DESC:INTRODUCTION

Aspects of the present application relate to novel and efficient process for the preparation of vilazodone hydrochloride, more specifically the present application involves novel intermediates and their use in the preparation of vilazodone hydrochloride. Another aspect of the present application relates to novel process for the preparation of key intermediates of vilazodone hydrochloride. Vilazodone hydrochloride prepared as per the process of present application is also useful in making pharmaceutically acceptable dosage forms.

Vilazodone hydrochloride is selective serotonin reuptake inhibitor, which also acts as partial agonist at serotonergic 5-HT1A receptors. It is mainly used for the treatment of major depressive disorder (MDD) and marketed as ViibrydTM in tablet dosage forms.

Vilazodone hydrochloride is chemically known as 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride, and has structural Formula I.

Formula I

Vilazodone hydrochloride is first time reported in US patent No. 5532241 (hereinafter referred as US’241) which covers vilazodone or a physiologically acceptable salt thereof; it also discloses the process of preparation of vilazodone hydrochloride which is depicted in following scheme;

The process disclosed in US’241 mainly involves the reaction of indole derivative of formula II with benzofuran derivative of formula III to give vilazodone acid which is then subjected to amidation to give vilazodone. US’241 also discloses the preparation of indole derivative of formula II by diazotization of p-cyano aniline followed by Japp-Klingemann coupling with ethyl cyclohexanone-2-carboxylate, the obtained indole derivative is further subjected to alkaline hydrolysis, decarboxylation, reduction and halogenation to afford indole derivative of formula II.

Another US patent No. 6509475B1 discloses the preparation of indole derivative of formula II by coupling of 5-cyano indole with chlorobutyryl chloride in presence of Lewis acid metal halides of the type R’-Al(Cl)2, wherein R’ is alkyl or aryl to afford 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile which is then reduced with complex hydride such as sodium borohydride with activation by Lewis acid metal halides of the type R’-Al(Cl)2, wherein R’ is alkyl or aryl to give indole derivative of formula II.

US patent No. 7799916 discloses following two methods for the preparation of vilazodone hydrochloride;

the first method involves reductive amination of piperazine derivative with formyl derivative of indole intermediate II to give vilazodone free base which is then treated with aqueous hydrochloric acid in tetrahydrofuran to afford vilazodone hydrochloride;

the second method involves transition-metal-catalyzed coupling (by means of Pd complexes) of 3-(4-piperazin-1-yl-buyl)indole-5-carbonitrile with 5-bromobenzofuran-2-carboxamide to give vilazodone free base which is then treated with aqueous hydrochloric acid to afford vilazodone hydrochloride.

Chinese patent application No. 102267932A discloses the coupling of activated hydroxy derivative of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with 5-(piperazin-1-yl)benzofuran-2-carboxamide to afford vilazodone.

Another Chinese patent application No. 102180868A discloses the preparation of vilazodone hydrochloride by cyanation of 5-(4-(4-(5-halo-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylic acid to give vilazodone acid which is then subjected to amidation to afford vilazodone; the disclosed process is depicted in following scheme;

The present application provides alternate process for the preparation of vilazodone, its salts; and its key intermediate, which are cost effective, safe and can be practiced on an industrial scale.

SUMMARY

In an aspect, the present application provides process for the preparation of vilazodone hydrochloride of formula I,

Formula I

which comprises:

a) reacting indole derivative of formula II;

Formula II

wherein X´ is halogen;

with phenyl piperazine derivative of formula III;

Formula III

wherein E is hydrogen or any suitable hydroxyl protecting group;

in presence of base, in a suitable solvent to give compound of following formula IV;

Formula IV

wherein E is hydrogen or any suitable hydroxyl protecting group;

b) deprotecting the hydroxy protecting group of compound of formula IV with a suitable deprotecting reagent to give hydroxy derivative of compound of formula V;

Formula V

c) ortho-formylating the compound of formula V to give ortho-formyl derivative of compound of formula VI;

Formula VI

d) cyclizing the ortho-formyl derivative of compound of formula VI in a suitable solvent, in presence of base and alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

to give vilazodone free base or its derivatives;

wherein R is -COOalkyl, -CONH2 or -CN;

e) optionally amidating the vilazodone ester derivative; OR optionally hydrolyzing the vilazodone nitrile derivative, to give vilazodone free base;

f) reacting the vilazodone free base with hydrochloric acid solution in a suitable solvent to give vilazodone hydrochloride of formula I.

g) optionally purifying the vilazodone hydrochloride.

In an another aspect of the present application provides process for the preparation of vilazodone hydrochloride of formula I,

Formula I

which comprises:

a) ortho-formylating the compound of formula V

Formula V
to give ortho-formyl derivative of compound of formula VI;

Formula VI

b) cyclizing the ortho-formyl derivative of compound of formula VI in a suitable solvent, in presence of base and alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

to give vilazodone free base or its derivatives;

wherein R is -COOalkyl, -CONH2 or -CN;

c) optionally amidating the vilazodone ester derivative; OR

optionally hydrolyzing the vilazodone nitrile derivative, to give vilazodone free base;

d) reacting the vilazodone free base with hydrochloric acid solution, in a suitable solvent to give vilazodone hydrochloride of formula I;

e) optionally purifying the vilazodone hydrochloride.

