TITLE OF THE INVENTION

A process for the preparation of venlafaxine hydrochloride

Technical field of invention

The invention relates to a process for the preparation of venlafaxine hydrochloride.

The invention also relates to a process for the preparation of l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride, a key intermediate of venlafaxine hydrochloride.

Venlafaxine is a non-tricyclic antidepressant chemically named as (±)-l-[2-(dimethyl amino)- 1- (4-methoxy phenyl)ethyl] cyclohexanol. It is widely used to treat depression and antisocial disorders. It is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents. The antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the Central Nervous System.

Background and prior art

The hydrochloride salt of venlafaxine is convenient to be formulated into tablets, capsule, lozenges, powders or the like for oral administration and is currently available under the trade name Effexor as a racemic mixture of (+) and (-) enantiomers and is indicated for the treatment of depression.

Processes for the preparation of Venlafaxine and it's acid addition salts and intermediates have been reported in US 4,761,501 (hereinafter referred as '501), Drugs of Future 1988, 13(9), 839- 840, US 5,043,466 (hereinafter referred as '466), international publication WO 00/59851, US 6,506,941 (hereinafter referred as '941), US 6,350,912 (hereinafter referred as '912), International publication WO 03/0500074, US 6,756,502 (hereinafter referred as '502), US 2004/0106818, US 2004/0181093, CN 1,225,356 and US 2005/0033088. The processes for the preparation of venlafaxine hydrochloride of the formula (VI)

Formula (VI) generally comprise the following steps :

1. Condensation of p-methoxy phenyl acetonitrile of the formula (I)

Formula (I) with cyclohexanone of the formula (II)

Formula (II) to obtain l-[cyano-l-(p-methoxy phenyl)methyl] cyclohexanol of the formula (III);

Formula (III)

2. Hydrogenation of l-[cyano-l -(p-methoxy phenyl)methyl] cyclohexanol of the formula (III) to obtain lr[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol of the formula (IV);

Formula (IV)

3. Symmetrical N-methylation of l-[2-amino-l-(4-methoxy phenyl) ethyl ] cyclohexanol of the formula (IV) in the presence of formic acid and formaldehyde (Eschweiler-Clarke reaction) to obtain Venlafaxin base of the formula (V);

Formula (V) and 4. Conversion of Venlafaxine base of the formula (V) into pharmaceutically acceptable acid addition salts thereof.

In US '501 condensation is carried out in the presence of n-butyl lithium as a catalyst and tetrahydrofuran as a solvent at temperature around -70 to -50°C. The n-butyl lithium is highly sensitive to moisture and air and can cause fire hazards and is therefore unsafe besides being expensive. The compound (III) is isolated in crystalline form and hydrogenated in a mixture of 20 % v/v ammonia-ethanol over 5 % Rhodium on alumina to obtain the compound (IV). Rhodium catalyst is expensive and uneconomical especially on plant scale. In order to save cost, the catalyst is recovered and recycled, thereby increasing the process steps. During recovery and recycling of the catalyst, there is the possibility of the catalytic effect of the recycled catalyst being reduced. The compound (IV) is treated with a mixture of formaldehyde, formic acid and water at 100° C to obtain venlafaxin base (V) which is purified by column chromatography using Mallinckrodt Silica CC7 silica gel as a stationary phase and ethanol: 2 N ammonia : ethyl acetate : cyclohexane in a ratio of 45:8:100:100 v/v as a mobile phase and converted it into venlafaxine hydrochloride (VI).

US '466 describes a process for the preparation of l-[cyano-l-(p-methoxy phenyl)methyl] cyclohexanol (III), a key intermediate of venlafaxine. p-Methoxy phenyl acetonitrile is condensed with cyclohexanone in the presence of lithium di-isopropylamide at a temperature below 1O ⁰ C. Lithium di-isopropylamide is also highly sensitive to moisture and air and unsafe besides being expensive.

CN1225356 describes a process for the preparation of l-[2-amino-l-(p-methoxyphenyl) ethyl] cyclohexanol, which is an important intermediate of venlafaxin. The process uses sodium

methylate, sodium ethylate, sodamide or sodium hydride as a substitute for n-butyl lithium or lithium diisopropylamide in the condensation step and borane as a substitute for catalyst Rhodium-aluminium trioxide in the hydrogenation step. The reagents used in this process are also sensitive to moisture and air and unsafe.

