EP2900658A2

EP2900658A2 - Processes and polymorphs of 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-piperazinyl]-2-benzofuran carboxamide and its salts

Info

Publication number: EP2900658A2
Application number: EP13842370.2A
Authority: EP
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Sunkara VISHNUVARDHAN
Original assignee: MSN Laboratories Pvt Ltd
Current assignee: MSN Laboratories Pvt Ltd
Priority date: 2012-09-27
Filing date: 2013-09-26
Publication date: 2015-08-05
Also published as: EP2900658A4; WO2014049612A3; WO2014049612A2

Abstract

The present invention relates to an improved process for the preparation of antidepressant drug i.e., 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la represented by the following structural formula: (1a)

Description

Process for the preparation of 5-[4-[4-(5-cvano-lH-indol-3-yi) butyll-l-piperazinyll-2-benzofuran carboxamide and its salts and polymorphs thereof

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 4014/CHE/2012 filed on 27^th Sept. 2012, 4629/CHE/2012 filed on 6^th Nov. 2012 and 5296/CHE/2012 filed on 18^th Dec. 2012 which are incorporated herein by reference.

Field of the invention:

The present invention provides an improved process for the preparation of antidepressant drug i.e., 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la represented by the following structural formula:

Formula- la

Further the present invention relates to novel crystalline forms of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1 and its pharmaceutically acceptable salts.

Further the present invention also relates to novel acid addition salts of 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and process for the preparation thereof.

Back ground of invention:

US 5,532,241 (hereafter referred to as "241") first disclosed 5-[4-[4-(5-cyano-lH-indol- 3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and its hydrochloride salt compound of formula- la which is commonly known as Vilazodone hydrochloride, an antidepressant agent, which acts as a serotonin reuptake inhibitor. "241" first disclosed the process for the preparation of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and its hydrochloride salt compound of formula-la by reacting 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2- carboxylic acid with 2-chloro-l-methylpyridinium methanesulfonate in the presence of N-methyl ' pyrrolidine and ammonia gas to provide compound of formula- 1 as free base. Further, free base of compound of formula- 1 is dissolved in propanolic hydrochloric acid solution to precipitate hydrochloride salt of compound of formula- la.

The major drawback of the "241" process is that, it involves reaction of 5-(4-(4-(5-cyano- lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid in the presence of 2-chloro-l- methylpyridinium methanesulfonate to provide compound of formula- 1 with low yield and purity. Whereas, the said 2-chloro-l -methylpyridinium methanesulfonate is an expensive reagent, not suitable for commercial scale-up process. Moreover, the said process requires tedious work-ups to provide compound of formula- 1.

The 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide compound of formula-1 is reported as a crystalline solid in example-2 of US 7799916B2. Further, the said patent does not provided any physical characteristic data. The crystalline 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained by the process of prior art is hereinafter designated as crystalline form-S. The PXRD of said crystalline form-S is characterized by its X-ray diffractogram having peaks at 5.2, 7.6, 10.5, 14.3, 14.9, 15.3, 16.0, 17.7, 18.5, 19.7, 20.5, 21.0, 22.0, 22.9, 24.2, 24.8, 26.1, 28.8, 29.6, 30.9, 33.0, 33.3 and 34.5 ± 0.2 degrees of two-theta having PXRD pattern as illustrated in figure- 1.

In view of the foregoing, there are still remains an unmet need for a process for preparation of vilazodone hydrochloride with high yield and also applicable for multi-kilogram production. The process of the present invention is inexpensive, environmental-friendly having straight forward workups, rendering it amenable to the large-scale production of vilazodone hydrochloride with high yield and purity.

US7834020 describes several crystalline forms of vilazodone hydrochloride, such as Form-I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI and process for their preparation.

C 102219783 A discloses crystalline form of vilazodone dihydrochloride and process for its preparation. Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile or improved shelf-life.

The present invention involves the novel crystalline forms of vilazodone free base as well as novel acid addition salts of vilazodone.

The present invention also provides novel acid addition salts of vilazodone in solid state form. The novel salts of vilazodone of the present invention can be used to prepare vilazodone free base in pure form, which in turn useful in the preparation of highly pure vilazodone hydrochloride.