Yet another aspect of the present application provides process for the preparation of indole derivative of formula II,

Formula II

wherein X´ is halogen;

which comprises:

a) diazotizing 4-cyano aniline;

to give corresponding diazonium salt;

b) reducing the diazonium salt to give hydrazine hydrochloride derivative of compound of following formula;

c) reacting the hydrazine hydrochloride derivative with compound of following formula;

wherein R is hydroxy or X´ and

X´ is halogen;

in presence of acid catalyst to give indole derivative of formula II;

d) optionally treating the product of step c) with acid catalyst, if step c) does not result in indole derivative of formula II; OR

if it is contaminated with hydrazone derivative of following formula,

wherein R is hydroxy or X´ and

X´ is halogen;

e) optionally treating the indole derivative obtained in step c) or step d) with halogenating reagents, if R is hydroxy, to give indole derivative of formula II;

f) optionally converting the indole derivative of formula II to vilazodone or its salts thereof.

Still yet another aspect of the present application provides the following compounds of formula IIIa, IIIb, and IVa;

Formula IIIa Formula IIIb

Formula IVa

their salts, solvates, hydrates, and their use in the preparation of vilazodone or its physiologically acceptable salt thereof.

Still yet another aspect of the present application provides pharmaceutical formulations comprising vilazodone hydrochloride, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a schematic illustration of the process for the preparation of vilazodone hydrochloride and its key intermediate.

DETAILED DESCRIPTION

An aspect of the present application provides an alternative, efficient and cost effective process for the preparation of vilazodone hydrochloride of formula I,

Formula I

which comprises:

a) reacting indole derivative of formula II;

Formula II

wherein X´ is halogen;

with phenyl piperazine derivative of formula III;

Formula III

wherein E is hydrogen or any suitable hydroxyl protecting group;

in presence of base, in a suitable solvent to give compound of following formula IV;

Formula IV

wherein E is hydrogen or any suitable hydroxyl protecting group;

b) deprotecting the hydroxy protecting group of compound of formula IV with a suitable deprotecting reagent to give hydroxy derivative of compound of formula V;

Formula V

c) ortho-formylating the compound of formula V to give ortho-formyl derivative of compound of formula VI;

Formula VI

d) cyclizing the ortho-formyl derivative of compound of formula VI in a suitable solvent, in presence of base and alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

to give vilazodone free base or its derivatives;

wherein R is -COOalkyl, -CONH2 or -CN;

e) optionally amidating the vilazodone ester derivative; OR

optionally hydrolyzing the vilazodone nitrile derivative, to give vilazodone free base;

f) reacting the vilazodone free base with hydrochloric acid solution, in a suitable solvent to give vilazodone hydrochloride of formula I.

g) optionally purifying the vilazodone hydrochloride.

Step a) can be carried out at a temperature of about 80-140ºC more preferably at about 90-120ºC. The reaction may be completed in about 3 to 15 hours; however reaction may be stirred for any period of time till the reaction is completed. The completion of reaction can be monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

Suitable bases which may be used include, but are not limited to ammonia, ammonium acetate, methylamine, ethylamine, butylamine, pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylamine and triethylamine; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal carbonate such as potassium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, alkali metal hydride such as sodium hydride; alkali metal acetate such as sodium acetate and potassium acetate; alkaline earth metal oxides such as calcium oxide and the like.

Suitable solvents which may be used include, but are not limited to C5-8 aliphatic or aromatic hydrocarbons such as hexane, pentane, heptane or benzene, toluene, xylene and cyclohexane; 1,4-dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, , dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof.

It is preferred to use second lot of base and solvent during the reaction to achieve the desired purity and yield of compound of formula IV.

The hydroxy protected phenyl piperazine derivative of formula III;

Formula III

wherein E is any suitable hydroxyl protecting group;

may be prepared by protecting the phenolic hydroxy group of 4-tert-butoxycarbonyl-1-(4-hydroxyphenyl)-piperazine of following formula;

with a suitable hydroxyl protecting group in presence of base in a suitable solvent followed by deprotecting the 4-tert-butoxycarbonyl group of piperazine ring with a suitable reagent known in the art. More specifically, 4-tert-butoxycarbonyl group deprotection may be achieved in presence of strong acids such as trifluoroacetic acid or its mixture in dichloromethane, or mineral acid-solvent mixture such as alcoholic hydrochloric acid solution or alkyl acetate-hydrochloric acid solution such as ethyl acetate-hydrochloric acid solution. The process of phenolic hydroxyl protection and deprotection of 4-tert-butoxycarbonyl group of piperazine ring may be carried out without the isolation of tert-butyl 4-(4-(pivaloyloxy)phenyl)piperazine-1-carboxylate of following formula IIIb;

or it may be isolated prior to 4-tert-butoxycarbonyl group deprotection of piperazine ring.
Suitable hydroxyl protecting group which may be used include, but are not limited to ethers such as alkyl ethers, branched alkyl ethers, alkyl phenyl ethers, allyl ethers, silyl ethers, tertiary-butyldiphenylsilylethyl ethers or carboxylic acid esters such as phenyl esters, alkyl esters, tertiary butyl esters or phenyl carbonates or acetals/ketals such as acetonide and benzylidene and the like. More specifically, pivolyl group may be used for the protection of phenolic hydroxyl group.

In general, the phenolic hydroxyl protection with pivaloyl chloride is completed in about 2-10 hrs while maintaining a temperature of about 0-20ºC, while the 4-tert-butoxycarbonyl group deprotection reaction is completed in about 2-9 hrs, more specifically in about 4-7 hrs.

Suitable solvents which can be used during the phenolic hydroxyl protection reaction include, but are not limited to 1,4-dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof. Suitable bases include, but are not limited to ammonia, ammonium acetate, methylamine, ethylamine, butylamine, pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylamine and triethylamine; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal carbonate such as potassium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, alkali metal hydride such as sodium hydride; alkali metal acetate such as sodium acetate and potassium acetate; alkaline earth metal oxides such as calcium oxide and the like.

