CROSS REFERENCE TO RELATED APPLICATION This patent application is a Patent of Addition of Indian Patent Application No. 2629/CHE/2012, having its complete specification filed on June 28, 2013, claiming the benefit of priority to Indian Provisional Patent Application filed on July 2, 2012, which is 5 incorporated herein by reference in its entirety.
FIELD OF THE INVENTION The present invention relates to an improved and industrially advantageous process for the preparation of highly pure vilazodone or a pharmaceutically acceptable salt thereof.
10
BACKGROUND OF THE INVENTION
U.S. Patent No. 5,532,241 (hereinafter referred to as the '241 patent) discloses a variety of piperidine and piperazine derivatives and their pharmaceutical^ acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives,
15 and methods of use thereof. These compounds are active on the central nervous system, especially in terms of 5-HT]A-agonist and 5-HT-reuptake inhibition. They are furthermore active as serotonin agonists and antagonists. These compounds and their physiologically acceptable acid addition salts can, therefore, be used as active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, and antihypertensives. Among them,
20 Vilazodone hydrochloride, 5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxamide hydrochloride, is a serotonergic antidepressant that is used for the treatment of major depressive disorder (MDD). Vilazodone hydrochloride is represented by the following structural formula:

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§ Vilazodone hydrochloride was approved by the FDA for use in the United States to
treat major depressive disorder and it is sold under the trade name VIIBRYD . It is orally
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administered as tablets containing 10 mg, 20 mg and 40 mg of vilazodone as the hydrochloride salt.
Various processes for the preparation of benzofuran-2-carboxamide derivatives, preferably vilazodone, their intermediate compounds, and their pharmaceutically acceptable salts are apparently disclosed in U.S. Patent Nos. US 5,532,241, US 5,723,614, US 5,977,112, US 5,418,237 and US 7,799,916; U.S. Patent Application Publication No. 2010/0036139A1; Chinese Patent Application Publication Nos. CN 102267932, CN 102267985, CN 102180868, CN 102796037, CN 102875538, CN 102659660 and CN102617558 and Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692; Drugs of the Future 2001, 26(3), 247, and Liebigs Ann. Chem. 1988, 749-752.
U.S. Patent No. 5,532,241 (hereinafter referred to as the '241 patent) describes several synthetic routes for preparing vilazodone. The synthetic routes are depicted in below scheme 1:

Scheme 1:



5-(1-Piperazinyt)benzofuran-2-carboxamide

ST

2-Chloro-1 -methylpyridinium methanes ulfonate
N-Methylpyrrolidone Dried NH3 gas
3-(4-Chlorobuty1)-1 H-indote-5-carbonitrile
Vilazodone
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5-[4-[4-(5-Cyano-1H-indol-3-yt)butyl]piperazin-1-yl]benzofuran-2-carboxylic acid

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According to one synthetic process, vilazodone is prepared by the condensation of
5-(l-pipearzinyl)benzofuran-2-carboxamide with 3-(4-chlorobutyl)-l#-indole-5-
carbonitrile. According to another synthetic process, vilazodone is prepared by reacting 5-[4_[4-(5-cyano-l//-indoI-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylic acid with 2-
5 chloro-1-methylpyridinium methanesulfonate in the presence of N-methylpyrrolidone to produce a reaction mass, followed by treatment with dried ammonia gas and subsequent working up to produce vilazodone.
Similar process for the preparation of vilazodone is also reported in Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692 (hereinafter referred to as
10 the 'JMC article'). As per the process reported in the JMC article (see column-1 of Page No. 4690), the vilazodone is prepared by reacting 5-[4-[4-(5-cyano-l//-indol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylic acid with 2-chloro-l-methylpyridinium iodide in the presence of N-methylpyrrolidone to produce a reaction mass, followed by drop wise addition of ethyldiisopropyl amine while introducing ammonia gas and
15 subsequent work up to produce vilazodone. The resulting vilazodone free base is then converted into its hydrochloride salt by dissolving vilazodone free base in hot 2-propanol to form a solution, followed by slow addition of HCI-saturated 2-propanol at room temperature until complete precipitation occurs to yield vilazodone hydrochloride (Melting Point: 277-279°C).
20 Indian Patent Application No. 2629/CHE/2012 (and its equivalents
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patents/patent applications WO2014/006637A2 and US9315456B2), filed by the present applicant (hereinafter referred to as the "Parent Patent Application"), discloses efficient, industrially advantageous and environmentally friendly processes for the preparation of vilazodone and its key intermediates in high yield and with high purity,
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25 which avoid the use of additional reaction steps, additional and expensive reagents and/or solvents.
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2629/CHE/2012, vilazodone is prepared by amidating methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate or an acid addition salt thereof with
| 30 ammonia in presence of an alcohol solvent, preferably methanol. This process solves the
drawbacks associated with the prior processes, and thereby making the process for the
S preparation of vilazodone or a pharmaceutical acceptable salt thereof commercially viable.
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The Parent Patent Application No. 2629/CHE/2012 also discloses an industrially advantageous and commercially viable process for the preparation of 5-(l-piperazinyl)benzofuran-2-carboxylic acid alkyl ester, in high yield and with high purity, using novel intermediates.
The processes for the preparation of Vilazodone using novel intermediate disclosed in the Parent Patent Application No. 2629/CHE/2012 is represented by the schematic diagram as depicted below:
Schematic Representation:


N °
CI

AICI,
Aqueous Methanol

NaCNBH,
HCI

5-Cyanoindo!e

4-Chlorobutyryl chloride

CN
3-(4-Hydroxybutyryl)-1 H-indole-5-carbonitrile

3-(4-Hydroxybutyl)-1H-indole-5-carbonitrile

p-Toluenesulfonyl chloride
Triethylamine Dichloromethane

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3-[4-(p-Toluenesulfonyloxy) butyl]-1 H-indole-5-carbonitrile

Methyl 5-(1-piperazinyl) benzofuran-2-carboxylate

Dimethylformamide

Triethylamine

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Vilazodone

Methanolic Ammonia

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Methyl 5-[4-[4-(5-Cyanoindol-3-yl)butyl] piperazin-1 -yl]benzofuran-2-carboxylate

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The Parent Patent Application No. 2629/CHE/2012 also teaches the use of acid
10 addition salts of alkyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-
carboxylate of formula II(ii) for preparing vilazodone or a pharmaceutical ly acceptable salt
thereof. Exemplary acid addition salts of the ester compound of formula II described in the
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PATENT OfFICt CHEMMAI

Parent Patent Application No. 2629/CHE/2012 include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate.
The object of the present invention is to provide an improved and industrially 5 advantageous process for the preparation of highly pure vilazodone hydrochloride.
SUMMARY OF THE INVENTION It has been surprisingly and unexpectedly found that the purity of vilazodone hydrochloride is increased when vilazodone is prepared by first converting the methyl 5-
10 [4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate intermediate into its hydrogen sulfate salt, followed by amidating the resulting hydrogen sulfate salt compound with ammonia in presence of an alcohol solvent, preferably methanol to produce vilazodone free base; and then converting the highly pure vilazodone free base obtained into its hydrochloride salt.
15 In one aspect, provided herein is an improved and industrially advantageous
process for the preparation of highly pure vilazodone hydrochloride by converting the
methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate
intermediate into its hydrogen sulfate salt, followed by amidating the hydrogen sulfate salt with ammonia in presence of an alcohol solvent, preferably methanol, to produce highly
20 pure vilazodone, which is then converted into its hydrochloride salt.
The process for the preparation of highly pure vilazodone hydrochloride as described in the present application is a further improvement of the process described in the Parent Patent Application No. 2629/CHE/2012.
25 DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of highly pure vilazodone hydrochloride, comprising:
a) treating methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate with sulfuric acid in a suitable solvent to produce its hydrogen sulfate salt; 30 b) amidating the hydrogen sulfate salt of methyl 5-[4-[4-(5-cyanoindol-3-yl) butyl]piperazin-l-yl]benzofuran-2-carboxylate with ammonia in presence of an alcohol solvent to produce highly pure vilazodone free base;
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c) providing a solution of the highly pure Vilazodone free base in an alcohol solvent at reflux temperature;
d) optionally, subjecting the hot solution obtained in step-(c) to carbon treatment or silica gel treatment to obtain a filtrate;
5 e) combining the solution of Vilazodone free base obtained in step-(c) or step-(d) with isopropanolic-HCl (hydrochloric acid saturated in isopropyl alcohol) to cause crystallization of vilazodone hydrochloride; and f) recovering the highly pure vilazodone hydrochloride obtained in step-(e).
The highly pure vilazodone or its hydrochloride salt obtained by the process
10 disclosed herein has a purity of greater than about 99.5%, preferably greater than about
99.8%, more preferably greater than about 99.9%, and most preferably greater than about
99.95% as measured by HPLC. For example, the purity of the highly pure vilazodone or its
hydrochloride salt thereof obtained by the process disclosed herein is about 99.5% to about
99.99% as measured by HPLC.
15 In one embodiment, the solvent used in step-(a) is selected from the group
consisting of methanol, ethanol, dimethylformamide, dichloromethane, and mixtures thereof. A most preferable solvent used in step-(a) is methanol.
In one embodiment, the treatment in step-(a) is carried out at a temperature of about
25°C to the reflux temperature of the solvent used, specifically at a temperature of about
20 40°C to the reflux temperature of the solvent used, and more specifically at the reflux
temperature of the solvent used. The reaction time may vary from about 20 minutes to
about 2 hours.
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The reaction mass containing the hydrogen sulfate salt of methyl 5-[4-[4-(5-
J cyanoindol-3-yl) butyl]piperazin-l-yl]benzofuran-2-carboxylate obtained in step-(a) may
25 be subjected to isolation and/or recrystallization from a suitable solvent by conventional
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o adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination
5- thereof.
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about 20°C to about 30°C, followed by stirring the mass for at least 10 minutes, preferably for about 20 minutes to about 1 hour, at the same temperature.
The solid separated is collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a 5 combination thereof.
The alcohol solvent used for amidation in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof. A most preferable alcohol solvent is methanol.
In one embodiment, the amidation reaction in step-(b) is carried out at a
10 temperature of about 0°C to about 80°C, specifically at a temperature of about 20°C to
about 70°C, and more specifically at a temperature of about 25°C to about 65°C. The
reaction time may vary from about 1 hour to about 15 hours, and more specifically from
about 2 hours to about 14 hours.
In another embodiment, the amidation reaction in step-(b) is advantageously carried 15 out by using ammonia gas under pressure of about 1 Kg/Cm to about 5 Kg/Cm , and preferably about 2 Kg/Cm2.
The reaction mass containing the vilazodone free base obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, an evaporation, a pH adjustment, a layer separation etc., followed by isolation and/or recrystallization from a 20 suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
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The solvent used for isolating and/or recrystallizing the pure vilazodone free base is
n? selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and
25 mixtures thereof.
f^ The solid obtained is collected by filtration, filtration under vacuum, decantation,
o centrifugation, filtration employing a filtration media of a silica gel or celite, or a

