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

Formula II
or its pharmaceutically acceptable salt, which comprises:
a) condensation of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile of Formula III
wherein Ts is tosyl group

Formula III

with 5-(piperazin-1-yl)benzofuran-2-carboxamide of Formula IV

Formula IV

in presence of base such as bicarbonate of alkali metal to provide 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide of formula V; and

Formula V

b) deprotection of the compound of formula V using base to provide vilazodone or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein the bicarbonate of alkali metal is potassium bicarbonate.

3. The process of claim 1, wherein the condensation reaction is conducted in presence of acetonitrile and water.

4. The process of claim 1, wherein the step a) is conducted at a temperature of about 80 to 85 °C.

5. The process of claim 1, wherein the base of step b) is sodium hydroxide.

6. The process of claim 1, wherein the step b) is conducted in presence of methanol.

7. The process of claim 1, wherein the yield of Vilazodone or a pharmaceutically acceptable salt is greater than or equal to 92%.

,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide (tosyl Vilazodone)of formula V:

Formula V
or a pharmaceutically acceptable salt thereof and its conversion to Vilazodone or its pharmaceutically acceptable salt.

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 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 indol-5-carbonitrile with 4-chlorobutyrylchloride to give 3-(4-chlorobutyryl)-1H-indol-5 -carbonitrile, which is
reduced with diborane to give 3-(4-chlorobutyl)-1H-indol-5-carbonitrile, which is then reacted 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.

PCT publication No. 2012/170209 discloses a process for the preparation of Tosyl Vilazodone of Formula II, which involves reaction of tert-butyl (5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carbonyl) carbamate with tosyl anhydride or tosyl halide to provide BOC-protected tosyl Vilazodone, which is further deprotected to provide Tosyl vilazodone of Formula II. However, the process involves larger number of steps including BOC protection and deprotection to provide tosyl Vilazodone of Formula II.

Chinese publication No. 102617558 discloses a process for the preparation of Vilazodone, which involves reaction of 3-(4-chlorobutyl)-1-(phenylsulfonyl or nitrophenylsulfonyl)-1H-indole-5-carbonitrile with 5-(piperazin-1-yl)benzofuran-2-carboxamide in presence of sodium carbonate and dimethyl formamide at a temperature of 120 °C to provide Tosyl Vilazodone of Formula II, which is then deprotected using potassium carbonate in presence of methanol and water. However, the process utilizes expensive reagents and higher temperature; therefore, this is not viable process for large scale development.

Chinese publication No. 103570698 discloses a process for the preparation of Vilazodone, which involves reaction of 3-(4-bromobutyl)-1-tosyl-1H-indole-5-carbonitrile with 5-(piperazin-1-yl)benzofuran-2-carboxamide in presence of triethyl amine and NMP at a temperature of 120 °C for 5 hours to provide Tosyl Vilazodone of Formula II, which is then deprotected using potassium carbonate in presence of methanol and water. However, the process utilizes expensive reagents and higher temperature; therefore, this is not viable process for large scale development.

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

Summary of the Invention

The present invention provides an improved process for the preparation of Vilazodone or a pharmaceutically acceptable salt thereof.

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:

a) condensation of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile of Formula III
wherein Ts is tosyl group

Formula III

with 5-(piperazin-1-yl)benzofuran-2-carboxamide of Formula IV

Formula IV

in presence of base such as bicarbonate of alkali metal to provide 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide of formula V; and

Formula V

b) deprotection of the compound of formula V using base to provide vilazodone or a pharmaceutically acceptable salt thereof.

The resultant Vilazodone or its pharmaceutically acceptable can be used for the treatment of major depressive disorder.

Description of the Invention

The term “pure” as used herein, unless otherwise defined, refers to 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide and Vilazodone or a pharmaceutically acceptable salt thereof that has purity of about 95 % or above.

