CLIAMS:
1. A process for preparing 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base (Formula-I) and its hydrochloride salt (Formula-Ia) comprising

Formula-I Formula-Ia

(a) condensing alkyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate hydrochloride with R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate in presence or absence of polar aprotic solvent, base and catalyst;
(b) Acidifying with alcoholic hydrochloride by adjusting pH to acidic to isolate alkyl-5-(4-[4-(5-cyano- R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride;
(c) Dissolving alkyl-5-(4-[4-(5-cyano- R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride in suitable solvent;
(d) Adding mixture of amide and alkoxide or azane source in presence of suitable solvent;
(e) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base;
(f) Acidifying the 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base in an organic solvent with alcoholic hydrochloride; and
(g) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride salt.

2. The process according to claim 1, wherein R1 is protecting group.

3. The process according to claim 1, wherein R1 is BOC and alkyl group is selected from methyl, ethyl, n-propyl,isopropyl and n-butyl.
4. The process according to claim 1, wherein R1 is H and alkyl group is selected from the group consisting of methyl, ethyl, n-propyl,isopropyl and n-butyl.

5. The process according to claim 1, wherein R1 is H and alkyl group is selected from the group consisting of methyl, n-propyl,isopropyl and n-butyl.

6. The process according to claims 1,3 & 4whereinthe polar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide , acetone, ethyl acetate.

7. The process according to claim 1, wherein the suitable base is selected from inorganic base or organic base.

8. The process according to claims 1, 3 & 4, wherein inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &alkali alkoxides such as sodium methoxide, sodium ethoxide& potassium tertiary butoxide.

9. The process according to claims 1 & 5, wherein the organic base is selected from the group consisting of trisubstituted amines such as triethylamine, diisopropyl ethylamine, N-methyl morpholine & N-methyl pyrrolidine.

10. The process according to claims 1,3 & 4, wherein the catalyst is selected from Potassium iodide, sodium iodide, sodium bromide, potassium bromide.

11. The process according to claims 1 & 5, wherein the catalyst is phase transfer catalyst selected from the group consisting of tetra-n-butyl ammonium bromide (TBAB), methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide
12. The process according to claim 1, wherein the alcoholic hydrochloride is selected from the group consisting of methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride.

13. The process according to claims 1 step (c), 3 & 4,wherein the suitable solvent is non-polar solvent selected from the group consisting of Dichloromethane, Heptane, Hexane, Toluene, 1,4-Dioxane,Chloroform and Diethyl ether.

14. The process according to claims 1, 3 & 4 wherein the amide is Formamide.

15. The process according to claims 1,3& 4, wherein the alkoxide is selected from sodium methoxideor sodium ethoxide.

16. The process according to claims 1&5, wherein the azane source is selected from the group consisting of ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base, hydrazine.

17. The process according to claim 1, wherein the suitable solvent used in step (d) is selected from the group consisting of tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide , acetone and ethyl acetate.

18. The process according to claim 1, wherein the organic solvent is selected from the group consisting of alcohol solvents such as methanol, ethanol, isopropanol and butanol.

19. The process according to any of the preceding claims wherein the purity of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base and its hydrochloride salt is 99.67 % and 99.71% respectively.

20. A process for preparing alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylic acid ester intermediates (Formula-II) comprising;

Formula-VII
(a) esterifying 5-(piperazin-1-yl)-benzofuran-2-carboxylic acid with alcohol solvent in presence of strong acid;
(b) Basifying by adjusting pH 8-9;
(c) Isolating alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylate; and
(d) Crystallizing in non-polar solvent.

21. The process according to claim 20, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol.

22. The process according to claim 20, wherein the strong acid is selected from sulfuric acid, methanesulfonic acid and p-toluene sulfonic acid.

23. The process according to claim 20, wherein the non-polar solvent is cycloalkane selected from cyclohexan and, cycloheptane. ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“A process for preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] free base and its hydrochloride salt”

2. APPLICANT:

(a) NAME: HARMAN FINOCHEM LIMITED

(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956

(c) ADDRESS: 107, Vinay Bhavya Complex, 159–A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to a commercially viable process for preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] free base and its hydrochloride salt.

BACKGROUND OF INVENTION:
Vilazodone chemically known as 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] (Formula-1), is a selective serotonin reuptake inhibitor and a 5HT1A receptor partial agonist, indicated for the treatment of major depressive disorder. 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] is marketed under the trade name Viibryd in the form of Hydrochloride salt.

Formula-I
US 5,532,241 A (herein after US‘241)discloses 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] and its physiologically acceptable salts as well as its process for preparation. US’241 discloses reaction of 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylic acid with 2-chloro-1-methylpyridinium methanesulfonate in the presence of N-methyl pyrrolidine and ammonia gas to provide 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] free base. This free base further dissolved in propanolic hydrochloric acid to give 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] hydrochloride salt.