In embodiments of step b) the optional hydroxyl deprotection reaction may be carried out depending on the nature of the hydroxyl protecting group and the choice of deprotecting agent to be used and reaction condition may be altered based on the choice of protecting-deprotecting reagents. Hydroxyl protecting groups may be removed, for example by acid or base catalyzed hydrolysis or reduction, for example, hydrogenation. Silyl ethers may require hydrogen fluoride or tetrabutylammonium fluoride for the deprotection. In an embodiment, the pivaloyl deprotection is carried out by treating the compound of formula IV with a mixture of alkali metal hydroxide base in presence of suitable solvent to afford the hydroxyl derivative of formula V. In general the reaction is carried out at ambient temperature in presence of lithium hydroxide which is either in anhydrous or hydrate form, after a period of time sodium hydroxide is added to the reaction mixture and further stirred the mixture for about 2-12 hrs while maintaining a temperature of about 40-70ºC.
Suitable solvents which can be used include, but are not limited to C3-10 ketone solvents specifically selected from acetone, ethyl methyl ketone, methyl isobutyl ketone; straight chain or branched C1-8 alcohol specifically methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; nitriles of general formula RCN wherein R is C2-5 alkyl; tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, halogenated solvents, water and/or mixtures thereof.

In embodiments of step c) the ortho formylation reaction of the compound of formula V is carried out in presence of a suitable formylation reagent, magnesium chloride and base, in a suitable solvent. In general the formylation reaction is completed in about 2-10 hours while maintaining a temperature of about 40-80ºC.

Examples of the suitable formylation reagent which may be used include, but are not limited to N,N-dimethylformamide, N-formylpiperidine, N-formylmorpholine, formates such as ethyl formate, paraformaldehyde and the like, a mixture of formic acid and acetic anhydride, and the like.

Suitable bases which can be used include, but are not limited to ammonia, ammonium acetate, methylamine, ethylamine, butylamine, pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylamine and triethylamine; alkali metal carbonate such as potassium carbonate, cesium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate and the like.

Suitable solvent which can be used include, but are not limited to ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, chloroform, 1,1,2,2-tetrachloroethane, 1,1,1-trichloroethane, 1,2-dichlorethane, 1,2,3-trichloropropane, tetrachloroethene, trichloroethene, cis- and trans-1,2-dichloroethene, 1,1-dichloroethene, cis-1,3-dichloropropene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 3-chlorotoluene and bromobenzene, aromatic hydrocarbons such as hexane, pentane, heptane, benzene, toluene, xylene, nitriles of general formula RCN wherein R is C2-5 alkyl such as acetonitrile and propionitrile; dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, saturated hydrocarbons and mixtures thereof.

In embodiments of step d) ortho-formyl derivative of compound of formula VI is cyclized to vilazodone free base or its ester or nitrile derivatives by reacting the formula VI with an alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

in presence of base, in a suitable solvent and optionally in presence of phase transfer catalyst.

The suitable alkyl halo derivatives are chloroacetamide, bromoacetamide, alkyl haloacetates such as methyl chloroacetate, ethyl bromoacetate, isopropyl chloroacetate, t-butyl chloroacetate and the like; chloroacetonitrile and bromoacetonitrile.

The reaction is performed at a temperature of about ambient temperature to about 160°C, more specifically from about 50°C to about 140°C, and most specifically from about 80°C to about 120°C. It is preferred to use catalytic amount of 4-dimethylaminopyridine during the reaction.

Suitable bases which can be used include, but are not limited to ammonia, ammonium acetate, methylamine, ethylamine, butylamine, pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylamine and triethylamine; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal carbonate such as potassium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, alkali metal hydride such as sodium hydride; alkali metal acetate such as sodium acetate and potassium acetate; alkaline earth metal oxides such as calcium oxide and the like.

The base may be used as pure or a mixture thereof in a given ratio with or without a phase transfer catalyst which may include, but are not limited to tetralkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate, crown ethers like 15-crown-5, 18-crown-6, and the like. Specifically, the phase transfer catalyst employed is tetrabutylammonium bromide.

Suitable solvents which can be used include, but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds, such as nitromethane or nitrobenzene; aliphatic amides such as N’,N’-dimethylacetamide, N’,N’-dimethylformamide optionally also mixtures of said solvents with one another.

In embodiments of step e) optional conversion of vilazodone ester or vilazodone nitrile derivatives to vilazodone free base can be achieved by the methods known in the prior art. In general the amidation of vilazodone ester can be carried out as per the reported methods of US patent No. 5532241 or it can be achieved by any conventional methods.

For example, the amidation reaction can be achieved by reacting vilazodone ester derivative with ammonia in the presence of a condensing agent.

The condensing agent which can be used include, but are not limited to N,N’,-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide monohydrochloride, N,N’,-carbonyldiimidazole, and benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate. These condensing agents may be used alone or in combination with a peptide-synthesis reagent such as N-hydroxysuccinimide and N-hydroxybenzotriazole.

The reaction of vilazodone ester derivative with ammonia is carried out in a solvent or in a solvent-free condition. The solvent which can be used include, but are not limited to toluene, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), tetrahydrofuran, dioxane, dimethyl ether, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyformamide, and dimethylsulfoxide or mixtures thereof. In addition, ammonia may be used as an aqueous solution, or in the form of "masked ammonia" as an amidating agent. Specifically, "masked ammonia" is an ammonium salt including ammonium carbonate, ammonium acetate, and ammonium formate, and the like. Usually the reaction may also be carried out in the presence of a base which can be used include, but are not limited to an inorganic base such as potassium carbonate and sodium bicarbonate and an organic base such as triethylamine, ethyldiisopropylamine, N-methyl morpholine, pyridine and 4-dimethylaminopyridine. The reaction temperature may vary and depends over the reaction condition; generally, it is about -30ºC to about 150ºC, specifically about -10ºC to about 70ºC. The reaction time is about 1 hour to about 48 hours.