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combination thereof.
g The alcohol solvent used in step-(c) is selected from the group consisting of
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30 methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof. A most preferable
5 alcohol solvent used in step-(c) is isopropyl alcohol.
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Step-(c) of providing a solution of vilazodone free base includes dissolving vilazodone free base in the alcohol solvent.
In one embodiment, the vilazodone free base is dissolved in the alcohol solvent at a temperature of about 50°C to the reflux temperature, specifically at a temperature of about
5 60°C to the reflux temperature, and more specifically at the reflux temperature. After complete dissolution of vilazodone, the resulting solution is stirred at reflux for at least 5 minutes, and specifically for about 10 minutes to about 30 minutes.
Alternatively, the solution in step-(c) is also prepared by suspending vilazodone free base in the alcohol solvent at room temperature, followed by heating the suspension at
10 a temperature of about 50°C to the reflux temperature to form a solution. After complete dissolution of vilazodone, the resulting solution is stirred at reflux for at least 5 minutes, and specifically for about 10 minutes to about 30 minutes.
The carbon treatment or silica gel treatment in step-(d) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or
15 silica gel at a temperature of about 50°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature for about 5 minutes to about 20 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing vilazodone free base by removing charcoal or silica gel. Specifically, finely powdered carbon is a special carbon or an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more
20 specifically 60-120 mesh.
Combining of the solution of vilazodone free base with isopropanolic-HCl in step-(e) is done in a suitable order, for example, the solution is added to the isopropanolic-HCl, or alternatively, the isopropanolic-HCl is added to the solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition
25 is specifically carried out under stirring at above 35°C for at least 5 minutes, specifically at a temperature of about 40°C to the reflux temperature of the solvent for about 10 minutes to about 1 hour. After completion of the addition process, the resulting mixture is cooled to a temperature below 35°C, preferably to a temperature of about 20°C to about 30°C, and then stirred at the same temperature for at least 10 minutes, and preferably for about 15
30 minutes to about 2 hours, to cause crystallization.
The recovering in step-(f) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment,

