WO2014087428A1

WO2014087428A1 - Process for preparation of vilazodone and intermediates thereof

Info

Publication number: WO2014087428A1
Application number: PCT/IN2013/000749
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Sunil Kumar Singh; Samir Naik; Sushanta Mishra; Deepak Shantaram PATEKAR; Yogesh Baburao Kajale; Vipin PANDEY
Original assignee: Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
Priority date: 2012-12-07
Filing date: 2013-12-05
Publication date: 2014-06-12

Abstract

Provided is a process for the preparation of vilazodone, its intermediate compounds and pharmaceutically acceptable salts thereof. Solvates of vilazodone and processes for their preparation are also provided. A process for the preparation of amorphous vilazodone hydrochloride is further provided.

Description

PROCESS FOR PREPARATION OF VILAZODONE AND INTERMEDIATES

THEREOF

PRIORITY

[0001] This application claims the benefit of Indian Provisional Applications 3462/MUM/2012 filed on December 7, 2012, 1610/MUM/2013 filed on May 3, 2013 and 2406/MUM/2013 filed on Jul 18, 2013 and United States Provisional Application 61/755,957 filed on January 23, 2013, entitled "PROCESS FOR PREPARATION OF VILAZODONE AND INTERMEDIATES THEREOF", the contents of which are incorporated herein by reference!

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of vilazodone, its intermediate compounds and pharmaceutically acceptable salts thereof. The present invention relates to solvates of vilazodone hydrochloride and processes for their preparation. The present invention relates to a process for the preparation of amorphous vilazodone hydrochloride.

Description of the Related Art

[0003] Vilazodone, chemically known as 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l - piperazinyl]-2-benzofurancarboxamide, is represented by the structure of formula I. Vilazodone hydrochloride, a selective serotonin reuptake inhibitor and a 5-HTi_A receptor partial agonist, is approved as VIIBRYD® tablets for treatment of major depressive disorder.

[0004] United States Patent Nos. US5532241, US5971 12, US6531503 and US7799916 disclose processes for preparation of vilazodone. The prior art processes are time consuming, tedious and laborious. The ensuing product obtained in these processes may contain impurities, the separation and removal of which pose as a challenge, which may require multiple purification steps thereby reducing the product yield.

[0005] Presently, we have developed a novel process and a novel intermediate for preparation of vilazodone and salts thereof. Our novel process involves use of novel intermediate compound of Formula XIII. [0006] The present invention provides solvates of vilazodone hydrochloride and processes for their preparation. The present invention also provides a process for the preparation of amorphous vilazodone hydrochloride.

[0007] The present invention provides amorphous vilazodone hydrochloride free of N- oxide impurity.

[0008] The process of the present invention is advantageous as it is high yielding, less time consuming and is industrially feasible.

SUMMARY OF THE INVENTION

[0009] The present invention provides a process for the preparation of vilazodone hydrochloride in amorphous form, the process comprising:

(a) dissolving a solvate of vilazodone hydrochloride in a solvent to form a solution; and (b) removing the solvent from the solution obtained in (a).

[0010] In another embodiment, the present invention provides amorphous vilazodone hydrochloride substantially free of N-oxide impurity.

[0011] In another embodiment, the present invention provides a crystalline n-propanol solvate of vilazodone hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 2, a

DSC thermogram as depicted in Figure 3; an IR spectrum as depicted in Figure 4; a TGA thermogram as depicted in Figure 5; and any combination thereof.

[0012] In another embodiment, the present invention provides a process for the preparation of crystalline n-propanol solvate of vilazodone hydrochloride, the process comprising:

(a) adding hydrochloric acid to vilazodone in n-propanol to form a reaction mass;

(b) precipitating out n-propanol solvate of vilazodone hydrochloride from the reaction mass obtained in (a); and

(c) isolating the crystalline n-propanol solvate of vilazodone hydrochloride.

[0013] In another embodiment, the present invention provides a crystalline n-butanol solvate of vilazodone hydrochloride.

[0014] In another embodiment, the present invention provides a process for the preparation of crystalline n-butanol solvate of vilazodone hydrochloride, the process comprising: (a) dissolving vilazodone in n-butanol to form a solution;

(b) adding hydrochloric acid to the solution obtained in (a);

(c) precipitating out n-butanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline n-butanol solvate of vilazodone hydrochloride.

[0015J In another embodiment, the present invention provides a crystalline ethanol solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 10.

[0016] In another embodiment, the present invention provides a process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, the process comprising:

(a) dissolving vilazodone hydrochloride in dimethyl sulfoxide to form a solution;

(b) adding ethanol to the solution obtained in (a);

(c) precipitating out ethanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline ethanol solvate of vilazodone hydrochloride.

[0017] In another embodiment, the present invention provides a crystalline ethyl acetate solvate of vilazodone hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1 1 , a DSC thermogram as depicted in Figure 12; a TGA thermogram as depicted in Figure 13; and any combination thereof.

[0018] In another embodiment, the present invention provides a process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, the process comprising:

(b) adding ethyl acetate to the solution obtained in (a);

(c) precipitating out ethyl acetate solvate of vilazodone hydrochloride; and

(d) isolating the crystalline ethyl acetate solvate of vilazodone hydrochloride.

[0019] In another embodiment, the present invention provides a crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride.

[0020] In another embodiment, the present invention provides a process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, the process comprising: (a) dissolving vilazodone hydrochloride in dimethyl sulfoxide to form a solution;

(b) adding tert-butylmethyl ether to the solution obtained in (a);

(c) precipitating out dimethyl sulfoxide solvate of vilazodone hydrochloride; and

(d) isolating the crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride.

[0021] In another embodiment, the present invention provides use of solvate of vilazodone hydrochloride selected from n-propanol solvate, n-butanol solvate, ethanol solvate, ethyl acetate solvate, or dimethyl sulfoxide solvate in the preparation of amorphous vilazodone hydrochloride.

[0022] In another embodiment, the present invention provides a process for the preparation of a compound of Formula XII,

the process comprising:

(a) reacting a compound of Formula IX wherein A is selected from the group consisting of-CHO and -C(OR₂)₂, R₂ is Ci-C₇ alkyl, with a compound of Formula X,

IX

to obtain a compound of formula XIII; and

(b) cyclizing the compound of formula XIII to obtain a compound of formula XII.

[0023] In another embodiment, the present invention provides a compound of formula XIII, or its salt thereof.

[0024] In another embodiment, the present invention provides use of compound of formula XIII, or its salt thereof, in the preparation of vilazodone, a compound of formula I or salts thereof. [0025] In another embodiment, the present invention provides use of vilazodone N-oxide, or its salt thereof, as a reference marker to detect the presence of vilazodone N-oxide, or its salt thereof, in a sample comprising vilazodone, or salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is a characteristic XRPD of vilazodone hydrochloride in amorphous form as obtained in Example 27.

[0027] Figure 2 is a characteristic XRPD of crystalline n-propanol solvate of vilazodone hydrochloride as obtained in Example 14.

[0028] Figure 3 is a DSC thermogram of crystalline n-propanol solvate of vilazodone hydrochloride as obtained in Example 14.

[0029] Figure 4 is an IR spectrum of crystalline n-propanol solvate of vilazodone hydrochloride as obtained in Example 14.

[0030] Figure 5 is a TGA thermogram of crystalline n-propanol solvate of vilazodone. hydrochloride as obtained in Example 14.

[0031] Figure 6 is a characteristic XRPD of crystalline n-butanol solvate of vilazodone hydrochloride as obtained in Example 15.