The hydrolysis of nitrile group of vilazodone nitrile derivative to an amide may be carried out by means of various nitrile hydrolysis reactions known in the art, for example, by applying, as appropriate, a method using hydrogen peroxide and an inorganic base, a method performed in an aliphatic alcohol or dimethy sulfoxide in the presence of an inorganic base, or a method involving hydrolysis in the presence of an acid.

Suitable bases which may be used include, but are not limited to alkali metal carbonate such as potassium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, and the like.

Suitable solvent which may be used include, but are not limited to dimethyl sulfoxide, dimethylformamide, dimethylacetamide; C1-4 alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like.

The reaction time is about 10 minutes to about 30 hours. The reaction temperature is in a temperature range of from about 10ºC to about 100ºC.

It is well known that most amide compounds are obtained by heating to hydrolyze nitrile compounds in an acidic or basic aqueous solution. However, because amide compounds will continue hydrolyzing to carboxylic acid compounds, the selectivity of this process is not high. Therefore the use of solid acidic materials as a catalyst is one of the embodiments of the present application and such catalysts in different forms can be used for selective hydrolysis of vilazodone nitrile derivative. The catalytic system for use in the hydrolysis of vilazodone nitrile derivative includes various transition metal catalysts, including copper catalyst, palladium catalyst, rhodium catalyst, platinum catalyst, cobalt catalyst, and nickel catalyst, which are successively reported to have certain activities when used in the selective hydrolysis of nitrile compounds.

In embodiments of step f) the hydrochloride salt of vilazodone free base is prepared in the usual manner, i.e., either by reaction of the free base with a solution of hydrochloric acid or purging of hydrogen chloride gas to the solution of vilazodone free base in a suitable solvent. More specifically, vilazodone free base is dissolved in a suitable solvent such as a ketone e.g. acetone or straight chain or branched C1-8 alcohol specifically methanol, ethanol, propanol, butanol, isopropanol and the like; nitriles of general formula
RCN wherein R is C2-5 alkyl such as acetonitrile, propionitrile and the like;

tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, halogenated solvents and/or mixture thereof and acidified with a suitable solvent containing an acid. It may have an advantage to dissolve vilazodone free base and acid in different solvents. The acid solution is added until the salt formation is complete; in general hydrochloride salt of vilazodone is obtained by treating isopropyl alcohol solution of vilazodone free base with a methanolic hydrochloric acid solution at a temperature of about 5-20ºC.

In embodiments of step g) vilazodone hydrochloride prepared as per the process of step e) is optionally purified as per the methods known in the prior art to get the desired purity of vilazodone hydrochloride. Purification may include, but are not limited to recrystallization, acid-base treatment or column chromatography.

The indole derivative of formula II which is used for the preparation of vilazodone may be prepared by any suitable methods known in the prior art or as per the method described herein below and it is also an embodiment of the present application. As per another aspect of the present application indole derivative of formula II may be prepared by the process comprising:

Formula II

wherein X´ is halogen;

a) diazotizing 4-cyano aniline;

to give corresponding diazonium salt;

b) reducing the diazonium salt to give hydrazine hydrochloride derivative of compound of following formula;

c) reacting the hydrazine hydrochloride derivative with compound of following formula;

wherein R is hydroxy or X´

and X´ is halogen;

in presence of acid catalyst to give indole derivative of formula II;

d) optionally treating the product of step c) with acid catalyst, if step c) does not result in indole derivative of formula II; OR

if it is contaminated with hydrazone derivative of following formula,

wherein R is hydroxy or X´

and X´ is halogen;

e) optionally treating the indole derivative obtained in step c) or step d) with halogenating reagents, if R is hydroxy, to give indole derivative of formula II;

f) optionally converting the indole derivative of formula II to vilazodone or its salts thereof.

In embodiments of step a) and step b), substituted anilines can be converted to the corresponding hydrazine by diazotization and subsequent reduction. The diazotization of the substituted aniline is typically accomplished by treating the amino compound by suspending it in a solution of a acid, such as sulfuric acid, hydrochloric acid, acetic acid, fluoroboric acid, phosphoric acid and/or another suitable acid followed by treating it with a nitrite salt such as sodium nitrite in aqueous or acidic medium, such as acetic acid or aqueous hydrochloric acid. Other various nitrite salts can also be employed in the practice of the present application such as nitrosylsulfuric acid or alkyl nitrite such as isobutyl nitrite.

In general, the diazotization of 4-cyano aniline with aqueous sodium nitrite solution is completed in about 1 to about 3 hours while maintaining a temperature of about -15 to 5ºC and the corresponding diazonium salt can be isolated as a precipitate from the acidic reaction solution or can be precipitated therefrom by neutralization with a base such as ammonia or a hydroxide, such as potassium hydroxide or it may be further reduced without the isolation to give the hydrazine hydrochloride derivative of compound of following formula;

In general, the reduction of diazonium salt can be achieved by using stannous chloride in a strong aqueous acid, such as concentrated hydrochloric acid or aqueous sulfuric acid or dithionite salt such as metal dithionite salt, more specifically the dithionite salt is sodium dithionite. Suitably the reduction of the diazonium salt is carried out at a temperature of about -10°C to +10°C. The resultant hydrazine hydrochloride salt is isolated by filtration.

In embodiments of step c) and step d) the hydrazine hydrochloride salt is reacted with a source of an aldehyde such as 6-chloro hexanal or 6-hydroxy hexanal in presence of acid catalyst in a suitable solvent to give corresponding indole derivative of formula II. In general, the reaction of hydrazine hydrochloride salt with the aldehyde source is carried out at a temperature of about ambient temperature to about 100°C and normally the reaction is completed in about 1 to 15 hours. Typically, the mole ratio of acid catalyst determines the formation of indole derivative of formula II or its contamination with hydrazone derivative of following formula,

wherein R is hydroxy or X´

and X´ is halogen.