The significant drawback of the said process involves in the use of very costly reagent such as 2-chloro-1-methylpyridinium methanesulfonate and hence is not commercially viable.
Journal of medicinal chemistry 47(19), 4684-4692, 2004 also describes the process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl](Scheme-I).

Scheme-I
US 7,799,916 B2 discloses a process for preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] hydrochloride by condensing 5-bromo-benzofuran-2- carboxamide with 3-(4-piperazin-1 -ylbutyl)-indole-5-carbonitrile in presence of tris(dibenzylideneacetone)-dipalladium.

US 6,509,475 B1 discloses a process for preparing 3-(4- chlorobutanoyl)-1 - indole-5-carbonitrile by treating 5-cyano indole with 4- chlorobutyryl chloride in presence of isobutylaluminium dichloride. It also discloses the preparation of3- (4-chlorobutyl)-1 --indole-5-carbonitrile by reducing 3-(4-chlorobutanoyl)-1 --indole-5- carbonitrile by sodium borohydride in presence of isobutylaluminium dichloride.

US 6,762,300 B2 teaches a process for the preparation of 5-(1 -piperazinyl)benzofuran-2-carboxamide by a one pot reaction between 5-bromo-salicyaldehyde, ethyl bromoacetate and formamide to produce 5- bromobenzofuran-2-carboxylate; reacting the product of the earlier step with 1 -benzyl piperazine in presence of transition metal catalyst to produce 5-(4-benzyl-1 -piperazinyl)- benzofuran-2-carboxamide and deprotecting the benzyl group from the product.

Various processes for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] and its pharmaceutically acceptable salts are disclosed in 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 Drugs of the Future 2001, 26(3), 247, and Liebigs Ann. Chem. 1988, 749-752.

The main drawback of reported prior art processes is lower yield with lower purity. Moreover the process work ups make the process more tedious and uneconomical. Therefore it is required to develop an efficient, advantageous and economical process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl].

The present invention describes an advantageous process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] with higher yield with higher purity.

SUMMARY OF THE INVENTION:
The present invention discloses an economical process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] free base and 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] hydrochloride salt.

In one aspect, the present invention provides process for R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate comprising
(a) Reacting 3-(4-chlorobutyl)-5-cyano-1H-indole-5-carbonitrile with protecting group in presence of non-polar solvent and base;
(b) Precipitating with non-polar solvent and
(c) Isolating R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate.
In another aspect, the present invention discloses the process for preparing alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride which comprises,
(a) condensing alkyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate hydrochloride with R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate in presence or absence of polar aprotic solvent, base and catalyst;
(b) Treating with tartaric acid solution to remove unreacted piperazine ester;
(c) Acidifying with alcoholic hydrochloride by adjusting pH acidic and
(d) Isolating alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride.

In one embodiment, the present invention describes the process of ester aminolysis to obtain 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide which comprises
(a) Dissolving alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride in suitable solvent
(b) Adding mixture of amide and alkoxide or azane source in presence of suitable solvent
(c) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base

In another embodiment the present invention provides the process for preparing 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride salt which comprises
(a) Dissolving 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base into organic solvent
(a) Acidifying with alcoholic hydrochloride and
(b) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride salt.

In another embodiment, the present invention also discloses process for preparing alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylic acid ester intermediates from 5-(piperazin-1-yl)-benzofuran-2- carboxylic acid which comprises
(a) esterifying 5-(piperazin-1-yl)-benzofuran-2-carboxylic acid with alcoholic solvent;
(b) Adding strong acid;
(c) Basifying by adjusting pH 8-9;
(d) Isolating alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylate; and
(e) Crystallizing in non-polar solvent.

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention discloses an advantageous process for preparing 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] free base (Formula-I) and 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] hydrochloride salt (Formula-Ia)

Formula-I Formula-Ia
In one aspect, the present invention describes process for R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate which comprises;
(a) Reacting 3-(4-chlorobutyl)-5-cyano-1H-indole-5-carbonitrile with protecting group in presence of non-polar solvent and base;
(b) Precipitating with non-polar solvent and
(c) Isolating R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate.

The process for preparingR1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate depicted in the following reaction Scheme II.

Scheme-II
The protecting group is preferably tert-Butyloxycarbonyl (BOC).The non-polar solventused in above process is selected from the group consisting of Dichloromethane, Heptane, Hexane, Toluene,1,4-Dioxane,Chloroform andDiethyl ether.

The base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate& metal alkoxides such as sodium ethoxide, sodium methoxide and potation tertiary butoxideand the organic base such as trisubstituted amines selected from the group consisting of triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.