US '912 describes a process for the preparation of venlafaxine which comprises reduction of the compound (III) with a formylating agent in the presence of protic solvent and Raney nickel catalyst at a temperature in the range of 30 to 60° C and at the hydrogen pressure in the range of 100 to 400 psi for 6 to 16 hours followed by purification of the venlafaxine base (V). The yield of venlafaxine is reported to be in the range of 15 to 30 %. Further the un-reacted nitrile is required to be isolated from the reaction mixture.

US '502 describes a process for the preparation of venlafaxine hydrochloride from epoxy nitrile intermediates. This process comprises additional steps to prepare the epoxy nitrile derivatives.

WO0059851 describes a process for the preparation of venlafaxin and its hydrochloride salt by condensing p-methoxy phenyl acetonitrile with cyclohexanone in the presence of lithium diisopropyl amide to obtain the compound (III) followed by hydrogenation in the presence of cobalt chloride and sodium borohydride in methanol to obtain the compound (IV). The compound (IV) is treated with formaldehyde and formic acid to give venlafaxine base (V), which is converted into its hydrochloride salt (VI). The hydrogenation of the compound (III) in the presence of cobalt chloride and sodium borohydride is also disclosed in WO0032556. The reagents used in this process are very expensive.

WO0250017 describes hydrogenation of the compound (III) in the presence of pretreated nickel or cobalt catalyst, alcohol and base such as NH ₃ , NH ₄ OH and NaOH. The nickel or cobalt catalyst is pretreated with a carboxylic acid or a salt or an anhydride thereof or with an ammonium salt or a vanadium-, a tungsten-, or a molybdenum compound. Pretreatment procedure is cumbersome and time consuming. Further the hydrogenation reaction carried out under basic conditions at above room temperature results in the cracking of the starting nitrile compound to produce 4-methoxyphenyl acetontrile, which may undergo hydrogenation to produce 4-methoxy phenethyl amine as an impurity. The phenethyl amine or phenalkyl amine impurities are very similar to the end products of primary amines in terms of physical and chemical properties. Therefore, it is very difficult to separate the desired end products from the undesired ones.

WO 03050074 describes a process for the preparation of venlafaxine hydrochloride and its polymorphs. P-methoxy phenyl acetonitrile is condensed with cylohexanone in the presence of inorganic base like alkaline earth metal hydroxides selected from lithium hydroxide, sodium hydroxide or potassium hydroxide to obtain l-[cyno-(4-methoxyphenyl)methyl]cyclohexanol followed by hydrogenation of the l-[cyno-(4-methoxyphenyl)methyl]cyclohexanol in the presence of Raney nickel catalyst at 60 psi under anhydrous ammonia in methanol at 30° C to obtain l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol. The hydrogenated product is formylated with formic acid and formaldehyde to yield venlafaxine, which is converted into its hydrochloride salt. Handling of the alkaline earth metal hydroxide like sodium hydroxide with a relatively strong base especially at industrial scale is very difficult.

US 20040181093 describes hydrogenation using a nickel or cobalt catalyst at temperature of about 5° C to 25° C to obtain compound (IV). The yield of the compound (IV) is reported to be about 70 %.

US 2004/0106818 describes a process for the preparation of venlafaxin hydrochloride by carrying out the condensation in the presence of metal hydride followed by the reduction of the compound (III) by the metal hydrides or by the Raney nickel catalyst and hydrogen and isolation of venlafaxin base (IV). The product obtained by hydrogenation of the compound (III) is purified by silica gel chromatography. The base is converted into its hydrochloride salt (V).

US2005/0033088 describes a process for the preparation of venlafaxine hydrochloride in which reduction of the compound (III) is carried out in an organic acid selected from propionic acid, acetic acid or formic acid and Pd/C as a hydrogenation catalyst under a pressure of 5 to 25 kg/cm2 and at 50-55° C temperature. The resulting acetate salt of the compound (IV) is formylated with formic acid and formaldehyde to give the final product (V). The yield of the acetate salt of the compound (IV) is reported to be about 45-55%.

The prior art processes use the base either in 1:0.5 to 3 mole with respect to p-methoxy phenyl acetonitrile and cyclohexanone or in excess. Use of increased quantity of base leads to self- condensation of two molecules of p-methoxy phenyl acetonitrile or cyclohexanone to form undesired side products. This reduces the yield and purity of the compound (III) thereby reducing yield of the final product and calling for purification of the final product using expensive procedures and techniques.

Objects of the invention

An object of the invention is to provide a simple, efficient and economical process for preparing venlafaxine hydrochloride in high yield with high purity.