Brief description of the invention:

The first aspect of the present invention is to provide a process for the preparation of 5- [4-[4-(5-cyano- 1 H-indol-3 -yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

The second aspect of the present invention is to provide crystalline form-S of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1. The third aspect of the present invention is to provide a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1, comprising of, amidating the ethyl 5-(4-(4-(5-cyano-lH- indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate compound of formula- 11 with a suitable amidation agent in the presence of a suitable base in a suitable solvent to provide crystalline from-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1.

The fourth aspect of the present invention is to provide crystalline 1,4-dioxane solvate form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride hereinafter designated as form-M.

The fifth aspect of the present invention is to provide process for the preparation of crystalline 1,4-dioxane solvate form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]- 2-benzofuran carboxamide hydrochloride.

The sixth aspect of the present invention is to provide a process for the preparation of 3- (4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of reacting 3-(4- chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6 with a suitable base in a suitable solvent to provide compound of formula-7.

The seventh aspect of the present invention is to provide novel crystalline form of 5-[4- [4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- 1 b hereinafter designated as form-N.

The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb.

The ninth aspect of the present invention is to provide crystalline form-M of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1.

The tenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.

The eleventh aspect of the present invention is to provide a novel crystalline form of 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1 hereinafter designated as form-N.

The twelfth aspect of the present invention is to provide a novel crystalline form of 5-[4- [4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la hereinafter designated as form-S. The thirteenth aspect of the present invention is to provide a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

The fourteenth aspect of the present invention is to provide a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.

The fifteenth aspect of the present invention is to provide acid addition salt of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12.

The sixteenth aspect of the present invention is to provide a process for the preparation of acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12.

The seventeenth aspect of the present invention is to provide novel crystalline form of 5- [4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate hereinafter designated as form-R.

The eighteenth aspect of the present invention is to provide a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

Brief description of figures:

Figure 1: Illustrates the PXRD pattern of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1. Figure 2: Illustrates the DSC thermogram of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1. Figure 3: Illustrates the PXRD pattern of crystalline 1,4-dioxane solvate form of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride. Figure 4: Illustrates the PXRD pattern of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methane sulfonate compound of formula- lb. Figure 5: Illustrates the PXRD pattern of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.

Figure 6: Illustrates the PXRD pattern of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1.

Figure 7: Illustrates the PXRD pattern of crystalline form-S of 5-[4-[4-(5-cyano- lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

Figure 8: Illustrates the PXRD pattern of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

Figure 9: Illustrates the DSC thermogram of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl) butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

Figure 10: Illustrates the IR spectrum of form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl) butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

Detailed description of invention:

As used herein the "suitable solvent" is selected from "alcoholic solvent" such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, "ether solvents" such as tetrahydrofuran, diethylether, methyl tert-butylether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl-2- pyrrolidone (NMP) and the like; "nitrile solvents" such as acetonitrile, isobutyronitrile and the like; "ketone solvents" such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and mixtures thereof.

As used herein the "base" is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert- butoxide, potassium ethoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tribiityl amine, 4-dimethylaminopyridine, N-methyl morpholine, imidazole and the like.

As used herein the "reducing agent" is selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH₃CN, triethylsilane, sodium borohydride/BF₃-etherate, vitride, sodiumborohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN and trifluoroacetic acid/sodiumborohydride.

As used herein the "amidation agent" is selected from ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines.

As used herein the "phase transfer catalyst" is selected from tetra alkyl/aryl ammonium halides such as tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenyl phosphonium bromide.

As used herein, the suitable "acid" is selected from "organic acids" such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfoic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid and the like. The suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.

The first aspect of the present invention provides a process for the preparation of 5-[4-[4- (5-cyano- 1 H-indol-3-yl) butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, comprising of the following steps:

a) Reacting lH-indole-5-carbonitrile compound of formula-2 with para toluene sulfonyl chloride in the presence of dimethylamino pyridine in methylene chloride provides 1 - tosyl-lH-indole-5-carbonitrile compound of formula-3,

b) reacting the compound of formula-3 with 4-chlorobutanoyl chloride compound of formula-4 in the presence of aluminium chloride in methylene chloride provides 3-(4- chlorobutanoyl)- 1 -tosyl- 1 H-indole-5-carbonitrile compound of formula-5,

