FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
"AN IMPROVED PROCESS FOR THE PREPARATION OF
VILAZODONE"
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

AN IMPROVED PROCESS FOR THE PREPARATION OF VILAZODONE FIELD OF THE INVENTION:
The present invention provides a process for the preparation of Vilazodone of formula
(I) or pharmaceutically acceptable salts thereof comprising direct amidation of Ethyl-5-
{4-[4-(5-cyano-3-indolyl)butyl]-l-piperazinyl} benzofuran-2-carboxylate of formula
(II) with ammonia. The present invention also relates to an improved process for the
preparation of vilazodone of formula (I) or its pharmaceutically acceptable salts with
cost effective and commercially viable process using green solvents, comprising less
synthetic steps and simple product isolation technique.
BACKGROUND OF THE INVENTION:
5-{4-[4-(5-cyano-3-indolyl)butyl]-l-piperazinyl}benzofuran-2-carboxamide hydrochloride also known by the name Vilazodone, is represented by the structural formula (I) as below:

Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSR1) activity and serotonin 5-HT1A receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD). It is administered orally, once daily, with food.

Vilazodone is available as 10 mg, 20 mg and 40 mg film-coated tablet and marketed under the trade name Viibryd® in USA.
Vilazodone and related compounds were first disclosed in US 5532241. This patent discloses preparation of vilazodone via reaction of l-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carboxybenzofuran-5-yl) piperazine with ammonia gas in the presence of 2-chloro-l-methylpyridinium methanesulfonate (CMPM).
Journal of medicinal chemistry, 2004, Vol 47, No. 19 discloses a process for preparation of vilazodone using commercially available ethyl-5-nitrobenzofuran-2-carboxylate (V), which was hydrogenated using raney nickel in methanol to give corresponding amine (VI). The piperazine (VII) was formed by reaction of said corresponding amine (VI) with bis (2-chloroethyl) ammonium chloride and subsequently piperazine (VII) was alkylated by the indole derivative 5-cyano-4-chlorobutylindole (HI) to form ethyl ester (II). The ester (II) was saponified with potassium carbonate in methanol to form (II-a). The resulting acid (II-a) was activated with Mukaiyama reagent and transferred into corresponding amide (I) with gaseous ammonia (Scheme-I).


(a) Pd/c, H2; (b) bis(2-chloroethyl) ammonium chloride; (c) 5-cyano-4-chlorobutylindole, K2C03, NMP (d) KOH, Methanol, 80°C; (e) 1 -methyl-2-chloropyridinium iodide, NH3
Drugs of the future 2001, 26 (3): 247-252 discloses process for preparation of vilazodone in two ways:
1) The condensation of indole-5-carbonitrile with 4-chlorobutyryl chloride gives 3-(4-chlorobutyryl)-l H indole- 5-carbonitrile, which is reduced with diborane yielding 3-(4 chlorobutyl)-l H-indole-5-carbonitrile. The obtained 3-(4-chlorobutyl)-lH-indole-5-carbonitrile is reacted with 5-(l-piperazinyl) benzofuran- 2-carboxylic acid gives the expected 1, 4-disubstituted piperazine. Finally, the carboxy group of 1,4-disubstituted

piperazine is converted into the carboxamide by reaction with 2-chloro-l-methylpyridinium methanesulfonate (CMPM), ammonia gas (Scheme-II).
Scheme-II

2) The hydrogenation of 5-nitrobenzofuran-2-carboxylic acid ethyl ester with H2 and Raney nickel in methanol gives the corresponding 5-aminobenzofuran compound, which is cyclized with bis(2-chloroethyl)amine in dichloromethane to afford 5-(l-piperazinyl)benzofuran- 2-carboxylic acid ethyl ester. It further reacts with di-tert-butyl

dicarbonate in tetrahydrofuran provides the protected amine compound 5-[4-(tert-butoxycarbonyl)-l-piperazinyl) benzofuran-2 carboxylic acid ethyl ester, which first is reacted with formamide and sodium alkoxide in N-methylpyrrolidone to provide the corresponding amide and deprotected by treatment with HCl/MeOH to give 5-(l-piperazinyl) benzofuran- 2-carboxamide. Finally, corresponding amide is condensed with 3-(4-chlorobutyl)-l H-indole-5-carbonitrile (Scheme-Ill).
Scheme -HI


US 7799916 also disclose a process for preparation of vilazodone by using 5-(l-piperazinyl) benzofuran-2-carboxamide with 3-(4-oxo-butyl)-lH-indole-5-carbonitrile in presence of sodium cyanoborohydride and methanol.
CN 102180868 also disclose a process for preparation of Vilazodone, which is as depicted in scheme-IV.
Scheme-IV

The above disclosed prior arts have disadvantages like use of expensive solvents and several reaction step process, which makes it expensive and commercially not viable.