Another object of the invention is to provide a process for preparing venlafaxine hydrochloride, which reduces formation of undesired impurities.

Another object of the invention is to provide a process for the preparation of venlafaxine hydrochloride, which eliminates elaborate work up and purification procedure like chromatography.

An object of the invention is to provide a simple, efficient and economical process for preparing l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride in high yield with high purity.

Another object of the invention is to provide a process for preparing l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride, which reduces formation of undesired impurities.

Detailed Description

According to the invention there is provided a process for the preparation of venlafaxine hydrochloride of the formula (VI):

Formula (VI) the process comprising a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone of the formula (II)

Formula (I) Formula (II) in the presence of a base selected from the group consisting of alkali metal alkoxides and a solvent selected from C ₄ alcohol at - 10 to 5° C in the molar ratio of the base to p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1, acidifying the reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5 to 5° C followed by addition of water and separation of the organic layer containing l-[cyano-l-(p- methoxy phenyl)methyl] cyclohexanol of the formula (III):

Formula (III) b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel and ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling off the solvent to obtain a residue containing l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol of the formula (IV):

Formula (IV) c. converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII):

Formula (VII)

by dissolving the residue in an organic solvent at temperature of 0 to 5° C followed by adding hydrogen chloride solution in an organic solvent to adjust pH of the solution to 1 to 1.5 at the same temperature, adding anti-solvent to precipitate the compound (VII) while maintaining the same temperature and filtering out and drying the compound (VII); d. dissolving the compound (VII) in methanol followed by adjusting the pH of the solution to 9 to 9.5 by adding methanolic sodium hydroxide solution at 0 to 5° C, distilling out the solvent from the solution to obtain residue followed by formylating it with formaldehyde and formic acid at 95 to 100° C to obtain l-[2-dimethyl amino- 1 -(4-methoxy phenyl)-ethyl] cyclohexanol of the formula (V) :

Formula (V) and converting it into venlafaxine hydrochloride (VI) by adding hydrochloric acid in isopropanol to adjust the pH of the reaction mixture to 1 to 1.5 followed by isolating it by filtration.

According to the invention there is also provided a process for the preparation of l-[2-amino-l- (4-methoxy phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII):

Formula (VII) the process comprising a. condensing p-methoxy phenyl acetonitrile of the formula (I) with cyclohexanone of the formula (II):

Formula (I) Formula (II)

in the presence of a base selected from the group consisting of alkali metal alkoxides and a solvent selected from C ₄ alcohol at - 10 to 5° C in the molar ratio of the base to p-methoxy phenyl acetonitrile or cyclohexanone in 0.1 to 0.4: 1, acidifying the reaction mixture with acetic acid to adjust the pH to 5 to 5.5 at - 5 to 5° C followed by addition of water and separation of the organic layer containing l-[cyano-l-(p- methoxy phenyl)methyl] cyclohexanol of the formula (III):

Formula (III) b. hydrogenating the organic layer with hydrogen in the presence of Raney nickel and ammonia at 10 to 12° C and pressure of 120-200 psi followed by distilling off the solvent to obtain a residue containing l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol of the formula (IV);

Formula (IV) and b. converting the compound (IV) into its salt namely l-[2-amino-l-(4-methoxy phenyl)ethyl] cyclohexanol hydrochloride of the formula (VII)

Formula (VII) by dissolving the residue in an organic solvent at temperature of 0 to 5° C followed by adding alcoholic solution of hydrogen chloride to adjust pH of the solution to 1 to 1.5 at the same temperature, adding anti-solvent to precipitate the compound (VII) while maintaining the same temperature and filtering out and drying the compound (VII).

Preferably, the alkali metal oxide used in step (a) is selected from sodium n-butoxide, potassium n-butoxide, sodium t-butoxide, potassium t-butoxide. Preferably the alkali metal alkoxide used in the condensation step (a) is sodium butoxide and is used in the molar ratio of 0.1 : 1 with respect to p-methoxy phenyl acetonitrile or cyclohexanone. Preferably the C ₄ alcohol used in step (a) is selected from n-butanol, isobutanol or tert-butanol. Preferably the condensation step

(a) is carried out at a temperature in the range of- 10 to -5° C. Preferably the hydrogenation step (b) is carried out at the pressure of 120psi. On completion of hydrogenation the catalyst is filtered and solvent is removed by distillation under vacuum to obtain residue. The organic solvent used to dissolve the residue in step (c) is ethyl acetate, di-isopropyl ether or n-butanol.