c) reducing the compound of formula-5 with sodium borohydride in the presence of trifluoroacetic acid in methylene chloride provides 3-(4-chlorobutyl)-l-tosyl-lH-indole- 5-carbonitrile compound of formula-6,

d) treating the compound of formula-6 with potassium carbonate in a mixture of methanol and tetrahydrofuran provides 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7,

e) treating the ethyl 5-(piperazin-l-yl)benzofuran-2-carboxylate hydrochloride compound of formula- 10a with potassium carbonate in acetonitrile to provide free base of formula- 10, which on in-situ condensation with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7 in the presence of triethylamine and potassium iodide in the presence or absence of tetrabutylammonium bromide provides ethyl 5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin- 1 -yl)benzofuran-2-carboxylate compound of formula- 11,

f) treating the compound of formula- 11 with aqueous hydrochloric acid in acetone provides ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate hydrochloride compound formula-l la,

g) amidating the compound of formula-l la with formamide in the presence of sodium methoxide in a mixture of dimethylformamide and methanol provides 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1, h) optionally isolating the compound of formula-1 as a solid, i) treating the compound of formula- 1 with hydrochloric acid in a suitable solvent or mixture of solvents provides 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- la.

The crystalline solid compound of formula- 1, on treatment with aqueous hydrochloric acid provides crystalline form- VIII of compound of formula- 1 a.

The prior reported processes including the present invention disclosed the usage of tnfluoroacetic acid and NaBH₄ for the reduction of keto group of 3-(4-chlorobutanoyl)-l-tosyl- lH-indole-5-carbonitrile compound of formula-5, that requires high amounts of tnfluoroacetic acid which is not advisable to conduct the experiments in laboratory and also not recommended for the commercial level process. Whereas, the process of the present invention involves the usage of T1CI4 and triethyl silane in lower amounts for the above said reduction step. Moreover, T1CI4 is cheaper & safe when compare to tnfluoroacetic acid, hence it is more advantageous and recommended for the commercial level process.

The preferred embodiment of the present invention is to provide an improved process for the preparation of 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6, comprising of reducing the compound of formula-5 with triethylsilane in presence of titanium tetrachloride in methylene chloride provides 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6.

The second aspect of the present invention provides crystalline form-S of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, characterized by:

a) its X-ray diffractogram having peaks at 5.2, 7.6, 10.5, 14.3, 14.9, 15.3, 16.0, 17.7, 18.5,

19.7, 20.5, 21.0, 22.0, 22.9, 24.2, 24.8, 26.1, 28.8, 29.6, 30.9, 33.0, 33.3 and 34.5 ± 0.2 degrees of two-theta; its PXRD pattern as illustrated in figure- 1.

b) its DSC thermogram showing an endotherm at 207.77°C as illustrated in figure-2. The third aspect of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, comprising of: a) adding a suitable solvent to ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride compound of formula- 1 la,

b) cooling the reaction mixture,

c) adding an amidating agent to the reaction mixture,

d) adding a suitable base and a suitable solvent to the reaction mixture,

e) stirring the reaction mixture,

f) adding water to the reaction mixture and stirring the reaction at a suitable temperature, g) filtering the precipitated solid and drying to get crystalline form-S of 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1. Wherein, the suitable base is selected from inorganic base or organic base and suitable solvent is selected from polar aprotic solvents, alcoholic solvents, ester solvents, ether solvents, keto solvents, chloro solvents and hydrocarbon solvents or mixture thereof; The step-(b), (c), (d) and (e) are carried out at a temperature ranges from -10 to 20°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 , comprising of:

a) adding dimethylformamide to ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride compound of formula-1 la,

b) cooling the reaction mixture to 0-10°C,

c) adding formamide to the reaction mixture at 0-10°C,

d) adding sodium methoxide and methanol to the reaction mixture at 0-10°C,

e) stirring the reaction mixture at 0-10°C,

f) adding water to the reaction mixture and stirring the reaction mixture at 25-30°C, g) filtering the precipitated solid and drying to get crystalline form-S of 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1.

US 5,532,241 discloses a process for the preparation of compound of formula-1 by the reaction of 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l-methylpyridinium methane sulfonate and N-methyl pyrrolidine in the presence of ammonia gas. However the said process involves the usage of expensive and complex reagent which leads to^* tedious and complicated workup process to provide compound of formula-1 with low yield. Further, the obtained free base of compound of formula- 1 is dissolved in isopropyl alcohol hydrochloride to precipitate hydrochloride salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-

1- piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la with melting point of 269-272°C.