[0032] Figure 7 is a DSC thermogram of crystalline n-butanol solvate of vilazodone hydrochloride as obtained in Example 15.

[0033] Figure 8 is an IR spectrum of crystalline n-butanol solvate¹ of vilazodone hydrochloride as obtained in Example 15.

[0034] Figure 9 is a TGA thermogram of crystalline n-butanol solvate of vilazodone hydrochloride as obtained in Example 15.

[0035] Figure 10 is a characteristic XRPD of crystalline ethanol solvate of vilazodone hydrochloride as obtained in Example 16.

[0036] Figure 1 1 is a characteristic XRPD of crystalline ethyl acetate solvate of vilazodone hydrochloride as obtained in Example 17.

[0037] Figure 12 is a DSC thermogram of crystalline ethyl acetate solvate of vilazodone hydrochloride as obtained in Example 17.

[0038] Figure 13 is an IR spectrum of crystalline ethyl acetate solvate of vilazodone hydrochloride as obtained in Example 17. [0039] Figure 14 is a TGA thermogram of crystalline ethyl acetate solvate of vilazodone hydrochloride as obtained in Example 17.

[0040] Figure 15 is a characteristic XRPD of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride as obtained in Example 18.

[0041] Figure 16 is a DSC thermogram of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride as obtained in Example 18.

[0042] Figure 17 is an IR spectrum of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride as obtained in Example 18.

[0043] Figure 18 is a TGA thermogram of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride as obtained in Example 18.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention provides a process for the preparation of vilazodone hydrochloride in amorphous form, the process comprising:

[0045] In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C. The term "C 1 -C7 alkyl", as used in the specification, means alkyl groups having 1 to 7 carbon atoms and includes groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. The term "salt thereof, as used in the specification, means salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and the like. The term "acid", as used in the specification, means organic and inorganic acids. Organic acids include acids such as formic acid, acetic acid, propanoic acid, butanoic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, lactic acid and the like. Inorganic acids include acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and the like.

[0046] In (a) of the process for the preparation of vilazodone hydrochloride in amorphous form, a solvate of vilazodone hydrochloride is dissolved in a solvent to form a solution.

[0047] The solvate of vilazodone hydrochloride includes solvate with methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, acetonitrile, acetone, butanone, tetrahydrofuran, chloroform, n-heptane, toluene, or dimethyl sulfoxide. Preferably, n- propanol solvate is used. [0048] The solvent used for dissolution of the solvate of vilazodone hydrochloride includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof. Preferably the solvent selected is ketone- water mixture, alcohol-water mixture, more preferably the solvent selected is acetone-water mixture, ethanol-water mixture.

[0049] In one embodiment, in (a) of the process for the preparation of amorphous vilazodone hydrochloride, the solvate of vilazodone hydrochloride is dissolved in a pretreated solvent to form a solution

[0050] The pretreated solvent comprises treating a solvent with nitrogen, ultrasound to remove free oxygen.

[0051] In one embodiment, n-propanol solvate of vilazodone hydrochloride is dissolved in acetone-water mixture bubbled with nitrogen to form a solution.

[0052] In one embodiment, water is bubbled with nitrogen prior to mixing with acetone or ethanol to prepare an acetone-water mixture or ethanol-water mixture.

[0053] In one embodiment, in (a) of the process for the preparation of amorphous vilazodone hydrochloride, the solvate of vilazodone hydrochloride is dissolved in a solvent at a temperature in the range of about 5°C to about 40°C to form a solution.

[0054] In one embodiment, n-propanol solvate of vilazodone hydrochloride is dissolved in acetone- water mixture at about room temperature to form a solution.

[0055] In one embodiment, a solvate of vilazodone hydrochloride is dissolved in a solvent bubbled with nitrogen at a temperature in the range of about 5°C to about 40°C to form a solution.

[0056] In one preferred embodiment, n-propanol solvate of vilazodone hydrochloride is dissolved in acetone- water mixture bubbled with nitrogen at about room temperature to form a solution. [0057] Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0058] In (b) of the process for the preparation of vilazodone hydrochloride in amorphous form, the solvent is removed from the solution obtained in (a).

[0059] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably solvent was removed by spray drying to give amorphous vilazodone hydrochloride.

[0060] In one embodiment, the present invention provides a process for the preparation of amorphous vilazodone hydrochloride substantially free of N-oxide impurity, the process comprising:

(a) (i) dissolving the solvate of vilazodone hydrochloride in a pretreated solvent to form a solution, and/or (ii) dissolving the solvate of vilazodone hydrochloride in a solvent at a temperature in the range of about 5°C to about 40°C to form a solution; and

(b) removing the solvent from the solution obtained in (a).

[0061] In one embodiment, the present invention provides a process for the preparation of amorphous vilazodone hydrochloride free of N-oxide impurity, the process comprising:

(a) dissolving a solvate of vilazodone hydrochloride in a solvent bubbled with nitrogen at a temperature in the range of about 5°C to about 40°C to form a solution; and

(b) removing the solvent from the solution obtained in (a) by spray drying to give amorphous vilazodone hydrochloride free of N-oxide impurity.

[0062] In one preferred embodiment, the present invention¹ provides a process for the preparation of amorphous vilazodone hydrochloride free of N-oxide impurity, the process comprising: (a) dissolving n-propanol solvate of vilazodone hydrochloride in acetone-water mixture bubbled with nitrogen at about room temperature to form a solution; and

[0063] The present invention provides amorphous vilazodone hydrochloride substantially free of N-oxide impurity.

[0064] In the present application, the term "substantially free" means the N-oxide impurity is less than 0.10% w/w with respect to vilazodone hydrochloride, as determined by high performance liquid chromatography (HPLC).

[0065] The present invention provides amorphous vilazodone hydrochloride wherein the N-oxide impurity is less than 0.10% w/w with respect to vilazodone hydrochloride, preferably less than 0.05% w/w, more preferably absent, as determined by high performance liquid chromatography (HPLC).

[0066] The present invention provides vilazodone N-oxide with relative retention time (PvRT) of about 1.09 with respect to vilazodone hydrochloride, as determined by HPLC.

[0067] The present invention provides amorphous vilazodone hydrochloride free of N- oxide impurity, obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:

Reagents, Solvents and Standards: Water (Milli Q or equivalent), Perchloric acid (70%) (AR Grade), Acetonitrile (HPLC Grade), Methanol (HPLC Grade)

Chromatographic Conditions:

Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.

Column: Inertsil ODS 3V, 250 x 4.6mm, 5μ; Column temperature: 30°C

Sample Cooler temperature: 25°C

Mobile Phase A: Buffer: Acetonitrile (90: 10, v/v); Buffer: 0.1% Perchloric acid in water Mobile Phase B: Acetonitrile: Methanol (60:40, v/v)

30 55 45

40 . . 35 65

55 35 65

58 80 20

65 80 20

Diluent: Buffer: Acetonitrile (1 : 1 , v/v)

Flow Rate: l .OmL/minute; Detection: UV 240nm; Injection Volume: 20μΙ.

Rinsing solvent: Acetonitrile: water (80:20, v/v)

The retention time of vilazodone hydrochloride is about 20.50 minutes under these conditions.

[0068] The present invention provides use of vilazodone N-oxide, or its salt thereof, as a reference marker to detect the presence of vilazodone N-oxide, or its salt thereof, in a sample comprising vilazodone, or salts thereof.

