CLIAMS:A process for the preparation of intermediate of Vilazodone of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises:
a) stirring of a solution containing aluminum chloride and 4-chlorobutanoyl chloride in dichloromethane at 5-25 °C;
b) adding a solution of 1H-indole-5-carbonitrile in nitromethane to the solution of step (a) at 5-25 °C; and
c) stirring the solution of step b) for 30 minutes to 2 hours to afford the compound of formula II in higher yield.

2. The process of claim 1, wherein the solution of step a) is prepared at a temperature of 5-25°C.

3. The process of claim 1, wherein the quantity of dichloromethane is about 2 to 5 times.

4. The process of claim 1, wherein the addition of step b) is carried out for a period of 10 minutes to 30 minutes.

5. The process of claim 1, wherein the quantity of nitromethane used for the reaction is about 1 to 3 times per equivalent of 1H-indole-5-carbonitrile.

6. The process of claim 1, wherein the compound of formula II has purity greater than 98%.

7. The process of claim 1, wherein the yield of compound of formula II is greater than about 90%.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of 3-(4-Chlorobutanoyl)-1H-indole-5-carbonitrile, which is key intermediate for 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.

Timo H. et al. in J. Med. Chem 2004, 47, 4684-4692 describes a process for preparing vilazodone which involves reaction of indol-5-carbonitrile is condensed with 4-chlorobutyrylchloride in presence of isobutyl-AlCl2 to give 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, which is reduced with sodium bis(2 -methoxyethoxy)-aluminium hydride to give 3-(4-chlorobutyl)-1H-indol-5-carbonitrile, which is then reacted 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 ammonia gas in presence of 1-methyl-2-chloropyridinium iodide to provide Vilazodone.

U.S. Patent Application No. 2013/0225818 A1 discloses a process for preparation of Vilazodone, which involves reaction of 1H-indol-5-carbonitrile with 4-chlorobutyryl chloride in the presence of aluminium chloride and dichloromethane at reflux to provide 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, which is then converted into Vilazodone.

Timo Heinrich et al., in Med. Chem. Lett. 2010, 1, 199–203 discloses a process for the preparation of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile which involves reaction of indol-5-carbonitrile with 4-chlorobutyrylchloride in presence of dichloromethane and AlCl3.

CN 102690224 A discloses a process for the preparation of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile which involves reaction of indol-5-carbonitrile with 4-chlorobutyrylchloride in presence of dichloromethane and AlCl3 at 0-5 °C for 5 hours and at room temperature for 5 hours. However, it takes longer hours and provides lower yield.

CN 102875440 A discloses a process for the preparation of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile which involves reaction of indol-5-carbonitrile with 4-chlorobutyrylchloride in presence of dichloromethane, nitromethane, AlCl3 at 0-10 °C and stirred for 2 hours to get 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile. However, the process gives lower yield.

CN 103058912 discloses a process for the preparation of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile which involves reaction of indol-5-carbonitrile with 4-chlorobutyrylchloride in presence of DCM, nitromethane, AlCl3 at -5-0 °C and stirred for 5 hours to get 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile. However, the process involves use of larger amount of dichloromethan and nitromethane, and the reaction proceeds for longer hours.

None of the prior art processes provides appreciated yield for the intermediate of Vilazodone, 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, therefore, there is a need to develop simple, industrially feasible and cost effective process for 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile.

Summary of the Invention

The present invention provides an improved process for the preparation of intermediate of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile using aluminium chloride and a solvent system of dichloromethane and nitromethane.

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

Formula II

or its pharmaceutically acceptable salt, which comprises:

a) stirring of a solution containing aluminum chloride and 4-chlorobutanoyl chloride in dichloromethane at 5-25 °C;
b) adding a solution of 1H-indole-5-carbonitrile in nitromethane to the solution of step (a) at 5-25 °C; and
c) stirring the solution of step b) for 30 minutes to 2 hours to afford the compound of formula II in higher yield.

The resultant intermediate of Vilazodone or its pharmaceutically acceptable salt can be converted to Vilazodone or a pharmaceutically acceptable salt thereof, which 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 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile or its pharmaceutically acceptable salt that has purity of about 98 % or above.