Thus, there exists a need of a process for the preparation of vilazodone of formula (I) or its pharmaceutically acceptable salts, which may be scaled up for commercial production and is also viable.
The present invention relates to an improved process for the preparation of vilazodone of formula (I) or pharmaceutically acceptable salts thereof with cost effective and commercially viable process, using green solvents, comprising less synthetic steps and simple product isolation technique,
SUMMARY OF THE INVENTION:
comprising;
(a) direct amidation of the compound of formula (II)

in the presence of suitable solvent; and
In one aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof,


(b) optionally converting compound of formula (I) to its pharmaceutically acceptable salt.
comprising;
(a) direct amidation of the compound of formula (II)
In another aspect, the present invention provides a process for the preparation of vilazodone of formula (I) or pharmaceutically acceptable salts thereof,


with ammonia in the presence of suitable solvent; and
(b) optionally converting compound of formula (I) to its pharmaceutically acceptable salt.
In yet another aspect, the present invention provides a process for the preparation of compound of formula (II),




comprising condensation of the compound of formula (III)
with the compound of formula (IV)
in the presence of suitable base and water.
In yet another aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof, comprising the step of;
(a) condensation of the compound of formula (III) with the compound of formula (IV) in the presence of suitable base and water to obtain the compound of formula (II);
(b) direct amidation of compound of formula (II) with ammonia in the presence of suitable solvent to obtain compound of formula (I); and

(c) optionally converting compound of formula (1) to its pharmaceutically acceptable salt.

with the compound of formula (IV)

In yet another aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof, starting from the compound of formula (II) prepared by condensation of the compound of formula (III)
in the presence of suitable base and water.
In yet another aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof with cost effective and commercially viable process, using green solvents, comprising less synthetic steps and simple product isolation technique.
In yet another aspect, the present invention provides a novel crystalline form of Vilazodone base as depicted in X-ray powder diffraction pattern of figure-1.
In yet another aspect, the present invention provides the pharmaceutical composition of Vilazodone of formula (I) and its pharmaceutically acceptable salts prepared according to the present invention.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING:
Figure-1: This figure indicates X-ray diffraction pattern of crystalline form of Vilazodone base obtained according to the instant invention.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The present invention relates, in general, to a novel process for the preparation of vilazodone of formula (I) or pharmaceutically acceptable salts thereof, which is illustrated in Scheme-V as below.
3-(4-chlorobutyI)-lH-indole-5-carbonitrile of formula (III) and ethyl-5-(piperazin-l-yl)-l-benzofuran-2-carboxylate of formula (IV) can be prepared by any known method disclosed in prior art process,
In one aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof, comprising;
(a) condensation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of formula (III) with Ethyl-5-(piperazin-l-yl)-l-benzofuran-2-carboxylate of formula (IV) in the

presence of suitable base and water to obtain Ethyl-5-{4-[4-(5-cyano-3-indolyl)butyl]-1 -piperazinyl} Benzofuran-2-carboxylate of formula (II);
(b) direct amidation of ethyl-5-{4-[4-(5-cyano-3-indolyl)butyl]-l-piperazinyl} benzofuran-2-carboxylate of formula (II) with ammonia in the presence of suitable solvent to obtain compound of formual (I); and
(c) optionally converting compound of formula (I) to its pharmaceutically acceptable salts.
Scheme-V

In step (a), 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of formula (III) is condensed with Ethyl-5-(piperazin-l-yl)-l-benzofuran-2-carboxylate of formula (IV) in the presence of suitable base and water to provide compound of formula (II).

The suitable base includes but are not limited to alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, calcium ethoxide and the like; alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like. Preferred base is potassium carbonate.
In step (a), reaction can be carried out at the temperature range of about room temperature to about reflux temperature of solvent system.
The compound as obtained in step (a) can be optionally purified or it can be directly taken for next step.
In Step (b), ethyl-5-{4-[4-(5-cyano-3-indolyl) butyl]-1-piperazinyl} benzofuran-2-carboxylate of formula (II) obtained in step-(a), undergoes direct amidation with ammonia in the presence of suitable solvent, wherein ammonia can be used in the form of gas or liquid.
The suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; N-methyl pyrrolidone, pyridine and water or mixture thereof. Preferred solvent is tetrahydrofuran and methanol.
The compound as obtained in step (b) can be optionally purified or it can be directly taken for next step.