Specifically, the higher mole ratio of acid catalyst has been employed for the satisfactory yield and purity of indole derivative of formula II, however if the desired yield and purity is not achieved then it is further treated with acid catalyst in a suitable solvent to cyclize the hydrazone derivative to get the desired yield and purity of indole derivative of formula II. It is found that the reaction end up with different compounds with variation in mole ratio of acid catalyst and reaction conditions such as temperature, reaction time or the quantities of reactants. The reaction conditions may be modified in such a way that it may results either indole derivative of formula II or hydrazone derivative of above formula.

Acid catalyst which may be used include, but are not limited to hydrochloric acid, sulfuric acid, polyphosphoric acid and p-toluenesulfonic acid or Lewis acids such as boron trifluoride, zinc chloride, iron chloride, and aluminium chloride.

Suitable solvent which may be used include, but are not limited to aliphatic esters such as isobutyl acetate, isopropyl acetate, ethyl acetate, butyl acetate, aliphatic amides such as N,N-dimethylacetamide, N,N-dimethylformamide, aliphatic ketones such as methyl isobutylketone, halogenated solvents such as ethylenedichloride, aromatic hydrocarbons such as toluene, N-methyl-2-pyrrolidone, ethylene glycol, methylene glycol, and mixtures thereof.

In embodiments of step e) optionally reacting the indole derivative obtained in step c) or step d), if R is hydroxy, with a halogenating agent in a suitable solvent to get the corresponding halide derivative of formula II.

The halogenating agents which may be used include, but are not limited to thionyl chloride, phosphorus oxychloride, phosphorus tribromide.

The suitable solvents which may be used include, but are not limited to halogenated aliphatic hydrocarbon such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; aromatic hydrocarbon solvent such as benzene, toluene, xylene, dimethylformamide or a mixture of two or more of these solvents. The reaction is carried out at a temperature of about -20ºC to about 80ºC.

In embodiments of step f) optionally the indole derivative of formula II may be converted to vilazodone or its salts thereof either by the disclosed process of the present application or by any known process of the prior art.

The aldehyde source such as 6-chloro hexanal and 6-hydroxy hexanal used during the preparation of indole derivative of formula II can be prepared by any known methods of the prior art, more specifically 6-chloro hexanal is prepared by treating hexane diol with a mineral acid such as hydrochloric acid in a suitable solvent and optionally in the presence of phase transfer catalyst to get the 6-chloro hexanol, the reaction being performed from room temperature to reflux temperature of the solvent and it is being completed in about 4 to 14 hours.

Suitable solvent which may be used include, but are not limited to C1-4 alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; ketones such as acetone, methylisobutyl ketone, methylethylketone; aliphatic or aromatic hydrocarbon solvents such as hexane, toluene, xylene or halogenated solvents such methylene chloride or mixtures thereof. The choice of solvent and strength of hydrochloric acid used depends upon the reaction conditions.

Phase transfer catalyst which may be used include, but are not limited to tetralkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate, crown ethers like 15-crown-5, 18-crown-6, and the like. Specifically the phase transfer catalyst employed is tetrabutylammonium bromide.

6-chloro hexanol is further oxidized with any suitable oxidizing reagent which may be used include, but are not limited to chromium trioxide (CrO3), manganese dioxide (MnO2), TEMPO/sodium hypochlorite, sulfur trioxide (SO3)/pyridine; more specifically 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO)-catalyzed oxidation is employed whereas oxidizing agent component comprises 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and a stoichiometric oxidant (e.g., sodium hypochlorite or N-chlorosuccinimide (NCS)) and most specifically the oxidizing agent component comprises TEMPO and sodium hypochlorite.

The amount of oxidizing agent, for example, in the case of TEMPO-sodium hypochlorite, TEMPO is used at 0.001 to 0.1 equivalents relative to compound 6-chloro hexanol, specifically 0.005 to 0.02 equivalents. Sodium hypochlorite is used at 1 to 5 equivalents, specifically 1 to 2 equivalents.

It is preferred to use suitable base during the oxidation which may include, but are not limited to sodium hydrogen carbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, and triethylamine, more specifically sodium hydrogen carbonate is used.

The TEMPO-sodium hypochlorite catalyzed oxidation is specifically carried out at a temperature of about -20°C to about 30°C and the reaction is completed in about 1 to 10 hours.

The source of second aldehyde i.e. 6-hydroxy hexanal can be prepared from 6-caprolactone by opening the lactone ring of 6-caprolactone with a suitable reducing agent such as diisobutylaluminium hydride (DIBAL-H) or lithiumaluminium hydride in an aprotic solvent which may be used include, but are not limited to halogenated solvents such as dichloromethane, ethylene chloride, tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether, ethyl acetate and mixtures thereof.

The reaction is completed in about 1 to 10hours while maintaining a temperature at about -78°C to about 20°C.

Yet another aspect of the present application provides the following compounds of formula IIIa, IIIb, and IVa;

Formula IIIa Formula IIIb

Formula IVa

its salts, solvates, hydrates, and their use for the preparation of vilazodone or a physiologically acceptable salt thereof.

Work up procedures, isolation and purification of the compounds and intermediates described above can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, chromatography, column chromatography, or by a combination of these procedures.

Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein given below. However, other equivalent separation or isolation procedures could, of course, also be used.

Still yet another aspect of the present application provides pharmaceutical formulations comprising vilazodone hydrochloride, together with one or more pharmaceutically acceptable excipients.