According to above process, the reaction is carried out at 40-45?C.
In another aspect, the present invention discloses the process for preparing alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl) butyl)piperazin-1-yl)benzofuran-2-carboxylate hydrochloride which comprises;
(a) condensingalkyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate hydrochloride with R1-3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate in presence or absence of polar aprotic solvent, base and catalyst;
(b) Treating the reaction mass of step (a) with tartaric acid solution to remove unreacted piperazine ester;
(c) Acidifying the reaction mass of step (b) with alcoholic hydrochloride by adjusting the pH to acidic and
(d) Isolating alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride.
The reaction scheme for preparing alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride is given in Scheme III.

Scheme-III
In the above process, the term ‘alkyl’ refers to methyl, ethyl, n-propyl, isopropyl, n-butyl while R1= protecting group. The protecting group for the said process is tert-butyloxycarbonyl (herein after referred as BOC).The polar aprotic solvent is selected from acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran, ethyl acetate. The base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine. The suitable catalyst is selected from Potassium iodide, sodium iodide, sodium bromide, potassium bromide. The reaction temperature for the aboveprocess is maintained at 70-85?C.

In another process variant, the term ‘alkyl’ refers to methyl, ethyl, n-propyl, isopropyl, n-butyl while R1= H. The polar aprotic solvent is selected from acetonitrile, dimethylformamide, dimethyl sulfoxide , acetone, tetrahydrofuran, ethyl acetate. The base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &sodium methoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine. The suitable catalyst is selected from Potassium iodide, sodium iodide, sodium bromide, potassium bromide. The reaction temperature for said process is 70-85?C.

In yet another process variant, whenR1= H, the term ‘alkyl’ refers to methyl, n-propyl, isopropyl, n-butyl and reaction is carried out without using any solvent. The base is selected from organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine and the catalyst is selected from phase transfer catalyst such as tetra-n-butyl ammonium bromide (TBAB), methyl tributyl ammonium chloride, methyl tributyl ammonium fluoride, tetrabutyl ammonium fluoride, tetrabutyl ammonium hydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide. The reaction temperature for the aboveprocess is maintained at 50-55?C.

The alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride.

In one embodiment, the present invention describes the process of ester aminolysisof alkyl-5-(4-[4-(5-cyano-R1-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride to obtain 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide which comprises;
(a) Dissolving alkyl-5-(4-[4-(5-cyano- R1-1H-indol-3-yl)butyl)piperazin-1-yl) benzofuran -2 -carboxylate hydrochloride in suitable solvent;
(b) Adding mixture of amide and alkoxide or azane source in presence of suitable solvent and
(c) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base.

The process of the present invention to obtain 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base is depicted in the reaction Scheme IV.

Scheme-IV
In the above process when R1= protecting group, the term alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl and the suitable solvent for step (a) is non-polar solvent selected from Dichloromethane, Heptane, Hexane, Toluene, 1,4-Dioxane,Chloroform, Diethyl ether. The suitable base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &sodium methoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.The term amide refers to Formamide andthe alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide. The suitable solvent for step (b) in the above process is selected from polar aprotic solvents. The polar aprotic solvents are tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide , acetone, ethyl acetate. The said reaction is carried out at 25-30?C.

In another process variant, when R1= H, the term alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl and the suitable solvent is non-polar solvent selected from Dichloromethane, Heptane, Hexane, Toluene, 1,4-Dioxane,Chloroform, Diethyl ether. The suitable base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &sodium methoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.The term acid amide refers toFormamide and the alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide. The suitable solvent for step (b) in above process is selected from polar aprotic solvents. The polar aprotic solvents are tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide , acetone, ethyl acetate. The said reaction is carried out at 25-30?C.

The main advantage involved in the of protection ofthe amine group of carbonitirle is self condensation& side reactions are avoided and hence achivesdesired product with less impurity formation as only one site is available for condensation.

Generally BOC deprotection process is carried out by hydrogenolysis, using deprotection agents such as concentrated strong acids like HCl, HBr, H2SO4, CH3COOH, CF3COOH or mixture thereof or strong acids in solution form. Specifically, the deprotecting agent for BOC deprotection is selected from the group consisting of alcoholic hydrochloric acid; hydrochloric acid in acetic acid; acetic acid in ethyl acetate; aq. Hydrochloric acid and trifluoroacetic acid. The alcohol may be selected from methanol, ethanol and isopropanol.

The another advantage of said process is eliminating deprotection step from the process. The ester is converted to amide simultaneously with deprotection. The alkoxide in said process itself acts as converting agent as well as deprotecting agent. This reduces the reaction time and avoids the cost of deprotecting agents as well.

In above said process when R1= H, the term alkyl refers to methyl, n-propyl, isopropyl, n-butyl and the suitable solvent is polar aprotic solvents. The polar aprotic solvents are tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide , acetone, ethyl acetate. Theazane source for step (b) is selected from the group consisting of ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base, hydrazine etc. The said reaction is carried out at 50-55?C.

