.42(VW), 5.55(VW), 5.63(M), 5.68(M), 5.76(VW), 6.5(S), 6.95(VS), 8.65(VW), 10.56(M), 13.06(M).

Example 4 :

Preparation of 1-f2-amino-(4-methoxyphenyl) ethyl] Cyclohexanol acetate (IV)

In an autoclave charged 150 gm 1-[cyano(4-methoxyphenyl)ethyl]cyclohexanol, and 675 ml water at RT. Stirred and cooled to 1O⁰C. Charged 30 gm Raney Nickel (prewashed with water to make it free of Alkali) and 150 ml liquor Ammonia (20%). Then pressurized the autoclave with hydrogen to 4 - 5 kg pressure and maintaind for 120 minutes below 12°C. After completion of 120 minutes slowly raised the temperature to about 50⁰C along with the increase in the hydrogen pressure to 7 to 8 kg. Maintained between 45 - 5O⁰C for about 20 hrs. Monitored reaction by TLC to ensure disappearance of starting material. After the completion of the reaction cooled the reaction to RT, released the hydrogen pressure and filtered through celite bed. Washed bed with 300 ml toluene. To the filtrate added 300 ml toluene. Shaken well and separated the organic layer. The organic layer was washed with 5% Sodium chloride solution. To the organic layer was added 45 ml methanol and 15 ml acetic acid. Stirred for 15 minutes and then again charged 15 ml acetic acid. Then heated to 75-8O⁰C and maintained for 15 mins. Cooled to 0 - 5°C. Filtered the product. Washed the product with 100 ml ethyl acetate and dried: 104 gm (Yield 53%, Melting range 152-153°C, HPLC purity 90%).

Claims

1. An improved process for the preparation of compound of formula

(IV)

comprising the step of hydrogenating a compound of formula:

(III) (IV)

in the presence of toluene, water, and a catalyst wherein said process yields 66% formula (IV) with 99% HPLC purity.

2. The improved process as claimed in claim 1 wherein the catalyst is Raney Nickel.

3. An improved process as claimed in any one of the preceding claims wherein the Raney Nickel is in the range of 10 to 50 % of compound of formula III.

4. An improved process for preparing compound of formula IV Comprising the step of hydrogenating a compound of formula

(III) (IV)

In the presence of water and a catalyst where in said process yields 53% of formula IV with 90% HPLC purity.

5. An improved process as claimed in claim 4 wherein the catalyst is Raney Nickel catalyst.

6. An improved process for preparing compound of formula III

(HI)

Comprising the steps of adding drop wise p-methoxyphenyl acetonitrile as a solution in tetrahydrofuran to the solution of butyl lithium in hexane at -5O⁰C to -75°C; and reacting cyclohexanone at a temperature below -50^°C wherein the said process yields 89% of compound of formula III with 99.8% purity.

7. An improved process for preparing Venlafaxine of formula (V) comprising the steps of:

(a) preparing compound of formula (III) as claimed in claim 5

(b) preparing compound of formula ((IV) as claimed in claim 1; (c) methylating the compound of formula (IV) with formaldehyde and formic acid mixture

wherein the purity of compound (V) is 99.9% with an isolated yield of 84%.

8. An improved process as claimed in claims 7 wherein Venlafaxine is prepared without isolating Venlafaxine freebase.

9. An improved process for the preparation of 1-[2-amino-1-(4- ' methoxyphenyl)ethyl cyclohexanol] acetate; 1-[cyano-(4-methoxyphenyl) methyl] Cyclohexanol; Venlafaxine and is as herein described and exemplified.