[0069] The present invention provides use of vilazodone N-oxide, or its salt thereof, as a reference marker to detect the presence of vilazodone N-oxide, or its salt thereof, in a sample comprising amorphous vilazodone hydrochloride.

.[0070]^'. The present invention provides stable amorphous vilazodone hydrochloride substantially free of N-oxide impurity.

[0071] The present invention provides storage stable amorphous vilazodone hydrochloride substantially free of N-oxide impurity.

[0072] The present invention provides a crystalline n-propanol solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 2, a DSC thermogram as depicted in Figure 3; an IR spectrum as depicted in Figure 4; a TGA thermogram as depicted in Figure 5.

[0073] Analysis by TGA showed the presence of 10 weight% to 1 1 weight % of n- propanol (theory of 1 : 1 solvate 1 1.16 weight %) which is further confirmed by presence of 50530 ppm of n-propanol in residual solvent analysis by GC analysis.

[0074] The present invention provides a process for the preparation of crystalline n- propanol solvate of vilazodone hydrochloride, the process comprising:

^'(c) isolating the crystalline n-propanol solvate of vilazodone hydrochloride. [0075] In (a) of the process for the preparation of crystalline n-propanol solvate of vilazodone hydrochloride, hydrochloric acid is added vilazodone in n-propanol to form a reaction mass. The hydrochloric acid may be in an aqueous, anhydrous or gaseous form. For example, aqueous hydrochloric acid or solvent containing hydrogen chloride or gas containing hydrogen chloride may be used. Preferably, aqueous hydrochloric acid is used. Suitable temperature for addition of hydrochloric acid may range from about 0°C to about 85°C. Preferably, addition of hydrochloric acid is carried at about 15°C to about 35°C.

[0076] In (b) of the process for the preparation of crystalline n-propanol solvate of vilazodone hydrochloride, n-propanol solvate of vilazodone hydrochloride is precipitated out by stirring the solution obtained in (a). The stirring time may range from about 30 minutes to about 5 hours, or longer. The temperature may range from about 0°C to about 85°C. Preferably, the solution is stirred for about 2 hours to about 3 hours at about 0°C to about 20°C.

[0077] In (c) of the process for the preparation of crystalline n-propanol solvate of vilazodone hydrochloride, the crystalline n-propanol solvate of vilazodone hydrochloride is isolated from the solution by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0078] The isolated crystalline n-propanol solvate of vilazodone hydrochloride may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hourSj or longer.

[0079] The present invention provides a crystalline n-butanol solvate of vilazodone hydrochloride.

[0080] The present invention provides a crystalline n-butanol solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 6, a DSC thermogram as depicted in Figure 7; an IR spectrum as depicted in Figure 8; a TGA thermogram as depicted in Figure 9.

[0081] Analysis by TGA showed the presence of 12 weight% to 13 weight % of n- butanol (theory of 1 : 1 solvate 13.42 weight %) which is further confirmed by presence of 55440 ppm of n-butanol in residual solvent analysis by GC analysis.

[0082] The present invention provides a process for the preparation of crystalline n- butanol solvate of vilazodone hydrochloride, the process comprising:

(a) dissolving vilazodone in n-butanol to form a solution;

(b) adding hydrochloric acid to the solution obtained in (a);

(c) precipitating out n-butanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline n-butanol solvate of vilazodone hydrochloride.

[0083] In (a) of the process for the preparation of crystalline n-butanol solvate of vilazodone hydrochloride, vilazodone is dissolved in n-butanol to form a solution. Suitable temperature for dissolution of vilazodone in n-butanol may range from about room temperature to about the reflux temperature of n-butanol. Preferably, vilazodone is dissolved in n-butanol at about 80°C to about 85°C. Stirring may be continued for any desired time period to achieve a complete dissolution of vilazodone. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0084] In (b) of the process for the preparation of crystalline n-butanol solvate, of vilazodone hydrochloride, hydrochloric acid is added to the solution obtained in (a). The hydrochloric acid may be in an aqueous, anhydrous or gaseous form. For example, aqueous hydrochloric acid or solvent containing hydrogen chloride or gas containing hydrogen chloride may be used. Preferably, aqueous hydrochloric acid is used. Suitable temperature for addition of hydrochloric acid may range from about 0°C to about 85°C. Preferably, addition of hydrochloric acid is carried at about room temperature.

[0085] In (c) of the process for the preparation of crystalline n-butanol solvate of vilazodone hydrochloride, n-butanol solvate of vilazodone hydrochloride is precipitated out by stirring the solution obtained in (b). The stirring time may range from about 30 minutes to about 3 hours, or longer. The temperature may range from about 0°C to about 85°C. Preferably, the solution is stirred for about 1 hour at about room temperature. [0086] In (d) of the process for the preparation of crystalline n-butanol solvate of vilazodone hydrochloride, the crystalline n-butanol solvate of vilazodone hydrochloride is isolated from the solution by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0087] The isolated crystalline n-butanol solvate of vilazodone hydrochloride may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0088] The present invention provides a crystalline ethanol solvate of vilazodone hydrochloride.

[0089] The present invention provides a crystalline ethanol solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 10.

[0090] The present invention provides a process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, the process comprising:

(b) adding ethanol to the solution obtained in (a);

(c) precipitating out ethanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline ethanol solvate of vilazodone hydrochloride.

[0091] In (a) of the process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, vilazodone hydrochloride is dissolved in dimethyl sulfoxide to form a solution. Suitable temperature for dissolution of vilazodone hydrochloride in dimethyl sulfoxide may range from about 35°C to about 150°C. Preferably, vilazodone hydrochloride is dissolved in dimethyl sulfoxide at about 90°C to about 100°C. Stirring may be continued for any desired time period to achieve a complete dissolution of vilazodone hydrochloride. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0092] In (b) of the process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, ethanol is added to the solution obtained in (a). The addition of ethanol may be carried out at a temperature in the range of about room temperature to about 150°C for a period in the range of about within 1 minute to about 10 minutes. Preferably, addition of ethanol is carried out at a temperature of about 90°C to about 100°C for a period of about within 1 minute.

[0093] In (c) of the process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, ethanol solvate of vilazodone hydrochloride is precipitated out from the solution obtained in (b). The temperature may range from about 0°C to about

150°C. The stirring time may range from about 30 minutes to about 3 hours, or longer.

Preferably, the solution is stirred at about room temperature for about 30 minutes.

[0094] In (d) of the process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, the crystalline ethanol solvate of vilazodone hydrochloride is isolated from the solution by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0095] The isolated crystalline ethanol solvate of vilazodone hydrochloride may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0096] The present invention provides a crystalline ethyl acetate solvate of vilazodone hydrochloride.

[0097] The present invention provides a crystalline ethyl acetate solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1 1, a DSC thermogram as depicted in Figure 12; a TGA thermogram as depicted in Figure 13. [0098] Analysis by TGA showed the presence of 14 weight% to 15 weight % of ethyl acetate (theory of 1 : 1 solvate 15.56 weight %) which is further confirmed by presence of 26053 ppm of ethyl acetate in residual solvent analysis by GC analysis

[0099] The present invention provides a process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, the process comprising:

(b) adding ethyl acetate to the solution obtained in (a);

(c) precipitating out ethyl acetate solvate of vilazodone hydrochloride; and

[0100] In (a) of the process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, vilazodone hydrochloride is dissolved in dimethyl sulfoxide to form a solution. Suitable temperature for dissolution of vilazodone hydrochloride in dimethyl sulfoxide may range from about 35°C to about 150°C. Preferably, vilazodone hydrochloride is dissolved in dimethyl sulfoxide at about 90°C to about 100°C. Stirring may be continued for any desired time period to achieve a complete dissolution of vilazodone hydrochloride. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0101] In (b) of the process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, ethyl acetate is added to the solution obtained in (a). The addition of ethyl acetate may be carried out at a temperature in the range of about room temperature to about 150°C for a period in the range of about within 1 minute to about 10 minutes. Preferably, addition of ethyl acetate is carried out at a temperature of about 90°C to about 100°C for a period of about within 1 minute.