Preferably, the hydrogen chloride solution in an organic solvent used to adjust the pH of the solution in step (c) is hydrogen chloride solution in isopropyl alcohol, di-isopropyl ether or n- butanol. Preferably, the anti-solvent used to precipitate the compound (IV) in step (c) is n- pentane, n-hexane or n-heptane, acetone or ethyl methyl ketone.

According to the invention the condensation step (a) is carried out with reduced amount of the base (0.1 to 0.4 mole of the base with respect to 1 mole of p-methoxy phenyl acetonitrile or cyclohexanone). 0.1 to 0.4 mole of the base is found to be sufficient to activate 1 mole of p- methoxy phenyl acetonitrile. As the amount of the base is reduced, self condensation of two molecules cyclohexanone and p-methoxy phenyl acetonitrile is eliminated and formation of undesired side products is reduced. The venlafaxine hydrochloride is obtained in high yield of 94 to 95 % with high purity of 99.2 to 99.9 %. The l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII) is also obtained in high yield of 88 to 90 % and purity of 94 to 95 % The process of the invention does not isolate the intermediate (III) and thus

reduces the number of process step and process duration. The venlafaxine hydrochloride obtained is a white crystalline solid and does not require any purification. The process is also simple, easy and convenient to carry out, efficient and economical.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

EXAMPLE 1:

a) Preparation of 1 -[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII) 10 gm of p-methoxy phenyl acetonitrile, 6.85 gm of cyclohexanone, 25 ml of n-butanol were mixed slowly with stirring while maintaining the temperature in the range of - 10 to - 5° C for 15 to 20 mins. 20% solution of sodium butoxide was added to the reaction mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in the range of -10 to - 5 ⁰ C. The reaction mixture was stirred for 120 minutes while maintaining the same temperature. The reaction mixture was acidified (pH about 5.5) with glacial acetic acid while maintaining the temperature in the range of -5 to 5 ⁰ C. 30 ml of water was added to the reaction mixture and was stirred for 10 minutes. The biphasic reaction mixture was allowed to settle and the organic layer was separated. To this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical butanol (100 ml) were added. The reaction mixture was transferred to autoclave vessel. H ₂ gas was flushed to increase the pressure to 120psi. The mixture was slowly heated at temperature of 10 to 12 ⁰ C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of the reaction was monitored with thin layer chromatography. After completion of reaction, the catalyst was filtered off and the solvent was distilled off to obtain residue. The residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 ⁰ C. 20 % solution of hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of n-hexane was added to the solution with stirring. Further the reaction mixture was stirred for 3 hours at 0 to 5 ⁰ C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII) was filtered and dried at 50 to 52 ⁰ C. % Yield : 90 % % Purity : 95 %

b) Preparation of venlafaxine hydrochloride (VI)

13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 5 ⁰ G. To this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to

9 to 9.5 and stirred it for 30 minutes at 0 to 5 ⁰ C. The reaction mixture was filtered and solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid, and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 ⁰ C. The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95 to 100 ⁰ C. The reaction was monitored with thin layer chromatography. The pH of reaction mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of 20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4O ⁰ C for 30 minutes while stirring and the organic layer was separated out. The solvent was distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 % hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The precipitated product was filtered and dried at 50-55 ⁰ C

% Yield : 95 % % Purity : 99.9% .

EXAMPLE 2: a) Preparation of l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII)

10 gm of p-methoxy phenyl acetonitrile, 6.85 gm of cyclohexanone, 25 ml of isobutanol were mixed slowly with stirring while maintaining the temperature in the range of -10 to -5° C for 15 to 20 mins. 20% solution of sodium isobutoxide was added to the reaction mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in the range of -10 to -5 ⁰ C. The reaction mixture was stirred for 120 minutes while maintaining the same temperature. The reaction mixture was acidified (pH about 5.5) with glacial acetic acid while maintaining the temperature in the range of -5 to 5°C. 30 ml of water was added to the reaction mixture and was stirred for 10 minutes. The biphasic reaction mixture was allowed to settle and the organic layer was separated. To this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical isobutanol (100 ml) were added. The reaction mixture was transferred to autoclave vessel. H ₂ gas was flushed to increase the pressure to 120psi. The mixture was slowly heated at temperature of 10 to 12 ⁰ C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of the reaction was monitored with thin layer chromatography. After completion of reaction,

the catalyst was filtered off and the solvent was distilled off to obtain residue. The residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 ⁰ C. 20 % solution of hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of n-hexane was added to the solution with stirring. Further the reaction mixture was stirred for 3 hours at 0 to 5 ⁰ C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII) was filtered and dried at 50 to 52 ⁰ C. % Yield : 89.1 % % Purity : 94.5 %

b) Preparation of venlafaxine hydrochloride (VI)