In another embodiment the present invention provides the process for preparing 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride salt which comprises;
(a) Dissolving 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base into an organic solvent
(b) Acidifying with alcoholic hydrochloride and
(c) Isolating 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride salt.
The reaction scheme for said process is given in Scheme V.

Scheme-V

In above said process the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol. The said reaction carried out at 75-80?C.
In another embodiment, the present invention also discloses process for preparing alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylic acid ester intermediates from 5-(piperazin-1-yl)-benzofuran-2- carboxylic acid comprises
(a) esterifying5-(piperazin-1-yl)-benzofuran-2-carboxylic acid with alcohol solvent in presence of strong acid;
(b) Basifying by adjusting the pH 8-9;
(c) Isolating alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylate and
(d) Crystallizing in non-polar solvent.

The process of the present invention to get alkyl-5-(piperazin-1-yl)-benzofuran-2-carboxylate is depicted in the reaction Scheme VI.

Scheme VI
According to above process, the term alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl. The alcohol solvent is selected from group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol. The strong acid used in above process is selected from sulfuric acid,methanesulfonic acid, p-toluene sulfonic acid. In the said process ammonia is used to basify the reaction mixture by maintaining pH 8-9. The non-polar solvent for crystallization is common cycloalkane. The common cycloalkane solvent is selected from cyclohexane, cycloheptane.

Examples:
Example: 1Preparation of tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate
To the solution of 10gm 3-(4-chlorobutyl)-1H-indole-5-carbonitrile and 12cc Triethylamine in 110cc MDC added 10 gmDi-tert-butyl dicarbonate. The reaction mixture was stirred at 40-45°C for 24 Hrs. After reaction completedMDC was distilled out completely below 40°C.Added 100 cc Heptane and stirred for 30 mins at 20-30°C.The solid was filtered and washed with 25 cc Heptane and dried at room temp to yield96.50%tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate.
HPLC Purity: 98.5%

Example: 2 Preparation of ethyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm Ethyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 25 gm Potassium Carbonate,12.5 gm tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.25gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125cc& washed with 50cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125cc water), layers separatedand the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate & filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 125ccAcetone. Added 12.5cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone, and dried at 40-60°C for 6-8hrs to obtain 61.36% ethyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.
HPLC Purity: 98.5%

Example-3 Preparation of methyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm methyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 26.17 gm Potassium Carbonate, 13.0 gm tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.25gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 24-36 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125cc& washed with 50cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125cc water), layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 125ccAcetone. Added 12.5cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone anddried at 55-60°C for 4-6 hrs to obtain 65.5% methyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.
HPLC Purity: 98.5%

Example-4 Preparation of n-propyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm n-propyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 23.92 gm Potassium Carbonate,12 gm tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.15gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125cc& washed with 50cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125cc water), layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 125ccAcetone. Added 14.5IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone,dried at 55-60°C for 4-6 hrs to obtain 70% n-propyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example-5 Preparation of isopropyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm isopropyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 23.92 gm Potassium Carbonate, 12.0 gm tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.15gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 24-36 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125cc& washed with 50cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125cc water), layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 125ccAcetone. Added 14cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone,dried at 55-60°C for 6-8hrs to obtain 68% isopropyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.
Example-6 Preparation of n-butyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm n-butyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 23 gm Potassium Carbonate,11.5 gm tert-butyl 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.10gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 35-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125cc& washed with 50cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125cc water), layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate & filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 125ccAcetone. Added 10cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone and. dried at 55-60°C for 4-6 hrs to obtain 72% n-butyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example:7Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm ethyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 27gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 410cc formamideand sodiummethoxide solution. The reaction mass was stirred for 8 hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrsto get 90% yield.
HPLC Purity: 99.35%

Example:8 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm methyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 27.8gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 410cc formamide and sodium methoxide solution. The reaction mass was stirred for 10-15hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 87% yield.
HPLC Purity: 99.0%

Example:9 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm n-propyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 26.45 gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 410cc formamide and sodium methoxide solution. The reaction mass was stirred for 10-15hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 87.5% yield.

Example:10 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm isopropyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 26.45gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 410cc formamide and sodium methoxide solution. The reaction mass was stirred for 10-15hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 90% yield.
HPLC Purity: 99.3%

Example:11 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm n-butyl-5-(4-[4-(5-cyano-boc-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 25.83gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 445.13gmformamide and sodium methoxide solution. The reaction mass was stirred for 10-15hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 90% yield.
HPLC Purity: 99.3%

Example: 12 Purification of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
The isopropyl alcohol dissolved 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base and heated at 80-85°C. Charcoalized the reaction mass and filtered.Cooled to 25-30°C and filtered. Washed with isopropyl alcohol anddried to get 92.30% titled product.
.HPLC Purity: 99.67 %