[0102] In (c) of the process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, ethyl acetate solvate of vilazodone . hydrochloride is precipitated out from the solution obtained in (b). The temperature may range from about 0°C to about 150°C. The stirring time may range from about 30 minutes^' to about 3 hours, or longer. Preferably, the solution is stirred at about room temperature for about 30 minutes. [0103] In (d) of the process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, the crystalline ethyl acetate solvate of vilazodone hydrochloride is isolated from the solution by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0104] The isolated crystalline ethyl acetate solvate of vilazodone hydrochloride may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0105] The present invention provides a crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride.

[0106] The present invention provides a crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 14, a DSC thermogram as depicted in Figure 15; a TGA thermogram as depicted in Figure 16.

[0107] Analysis by thermogravimetry showed the presence of 13 weight% to 14 weight % of dimethyl sulfoxide (theory of 1 :1 solvate 14.0 weight %) which is further confirmed ;, by presence of 107964 ppm of dimethyl sulfoxide in residual solvent analysis by HPLC analysis.

[0108] The present invention provides a process for the preparation . of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, the process comprising:

(b) adding tert-butylmethyl ether to the solution obtained in (a);

[0109] In (a) of the process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, vilazodone hydrochloride is dissolved in dimethyl sulfoxide to form a solution. Suitable temperature for dissolution of vilazodone hydrochloride in dimethyl sulfoxide may range from about 35°C to about 150°C. Preferably, vilazodone hydrochloride is dissolved in dimethyl sulfoxide at about 90°C to about 100°C. Stirring may be continued for any desired time period to achieve a complete dissolution of vilazodone hydrochloride. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0110] In (b) of the process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, tert-butylmethyl ether is added to the solution obtained in (a). The addition of tert-butylmethyl ether may be carried out at a temperature in the range of about room temperature to about 150°C. Preferably, addition of tert-butylmethyl ether is carried out at a temperature of about 90°C to about 100°C.

[0111] In (c) of the process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, dimethyl sulfoxide solvate of vilazodone hydrochloride is precipitated out from the solution obtained in (b). The temperature may range from about 0°C to about 150°C. The stirring time may range from about 30 minutes to about 3 hours, or longer. Preferably, the solution is stirred at about room temperature for about 1 hour.

[0112] In (d) of the process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, the crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride is isolated from the solution by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0113] The isolated crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0114] The present invention provides use of solvate of vilazodone hydrochloride selected from n-propanol solvate, n-butanol solvate, ethanol solvate, ethyl acetate solvate, or dimethyl sulfoxide solvate in the preparation of amorphous vilazodone hydrochloride. [0115] The present invention provides amorphous vilazodone hydrochloride and crystalline solvates of vilazodone hydrochloride, obtained by the above processes, as characterized and analyzed by following techniques:

A. X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV ; tube current 40mAmp. The samples were scanned in the full 2Θ range of 2-50° with a "time-per-step" optimized to 50 sec.

B. DSC (Mettler Toledo 822e): Temperature range is "30°C to 350°C" and heating rate is 10°C/minute.

C. IR spectra were recorded using IR instrument- Perkin Elmer Spectrum One FTIR.

D. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at . 30-350°C at the rate of 10°C/min.

[0116] The present invention provides a process for the preparation of a compound of Formula XII,

the process comprising:

(a) reacting a compound of Formula IX wherein A is selected from the group consisting of -CHO and -C(OR₂)₂, R₂ is C 1 -C7 alkyl, with a compound of Formula X,

to obtain a compound o

XIII

(b) cyclizing the compound of formula XIII to obtain a compound of formula XII.

[0117] In (a) of the process for the preparation of the compound of Formula XII, the compound of Formula IX wherein A is selected from the group consisting of -CHO and -C(OR₂)₂, R₂ is Ci-C alkyl, is reacted with the compound of Formula X to obtain the compound of formula XIII.

[0118] In one embodiment, the present invention provides a process for the preparation of the compound of Formula XII, comprising reacting the compound of Formula IX wherein A is -CHO, with a compound of Formula X to obtain the compound of formula XIII.

[0119] In one embodiment, the present invention provides a process for the preparation of the compound of Formula XII, comprising reacting the compound of Formula IX wherein A is -C(OR₂)₂, R₂ is Ci-C₇ alkyl, with a compound of Formula X to obtain the compound of formula XIII.

[0120] The reaction may be carried out in the presence of a suitable acid such as acetic acid, sulphuric acid, phosphoric acid, polyphosphoric acid. Preferably, sulphuric acid is used.

[0121] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is methanol-water mixture.

[0122] The reaction may be carried out at a temperature in the range of about 0°C to about 100°C. The reaction is carried out for a period of about 2 hours to about 10 hours. Preferably the reaction is carried out at a temperature about 15°C to about 35°C for a period of about 2 hours to about 6 hours.

[0123] In one embodiment, the present invention provides a process for the preparation of the compound of Formula XII wherein the product of step (a) is not isolated.

[0124] In (b) of the process for the preparation of the compound of Formula XII, the compound of formula XIII is cyclized to obtain the compound of formula XII.

[0125] The reaction may be carried out in the presence of a suitable acid such as acetic acid, sulphuric acid, phosphoric acid, polyphosphoric acid. Preferably, polyphosphoric acid is used. [0126] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to ethers such as tetrahydrofuran, dioxane and the like; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene and the like; dimethyl formamide; dimethyl acetamide; or mixtures thereof. Preferably the solvent selected is dioxane.

[0127] The present invention provides a process for the preparation of amorphous vilazodone hydrochloride, the process comprising:

(a) converting th ula XI,

wherein R may be -ORi and Ri is selected from the group consisting of C 1 -C7 alkyl, phenyl or benzyl;

(b) treating the compound of formula XI with a source of ammonia to obtain vilazodone, a compound of formula I;

(c) optionally, converting vilazodone to vilazodone hydrochloride or solvate thereof; and (d) optionally converting the solvate of vilazodone hydrochloride to amorphous vilazodone hydrochloride.

[0128] In (a) of the process for the preparation of amorphous vilazodone hydrochloride, the compound of formula XII is reacted with a com ound of formula VIII,

wherein R may be -ORi and Ri is selected from the group consisting of Ci-C₇ alkyl, phenyl or benzyl to give the compound of formula XI wherein R may be as defined above. [0129] The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, Ν,Ν-diisopropylethylamine; ammonia, pyridine, piperidine, 4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7_^ ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium carbonate.

[0130] The reaction may be carried out in the presence of an alkali metal halide such as lithium chloride, sodium iodide, potassium iodide and the like; alkaline earth metal halide such as magnesium chloride and the like. Preferably, sodium iodide is used.

[0131] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is dimethyl formamide-acetone mixture.

[0132] In one embodiment, the compound of formula XII is reacted with a compound of formula VIII to give the compound of formula XI wherein R may be -OC₂H₅.