In an aspect, the present application provides pharmaceutical formulations comprising vilazodone hydrochloride, together with one or more pharmaceutically acceptable excipients. Vilazodone hydrochloride together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes, which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Protection and deprotection of functional groups may be performed by methods known in the art (see, for example, Green and Wuts Protective Groups in Organic Synthesis. John Wiley and Sons, New York, 1999.).

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

EXAMPLE 1: Preparation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile

Step I: Preparation of 6-hydroxy hexanal:

Tetrahydrofuran (125 ml) and dichloromethane (125 ml) were taken into a round bottom flask and 6-caprolactone (5.0g) was added and cooled to about -60°C.

Diisobutylaluminium hydride (DIBAL-H) (1M solution in toluene) (32 ml) was added to the cooled reaction mixture and stirred till reaction completion. After the reaction was completed, water (50 ml) was added to the reaction mass and stirred for about 10 minutes. The reaction mixture was filtered over hyflow bed and the filtrate was dried over sodium sulfate. The filtrate was then distilled off under reduced pressure to give 4.1 g (yield: 80.5%) of the title compound.

Step II: Preparation of 4-(2-(6-hydroxyhexylidene) hydrazinyl) benzonitrile

4-cyanophenyl hydrazine hydrochloride (5.0 g), 6-hydroxy hexanal (4.4 g), and N,N-Dimethyl acetamide (DMAC) were taken into a round bottom flask and stirred at room temperature. 4% sulfuric acid solution (50 ml) was added to the reaction mass and heated to about 50°C. The reaction mass was maintained at the same temperature for reaction completion. After the reaction was completed, heating was removed and the reaction mass was quenched with water. The aqueous layer was separated and extracted into ethyl acetate. The ethyl acetate layer was washed with water and distilled off at reduced pressure to yield 4.5 g (yield: 66.0%) of the title compound.

Step III: Preparation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile

4-(2-(6-hydroxyhexylidene) hydrazinyl) benzonitrile (1.0 g) and isopropyl acetate (15 ml) were taken into a round bottom flask and stirred for about 10 minutes. A solution of phosphoric acid in water (6 g in 10 ml) was added to the reaction mixture and heated to about 75°C. The reaction mixture was maintained at the same temperature till reaction completion. After the reaction was completed, water (20 ml) was added to the reaction mixture and stirred followed by addition of ethyl acetate. The organic layer was separated and washed with 10% sodium bicarbonate solution. The organic layer was distilled off to dryness to provide 0.75 g (yield: 80.9%) of the title compound.

EXAMPLE 2: Preparation of 3-(4-chlorobutyl)-indole-5-carbonitrile (Formula II)

Step I: Preparation of 6-chloro hexanol

Hexane diol (20.0 gm), toluene (100 ml) and tetra butyl ammonium bromide (TBAB) (10.8 gm) were charged into a round bottom flask at ambient temperature. Then concentrated hydrochloric acid (25.0 ml) was added at ambient temperature. The resulting mixture was refluxed at 105-110ºC for 8-10 hrs. After completion of the reaction, the mixture was cooled and quenched with water (200 ml), organic layer was separated and washed with water (200 ml). The organic layer was distilled off at 25-30ºC to afford the title compound 18.8 gm (yield: 81.5%).

Step II: Preparation of 6-chloro hexanal

6-chloro hexanol (15.0 g) and dichloromethane (105 ml) were taken into a round bottom flask and 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (0.17g) was added to it and cooled to about 0°C. A solution of sodium bicarbonate (18.4 g) and potassium bromide (1.3 g) in water (105 mL) was added to the reaction mixture followed by addition of sodium hypochlorite solution (15.3 ml). The reaction mass was stirred at the same temperature for about 3 hours for reaction completion. After the reaction was completed, the reaction mass was quenched with sodium thiosulphate solution and the organic layer was separated. The aqueous layer was extracted into dichloromethane and the combined organic layer was distilled off to give 10.4 g (yield: 70.4%) of the title compound.

Step III: Preparation of 4-cyanophenyl hydrazine hydrochloride

4-cyano aniline (5.0 g) and concentrated hydrochloric acid (55 ml) were taken into a round bottom flask, cooled to about -5°C, solution of sodium nitrite (3.15 g) in demineralized water (30.0 ml) was added at -5°C and maintained till reaction completion.

After reaction completion the reaction mass was filtered and the filtrate was slowly added to a solution of stannous chloride (24.1 g) in concentrated hydrochloric acid (40 ml) at 0°C and maintained at room temperature for reaction completion. After the reaction was completed, the reaction mass was filtered and the filtered cake was washed with ethanol.

The wet compound was dried at about 45°C to yield 6.0 g (yield: 83.5%) of the title compound.

Step IV: Preparation of 4-(2-(6-chlorohexylidene) hydrazinyl) benzonitrile

4-Cyano phenyl hydrazine hydrochloride (1.0 g), and isobutyl acetate (10 ml) were taken into a round bottom flask and stirred. 6-chloro hexanal (0.94 g) and zinc chloride (1.2 g) were added to the reaction mass and stirred till reaction completion at room temperature. After the reaction was completed, water (10 ml) and ethyl acetate (10 ml) were added to the reaction mass and stirred for about 10 minutes. The organic layer was separated and washed with 10% aqueous sodium bicarbonate solution. The organic layer was distilled off under vacuum to yield 1.1 g (yield: 74.8%) of the title compound.