Example :13Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride
To the1720cc isopropyl alcohol 40 gm 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base was added and heated at reflux temperature. Added 80 cc water. Added isopropanolic hydrochloride at 75-80°C.cooled the reaction mass, filtered and washed the product with isopropyl alcohol. Dried at 50-55°C for 8 hrs to obtain 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide hydrochloride.
HPLC Purity:99.71 %

Example: 14 Preparation of Methyl 5-(Piperazin -1-yl)-benzofuran- 2-carboxylate
To the 500ccmethanol added 100 g Piperazin-1-yl Benzofuran- 2-carboxylic acid and the reaction mixture was cooled to 0-5°C. Added 500- 600 ccSulphuric acid and maintained at 70-75°C for 1-3 hrs. Cooled to 0-5°C. Liquor Ammonia was added to adjust basic pH 8- 9. Product was isolated in Methylene Dichloride (2 x 100 cc). Distilled out MDC and degassed, stripped out with 100 cc Cyclohexane and product was crystallized in Cyclohexane. Filtered the solid & washed with 100 cc Cyclohexane. Solid dried at 50-60°C for 6-8hrs to get 90% of titled product.

Example: 15 Preparation of Isopropyl 5-(Piperazin -1-yl)-benzofuran- 2-carboxylate
To the 25 ml Isopropyl Alcohol added 5 g Piperazin -1-yl Benzofuran- 2-carboxylic acid and cooled to 0-5°C. Added 25-35 ccSulphuric acid and maintained at 70-75°C for 1-3 hrs. Cooled to 0-5°C. Liquor Ammonia was added slowly to adjust basic pH 8- 9. Product was isolated in Methylene Dichloride (2 x 25 ml). Distilled out MDC and degassed, stripped out with 15 cc Cyclohexane and product was crystallized in Cyclohexane, Filtered the solid & washed with 5 cc Cyclohexane. Solid dried at 50-60°C for 6-8hrs to obtain 85% of titled product.

Example :16 Preparation of n-Propyl 5-(Piperazin -1-yl)-benzofuran- 2-carboxylate
To the 25 ml n-Propyl Alcohol added 5 g Piperazin -1-yl Benzofuran- 2-carboxylic acid and the reaction mixture was cooled to 0-5°C. Added 25-35 ccSulphuric acid and maintained at 70-75°C for 1-3 hrs. Cooled to 0-5°C. Liquor Ammonia was added slowly to adjust basic pH 8- 9. Product was isolated in Methylene Dichloride (2 x 25 ml). Distilled out MDC and degassed, stripped out with 15 cc Cyclohexane and product was crystallized in Cyclohexane. Filtered the solid & washed with 5 cc Cyclohexane. Solid dried at 50-60°C for 6-8hrs to get 90% titled product.

Example:17 Preparation of n-butyl 5-(Piperazin -1-yl)-benzofuran- 2-carboxylate
To the 25 ml n-butyl alcohol added 5 g Piperazin -1-yl Benzofuran- 2-carboxylic acid reaction mixture was cooled to 0-5°C, 25-35 ml Sulphuric acid was added to get clear solution, maintained reaction mixture at 70-75°C for 1-3 hrs. Reaction was completed by HPLC monitoring, Cooled to 0-5°C. Liquor Ammonia was added slowly to adjust basic pH 8- 9. Product was isolated in Methylene Dichloride (2 x 25 cc). Distilled out MDC and degassed, stripped out with 15 cc Cyclohexane and product was crystallized in Cyclohexane. Filtered the solid& washed with 5 ml Cyclohexane.Solid dried in air tray dryer at 50-60°C for 6-8hrs to get 85% titled product.

Example: 18 Preparation of Ethyl 5-(Piperazin -1-yl)-benzofuran- 2-carboxylate
To the 500cc ethanol added 100 g Piperazin-1-yl Benzofuran- 2-carboxylic acid and the reaction mixture was cooled to 0-5°C. Added 500- 600 cc Sulphuric acid and maintained at 70-75°C for 1-3 hrs. Cooled to 0-5°C. Liquor Ammonia was added to adjust basic pH 8- 9. Product was isolated in Methylene Dichloride (2 x 100 cc). Distilled out MDC and degassed, stripped out with 100 cc Cyclohexane and product was crystallized in Cyclohexane. Filtered the solid & washed with 100 cc Cyclohexane. Solid dried at 50-60°C for 6-8hrs to get 88% of titled product.

Example: 19 Preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base (Insitu)
To the 90cc Acetonitrile added 10 g Methyl-5-(Piperazin -1-yl)-benzofuran- 2-carboxylate , 8.94 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile, 2.64 g Potassium Carbonate, 25.50 g Potassium Iodide and 1.2 g TBAB in catalytic amount. Heated to reflux reaction mass for 24 -30 hrs. Cooled to 25-30°C.Added 500 cc aqueous ammonia and 310 cc Acetonitrile and maintained for 72 hrs. Filtered the product at 0-5°C after 2 hrs stirring.Washed with water and dried at 60°C to obtain 65% 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base.