[0133] In (b) of the process for the preparation of amorphous vilazodone hydrochloride, the compound of formula XI is treated with a source of ammonia to obtain vilazodone, a compound of formula I. [0134] The source of ammonia includes but is not limited to formamide, aqueous ammonia, methanolic ammonia and the like. Preferably methanolic ammonia is used.

[0135] Vilazodone, the compound of formula I is purified by treatment with a suitable solvent and optionally in the presence of a suitable base.

[0136] The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water or mixtures thereof. Preferably the solvent selected is dimethyl formamide-water mixture.

[0137] The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium hydroxide.

[0138] The present invention provides a compound of formula XIII, or its salt thereof.

XIII [0139] The present invention provides use of compound of formula XIII, or its salt thereof, in the preparation of vilazodone, a compound of formula I or salts thereof.

Scheme II

[0142] In one embodiment the present invention provides a process for preparation of vilazodone, a compound of Formula I, as depicted in Scheme III below.

Scheme III

[0143] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

[0144] EXAMPLE 1: Preparation of 6-chlorohexanal (compound of formula IX, wherein A = -CHO)

A mixture of dimethyl sulfoxide (57.19g, 0.732mol) and methylene chloride (600mL) under nitrogen atmosphere was cooled to about -78°C and oxalyl chloride (55.74g, 0.439mol) was added drop wise at about the same temperature. The reaction mixture was stirred for about lOmin. A solution of 6-chlorohexanol (50g, 0.366mol) in methylene chloride (lOOmL) was slowly added to the reaction mixture at about -78°C. After completion of addition, the reaction mixture was stirred for about 30min and triethy] amine (148g, 1.464mol) was added drop wise at about -78°C. After completion of reaction, the temperature of the reaction mixture was raised to about room temperature and water (500mL) was added to the reaction mixture. The reaction mixture was stirred for about 30min and the two layers were separated. The organic layer was washed with 5% aqueous citric acid (400mL) and finally with water, dried over sodium sulphate and concentrated under vacuum at about 35°C to about 40°C to give 46.5g (94%) of 6- chlorohexanal as transparent oily mass.

[0145] EXAMPLE 2: Preparation of 4-[(2E)-2-(6- chlorohexylidene)hydrazinyl]benzonitrile (compound of formula XIII)

Water (250mL) was added to a solution of 6-chlorohexanal (23.8g, G.176mol) prepared as in Example 1 , in methanol (250mL) at about room temperature. The reaction mixture was stirred for about lOmin and then sulphuric acid (lOg, 0.102mol) was slowly added at about room temperature. The reaction mass was stirred for about lOmin and 4- cyanophenylhydrazine hydrochloride (25g, 0.147mol) was added lot wise at about room temperature. After completion of reaction, the precipitated solid was filtered, washed with water; dried at about 50°C to about 55°C for about 12h to give 35g of 4-[(2£)-2-(6- chlorohexylidene)hydrazinyl]benzonitrile.

[0146] EXAMPLE 3: Preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitri]e (compound of formula XII)

To a mixture of 4-[(2E)-2-(6-chlorohexylidene)hydrazinyl]benzonitrile (lOg, 0.04mol) prepared as in Example 2, in toluene (400mL), phosphoric acid (17.5gm, 0.178mol) was slowly added at about room temperature. , After completion of addition, the reaction mixture was stirred at about the same temperature for about lOmin. The temperature of the reaction mixture was raised to about 50°C to about 60°C and the reaction mixture was stirred for about l Oh at about the same temperature. After completion of reaction, the reaction mixture was cooled to about room temperature and water (200mL) was added at about the same temperature. The pH of the reaction mixture was adjusted to about 7 to

.0,

about 8 using aqueous sodium bicarbonate solution. The reaction mixture was stirred for about 20min and the two layers were separated. The organic layer was concentrated under vacuum at about 35°C to about 40°C to afford 3-(4-chlorobutyl)-lH-indole-5- carbonitrile as a solid.

[0147] EXAMPLE 4: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l- piperazinyl]- 2-benzofurancarboxylic acid ethyl ester hydrochloride (hydrochloride salt of compound of formula XI, wherein R = OC₂H₅)

A mixture of ethyl 5-(l-piperazinyl)benzofuran-2-carboxylate . hydrochloride (50g, 0.160mol), 3-(4-chlorobutyl)-lH-indole-5-carbonit^'rile (44.92g,0.193mol) prepared as in Example 3 and potassium iodide (26.7g, 0.160mol) in acetonitrile (lOOOmL) was stirred at about room temperature for about l Omin and triethyl amine (65.12g, 0.643mol) and potassium carbonate (44.4g, 0.320mol) were added to it at about the same temperature. After completion of addition, the reaction mixture was stirred at about room temperature for about 1 Omin. The temperature of the reaction mixture was raised to about 70°C to about 80°C and the reaction mixture was stirred for about 20h at about the same temperature. After completion of reaction, the reaction mixture was cooled to- about 50°C to about 55°C, filtered, then washed with acetonitrile (l OOmL). The filtrate was subjected to vacuum distillation at about 45°C to about 55°C to give a thick residue. The residue was taken in ethyl acetate (500mL) and water (400mL) was added. The reaction mixture was stirred for about 20min and the two layers were separated. Water (250mL) was added to the organic layer at about room temperature and the pH of the reaction mixture was adjusted to about 2 to about 3 with isopropyl alcohol hydrochloride (25% IPA-HC1). The reaction mixture was stirred for about lh at about room temperature. The precipitated solid was filtered, washed with ethyl acetate (l.OOmL), dried at about 50°C to about 60°C for about lOh to afford 48g of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l -piperazinyl]- 2- benzofurancarboxylic acid ethyl ester hydrochloride as a solid. [0148] EXAMPLE 5: Preparation of compound of formula XIV (R = OC₂H₅)

A mixture of ethyl 5-(l -piperazinyl)benzofuran-2-carboxylate hydrochloride (25g, 0.08mol), 4-[(2E)-2-(6-chlorohexylidene)hydrazinyl]benzonitrile (22. lg, 0.088mol) prepared as in Example 2 and potassium iodide (13.28g, 0.80mol) in acetonitrile (5000mL) was stirred at about room temperature for about lOmin and triethyl amine (32.4g, 0.32mol) and potassium carbonate (22g, 0.160mol) were added at about the same temperature. After completion of addition, the reaction mixture was stirred at about room temperature for about 1 Omin. The ternperature of the reaction mixture was raised to about 70°C to about 80°C and the reaction mixture was stirred for about 20h at about the same temperature. After completion of reaction, the reaction mixture was cooled to about 50°C to about 55°C, filtered and washed with acetonitrile (50mL). The filtrate was subjected to vacuum distillation at about 45°C to about 55°C to give a thick residue. The residue was taken in ethyl acetate (175mL) and water (l OOmL) was added. The reaction mixture was stirred for about 20min and the two layers were separated. The organic layer was washed with 20% sodium chloride solution, the pH adjusted to about 2 to about 3 with isopropyl alcohol hydrochloride (25% IPA-HC1) and stirred for about an hour at about room temperature. The precipitated solid was filtered, washed with ethyl acetate (50mL), dried at about 50°C to about 60°C for about l Oh to give the title compound (which can also be used in situ for the preparation of compound of formula XI).