vilazodone hydrochloride can be recovered by filtration employing a filtration media of,
for example, a silica gel or celite.
Unless otherwise specified, the methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-
l-yl]benzofuran-2-carboxylate used as starting material in the process described in the 5 present invention can be obtained, for example, by the processes described in the parent
Patent Application No. 2629/CHE/2012 or by the processes known in the art.
As used herein, the term "reflux temperature" means the temperature at which the
solvent or solvent system refluxes or boils at atmospheric pressure. As used herein, the
term "room temperature" refers to a temperature of about 20°C to about 35°C. For 10 example, "room temperature" can refer to a temperature of about 25°C to about 30°C.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC using Shimadzu LC-2010 CHT system with
UV detector or its equivalent under the following conditions: Column = Kromasil-100-5-
C18 250mm x 4.6 mm; 5uin or Equivalent; Detector wavelength = 240 nm; Flow 15 Rate = 1.0 ml/minute; Injection volume = 10uL; Oven temperature = 50°C; Run time = 95
minutes; Diluent = Methanol; Sample Cooler: 5°C.
Buffer Preparation: Take 2000 mL of water into a suitable container, add 2 mL of Trifluoro
acetic acid and mix well. Then adjust pH of the buffer to 3.00 (+ 0.05) with Triethyl amine.
Mobile Phase-A: Prepare a mixture of Buffer and Methanol in the ratio of 80:20 v/v, filter 20 through 0A5\i membrane and degas. Mobile Phase-B: Prepare a mixture of Buffer,
Methanol and Trifluoro acetic acid in the ratio of 20:80:0.03% v/v/v, filter through 0.45 \i
membrane and degas.
The following examples are given for the purpose of illustrating the present
invention and should not be considered as limitation on the scope or spirit of the invention.
25
EXAMPLES
Example 1 Preparation of Highly Pure Vilazodone Hydrochloride Step-1: Preparation of methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-
30 yl]benzofuran-2-carboxylate hydrogen sulfate salt
Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate (30 g,
Purity by HPLC: 99%) and methanol (600 ml) were taken into a reaction flask at room
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temperature and the mixture was heated to reflux, followed by the slow addition of sulfuric acid (9 g) at reflux temperature to obtain a clear solution. The resulting solution was stirred for 30 minutes at reflux temperature. The reaction mass was cooled to room temperature and then stirred for 30 minutes at the same temperature. Solid separation was observed. 5 The separated solid was filtered, washed with methanol (30 ml) and then dried the material at 50-60°C for 6 hours to produce 32.5 g of pure methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate hydrogen sulfate salt (Purity by HPLC:
99.85%).
Step-2: Preparation of Highly Pure Vilazodone free base
10 Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate
hydrogen sulfate salt (25 g, obtained in above Step-1) and methanol (1000 ml) were taken into an autoclave ^vessel at room temperature, followed by applying ammonia gas pressure (2 Kg/cm2). The resulting mass was heated to 60-65°C and then stirred for 12 hours at the same temperature. The reaction mass was initially cooled to room temperature and then
15 cooled to 0-5°C. The separated solid was filtered, washed with methanol (25 ml) and then dried at 80-85°C for 6 hours to produce 18.5 g of highly pure Vilazodone free base (Purity
by HPLC: 99.85%).
Step-3: Preparation of Highly Pure Vilazodone Hydrochloride
Vilazodone free base (10 g, obtained in above Step-2) and isopropyl alcohol (750 ml) were 20 taken into a reaction flask and the mixture was heated to reflux temperature to obtain a clear solution, followed by stirring the mass for 10 minutes at the same temperature. The resulting mass was filtered and the filtrate was cooled to 40°C, followed by the addition of isopropanoIic-HCl (6 ml) at the same temperature. The reaction mass was cooled to room temperature and then stirred for 30 minutes at room temperature. The separated solid was 25 filtered, washed with isopropyl alcohol (20 ml) and then dried the material at 100-110°C for 8 hours to produce 10 g of highly pure Vilazodone hydrochloride (Purity by HPLC:
99.97%).
Example 2
Preparation of Highly Pure Vilazodone Hydrochloride 30 Step-1: Preparation of methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate hydrogen sulfate salt