Example: 20 Preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base (Insitu)
To the 90cc Acetonitrile added 10 g n-propyl-5-(Piperazin -1-yl)-benzofuran- 2-carboxylate , 8.072 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile, 2.39 g Potassium Carbonate, 22.99 g Potassium Iodide and 1.12 g TBAB catalytic amount. Heated to reflux reaction mass for 24 -30 hrs. Cooled to 25-30°C. Added 500 cc aqueous ammonia and 310 cc Acetonitrile and maintained for 72 hrs. Filtered the product at 0-5°C after 2 hrs stirring.Washed with water and dried at 60°C to obtain 72% 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base.

Example: 21 Preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base (Insitu)
To the 90cc Acetonitrile added 10 g isopropyl-5-(Piperazin -1-yl)-benzofuran- 2-carboxylate , 8.072 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile, 2.39 g Potassium Carbonate, 22.99 g Potassium Iodide and 1.12 g TBAB catalytic amount. Heated to reflux reaction mass for 24 -30 hrs. Cooled to 25-30°C. Added 500 cc aqueous ammonia and 310 cc Acetonitrile and maintained for 72 hrs. Filtered the product at 0-5°C after 2 hrs stirring.Washed with water and dried at 60°C to obtain 70% 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base.

Example: 22 Preparation of 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base (Insitu)
To the 90cc Acetonitrile added 10 g n-butyl-5-(Piperazin -1-yl)-benzofuran- 2-carboxylate , 7.72 g of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile, 2.29 g Potassium Carbonate, 22.0 g Potassium Iodide and 1.07 g TBAB catalytic amount. Heated to reflux reaction mass for 24 -30 hrs. Cooled to 25-30°C. Added 500 cc aqueous ammonia and 310 cc Acetonitrile and maintained for 72 hrs. Filtered the product at 0-5°C after 2 hrs stirring.Washed with water and dried at 60°C to obtain 70% 2-benzofurancarboxamide, 5-[4-[4-(5cyano-1H-indol-3-yl)butyl]-1-piperazinyl] Base.

Example: 23 Preparation of methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm methyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 26.17gm Potassium Carbonate, 9.11 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.25gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125 cc & washed with 50 cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125 cc water). layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 200cc Acetone. Added 15cc IPA HCl at 50-55°C. Adjusted the pH to acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone. Dried at 55-60°C for 4-6 hrs to obtain 70% methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.
HPLC Purity: 92.2%

Example: 24 Preparation of ethyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm Ethyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 25gm Potassium Carbonate, 8.7 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.20gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125 cc & washed with 50 cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125 cc water), layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 200cc Acetone. Added 10cc IPA HCl at 50-55°C. Adjusted the pH to acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone. Dried at 55-60°C for 4-6 hrs to obtain 75% ethyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.
HPLC Purity: 92.2%

Example: 25 Preparation of n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm n-propyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 26.95 gm Potassium Carbonate, 9.38 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.29gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125 cc & washed with 50 cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125 cc water). layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 200cc Acetone. Added 15cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone. Dried at 55-60°C for 4-6 hrs to obtain 75% n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example: 26 Preparation of isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm isopropyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 26.95 gm Potassium Carbonate, 9.38 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.29gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125 cc & washed with 50 cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125 cc water). layers separated and the MDC layer was washed with 50 cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 200cc Acetone. Added 15cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone. Dried at 55-60°C for 4-6 hrs to obtain 75% isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example: 27 Preparation of n-butyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 125cc Acetonitrile 12.5 gm n-butyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride was suspended. Added 25.8 gm Potassium Carbonate, 8.98 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 1.25gm potassium iodide at ambient temperature. The reaction mixture was stirred at 80-85°C for 36-48 Hrs. Cooled to room temp. The reaction mass filtered and washed with Acetonitrile. The filtrate was concentrated. The residue was dissolved in MDC 125 cc & washed with 50 cc water. Added Tartaric acid solution (Tartaric acid (5 gm) dissolved in 125 cc water). layers separated and the MDC layer was washed with 50cc water. The MDC layer was dried with sodium sulphate& filtered through cotton. The MDC layer was concentrated & the residue was dissolved in 200cc Acetone. Added 15-20cc IPA HCl at 50-55°C. Adjusted the pH acidic and maintained for 45-60 mins at reflux temperature. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hrs. The solid was filtered and washed with Acetone. Dried at 55-60°C for 4-6 hrs to obtain 75% n-butyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example:28 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm ethyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 32.36gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 495cc formamide and 146.21 sodium methoxide solution. The reaction mass was stirred for 18-25hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 90% yield.
HPLC Purity: 99.38%

Example:29 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 33.28gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 507cc formamide and sodium methoxide solution. The reaction mass was stirred for 15-20hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 85% yield.
HPLC Purity: 99.0%

Example:30 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 31.49gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 480cc formamide and sodium methoxide solution. The reaction mass was stirred for 15-20hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 85% yield.