[0149] EXAMPLE 6: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l- piperazinyl]-2-benzofurancarboxylic acid ethyl ester hydrochloride (hydrochloride salt of compound of formula XI, wherein R = OC₂Hs)

To a mixture of compound of formula XIV, wherein R = OC₂H₅ (lOg, 0.019mol) prepared as in Example 5, in toluene (200mL), phosphoric acid (8.32g, 0.084mol) was slowly added at about room temperature. After completion of addition, the reaction mixture was stirred at about room temperature for about l Omin. The temperature of the reaction mixture was raised to about 50°C to about 60°C and the reaction mixture was stirred for about lOh at about the same temperature. After completion of reaction, the reaction mixture was cooled to about room temperature and water (lOOmL) was added at about the same temperature. The pH of the reaction mixture was adjusted to about 7 to about 8 using aqueous sodium bicarbonate solution. The reaction mixture was stirred for P T/IN2013/000749 about 20min and the two layers were separated. The organic layer was distilled off completely under vacuum at about 35°C to about 40°C to afford a thick oily mass. The oily mass was taken in ethyl acetate (150mL) at about room temperature. The pH of the reaction mixture was adjusted to about 2 to about 3 with isopropyl alcohol hydrochloride (25% IPA-HC1) and was stirred for about lh at about room temperature. The precipitated solid was filtered, washed with ethyl acetate (lOOmL), dried at about 50°C to about 60°C for about lOh to give 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l-piperazinyl]-2- benzofurancarboxylic acid ethyl ester hydrochloride as a solid. [0150] EXAMPLE 7: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l- piperazinyI]-2-benzofurancarboxamide (vilazodone)

A mixture of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l-piperazinyl]-benzofuran-2- carboxylic acid ethyl ester. hydrochloride (45g, 0.088mol) in dimethyl sulfoxide (225mL) was stirred at about room temperature for about lOmin and formamide (39.97g, 0.88mol) was added at about the same temperature. After completion of addition, the reaction mixture was stirred at about room temperature for about lOmin. The reaction mixture was cooled to about 0°C to about 5°C and sodium methoxide (25% solution in methanol, 95.88g, 0.443mol) was added to the reaction mixture at about 0°C to about 5 °C. After completion of addition, the reaction mixture was stirred at about the same temperature for about 30min. The temperature of the reaction mixture was raised to about room temperature and the reaction mixture was stirred for about lh at about the same temperature. After completion of reaction, water (450mL) was slowly added at about room temperature and the mixture was stirred for about lh. The precipitated solid was filtered, washed with water (45mL), dried at about 50°C to about 60°C for about 1 Oh to give 34.5g of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l -piperazinyl]-2- benzofurancarboxamide as a solid.

[0151] EXAMPLE 8: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l- piperazinyl]-2-benzofurancarboxamide hydrochloride (vilazodone hydrochloride) 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l -piperazinyl]-2-benzofurancarboxamide (15g, 0.033mol) was dissolved in isopropyl alcohol (750mL) at about 80°C to about 85°C to get a clear solution. The clear solution was treated with Norit™ charcoal (1.5g) at about 80°C to about 85°C and the reaction mixture was stirred at about the same temperature for about 30min. The reaction mixture was filtered through Hyflo and washed with hot isopropyl alcohol (15mL). The pH of the filtrate was adjusted to about 2 to about 3 with concentrated hydrochloric acid. The reaction mixture was stirred for about lh at about room temperature. The precipitated solid was filtered and washed with isopropyl alcohol (30mL). The material was dried at about 45°C to about 55°C for about lOh to give 15.8g of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l -piperazinyl]-2-benzofurancarboxamide hydrochloride as a white solid. [0152] EXAMPLE 9: Preparation of 6-chlorohexanal (compound of formula IX, wherein A = -CHO)

Dimethyl sulfoxide (85.78g) was added to stirred methylene chloride (1200mL) at about - 78°C under nitrogen atmosphere. Oxalyl chloride (1 1 1.49g) was added drop wise at about the same temperature. The reaction mixture was stirred for about 30min under nitrogen atmosphere. A solution of 6-chlorohexanol (lOOg) in methylene chloride (200mL) was added to the above reaction mixture at about -78°C. The reaction mixture was stirred for about 30min at about the same temperature. Triethyl amine (222.2 l g) was drop wise added to the reaction mixture at about -78°C. After completion of reaction, the temperature was raised up to about room temperature. Purified water (lOOOmL) was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with aqueous hydrochloric acid and purified water, dried, concentrated under vacuum and degassed well to give 95g of oily residue.

[0153] EXAMPLE 10: Preparation of 4-[2-(6- chlorohexylidene)hydrazinyl]benzonitrile (compound of formula XIII)

A suspension of 6-chlorohexanal (lOOg), 4-cyanophenylhydrazine hydrochloride (109.68g), methanol (1 lOOmL) and water (1 lOOmL) was stirred for about lOmin to about 15min and sulphuric acid (43.68g) was added drop wise at about room temperature within about 30min to about 45min under vigorous stirring. The reaction mixture was stirred for about 4h to about 5h at about the same temperature. After completion of reaction, the precipitated solid was filtered, washed with purified water and dried at about 35°C to about 45°C under vacuum for about 12h to give 150g of 4-[2-(6- chlorohexylidene)hydrazinyl]benzonitrile.

[0154] EXAMPLE 11: Preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (compound of formula XII)

4- [2-(6-chlorohexylidene)hydrazinyl]benzonitrile (100g) was added to a mixture of polyphosphoric acid (130g) and 1 ,4-dioxane (lOOOmL) at about 60°C to about 65 °C and the temperature of the reaction mixture was raised to about 90°C to about 100°C. After completion of reaction, the reaction mixture was cooled to about 70°C to about 80°C and the organic layer was decanted. The organic layer was concentrated under vacuum at about 40°C to about 50°C to give a residue which was taken in toluene and washed with water and aqueous sodium bicarbonate solution. The solvent was removed under vacuum to give a solid which was dissolved in methylene chloride at about 35°C to about 45°C to get a clear solution. n-Heptane was slowly added to the above clear solution at about the same temperature. The precipitated solid was cooled to about room temperature, filtered, dried at about 50°C to about 60°C under vacuum for about 12h to give 70g of 3-(4- chlorobutyl)-lH-indole-5-carbonitrile. The solid product was dissolved in toluene (150mL) at about 60°C to about 70°C The solution was cooled to about 10°C to about 20°C and the precipitated solid was stirred for about 3h. The solid was filtered, washed with toluene and dried at about 50°C to about 60°C to give 3-(4-chlorobutyl)-lH-indole-

5- carbonitrile.

[0155] EXAMPLE 12: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l- piperazinyl]-2-benzofurancarboxylic acid ethyl ester hydrochloride (hydrochloride salt of compound of formula XI, wherein R = OC2H5)

To a mixture of dimethyl formamide (800mL) and acetone (200mL), ethyl 5-(l- piperazinyl)benzofuran-2-carboxylate dihydrochloride monohydrate (lOOg), 3-(4- chlorobutyl)-lH-indole-5-carbonitrile (63.7g), sodium iodide (48.1 lg) and sodium carbonate (102.05g) were added at about room temperature. The reaction mixture was slowly heated to about 85°C to about 95°C. After completion of reaction, the reaction mixture was cooled to about room temperature, filtered and concentrated under vacuum at about 60°C to about 70°C till the volume of the reaction mixture reaches up to about 200mL to about 250mL. Purified water and ethyl acetate was added to the above residual reaction mixture at about room temperature. The reaction mixture was stirred and the two layers were separated. Purified water was added to the organic layer at about room temperature. Isopropyl alcohol hydrogen chloride (25% IPA-HC1) was slowly added to the reaction mixture at about room temperature till the pH reaches to about 2 to about 3. The solid obtained was stirred for about lh, filtered, washed with ethyl acetate and dried. The solid was dissolved in a mixture of acetonitrile and purified water at about 75 °C to about 85°C. The reaction mixture was cooled to about room temperature, filtered and dried to give lOOg of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l-piperazinyl]- 2- benzofurancarboxylic acid ethyl ester hydrochloride.