Journal of medicinal chemistry-2004, 47, 4684-4692 discloses the reaction of 5-(4-(4-(5- cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l- methylpyridinium iodide in the presence of ethyl diisopropyl amine to provide compound of formula- 1. The said process involves the usage of fairly expensive or unfriendly reagent like 2- chloro-l-methylpyridinium iodide, which leads to low yield of compound of formula- 1 with complicated purification process.

Whereas, the present invention is carried out in the presence of formamide and sodium methoxide, which are cheaper reagents and are environmental user friendly reagents when compared to the prior art. Moreover the present invention also reduces the cycle time of the reaction and avoids tedious work up process to provide compound of formula- 1 as crystalline solid with high yield and purity.

The compound of formula- 1 obtained according to the present invention having HPLC purity of greater than 99.5%, which is further useful in the preparation of highly pure compound of formula- la.

The fourth aspect of the present invention provides crystalline 1,4-dioxane solvate form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride hereinafter designated as form-M characterized by its powder X-ray diffractogram having peaks at 2.7, 10.6, 13.5, 13.8, 14.6, 16.2, 17.2, 18.0, 19.1, 19.7, 20.3, 21.1, 21.8, 22.2, 22.8, 26.5, 27.3, 28.0 and 31.3 ± 0.2 degrees of two-theta as illustrated in figure-3.

The fifth aspect of the present invention provides a process for the preparation of crystalline 1,4-dioxane solvate form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-

2- benzofuran carboxamide hydrochloride, comprising of;

a) Dissolving the compound of formula- 1 in 1 ,4-dioxane by heating to reflux temperature, b) adding aqueous hydrochloric acid to the above reaction mixture, c) filtering the precipitated solid and drying to get the crystalline form-M of 1,4-dioxane solvate compound of formula- 1 a.

In another aspect of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride, comprising of;

a) Dissolving the compound of formula- 1 in a mixture of 1,4-dioxane and ethanol by heating,

b) adding aqueous hydrochloric acid to the above reaction mixture,

c) filtering the precipitated solid and drying to get the crystalline form-M of 1,4-dioxane solvate compound of formula- 1 a.

The 1,4-dioxane solvate crystalline form-M is useful for the preparation of pure 5-[4-[4- (5-cyano- 1 H-indol-3-yl) butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

The sixth aspect of the present invention provides a process for the preparation of 3-(4- chlorobutyl)- 1 H-indole-5-carbonitrile compound of formula-7, comprising of:

a) Adding a suitable solvent to 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6,

b) adding a suitable base and a suitable solvent to the reaction mixture,

c) stirring the reaction mixture,

d) distilling off the solvent from the reaction mixture and cooling,

e) adding water to the reaction mixture and stirring,

f) filtering the precipitated solid and adding a suitable solvent,

g) heating the reaction mixture to reflux temperature and stirring,

h) cooling the reaction mixture,

i) filtering the precipitated solid to provide 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7.

Wherein, the suitable base is selected from inorganic bases and organic bases as defined above and the suitable solvent is selected from ether solvents, alcoholic solvents, chloro solvents and mixture thereof and the suitable temperature is 25°C - 40°C. The preferred embodiment of the present invention provides a process for the preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of,

a) adding tetrahydrofuran to the 3-(4-chlorobutyl)- i-tosyI- lH-indole-5-carbonitrile compound of formula-6,

b) adding sodium methoxide and methanol to the reaction mixture,

c) stirring the reaction mixture at 30-35°C,

d) distilling off the solvent from the reaction mixture and cooling to 30-35°C,

e) adding water to the reaction mixture and stirring,

f) filtering the precipitated solid and adding cyclohexane to the obtained solid,

g) heating the reaction mixture to reflux temperature and stirring,

h) cooling the reaction mixture to 30-35°C,

The seventh aspect of the present invention provides novel crystalline form of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb hereinafter designated as form-N, characterized by its powder X-ray diffractogram having peaks at 5.6, 6.3, 7.0, 7.4, 9.5, 10.3, 1 1.7, 12.6, 13.7, 14.2, 14.7, 15.0, 15.2, 16.3, 16.7, 17.1, 17.9, 18.4, 18.7, 19.1, 19.5, 19.8, 20.4, 20.8, 21.8, 22.4, 22.8, 23.7, 24.3, 24.6, 25.0, 25.8, 26.2, 26.5, 27.7, 28.5, 29.0, 30.9, 31.5, 32.3, 34.3, 35.3 and 42.5 ± 0.2 degrees of two- theta as illustrated in figure-4.