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Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate (30 g, Purity by HPLC: 98.4%) and methanol (600 ml) were taken into a reaction flask at room temperature and the mixture was heated to reflux, followed by the slow addition of sulfuric acid (9 g) at reflux temperature to obtain a clear solution. The resulting solution was stirred 5 for 30 minutes at reflux temperature. The reaction mass was cooled to room temperature and then stirred for 30 minutes at the same temperature. Solid separation was observed. The separated solid was filtered, washed with methanol (30 ml) and then dried the material at 50-60°C for 6 hours to produce 31 g of pure methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate hydrogen sulfate salt (Purity by HPLC:
10 99.6%).
Step-2: Preparation of Highly Pure Vilazodone free base
Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate
hydrogen sulfate salt (25 g, obtained in above Step-1) and methanol (1000 ml) were taken into an autoclave vessel at room temperature, followed by applying ammonia gas pressure 15 (2 Kg/cm2). The resulting mass was heated to 60-65°C and then stirred for 12 hours at the same temperature. The reaction mass was initially cooled to room temperature and then cooled to 0-5°C. The separated solid was filtered, washed with methanol (25 ml) and then dried at 80-85°C for 6 hours to produce 18 g of highly pure Vilazodone free base (Purity
by HPLC: 99.6%). 20 Step-3: Preparation of Highly Pure Vilazodone Hydrochloride
Vilazodone free base (10 g, obtained in above Step-2) and isopropyl alcohol (750 ml) were taken into a reaction flask and the mixture was heated to reflux temperature to obtain a clear solution, followed by stirring the mass for 10 minutes at the same temperature. The resulting mass was filtered and the filtrate was cooled to 40°C, followed by the addition of 25 isopropanolic-HCl (6 ml) at the same temperature. The reaction mass was cooled to room temperature and then stirred for 30 minutes at room temperature. The separated solid was filtered, washed with isopropyl alcohol (20 ml) and then dried the material at 100-110°C for 8 hours to produce 10 g of highly pure Vilazodone hydrochloride (Purity by HPLC: 99.85%).

We claim:
1. A process for the preparation of highly pure vilazodone hydrochloride, comprising:
a) treating methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1 -yl]benzofuran-2-
carboxylate with sulfuric acid in a suitable solvent to produce its hydrogen sulfate
5 salt;
b) amidating the hydrogen sulfate salt of methyl 5-[4-[4-(5-cyanoindol-3-yl)
butyl]piperazin-l-yl]benzofuran-2-carboxylate with ammonia in presence of an
alcohol solvent to produce highly pure vilazodone free base;
c) providing a solution of the highly pure Vilazodone free base in an alcohol solvent
10 at reflux temperature;
d) optionally, subjecting the hot solution obtained in step-(c) to carbon treatment or silica gel treatment to obtain a filtrate;
e) combining the solution of Vilazodone free base obtained in step-(c) or step-(d) with isopropanolic-HCl (hydrochloric acid saturated in isopropyl alcohol) to cause
15 crystallization of vilazodone hydrochloride; and
f) recovering the highly pure vilazodone hydrochloride obtained in step-(e).
2. The process of claim 1, wherein the highly pure vilazodone or its hydrochloride salt
obtained has a purity of greater than about 99.5% as measured by HPLC.
3. The process of claim 1, wherein the highly pure vilazodone or its hydrochloride salt
20 obtained has a purity of about 99.5% to about 99.99% as measured by HPLC.
4. The process of claim 1, wherein the solvent used in step-(a) is selected from the group
consisting of methanol, ethanol, dimethylformamide, dichloromethane, and mixtures
thereof; wherein the alcohol solvent used for amidation in step-(b) is selected from the
group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures
25 thereof.
5. The process of claim 4, wherein the solvent used in step-(a) is methanol; wherein the alcohol solvent used for amidation in step-(b) is methanol.
6. The process of claim 1, wherein the alcohol solvent used in step-(c) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures
30 thereof.
7. The process of claim 1, wherein the alcohol solvent used in step-(c) is isopropyl
alcohol.
13
TENT OFFICE CHEMHA1 &2'8&'281S 11*15

8. The process of claim 1, wherein the recovering in step-(f) is carried out by methods
such as filtration, filtration under vacuum, decantation, centrifugation or a combination
thereof.
9. The process of claim 1, wherein the amidation reaction in step-(b) is carried out by using ammonia gas under pressure of about 1 Kg/Cm to about 5 Kg/Cm .
10. The process of claim 9, wherein the amidation reaction in step-(b) is carried out by using ammonia gas under pressure of about 2 Kg/Cm .

th,
10

Dated this Twenty Sixth (26tn) day of July 2016

(Signed)
15

SURESH VELAGALA
General Manager - IPM Division
SYMED LABS LIMITED

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