In step (c), the compound of formula (I) can be optionally converted into its pharmaceutically acceptable salt using know process in art.
The solvent used for the preparation of pharmaceutically acceptable salt can be one or more organic solvents. Examples of such solvents without limitation includes alcohols such as methanol, ethanol, propanol, isopropanol; dichloromethane. chloroform, dichloromethane, toluene, ethyl acetate, isopropyl ether, methyl tertiary butyl ether, diethyl ether or petroleum ether, etc. It can be further purified or re-crystallized from the same or different solvent or mixture of solvents mentioned above if required.
In another aspect, the present invention provides a process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof,

comprising;
(a) direct amidation of the compound of formula (II)

with ammonia in the presence of suitable solvent; and
(b) optionally converting compound of formula (I) to its pharmaceutically acceptable
salt.
The suitable solvents are as described herein above.


condensation of the compound of formula (III)

with the compound of formula (IV)

In yet another aspect, the present invention provides a process for the preparation of compound of formula (II), comprising;
(IV)
in the presence of suitable base and water,
The suitable base is described herein above.
In yet another aspect, the present invention provides a process for the preparation of vilazodone of formula (I) or pharmaceutically acceptable salts thereof with cost effective and commercially viable process, using green solvents, comprising less synthetic steps and simple product isolation technique.
Surprisingly, it has been found that the following unrequired intermediates and/or impurities of compound of formula (II), (II-a), (VIII) & (IX) have been efficiently removed from Vilazodone of formula (I) or its pharmaceutically acceptable salt when it

is prepared according, to the present inventiom i.e..via direct amidation of compound of formula (II) with ammonia.

In yet another aspect, the present invention provides the pharmaceutical composition of vilazodone of formula (I) or pharmaceutically acceptable salts thereof.

The pharmaceutical compositions of the present invention comprise vilazodone of formula (I) or pharmaceutically acceptable salts thereof, as an active ingredient and may also contain a pharmaceutically acceptable carrier selected from diluent, additive, filler. lubricant, solvent, binder, stabilizer and the like and optionally other ingredients used in pharmaceutical formulations. The compositions may also comprise one or more additional therapeutic agents. The compositions of this invention include compositions suitable for oral, rectal, topical, parenteral, ocular, pulmonary, or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of the pharmacy.
Dosage forms include tablets, troches, dragees, powders, syrups, patches, liposomes, injections, dispersions, suspensions, solutions, capsules, creams, ointments and aerosols. Compositions which provide from 0.1 to 10.0 mg of the active ingredient are preferred.
The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples :-
Examplc-1: Preparation of 3-(4-chlorobutanoylchloride)-lH-indole-5-carbonitrile
750 ml of methylene dichloride and 136.48 gm of anhydrous aluminium chloride were charged under nitrogen atmosphere into round bottom flask at 25±3°C. The above reaction mass was cooled to 7±2°C. 88.27 gm of 4-chlorobutyryl chloride was added into the reaction mass through dropping funnel within 35-40 minutes at 7±2°C. The temperature of above reaction mass was raised to 27±2°C and stirred for 1 hour. The above reaction mass was cooled and solution of lH-indole-5-carbonitrile (50 gm in 250 ml methylene dichloride) was added to the reaction mass within 40-60 minutes at