[0156] EXAMPLE 13: Preparation If 5-[4-[4-(5-cyano-lH-indol-3yI)butyl]-l- piperr.zinyl]-2-benzofurancarboxamide (vilazodone)

A mixture of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l-piperazinyl]-benzofuran-2- carboxylic acid ethyl ester hydrochloride (lOOg) and 15-25% methanolic ammonia (1500mL) was slowly heated to about 60°C to about 70°C in an autoclave and stirred for about lOh to about 12h. After completion of reaction, the reaction mixture was cooled to about 45 °C to about 55°C and concentrated under vacuum at about the same temperature to give a solid. The solid obtained was dissolved in dimethyl formamide (400mL) at about 40°C to about 50°C and 5% aqueous sodium hydroxide solution (200mL) was slowly added at about the same temperature. The precipitated solid was cooled to about room temperature, filtered and dried to give 75g of vilazodone.

[0157] EXAMPLE 14 Preparation of crystalline n-propanol solvate of vilazodone hydrochloride

A mixture of vilazodone (l Og) in n-propanol (400mL) was stirred at about 80°C to about 85°C to get a clear solution. The reaction mixture was cooled to about room temperature and the pH was adjusted to about 2 to about 3 by adding aqueous hydrochloric acid. The precipitated solid was stirred for about lh at about room temperature. The solid was filtered and dried under vacuum at about 40°C to about 45°C for about 15h to give crystalline n-propanol solvate of vilazodone hydrochloride.

XRPD peaks of crystalline n-propanol solvate of vilazodone hydrochloride:

[0158] EXAMPLE 15 Preparation of crystalline n-butanol solvate of vilazodone hydrochloride

A mixture of vilazodone (lOg) in n-butanol (400mL) was stirred at about 80°C to about 85°C to get a clear solution. The reaction mixture was cooled to about room temperature and the pH was adjusted to about 2 to about 3 by adding aqueous hydrochloric acid. The precipitated solid was stirred for about lh at about room temperature. The solid was filtered and dried under vacuum at about 40°C to about 45°C for about 15h to give crystalline n-butanol solvate of vilazodone hydrochloride.

XRPD peaks of crystalline n-butanol solvate of vilazodone hydrochloride:

[0159] EXAMPLE 16 Preparation of crystalline ethanol solvate of vilazodone hydrochloride

A mixture of vilazodone hydrochloride (0.5g) in dimethyl sulfoxide (4mL) was stirred at about 90°C to about 100°C to get a clear solution and ethanol (8mL) was added to the solution within one minute at about the same temperature. The reaction mixture was cooled to about room temperature and the precipitated solid was stirred for about 30min at about room temperature. The solid was filtered and dried under vacuum at about 50°C to about 55°C for 15h to give crystalline ethanol solvate of vilazodone hydrochloride. XRPD peaks of crystalline ethanol solvate of vilazodone hydrochloride:

[0160] EXAMPLE 17 Preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride

A mixture of vilazodone hydrochloride (0.5g) in dimethyl sulfoxide (4mL) was. stirred at about 90°C to about 100°C to get a clear solution and ethyl acetate (8mL) was added to the solution within lmin at about the same temperature. The reaction mixture was cooled to about room temperature and the precipitated solid was stirred for about 30min at about room temperature. The solid was filtered and dried under Vacuum at about 50°C to about 55°C for 15h to give crystalline ethyl acetate solvate of vilazodone hydrochloride.

XRPD peaks of crystalline ethyl acetate solvate of vilazodone hydrochloride:

[0161] EXAMPLE 18 Preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride,

A mixture of vilazodone hydrochloride (5g) in dimethyl sulfoxide^(20mL) was stirred at about 90°C to about 100°C to get a clear solution and tert-butylmethyl ether (40mL) was added to the solution at about the same temperature. The reaction mixture was cooled to about room temperature and the precipitated solid was stirred for about l h at about room temperature. The solid was filtered and dried under vacuum at about 50°C to about 55°C for 15h to give crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride.

XRPD peaks of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride:

[0162] EXAMPLE 19 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (15g) was stirred in ethanol-water mixture (600mL) at about 70°C to about 80°C to get a clear solution. The solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned below. The product was collected from cyclone and dried under vacuum at about 60°C to about 70°C for about 24h to give amorphous vilazodone hydrochloride.

[0163] EXAMPLE 20 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (200g) was dissolved in a 7:3 mixture (14L) of acetone-water (bubbled with nitrogen to remove free oxygen) at about 25°C to about 30°C to get a clear solution. The clear solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned in Example 19 to give amorphous vilazodone hydrochloride.

HPLC purity: 99.8%

Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.01% w/w, as determined by HPLC.

[0164] EXAMPLE 21 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (l_.OOg) was dissolved in a 7:3 mixture (7L) of acetone-water (not bubbled with nitrogen) at about 25°C to about 30°C to get a clear solution. The clear solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned in Example 19 to give amorphous vilazodone hydrochloride.

HPLC purity: 99.45% Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.08% w/w, as determined by HPLC.

[0165] EXAMPLE 22 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (50g) was dissolved in a 7:3 mixture of acetone-water (bubbled with nitrogen to remove free oxygen) at about 50°C to about 60°C to get a clear solution. The clear solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned in Example 19 to give amorphous vilazodone hydrochloride.

HPLC purity: 99.32%,

Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.1% w/w, as determined by HPLC.

[0166] EXAMPLE 23 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (l OOg) was dissolved in a 7:3 mixture (4L) of ethanol-water at about 70°C to about 80°C to get a clear solution. The clear solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned in Example 19 to give amorphous vilazodone hydrochloride.

HPLC purity: 99.03 %

Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.35% w/w, as determined by HPLC.

[0167] EXAMPLE 24 Preparation of vilazodone N-oxide

Hydrogen peroxide (12mL) was added to a suspension of vilazodone (3g) in ethanol (50mL) at about room temperature and the reaction mixture was stirred for about 24h at about the same temperature. After completion of reaction, the reaction mass was quenched in 20% w/w solution of sodium metabisulphite at about 10°C to about 15°C and stirred for about 30min. The precipitated solid was filtered and dried at about 45°C to about 50°C for about 12h. The solid was purified by preparative HPLC to get pure vilazodone N-oxide. [0168] EXAMPLE 25: Preparation of 5-[4-[4-(5-cyano-lH-indol-3yl)butyI]-l- piperazinyl]-2-benzofurancarboxamide (vilazodone)

A mixture of 5-[4-[4-(5-cyano-lH-indol-3yl)butyl]-l-piperazinyl]-benzofuran-2- carboxylic acid ethyl ester hydrochloride (lOOg) and 15-25% methanolic ammonia (1500mL) was slowly heated to about 60°C to about 70°C. After completion of reaction, the reaction mixture was cooled to about 45 °C to about 55°C and concentrated under vacuum at about the same temperature to give a solid. The solid obtained was taken into n-propanol and the pH of the mixture was adjusted to about 2 to about 3 by adding aqueous hydrochloric acid at about room temperature. The precipitated solid was stirred for about lh at about 10°C to about 15°C. The solid was filtered, washed with n-propanol and dried. The solid obtained was dissolved in dimethyl formamide at about 40°C to about 50°C and 5% aqueous sodium hydroxide solution was slowly added at about the same temperature. The precipitated solid was cooled to about room temperature and stirred for about 3h at about the same temperature. The solid was filtered, washed with water and dried.

