CLIAMS:1. A process for the preparation of Vilazodone of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide of Formula III:

Formula III

with 3-(4-chlorobutyl)-5-cyanoindole of formula IV:

Formula IV
in presence of water and nitrile solvent.

2. The process of claim 1, wherein the nitrile solvent is selected from acetonitrile and propionitrile.
3. The process of claim 1, wherein the ratio of mixture of solvent is in the range of 1: 0.25 to 1:10.

4. The process of claim 1, wherein the base is selected from inorganic base or organic base.

5. The process of claim 1, wherein the base is potassium bicarbonate.

6. The process of claim 1, wherein the pharmaceutically acceptable salt is Vilazodone hydrochloride.

7. A process for the preparation of pure Vilazodone hydrochloride of formula I:

Formula I

which comprises:

a) reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide or its salt with 3-(4-chlorobutyl)-5-cyanoindole or its salt in presence of base, water and nitrile solvent to provide Vilazodone or its salt; and

b) treating Vilazodone or its salt with concentrated hydrochloric acid in presence of water and alcohol to provide pure Vilazodone hydrochloride.

8. The process of claim 7, wherein the nitrile is acetonitrile and base is potassium bicarbonate.

9. The process of claim 7, wherein the salt is other than hydrochloride salt of Vilazodone.

10. The process of claim 7, wherein the purity of Vilazodone hydrochloride is greater than 99 %.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of Vilazodone or its pharmaceutically acceptable salt. The present invention particularly relates to a process for the preparation of Vilazodone or its pharmaceutically acceptable salt by using water and nitrile solvent.

Background of the invention

Vilazodone hydrochloride (VIIBRYD), chemically known as 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxamide hydrochloride, is a a selective serotonin reuptake inhibitor and a 5HT1A receptor partial agonist., represent as Formula I:

Formula I

Vilazodone hydrochloride is indicated for the treatment of major depressive disorder (MDD) and available as Tablet under the trade name VIIBRYD.

U.S. Patent No. 5,532,241 describes Vilazodone and process for the preparation thereof. The process involves reaction of 3-(4-chlorobutyl)-1H-indol-5-carbonitrile with 5-(1-piperazinyl)benzofuran-2-carboxylic acid to provide 5-{4-[4-(5-cyano-1H-indol-3-yl)-4-hydroxy-butyl]-piperazin-1-yl}benzofuran-2-carboxylate methyl. Finally, the carboxyl group of the piperazine is converted into the carboxamide by the reaction with 2-chloro-1-methylpyridinium methanesulphonate (CMPM) and ammonia gas.

Timo H. et al. in J. Med. Chem 2004, 47, 4684-4692 pp. 4684-4692 describes a process for preparing vilazodone which involves reaction of 3-(4-chlorobutyl)-1H-indol-5-carbonitrile with 5-piperazin-1-yl-benzofuran-2-carboxylate hydrochloride to give ethyl 5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl}benzofuran-2-Carboxylate, which is converted to 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}benzofuran-2-carboxylic acid which is then reacted with 1-methyl-2-chloropyridinium iodide to provide Vilazodone.

PCT application No. 2013/114338 A1 discloses a process for the preparation of Vilazodone which involves reaction of 5-Piperazin-l-ylbenzofuran-2-carboxamide with 3-(4-chlorobutyl)indole-5-carbonitrile in presence of water and other solvents such as DMF, Toluene, 1-propanol and 2-propanol.

None of the prior art processes provides appreciated yield and purity of the Vilazodone or its pharmaceutically acceptable salt, therefore, there is a need to develop simple, industrially feasible and cost effective process for providing pure Vilazodone or its pharmaceutically acceptable salt.

Summary of the Invention

The present invention provides a process for the preparation of Vilazodone or its pharmaceutically acceptable salt. Further, the present invention also provides a process for the preparation of Vilazodone hydrochloride salt having purity greater than 99 %.

In an aspect, the present invention provides a process for the preparation of Vilazodone of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide of Formula III:

Formula III

with 3-(4-chlorobutyl)-5-cyanoindole of formula IV:

Formula IV
in presence of water and nitrile solvent.

In another aspect, the present invention provides a process for the preparation of pure Vilazodone hydrochloride of Formula I:

Formula I

which comprises:

a) reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide with 3-(4-chlorobutyl)-5-cyanoindole in presence of base, water and nitrile solvent to provide Vilazodone free base; and

b) treating Vilazodone free base with concentrated hydrochloric acid in presence of water and alcohol to provide pure Vilazodone hydrochloride.

The resultant Vilazodone or its pharmaceutically acceptable salt of the present invention can be used for the preparation of pharmaceutical composition and for the treatment of major depressive disorder.

Description of the Invention

The term “pure” as used herein, unless otherwise defined, refers to Vilazodone or its pharmaceutically acceptable salt that has purity of about 99 % or above.

The intermediates of the Vilazodone, 5-(piperazin-1-yl) benzofuran-2-carboxamide and 3-(4-chlorobutyl)-5-cyanoindole, as used herein may be free base or its salt.

The salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention provides a process for the preparation of Vilazodone of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide of Formula III:

Formula III

with 3-(4-chlorobutyl)-5-cyanoindole of formula IV:

Formula IV
in presence of water and nitrile solvent.

The use of water and nitrile solvent provides greater yield and purity of Vilazodone or its pharmaceutically acceptable salt. The inventors of the present invention also found that the ratio of water and nitrile solvent plays an important role to produce greater yield and purity. The ratio of the solvents may range from 1: 0.25 to 1:10.

The suitable acetonitrile includes but are not limited to acetonitrile, propionitrile and the like.

The reaction in between 5-(piperazin-1-yl) benzofuran-2-carboxamide and 3-(4-chlorobutyl)-5-cyanoindole may be performed in presence of base, for example, inorganic base or organic base. The suitable inorganic base includes but are not limited to sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or potassium bicarbonate and the like. The suitable organic base includes but are not limited to triethyl amine, diisopropyl ethyl amine, methyl amine, and the like.

The reaction in between 5-(piperazin-1-yl) benzofuran-2-carboxamide and 3-(4-chlorobutyl)-5-cyanoindole may be performed in presence of alkali metal halides, for example, potassium iodide and sodium iodide.

The reaction may be performed at a temperature of about 25 to about 90 ºC or from about 70 to about 85 ºC. The reaction may be carried out for a period of about 1 hour to about 10 hours or more.

Optionally, the obtained Vilazodone or its pharmaceutically acceptable salt may be purified using suitable techniques such as recrystallization, anti-solvent technique, crash cooling and the like.

The Vilazodone or its pharmaceutically acceptable salt obtained from the present invention may have yield greater than 90%.

In another aspect, the present invention provides a process for the preparation of pure Vilazodone hydrochloride, which comprises:

a) reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide or its salt with 3-(4-chlorobutyl)-5-cyanoindole or its salt in presence of base, water and nitrile solvent to provide Vilazodone or its salt; and

b) treating Vilazodone or its salt with concentrated hydrochloric acid in presence of water and alcohol to provide pure Vilazodone hydrochloride.

The step a) involves reaction of 5-(piperazin-1-yl) benzofuran-2-carboxamide or its salt with 3-(4-chlorobutyl)-5-cyanoindole or its salt in presence of base, water and nitrile solvent to provide Vilazodone or its salt.

The reaction may be carried out in presence of base, for example, inorganic base and organic base. The suitable inorganic base is selected from sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or and potassium bicarbonate. The suitable organic base is selected from triethyl amine, diisopropyl ethylamine, methyl amine and NMP.

The reaction in between 5-(piperazin-1-yl) benzofuran-2-carboxamide and 3-(4-chlorobutyl)-5-cyanoindole may be performed in presence of alkali metal halides, for example, potassium iodide and sodium iodide.

The reaction may be performed at a temperature of about 25 to about 90 ºC or from about 70 to about 85 ºC. The reaction may be carried out for a period of about 1 hour to about 10 hours or more.

The resultant compound Vilazodone or its salt may be purified by using water, organic solvent or mixture thereof. The obtained compound may be directly utilized for further reaction.

The step b) involves treating Vilazodone or its salt with concentrated hydrochloric acid in presence of water and alcohol to provide pure Vilazodone hydrochloride.

The Vilazodone or its salt treated with hydrochloric acid in presence of alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol and the like in combination with water.

The reaction may be performed at a temperature of about 20 to about 40 ºC or above to complete the conversion of Vilazodone or its salt to Vilazodone hydrochloride. The reaction may be performed for a period of 30 minutes to 2 hours or more.

The resultant Vilazodone hydrochloride may be isolated by using known techniques such as filtration, centrifugation and the like.

Optionally, the Vilazodone hydrochloride is purified using water, organic solvent or mixture thereof to provide pure Vilazodone hydrochloride.

The resultant compound may be dried at a temperature of about 30 to about 50 or more for a period of 2 hours to 5 hours or more to get desired quality of the compound as required by the ICH guidelines.

The overall process of the present invention is as follows:

In another aspect, the present invention relates to pharmaceutical composition comprising Vilazodone or its pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the treatment of major depressive disorder.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: A process for the preparation of Vilazodone

5-(piperazin-1-yl) benzofuran-2-carboxamide (316 g) was charged into demineralized water (2.37 liters). Potassium bicarbonate (258 g) followed by 3-(4-chlorobutyl)-5-cyanoindole (296 g) with acetonitrile (0.790 liter) and finally potassium Iodide (214 g) were charged into reaction mixture. The reaction was stirred for 24 hours at 78-82 ºC. After completion of the reaction, the reaction mass was filtered to get titled product.

Yield: 90%

Example-2: Process for the preparation of Vilazodone hydrochloride

Vilazodone (1392 g) was charged into the mixture of Isopropyl alcohol (3.4 liters) and demineralized water (0.980 liter). Concentrated HCl (362 ml) was charged to the mixture and stirred for 3 hours. The resultant suspension was filtered to afford Vilazodone HCl.

Yield: 95%w/w
Purity: 99.42%