7±2°C. The above reaction mass was stirred for 4-5 hour at 7±2oC. After completion of the reaction, 1500 ml of water was added slowly at 10±5°C. The reaction mass was maintained for 2 hours at 10±5°C, filtered and the obtained solid product was washed with 2 equal portions of 150 ml of water. Dried under vacuum at 60±2°C till water NMT1.0%. (Dry wt.:50gm).
Example 2: Preparation of 3-(4-chloroburyl)-lH-indole-5-carbonitrile (III)
1000 ml of dry tetrahydrofuran and 50 gm of 3-(4-chIorobutanoylchloride)-IH-indole-5-carbonitrile were charged in round bottom flask at 30±2°C. The above reaction mass was heated to 45±3°C and stirred at the same temperature for 15-20 minutes to obtain the clear solution The reaction mixture was cooJed to 29±3°C and 11.50 gm of sodium borohydride was added to the reaction mixture within 15-20 minutes at temperature of 29±3°C. The obtained reaction mass was stirred for 30-35 minutes at 29±3°C. 43 gm solution of BF3-Etherate (37.4 ml BF3-Etherate in 38 ml of THF) was added to the reaction mass through dropping funnel in 70-90 minutes at 29±3oC. The obtained reaction mass was stirred for 15-30 minutes at 29±3°C. After completion of the reaction, 250 ml of water was added slowly to the reaction mass at 27±3°C. The obtained reaction mass was stirred for 30 minutes at 27±3°C. 500 ml of ethyl acetate was added at 27±3°C and stirred for 10 minutes and the layers were separated at the same temperature. Aqueous layer was extracted with 250 ml of ethyl acetate. Both organic layers were combined and washed with two equal portions of 250 ml of water, The organic layer was further washed with 250 ml of 5% sodium chloride solution at 27±3°C and dried over sodium sulphate. The solvent was distilled out under vacuum at 40±2°C and residue was passed through column chromatography to obtain the title compound. (Dry weight: 15.0 gm)
Example-3: Preparation of Ethyl-5-{4-[4-(5-cyano-3-indolyl) butyl]-l-piperazinyl} benzofuran-2-carboxylate HC1 (II)

50 ml of water, 5 gm of Ethyl-5-(piperazin-l-yl)-l-benzofuran-2-carboxylate, 4.66 gm of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile and 5.03 gm of potassium carbonate were charged into the round bottom flask at 25±3°C. The reaction mass was heated to reflux for 4-6 hours at 83±3°C. After completion of the reaction, obtained reaction mass was cooled to 25±3°C followed by addition of 125 ml of water and 100 ml of ethyl acetate to the reaction mass and aqueous and organic layers were separated. Further, the aqueous layer was extracted with 40 ml of ethyl acetate and combined ethyl acetate layer was washed with dilute hydrochloric acid solution. Again ethyl acetate layer was washed with 30 ml of 7% of sodium bicarbonate solution. The ethyl acetate layer was distilled out and 150 ml of acetone was charged to the residue and added with saturated solution of isopropanolic hydrochloride. The reaction mass was stirred for 2 hours at 25±3°C. The obtained solid product was filtered and dried under vacuum at 50±2°C to obtain the title compound. (Dry weight: 4.8 gm).
Example-4: Preparation of 5-{4-[4-(5-cyano-3-indolyl) butyl]-l-piperazinyl} benzofuran-2-carboxamide (I)
20 ml of water, 10 gm of ethyl-5-{4-[4-(5-cyano-3-indolyl) butyl]-1-piperazinyl} benzofuran-2-carboxylate HC1 and 200 ml of ethyl acetate were charged into the round bottom flask at 27±2°C. The reaction mass was cooled to 20±3°C and saturated with sodium bicarbonate solution. Further, the reaction mass was stirred for 1-2 hours at 20±3°C. After separation of the layers, the aqueous layer was extracted with 100 ml ethyl acetate. Again the layers were separated and organic layer was dried over sodium sulphate. The organic solvent was distilled out and the remaining residue was dissolved in 60 ml methanol and 40 ml of tetrahydrofuran at 35±3°C. The above reaction mass was charged in closed vessel. The reaction mass was cooled to 5±3°C. Further, ammonia gas was purged to the reaction mass for 3 hours at 5±3°C. The reaction mass was heated for 18-20 hours to 30±3°C. After completion of the reaction, the methanol was distilled out under vacuum at 35±5°C until 10 volume of solvent remain in the reaction mass. The reaction mass was cooled to 27±3°C. The solid product was filtered