[0169] EXAMPLE 26 Preparation of crystalline n-propanol solvate of vilazodone hydrochloride

A mixture of vilazodone (lOg) in n-propanol (l OOmL) was stirred at about 20°C to about 30°C. The pH of the reaction mixture was adjusted to about 2 to about 3 by adding aqueous hydrochloric acid. The reaction mixture was stirred for about 20min at about the same temperature. The reaction mixture was then cooled to about 0°C to about 10°C and was stirred at about the same temperature for about 2h. The precipitated solid was filtered and dried under vacuum at about 35°C to about 45°C for about l Oh to give crystalline n- propanol solvate of vilazodone hydrochloride.

[0170] EXAMPLE 27 Preparation of amorphous vilazodone hydrochloride

n-Propanol solvate of vilazodone hydrochloride (lOg) was dissolved in a 7:3 mixture (600mL) of acetone (free from diacetone alcohol) and water (bubbled with nitrogen to remove free oxygen) at about 25 °C to about 30°C to get a clear solution. The clear solution was filtered and the filtrate was spray dried in JISL mini spray drier LSD-48 under the conditions mentioned below to give amorphous Vilazodone hydrochloride.

HPLC purity: 99.8%

Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.03% w/w, as determined by HPLC.

Amorphous vilazodone hydrochloride was stored at 40°C and 75% relative humidity. The content of vilazodone N-oxide impurity was measured at the end of two months and was found to be 0.04% w/w, as determined by HPLC.

[0171] COMPARATIVE EXAMPLE 1 Preparation of vilazodone hydrochloride (Example 15, Method 2 of US7834020)

500mg of vilazodone hydrochloride Form-IV was dissolved in a mixture of l OOmL of acetonitrile and l OOmL of water. The solution was spray dried in JISL mini spray drier LSD-48 to give vilazodone hydrochloride.

Vilazodone N-oxide impurity with relative retention time (RRT) of 1.09: 0.13% w/w, as determined by HPLC.

Claims

CLAIMS:

1. A process for the preparation of vilazodone hydrochloride in amorphous form, the process comprising:

2. The process of claim 1 , wherein the solvate of vilazodone hydrochloride is solvate with methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, acetonitrile, acetone, butanone, tetrahydrofuran, chloroform, n-heptane, toluene, or dimethyl sulfoxide.

3. The process of claim 1 , wherein the solvent is selected from the group consisting of ketones, alcohols, ethers, water, or mixtures thereof.

4. The process of claim 1, wherein the step (a) comprises:

(i) dissolving the solvate of vilazodone hydrochloride in a pretreated solvent to form a solution, and/or

(ii) dissolving the solvate of vilazodone hydrochloride in a solvent at a temperature in the range of about 5°C to about 40°C to form a solution.

5. The process of claim 4, wherein the pretreated solvent comprises treating the solvent with nitrogen, ultrasound.

6. The process of claim 1 , wherein the solvent is removed from the solution by spray drying.

7. The process of claim 4, wherein the amorphous vilazodone hydrochloride is substantially free of N-oxide impurity.

8. Amorphous vilazodone hydrochloride substantially free of N-oxide impurity.

9. Amorphous vilazodone hydrochloride according to claim 8, wherein the N-oxide impurity is less than 0.10% w/w with respect to vilazodone hydrochloride, as determined by high performance liquid chromatography (HPLC).

10. A crystalline n-propanol solvate of vilazodone hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 2, a DSC thermogram as depicted in Figure 3; an IR spectrum as depicted in Figure 4; a TGA thermogram as depicted in Figure 5; and any combination thereof.

1 1. A process for the preparation of crystalline n-propanol solvate of vilazodone hydrochloride, the process comprising:

(c) isolating the crystalline n-propanol solvate of vilazodone hydrochloride.

12. A crystalline n-butanol solvate of vilazodone hydrochloride.

13. The solvate of claim 12, characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as^* depicted in Figure 6, a DSC thermogram as depicted in Figure 7; an IR spectrum as depicted in Figure 8; a TGA thermogram as depicted in Figure 9; and any combination thereof.

14. A process for the preparation of crystalline n-butanol solvate of vilazodone hydrochloride, the process comprising:

(a) dissolving vilazodone in n-butanol to form a solution;

(b) adding hydrochloric acid to the solution obtained in (a);

(c) precipitating out n-butanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline n-butanol solvate of vilazodone hydrochloride.

15. A crystalline ethanol solvate of vilazodone hydrochloride characterized by an X- ray powder diffraction (XRPD) pattern as depicted in Figure 10.

16. A process for the preparation of crystalline ethanol solvate of vilazodone hydrochloride, the process comprising:

(b) adding ethanol to the solution obtained in (a);

(c) precipitating out ethanol solvate of vilazodone hydrochloride; and

(d) isolating the crystalline ethanol solvate of vilazodone hydrochloride.

17. A crystalline ethyl acetate solvate of vilazodone hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1 1 , a DSC thermogram as depicted in Figure 12; a TGA thermogram as depicted in Figure 13; and any combination thereof.

18. A process for the preparation of crystalline ethyl acetate solvate of vilazodone hydrochloride, the process comprising: (a) dissolving vilazodone hydrochloride in dimethyl sulfoxide to form a solution;

(b) adding ethyl acetate to the solution obtained in (a);

(c) precipitating out ethyl acetate solvate of vilazodone hydrochloride; and

19. A crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride.

20. The solvate of claim 19, characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 14, a DSC thermogram, as depicted in Figure 15; a TGA thermogram as depicted in Figure 16; and any combination thereof.

21. A process for the preparation of crystalline dimethyl sulfoxide solvate of vilazodone hydrochloride, the process comprising:

(b) adding tert-butylmethyl ether to the solution obtained in (a);

• 22. The use of solvate of vilazodone hydrochloride selected from n-propanol solvate, n-butanol solvate, ethanol solvate, ethyl acetate solvate, or dimethyl sulfoxide solvate in the preparation of amorphous vilazodone hydrochloride.

23. A process for the preparation of a compound of Formula XII,

the process comprising:

(a) reacting a compound of Formula IX wherein A is selected from the group consisting of-CHO and -C(OR₂)₂, R₂ is C 1 -C7 alkyl, with a compound of Formula X,

IX X

to obtain a compound o

XIII (b) cyclizing the compound of formula XIII to obtain a compound of formula XII.

24. The process of claim 23, further comprising:

(a) converting the compound of formula XII to a compound of formula XI,

wherein R may be -ORi and R_\ is selected from the group consisting of C 1 -C7 alkyl, phenyl or benzyl; ·

25. A compound of

XIII

26. The use of compound of formula XIII, or its salt thereof, in the preparation of vilazodone, a compound of formula I or salts thereof.

27. The use of compound of formula XIII according to claim 26, wherein the salt of vilazodone is vilazodone hydrochloride in amorphous form.

28. The use of vilazodone N-oxide, or its salt thereof, as a reference marker to detect the presence of vilazodone N-oxide, or its salt thereof, in a sample comprising vilazodone, or salts thereof.

29. The use of vilazodone N-oxide according to claim 28, wherein the salt of vilazodone is vilazodone hydrochloride in amorphous form.