The eighth aspect of the present invention provides a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb, comprising of:

a) Dissolving the compound of formula- 1 in a suitable solvent by heating to reflux temperature,

b) adding methane sulfonic acid to the above reaction mixture,

c) cooling the reaction mixture,

d) filtering the precipitated solid and drying to get the crystalline form-N of compound of formula- lb. P

WO 2014/049612

Wherein, the suitable solvent used is selected from ether solvents, polar aprotic solvents, hydrocarbon solvents, ester solvents, chloro solvents or mixtures thereof.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methane sulfonate compound of formula- lb, comprising of:

a) Dissolving the compound of formula- 1 in tetrahydrofuran by heating to reflux temperature,

b) adding methane sulfonic acid to the above reaction mixture,

c) cooling the reaction mixture,

d) filtering the precipitated solid and drying to get the crystalline form-N compound of formula- lb.

The crystalline form-S of compound of formula- 1 of the present invention can be useful in the preparation of salts of compound of formula- 1 i.e., crystalline form-M and crystalline form-N. The crystalline form-M of 1,4-dioxane solvate compound of formula- la is also useful in the preparation of highly pure compound of formula- la. Further, the crystalline form-N of compound of formula- lb is useful in the preparation of highly pure compound of formula- la. The ninth aspect of the present invention provides novel crystalline form-M of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 characterized by its X-ray powder diffraction pattern having peaks at 5.8, 7.4, 1 1.0, 13.4, 13.8, 16.1, 17.2, 18.5, 19.1, 20.0, 20.8, 21.4, 21.9, 24.3, 25.3, 26.8, 27.2, 28.0 and 27.5 ± 0.2 degrees of two-theta as illustrated in figure-5.

The tenth aspect of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, which comprises of;

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 in a suitable solvent,

b) heating the reaction mixture,

c) filtering the reaction mixture,

d) distilling off the solvent from filtrate, e) slurrying the compound obtained in step d) in a suitable solvent,

f) optionally heating the reaction mixture,

g) filtering the precipitated solid and drying the compound to provide crystalline form-M of compound of formula-I.

Wherein in step-a) & e) the suitable solvent is . selected from nitrile solvents, ketone solvents, alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 , which comprises of;

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 in acetonitrile,

b) heating the reaction mixture to 80-85°C and stirring,

c) filtering the reaction mixture,

d) distilling off the solvent from filtrate,

e) slurrying the compound obtained in step d) in acetonitrile,

f) filtering the solid and drying the compound to provide crystalline form-M of compound of formula-I. The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, which comprises of;

b) heating the reaction mixture to 80-85°C and stirring,

c) filtering the reaction mixture,

d) distilling off the solvent from filtrate,

e) slurrying the compound obtained in step d) in water,

f) heating the reaction mixture to 90-95 °C and stirring,

g) cooling the reaction mixture to 25-30°C, h) filtering the solid and drying the compound to provide crystalline form-M of compound of formula-I.

- ' The eleventh aspect of the present invention provides a novel crystalline form-N of 5-[4-

5 [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 characterized by its X-ray powder diffraction pattern having peaks at 6.0, 7.6, 1 1.3, 14.0, 16.3, 17.5, 18.8, 20.3, 21.1, 21.8, 22.2, 24.6, 25.6, 28.2, 29.9 and 36.2 ± 0.2 degrees of two- theta as illustrated in figure-6. 0 The twelfth aspect of the present invention provides a novel crystalline form-S of 5-[4-[4-

(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la characterized by its X-ray powder diffraction pattern having peaks at 4.9, 9.0, 10.6, 12.6, 12.8, 13.8, 14.4, 15.2, 16.2, 17.7, 18.8, 19.9, 20.7, 21.4, 22.3, 22.6, 23.9, 24.5, 25.8, 27.0, 27.4, 28.1, 28.6 and 30.0 ± 0.2 degrees of two-theta as illustrated in figure-7. 5

The thirteenth aspect of the present invention provides a process for the preparation of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, which comprises of;

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran0 carboxamide hydrochloride compound of formula- la in formic acid,

b) slowly adding a suitable solvent to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the precipitated solid and drying to get crystalline form-S of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of5 formula- la.