and washed with methanol. The obtained wet cake was dissolved into 45 ml of tetrahydrofuran at 27±3°C. The obtained reaction mass was heated to 45±3°C till clear solution was obtained. Charged the obtained clear solution with 1.0 gm of charcoal and filtered through hyflow super cell bed. The clear filtrate was distilled under vacuum at 45±3°C and 82 ml of acetonitrile was added to the reaction mass and was stirred for 30 minutes at 45±3°C. The reaction mass was cooled and filtered. The reaction mass was washed with 2 portion of 10 ml of acetonitrile. The solid product was dried to obtain the title compound (Dry weight: 6.0 gm).
Example-5: Preparation of 5-{4-[4-(5-cyano-3-indolyI) butyl]-l-piperazinyl} benzofuran-2-carboxamide HC1
750 ml of methanol and 50.0 gm of 5-{4-[4-(5-cyano-3-indolyl) butyl]-1-piperazinyl} benzofuran-2-carboxamide were charged in round bottom flask at 27±3°C. 56 ml of saturated-2-propanol HC1 was added drop wise into reaction mass over a period of 20-30 minutes at 27±3°C. The obtained reaction mass was stirred for 1-2 hours at 27±3°C. After completion of the reaction, the reaction mass was filtered and washed with 50 ml of methanol. The solid product was dried under vacuum at 35±3°C for 24 hours. The obtained dried material was charged with 1000 ml of ethyl acetate into round bottom flask at 27±3°C. The reaction mass was heated to 60±3°C and stirred for 90-120 minutes. The above reaction mass was cooled to 27±3°C and added 250 ml of water and stirred for 1 hour at 27±3°C. The solid product was filtered and washed with 50 ml of water. The solid product was dried under vacuum to obtain the title compound. (Dry weight 47 gm)
Example-6: Preparation of 5-{4-[4-(5-cyano-3-indolyl) butyl]-1-piperazinyl} benzofuran-2-carboxamide (I)
100 gm of ethyl-5-{4-[4-(5-cyano-3-indolyl) butyl]-1-piperazinyl} benzofuran-2-carboxylate was dissolved in 400 ml of tetrahydrofuran at 35±3°C. The reaction mass

was charged into a closed vessel. 600 ml of methanol was added to the reaction mass at 27±3°C and the reaction mass was further cooled to 8±3°C. The reaction mass was purged with ammonia gas for 90-120 minutes at 8±3°CThe temperature of reaction mass was raised to 28±3°C. After completion of the reaction, the ammonia gas pressure was slowly released and the solid product was filtered, washed and dried to obtain the title compound (Wet weight: 80.0 gm).
Example-7: Purification of 5-{4-[4-(5-cyano-3-indolyl) butyl]-l-piperazinyl} benzofuran-2-carboxamide (I)
400 ml of tetrahydrofuran and 80.0 gm of the wet cake (obtained in example-6) were charged in round bottom flask at 27±3°C. The reaction mass was heated to 45±3°C till clear solution is obtained. 4.0 gm of activated charcoal was added to the reaction mass and the reaction mass was stirred for 30 minutes. The filtrate was distilled out under vacuum at 45±3°C. 800 ml of acetonitrile was charged into the reaction mass at 45±3°C and the reaction mass was cooled to 28±3°C. The obtained solid product was washed with acetonitrile, filtered and dried under vacuum.

We Claim:

(a) direct amidation of the compound of formula (II)

1. A process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof, comprising:
with ammonia in the presence of suitable solvent; and
(b) optionally converting compound of formula (I) to its pharmaceutically acceptable
salt.
2. The process according the claim 1, wherein the solvent is selected from the group comprising of alcohols, ketones, aliphatic ethers, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated solvent, nitriles, polar aprotic solvent, N-methyl pyrrolidine, pyridine, water or mixture thereof.


condensation of the compound of formula (III)

with the compound of formula (IV)

3. The process according the claim 2, wherein the solvent is mixture of tetrahydrofuran and methanol.
4. The process according to claim 1, wherein the direct amidation is carried out by using ammonia in the form of gas or liquid.
5. A process for the preparation of compound of formula (II) comprising:
in the presence of suitable base and water.
6. A process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts thereof, comprising:

(a) condensation of the compound of formula (III) with the compound of formula (IV) in the presence of suitable base and water to obtain the compound of formula (II);
(b) direct amidation of compound of formula (II) with ammonia in the presence of suitable solvent to obtain compound of formula (I); and
(c) optionally converting compound of formula (I) to its pharmaceutically acceptable salt.

with the compound of formula (IV)

7. The process according to claim 1, wherein a compound of formula (II) is prepared by condensation of the compound of formula (III)
in the presence of suitable base and water.
8. The process according to any preceding claims, wherein the suitable base is selected from alkali metal alkoxide, alkali earth metal hydroxide or alkali metal carbonate.
9. A novel crystalline form of Vilazodone base as depicted in X-ray powder diffraction pattern of figure-1.

10. A process for the preparation of Vilazodone of formula (I) or pharmaceutically acceptable salts, substantially as herein described, particularly with reference to the foregoing examples.