13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 5 ⁰ C. To this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to

9 to 9.5 and stirred it for 30 minutes at 0 to 5 ⁰ C. The reaction mixture was filtered and solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid, and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 ⁰ C. The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95- 100 ⁰ C. The reaction was monitored with thin layer chromatography. The pH of reaction mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of 20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4O ⁰ C for 30 minutes while stirring and the organic layer was separated out. The solvent was distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 % hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The precipitated product was filtered and dried at 50-55 ⁰ C

% Yield : 94.5 % % Purity : 99.5 % .

EXAMPLE 3: a) Preparation of 1 - [2-amino- 1 -(4-methoxy phenyl)ethyl] cyclohexanol hydrochloride (VII)

10 gm of p-methoxy phenyl acetonitrile, 6.8 gm of cyclohexanone, 25 ml of tert-butanol were mixed slowly with stirring while maintaining the temperature in the range of -10 to -5° C for 15 to 20 mins. 20% solution of sodium tert-butoxide was added to the reaction mixture slowly over a period of 25 to 30 minutes while maintaining the temperature in

the range of -10 to -5 ⁰ C. The reaction mixture is stirred for 120 minutes while maintaining the same temperature. The reaction mixture was acidified (pH about 5.5) with glacial acetic acid while maintaining the temperature in the range of -5 to 5 ⁰ C. 30 ml of water was added to the reaction mixture and was stirred for 10 minutes. The biphasic reaction mixture was allowed to settle and the organic layer was separated. To this organic layer, 12 gm Raney nickel catalyst and 10 % ammonical tert-butanol (100 ml) were added. The reaction mixture was transferred to autoclave vessel. H ₂ gas was flushed to increase the pressure to 120psi. The mixture was slowly heated at temperature of 10 to 12 ⁰ C under the hydrogen pressure of 120 psi for 6 to 7 hrs. The completion of the reaction was monitored with thin layer chromatography. After completion of reaction, the catalyst was filtered off and the solvent was distilled off to obtain residue. The residue was dissolved in 60 ml ethyl acetate and cooled to 0-5 ⁰ C. 20 % solution of hydrogen chloride in isopropyl alcohol was added to the solution with stirring to adjust the pH to 1-1.5. The reaction mixture was further stirred for 30 to 35 minutes. 7.5 ml of n-hexane was added to the solution with stirring. Further the reaction mixture was stirred for 3 hours at 0 to 5 ⁰ C. Precipitated l-[2-amino-l-(4-methoxy phenyl)ethyl]cyclohexanol hydrochloride (VII) was filtered and dried at 50 to 52 ⁰ C. % Yield : 88.5 % % Purity : 94.1 %

Preparation of venlafaxine hydrochloride (VI)

13 gm of compound (VII) was dissolved in 25 ml of methanol and cooled to 0 to 5 ⁰ C. To this solution, 10 % methanolic sodium hydroxide solution was added to adjust the pH to 9 to 9.5 and stirred it for 30 minutes at 0 to 5 ⁰ C. The reaction mixture was filtered and solvent was distilled out. To the residue obtained, 1 ml of water, 20 gm of Formic acid, and 14 gm of Formaldehyde were added while maintaining the temperature at 20-25 ⁰ C. The reaction mixture was refluxed for about 14 to 15 hrs at a temperature of about 95- 100 ⁰ C. The reaction was monitored with thin layer chromatography. The pH of reaction mixture was adjusted to 9-9.5 by using 20% sodium hydroxide followed by addition of 20 ml of Ethyl acetate to the reaction mixture. The reaction mixture was heated to 4O ⁰ C for 30 minutes while stirring and the organic layer was separated out. The solvent was distilled out from the organic layer to obtain residue. The residue was dissolved in 20 ml of ethyl acetate. The pH of reaction mixture was adjusted to 1-1.5 by adding 20 % hydrogen chloride in isopropanol to precipitate venlfaxine hydrochloride. The precipitated product was filtered and dried at 50-55 ⁰ C

% Yield : 94.1 %

0 %, Purity: 99.2%.