Step V: Preparation of 3-(4-chlorobutyl)-indole-5-carbonitrile (Formula II)

4-(2-(6-Chlorohexylidene) hydrazinyl) benzonitrile (1.0 g) and isopropyl acetate (10 ml) were taken into a round bottom flask and phosphoric acid (0.78 g) was added to it. The reaction mixture was heated to about 80°C and maintained till reaction completion. After the reaction was completed, water (10 ml) was added to the reaction mass and temperature was brought down to room temperature. Ethyl acetate was added to the reaction mass and the organic layer was separated. The aqueous layer was extracted into ethyl acetate. The combined ethyl acetate layer was washed with 10% aqueous sodium bicarbonate solution and distilled off at about 55°C under vacuum to yield 0.8 g (yield: 85.5%) of the title compound.

Example 3: Alternate Preparation of 3-(4-chlorobutyl)-indole-5-carbonitrile (Formula II)

Dimethyl acetamide (500 ml) and aqueous sulfuric acid (4%, 500 ml) were charged in a round bottom flask and 4-Cyano phenyl hydrazine hydrochloride (100 g) followed by 6-chlorohexanal (95.29 g) was added to it. The reaction mass was stirred at about 27°C for 1 hour and quenched by water (500 ml). The reaction mass was extracted with toluene (2x500 ml). The organic layer was washed with sodium chloride solution (5% w/v, 500 ml) and charged in a separate round bottom flask. Phosphoric acid (85%, 340 g) was added to it and heated to about 100°C for about 2 hours and 30 minutes. The reaction mass was cooled and the aqueous layer was separated out. The organic layer was washed with sodium bicarbonate solution (10% w/v, 1000 ml), followed by sodium chloride solution (5% w/v, 500 ml). The organic layer was distilled under vacuum to provide crude product. The crude product was dissolved in ethyl acetate (200 ml) and cyclohexane was added (1000 ml). the reaction mass was stirred at about 27°C for 2 hours and the precipitated solid was filtered, washed with cyclohexane and dried at 55°C under vacuum to yield 107.08 g (yield:78.0%) of the title compound

EXAMPLE 4: Preparation of 4-(piperazin-1-yl)phenyl pivalate (Formula IIIa)

4-Tert-butoxycarbonyl-1-(4-hydroxyphenyl)-piperazine (30 g), triethyl amine (27 ml) and dichloromethane (300 ml) were charged into a round bottom flask at 0-5ºC. To the resulted mixture pivaloyl chloride (50 ml) was slowly added and stirred the reaction mass at 0-5ºC for 3 hrs. After completion of the reaction, quenched the reaction mass with water (300 ml) and separated the organic layer. The aqueous layer was extracted with dichloromethane (150 ml) and combined the organic layers. The combined organic layer was washed with water (4X300 ml) and distilled off at 40-45ºC to afford residue. The solid residue was stirred with ethyl acetate-hydrochloric acid solution (600 ml) at ambient temperature for 5 hrs. The resulted slurry was filtered and washed the solid with ethyl acetate (300 ml), the solid was dried to afford the title compound (27.0 g) (yield: 95.5%).

EXAMPLE 5: Preparation of 4-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-phenyl pivalate (Formula IVa)

3-(4-chlorobutyl)-1H-indole-5-carbonitrile (0.9 g) (Formula II), triethyl amine (1.5 ml) and N-methylpyrrolidone (5.0 ml) were charged into a round bottom flask at ambient temperature, to the resulted mixture 4-(piperazin-1-yl)phenyl pivalate (1.0 g) (Formula IIIa) was added and stirred the reaction mass at 110-115ºC for 7 hrs. The mixture was cooled to ambient temperature and second lot of triethyl amine (1.5 mL) and N-methylpyrrolidone (5.0 mL) were charged, the temperature was increased to 110-115ºC and the mixture is further stirred for 5 hrs. After completion of the reaction, the reaction mixture was cooled to ambient temperature and quenched with water (10mL).

Dichloromethane (20 mL) was added to the quenched mixture and stirred the reaction mass for 45minutes. Organic layer was separated and washed with water (3X10 ml). The organic layer was distilled off at 35-40ºC to afford the title compound (1.0 g) (yield: 57.4%).

EXAMPLE 6: Preparation of 3-[4-(4-p-hydroxyphenyl-piperazino)-butyl]-indol-5-carbonitrile (Formula V)

4-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)phenyl pivalate (0.5 g) (Formula IVa), lithium hydroxide hydrate (0.1 g) and tetrahydrofuran-water (8:1) (31 ml) were charged into a round bottom flask at ambient temperature, the resulted mixture was stirred overnight at ambient temperature. The mixture was heated to 60-65ºC and sodium hydroxide (4.0 g) was added and further stirred for 4 hrs. After completion of the reaction, mixture was cooled to ambient temperature and quenched with water (20mL).

The quenched mixture was extracted with ethyl acetate (2X10 ml) and organic layer was washed with water (4X20 ml). The organic layer was distilled off at 35-40ºC to afford the title compound (0.3 g) (yield: 75.0%).

EXAMPLE 7: Preparation of 3-{4-[4-(3-formyl-4-hydroxy-phenyl)piperazin-1-yl]-butyl}-1H-indole-5-carbonitrile (Formula VI)

A mixture of 3-[4-(4-p-hydroxyphenyl-piperazino)-butyl]-indol-5-carbonitrile (10.0 g) (Formula V) in tetrahydrofuran (100 ml) was added to a mixture of magnesium chloride (13.0 g), triethyl amine (17.3 ml), paraformaldehyde (6.4 g) and tetradydrofuran (250 ml) at ambient temperature, the resulted mixture was heated to 60-65ºC and stirred for 4hrs.