Example:31 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 31.49gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 480cc formamide and sodium methoxide solution. The reaction mass was stirred for 15-20hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 85% yield.

Example:32 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 1000cc dichloromethane 120gm n-butyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride and 30.67gm potassium carbonate solution was added. Layers separated and organic layer washed with water, dried with sodium sulphate. The organic layer was concentrated and residue was dissolved in 510cc tetrahydrofuran. Added 468cc formamide and sodium methoxide solution. The reaction mass was stirred for 15-20hrs at 20-30°C. The solid was filtered and washed with tetrahydrofuran and water solution. The obtained 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base dried at 40°C for 8 hrs to get 85% yield.

Example 33:Preparation of methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 400cc triethyl amine added 100 gm methyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride, 66.65 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 79.3 gm TBAB and heated at 85-90°C under stirring for 10 Hrs. 400cc Acetone was charged and refluxed at 55-60°C with stirring for 30-45 min. the reaction mass was cooled to 45-50°C. Added 5.0gm activated carbon and refluxed for 15-30 min. cooled to 15-20°C and filtered. Washed with acetone. Added 100 cc IPA.HCl at 50-55°C to adjust the pH 2.0 under stirring and maintained for 45-60 min at reflux. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hours and then maintained at 0-5°C for 45-60 min under stirring. The solid was filtered and washed with acetone. Dried at 55-60°C for 4-6 hrs to obtain 70% methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example 34:Preparation of n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 400cc triethyl amine added 100 gm n-propyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride, 60.88 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 72.50 gm TBAB and heated at 85-90°C under stirring for 10 Hrs. 400cc Acetone was charged and refluxed at 55-60°C with stirring for 30-45 min. the reaction mass was cooled to 45-50°C. Added 5.0gm activated carbon and refluxed for 15-30 min. cooled to 15-20°C and filtered. Washed with acetone. Added 100 cc IPA.HCl at 50-55°C to adjust the pH 2.0 under stirring and maintained for 45-60 min at reflux. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hours and then maintained at 0-5°C for 45-60 min under stirring. The solid was filtered and washed with acetone. Dried at 55-60°C for 4-6 hrs to obtain 70% n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example 35:Preparation of isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 400cc triethyl amine added 100 gm isopropyl-5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride, 60.88 gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 72.50 gm TBAB and heated at 85-90°C under stirring for 10 Hrs. 400cc Acetone was charged and refluxed at 55-60°C with stirring for 30-45 min. the reaction mass was cooled to 45-50°C. Added 5.0gm activated carbon and refluxed for 15-30 min. cooled to 15-20°C and filtered. Washed with acetone. Added 100 cc IPA.HCl at 50-55°C to adjust the pH 2.0 under stirring and maintained for 45-60 min at reflux. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hours and then maintained at 0-5°C for 45-60 min under stirring. The solid was filtered and washed with acetone. Dried at 55-60°C for 4-6 hrs to obtain 70% isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example 36:Preparation of methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride
To the 400cc triethyl amine added 100 gm n-butyl 5-(piperazin-1-yl)-1-benzofuran-2-carboxylate Hydrochloride, 58.55gm 3-(4-chlorobutyl)-5-cyano-1H-indole-1-carboxylate, 70 gm TBAB and heated at 85-90°C under stirring for 10 Hrs. 400cc Acetone was charged and refluxed at 55-60°C with stirring for 30-45 min. the reaction mass was cooled to 45-50°C. Added 5.0gm activated carbon and refluxed for 15-30 min. cooled to 15-20°C and filtered. Washed with acetone. Added 100 cc IPA.HCl at 50-55°C to adjust the pH 2.0 under stirring and maintained for 45-60 min at reflux. The reaction mixture was cooled to 20-30°C under stirring for 2-3 hours and then maintained at 0-5°C for 45-60 min under stirring. The solid was filtered and washed with acetone. Dried at 55-60°C for 4-6 hrs to obtain 85% n-butyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Example:37 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 400 cc dimethylsulfoxide added 100gm methyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride at 20-30°C. Charged ammonia gas with 5-6 kg pressure. The reaction mixture was maintained at 30-35°C for 16-18 hrs. after completion of reaction ammonia gas was released the temperature of reavtion mass was raised to 50-55°C for 15-30 min. The reaction mixture was filtered and washed with hot 75cc dimethylsulfoxide. Charged the filtrated in hot 2000ccDM water at 80-85°C. The reaction mix was maintained at 80-85°C for 30-45 min. The solid was filtered and washed with hot water and dried. The wet cake was charged with 450cc dimethylformamide and the temperature of reaction mix was raised to 50-55°C. Sodium hydroxide solution (dissolve 9.8gm in 10cc DM water) and activated carbon were added to the reaction mass at 50-55°C and maintained for 30-45 min. The reaction mixture was filtered and washed with hot DMF:DM water mix[(38.5cc+19.2cc)X 2]. The reaction mixture was cooled for 2-3 hours at 20-30°C and filtered the solid. Wet cake was dissolved in 350cc DMSO at 50-55°C and charged this clear solution in 1500cc hot water at 80-85°C within 1 hour and maintained for 30-45 min. The solid was filtered and washed with (75ccX3) DM water at 80-85°C. Dried at 55-60°Cto get 80% titled compound.