The intermediates of the Vilazodone, compound of Formula III, Formula IV and Formula V, 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:

a) condensation of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile of Formula III
wherein Ts is tosyl group

Formula III

with 5-(piperazin-1-yl)benzofuran-2-carboxamide of Formula IV

Formula IV

in presence of base such as bicarbonate of alkali metal to provide 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide of formula V; and

Formula V

b) deprotection of the compound of formula V using base to provide vilazodone or a pharmaceutically acceptable salt thereof.

The inventors of the present invention found that the prior art processes give lower yield and purity, and further concluded that an unusual and specific reaction conditions of the present invention improves the yield as well as purity of the intermediate of Vilazodone, which improves directly the yield and purity of Vilazodone or a pharmaceutically acceptable salt thereof.

The step a) involves condensation of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile of Formula III with 5-(piperazin-1-yl)benzofuran-2-carboxamide of Formula IV in presence of base such as bicarbonate of alkali metal to provide 5-(4-(4-(5-cyano-1-tosyl-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide of formula V.

The base is used for condensation is selected from bicarbonate of alkali metal such as sodium bicarbonate and potassium bicarbonate. The condensation reaction is usually conducted in presence of solvent such as nitrile or a mixture of nitrile solvent and water. The nitrile solvent includes but is not limited to acetonitrile, propionitrile and the like.

In an embodiment, the present invention provides a process for the preparation of tosyl Vilazodone or a pharmaceutically acceptable salt thereof, which comprises condensation of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile of Formula III with 5-(piperazin-1-yl)benzofuran-2-carboxamide of Formula IV in presence of potassium bicarbonate and a mixture of acetonitrile and water. The ratio of the mixture of acetonitrile and water is about 25:75.

The condensation reaction of the present invention uses alkali metal iodide such as potassium iodide or sodium iodide to fasten the reaction.

The reaction may be carried out at a temperature of 25 to 90 °C or 80 to 85 °C for a period of 30 minutes to 5 hour or more to complete the reaction.

After completion of the reaction, the reaction mixture is charged into water and then subjected for isolation of precipitated solid using known filtration technique.

The step b) deprotecting the tosyl Vilazodone of formula V using base to provide vilazodone or a pharmaceutically acceptable salt thereof.

The resultant tosyl Vilazodone or a pharmaceutically acceptable salt thereof of step a) is treated with base such as sodium hydroxide in presence of methanol to provide Vilazodone or a pharmaceutically acceptable salt thereof. The reaction may be conducted at a temperature of about 20 to about 70 °C or 60 to 65 °C.

The reaction may be stirred for a period of 30 minutes to 2 hours to enhance the yield of the product. After completion of the reaction, the suspension is filtered and dried.

The resultant compound, Vilazodone or a pharmaceutically acceptable salt thereof, may have the yield greater than or equal to 92%.

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:
Tosyl Vilazodone free base

A mixture of 3-(4-Chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile (3.9 g, 0.01 mol), 5-(piperazie-1-yl)benzofuran-2-carboxaide (2.45 g, 0.01 mol), potassium bicarbonate (2 g, 0.02 mol), potassium iodide (1.6 g, 0.01 mol) in 25 mL mixture of Acetoitrile/water (2.5:7.5) was stirred at 80 oC for 15 hours. The sample was analyzed in TLC to ensure absence of 3-(4-chlorobutyl)-1-tosyl-1H-indole-5-carbonitrile. The reaction mixture was poured into water and then filtered the solid to get 2.8 g of Tosyl Vilazodone.

Example 2:

Vilazodone free base

A mixture of tosyl vilazodone (2.8 g, 0.0047 mol) and sodium hydroxide (0.22 g, 0.0056 mol) in 25 mL methanol was stirred at 65 oC for 2 hours. The sample was analyzed in TLC to ensure absence of tosyl vilazodone. The reaction mixture was filtered and dried to get 1.9 g (92 %) of vilazodone.

Mass: 442.3 (M+1)