After completion of the reaction, the reaction mixture was cooled to 10ºC and quenched with 10% hydrochloric acid solution (100 ml). Ethyl acetate (100 ml) was added to the quenched mixture and separated the organic layer, aqueous layer was extracted with ethyl acetate (2X100 ml). The combined organic layer was washed with 10% hydrochloric acid solution (100 ml), water (2X50mL) and 5% sodium chloride solution (50 ml). The organic layer was distilled off at 30-35ºC to afford the title compound (1.0 g) (yield: 9.3%).

EXAMPLE 8: Preparation of vilazodone free base

3-{4-[4-(3-formyl-4-hydroxy-phenyl)piperazin-1-yl]-butyl}-1H-indole-5-carbonitrile (2.0 g) (Formula VI), potassium carbonate (2.0g), bromoacetamide (0.72 g), tetra-N-butylammonium bromide (0.008 g), 4-dimethylaminopyridine (0.02 g) and a mixture of toluene (20.0 ml) and dimethylformamide (4.0 ml) were charged into a round bottom flask at ambient temperature. The resulting mixture was refluxed at 105-110ºC for 6 hrs.

After completion of the reaction, the mixture was cooled and quenched with water (40 ml). The resulting mass was extracted with ethyl acetate (3X20 ml) and organic layers were separated, the combined organic layer was washed with water (3X10 ml). The organic layer was distilled off at 35-40ºC to afford the title compound (1.5 g) (yield: 68.4%).

EXAMPLE 9: Preparation of vilazodone hydrochloride (Formula I)

To a stirred solution of vilazodone free base (1.5 g) in isopropyl alcohol (30.0 ml), slowly added 1~2N methanolic hydrochloric acid solution (3.0 ml) at 5-10ºC. The mixture was stirred for 1 hr. The resulted slurry was filtered and washed the solid with isopropyl alcohol (15 ml), the solid was dried to afford the title compound (0.4 g) (yield: 24.7%).

CLAIMS:We claim:

1. A process for the preparation of vilazodone hydrochloride of formula I,

Formula I

which comprises;

a) reacting indole derivative of formula II;

Formula II

wherein X´ is halogen;

with phenyl piperazine derivative of formula III;

Formula III

wherein E is hydrogen or any suitable hydroxyl protecting group;

in presence of base, in a suitable solvent to give compound of following formula IV;

Formula IV

wherein E is hydrogen or any suitable hydroxyl protecting group;

b) deprotecting the hydroxy protecting group of compound of formula IV with a suitable deprotecting reagent to give hydroxy derivative of compound of formula V;

Formula V
c) ortho-formylating the compound of formula V to give ortho-formyl derivative of compound of formula VI;

Formula VI

d) cyclizing the ortho-formyl derivative of compound of formula VI in a suitable solvent, in presence of base and alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

to give vilazodone free base or its derivatives;

wherein R is -COOalkyl, -CONH2 or -CN;

e) optionally amidating the vilazodone ester derivative; OR
optionally hydrolyzing the vilazodone nitrile derivative, to give vilazodone free base;

f) reacting the vilazodone free base with hydrochloric acid solution in a suitable solvent to give vilazodone hydrochloride of formula I;

g) optionally purifying the vilazodone hydrochloride.

2. The process of claim 1, wherein the compound of formula III is

3. The process of claim 1, further comprising a process for the preparation of compound of formula IIIa by protecting the phenolic hydroxy group of 4-tert-butoxycarbonyl-1-(4-hydroxyphenyl)-piperazine of following formula to produce compound of formula IIIb;
and deprotecting the 4-tert-butoxycarbonyl group.

4. The process of claim 1, wherein the compound of formula IV is

5. A process for the preparation of vilazodone hydrochloride of formula I,

Formula I

which comprises;

a) ortho-formylating the compound of formula V

Formula V

to give ortho-formyl derivative of compound of formula VI;

Formula VI

b) cyclizing the ortho-formyl derivative of compound of formula VI in a suitable solvent in presence of base and alkyl halo derivative of following formula;

wherein X is halogen and Y is -COOalkyl, -CONH2 or -CN;

to give vilazodone free base or its derivatives;

wherein R is -COOalkyl, -CONH2 or -CN;

c) optionally amidating the vilazodone ester derivative; OR optionally hydrolyzing the vilazodone nitrile derivative, to give vilazodone free base;

d) reacting the vilazodone free base with hydrochloric acid solution, in a suitable solvent to give vilazodone hydrochloride of formula I.

e) optionally purifying the vilazodone hydrochloride.

6. The process of claim1 or claim 5, wherein alkyl halo derivative of following formula is chloroacetamide; or bromoacetamide; or alkyl haloacetates such as methyl chloroacetate, ethyl bromoacetate, isopropyl chloroacetate, t-butyl chloroacetate and the like; or chloroacetonitrile; or bromoacetonitrile.

7. A process for the preparation of indole derivative of formula II,

Formula II

wherein X´ is halogen;

which comprises;

a) diazotizing 4-cyano aniline;

to give corresponding diazonium salt;

b) reducing the diazonium salt to give hydrazine hydrochloride derivative of compound of following formula;

c) reacting the hydrazine hydrochloride derivative with compound of following formula;

wherein R is hydroxy or X´ and X´ is halogen;

in presence of acid catalyst to give indole derivative of formula II;

d) optionally treating the product of step c) with acid catalyst, if step c) does not result in indole derivative of formula II; OR

if it is contaminated with hydrazone derivative of following formula,

wherein R is hydroxy or X´

and X´ is halogen;

e) optionally treating the indole derivative obtained in step c) or step d) with halogenating reagents, if R is hydroxy, to give indole derivative of formula II;

f) optionally converting the indole derivative of formula II to vilazodone or its salts thereof.

8. The process of claim 6, wherein the compound of formula is 6-chloro hexanal or 6-hydroxy hexanal.

9. A compound of formula IIIa

10. A compound of formula IIIb

11. A compound of formula IVa