Example:38 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 400 cc dimethylsulfoxide added 100gm n-propyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride at 20-30°C. Charged ammonia gas with 5-6 kg pressure. The reaction mixture was maintained at 30-35°C for 16-18 hrs. after completion of reaction ammonia gas was released the temperature of reavtion mass was raised to 50-55°C for 15-30 min. The reaction mixture was filtered and washed with hot 75cc dimethylsulfoxide. Charged the filtrated in hot 2000ccDM water at 80-85°C. The reaction mix was maintained at 80-85°C for 30-45 min. The solid was filtered and washed with hot water and dried. The wet cake was charged with 450cc dimethylformamide and the temperature of reaction mix was raised to 50-55°C. Sodium hydroxide solution (dissolve 9.8gm in 10cc DM water) and activated carbon were added to the reaction mass at 50-55°C and maintained for 30-45 min. The reaction mixture was filtered and washed with hot DMF:DM water mix[(38.5cc+19.2cc)X 2]. The reaction mixture was cooled for 2-3 hours at 20-30°C and filtered the solid. Wet cake was dissolved in 350cc DMSO at 50-55°C and charged this clear solution in 1500cc hot water at 80-85°C within 1 hour and maintained for 30-45 min. The solid was filtered and washed with (75ccX3) DM water at 80-85°C. Dried at 55-60°C to get 80% titled compound.

Example:39 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 400 cc dimethylsulfoxide added 100gm isopropyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride at 20-30°C. Charged ammonia gas with 5-6 kg pressure. The reaction mixture was maintained at 30-35°C for 16-18 hrs. after completion of reaction ammonia gas was released the temperature of reavtion mass was raised to 50-55°C for 15-30 min. The reaction mixture was filtered and washed with hot 75cc dimethylsulfoxide. Charged the filtrated in hot 2000ccDM water at 80-85°C. The reaction mix was maintained at 80-85°C for 30-45 min. The solid was filtered and washed with hot water and dried. The wet cake was charged with 450cc dimethylformamide and the temperature of reaction mix was raised to 50-55°C. Sodium hydroxide solution (dissolve 9.8gm in 10cc DM water) and activated carbon were added to the reaction mass at 50-55°C and maintained for 30-45 min. The reaction mixture was filtered and washed with hot DMF:DM water mix[(38.5cc+19.2cc)X 2]. The reaction mixture was cooled for 2-3 hours at 20-30°C and filtered the solid. Wet cake was dissolved in 350cc DMSO at 50-55°C and charged this clear solution in 1500cc hot water at 80-85°C within 1 hour and maintained for 30-45 min. The solid was filtered and washed with (75ccX3) DM water at 80-85°C. Dried at 55-60°C to get 80% titled compound.

Example:40 Preparation of 5-[4-[4-(5-Cyanoindole-3-yl)butyl]Piperazine-1-yl]benzofuran-2-carboxamide free base
To the 400 cc dimethylsulfoxide added 100gm n-butyl-5-(4-[4-(5-cyano-1H-indol-3-yl) butyl) piperazin-1-yl)benzofuran-2-carboxylate hydrochloride at 20-30°C. Charged ammonia gas with 5-6 kg pressure. The reaction mixture was maintained at 30-35°C for 16-18 hrs. after completion of reaction ammonia gas was released the temperature of reavtion mass was raised to 50-55°C for 15-30 min. The reaction mixture was filtered and washed with hot 75cc dimethylsulfoxide. Charged the filtrated in hot 2000ccDM water at 80-85°C. The reaction mix was maintained at 80-85°C for 30-45 min. The solid was filtered and washed with hot water and dried. The wet cake was charged with 450cc dimethylformamide and the temperature of reaction mix was raised to 50-55°C. Sodium hydroxide solution (dissolve 9.8gm in 10cc DM water) and activated carbon were added to the reaction mass at 50-55°C and maintained for 30-45 min. The reaction mixture was filtered and washed with hot DMF:DM water mix[(38.5cc+19.2cc)X 2]. The reaction mixture was cooled for 2-3 hours at 20-30°C and filtered the solid. Wet cake was dissolved in 350cc DMSO at 50-55°C and charged this clear solution in 1500cc hot water at 80-85°C within 1 hour and maintained for 30-45 min. The solid was filtered and washed with (75ccX3) DM water at 80-85°C. Dried at 55-60°C to get 80% titled compound.