The intermediates of the Vilazodone, 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, 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 intermediate of Vilazodone of Formula II:

Formula II

or its pharmaceutically acceptable salt, which comprises:
a) stirring of a solution containing aluminum chloride and 4-chlorobutanoyl chloride in dichloromethane at 5-25 °C;
b) adding a solution of 1H-indole-5-carbonitrile in nitromethane to the solution of step (a) at 5-25 °C; and
c) stirring the solution of step b) for 30 minutes to 2 hours to afford the compound of formula II in higher yield.

The inventors of the present invention found that the prior art processes give yield not more than 85% 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, 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile.

The step a) involves stirring of a solution containing aluminum chloride and 4-chlorobutanoyl chloride in dichloromethane at 5-25 °C.

Aluminum chloride and 4-chlorobutanoyl chloride are combined and dissolved in a dichloromethane at a temperature of about 5-25 °C or 5-20 °C.

The solvent for the dissolution may also include chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, ethyl acetate and the like.

The stirring of the reaction solution may be carried out for a period of 10 minutes to 1 hour or more to obtain particle free solution. The solution may be filtered though hyflow and washed with dichloromethane to get particle free filtrate.

The quantity of dichloromethane used for the reaction may range from 2 to 5 times per equivalent of 1H-indole-5-carbonitrile.

The step b) involves addition of solution of 1H-indole-5-carbonitrile and nitromethane to the solution of step (a) at 5-25 °C.

1H-indole-5-carbonitrile is dissolved in nitromethane at a temperature of 5-25 °C and it may be stirred for a period of 10 minutes to about 1 hour.

The obtained solution is added to the reaction solution of step a) for a period of 10 minutes to 30 minutes or more without affecting exothermic reaction and degradation.

The quantity of nitromethane used for the reaction is about 1 to 3 times per equivalent of 1H-indole-5-carbonitrile. Nitroethane is also useful as a solvent for the dissolution of 1H-indole-5-carbonitrile.

The step c) involves stirring the solution of step b) for 30 minutes to 2 hours at room temperature to afford the compound of formula II in higher yield.

The resultant solution is allowed to reach the room temperature and stirred for a period of about 30 minutes to 2 hours.

The use of small quantity of dichloromethane and nitromethane affects the reaction positively to complete within 3 hours or within 2 hours.

The reaction is stirred preferably at room temperature to afford yield greater than 90 % of 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile.

After completion of the reaction, the reaction mixture may be cooled to below 15 °C and then treated with acid, for example, hydrochloric acid, to precipitate the compound of Formula II. The acid can be aqueous, organic solution includes alcoholic, ketonic and the like or it may be gaseous state. Then the solid may be filtered and dried at a suitable temperature using vacuum.

The resultant compound of formula II, 3-(4-chlorobutyryl)-1H-indol-5-carbonitrile, may have the purity greater than or equal to 98% and it is used for the preparation of pure Vilazodone or a pharmaceutically acceptable salt thereof.

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:
Preparation of 3-(4-Chlorobutanoyl)-1H –indole-5-carbonitrile

To a stirred solution of Aluminum chloride (243 g, 1.82 mol) and 4-chlorobutanoyl chloride (257 g, 1.82 mol) in dichloromethane (1 L) at 5 – 25 oC was added, dropwise over 30 min, (200 g, 1.40 mol) of 1H-indole-5-carbonitrile in nitromethane (600 ml). The solution was stirred for 2 h at ambient temperature. Sample analyzed in HPLC to ensure limit (NMT 0.5 %) of 1H-indole-5-carbonitrile. The reaction mixture was cooled to 5 – 10 oC and acidify with 2 L mixture of HCl : water (1:1). The solid product was filtered and washed with warm water (2 L) to get 317 g (92 %) of 3-(4-Chlorobutanoyl)-1H –indole-5-carbonitrile.

HPLC purity: 98.06 %

1H NMR, dppm (DMSO-d6): 2.06 – 2.10 (2H, m, CH2), 3.02 – 3.05 (2H, t, CH2), 3.69 – 3.72 (2H, t, CH2), 7.56 – 7.65 (2H, m, ArH), 8.52 – 8.53 (2H, s, ArH) 12.42 (1H, br s, NH).

13C NMR, dppm (DMSO-d6): 27.82, 36.34, 45.48, 104.43, 114.10, 116.72, 120.60, 125.53, 126.16, 126.77, 136.58, 138.90, 194.76.

Mass Spectrometry: The protonated molecular ion at m/z 247.0 (M+) confirms the mass, which corresponds to molecular formula of C13H11N2ClO.