Wherein, in step-b) the suitable solvent is selected from chloro solvents, ketone solvents, ester solvents, alcohol solvents, hydrocarbon solvents, ether solvents, polar aprotic and polar solvents like water and/or their mixtures thereof.

The preferred embodiment of the present invention provides a process for the preparation0 of crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butylJ-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, which comprises of; a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la in formic acid,

b) adding ethyl acetate to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the precipitated solid and drying to get crystalline form-S of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

The fourteenth aspect of the present invention provides a process for the preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1, comprises of,

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran

carboxamide compound of formula- 1 in a suitable solvent,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the precipitated solid and drying to provide crystalline form-M of compound of formula- 1.

Wherein, in step-a) the suitable solvent is selected from ketone solvents, hydrocarbon solvents, ester solvents, ether solvents and chloro solvents, alcohol solvents, polar aprotic solvents, polar solvents and/or their mixture thereof.

The fifteenth aspect of the present invention provides acid addition salts of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12 with a proviso that, the acid is other than hydrochloride acid or methane sulfonic acid.

Formula- 12 Wherein, the term "Acid" represents inorganic acids such as hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, pyruvic acid, hexanoic acid, ethane sulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzene sulfonic acid, para toluene sulfonic acid, 4-methylbenzene sulfonic acid, naphthalene- 1,5-disulfonic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 4-amino benzoic acid, 4- hydroxybenzoic acid, 2-acetoxybenzoic acid, 2,4,6-trimethyl benzoic acid, succinic acid, mandelic acid, acetyl mandelic acid, lactic acid, stearic acid, carbonic acid, glutamic acid, gluconic acid, glycolic acid, malonic acid, aspartic acid, phthalic acid, cinnamic acid, 4-hydroxy cinnamic acid, salicylic acid, acetyl salicylic acid, orotic acid, oleic acid, nicotinic acid and their hydrates or solvates thereof.

The preferred embodiment of the present invention provides acid addition salts of 5- [4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12 in crystalline solid form, wherein the suitable acid is preferably selected from hydrobromic acid, phosphoric acid, nitric acid, benzene sulfonic acid and para toluene sulfonic acid.

Further the acid-addition salt compounds of general formula- 12 can be converted into pure 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 by treating the compound of formula- 12 with a suitable base in a suitable solvent.

Wherein the suitable base is selected form alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof. The sixteenth aspect of the present invention provides a process for the preparation of acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12, comprises of reacting the compound of formula- 1 with a suitable acid in a suitable solvent provides corresponding acid addition salt compound of general formula- 12.

Wherein, the suitable acid is same as defined in fifteenth aspect of the present invention; and the suitable solvent is selected from ketone solvents, hydrocarbon solvents, ester solvents, ether solvents and chloro solvents, alcohol solvents, polar solvents, polar aprotic solvents, nitrile solvents or mixtures thereof.

The seventeenth aspect of the present invention provides novel crystalline form of 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate hereinafter designated as form-R, characterized by:

a) Its powder X-ray diffractogram having peaks at 5.6, 7.6, 8.3, 9.7, 10.8, 1 1.2, 13.1, 14.0, 14.6, 15.0, 15.3, 15.6, 16.0, 16.6, 17.3, 18.0, 19.6, 20.5, 21.3, 21.5, 22.3, 22.6, 23.2, 24.7, 25.1, 25.8, 26.2, 26.8, 27.2, 28.5, 29.2, 29.5, 29.9, 30.6, 31.0, 32.6, 33.3, 34.0, 35.5, 43.4 and 45.5 ± 0.2 degrees of two-theta having PXRD pattern as illustrated in figure-8;

b) its DSC thermogram showing endotherms at 131.7, 172.2, 190.8 and a sharp peak at 287.3°C as illustrated in figure-9;

c) its IR spectrum having absorption bands at 1672, 1385, 1196, 1022, 934, 886, 873, 807 and 770 ± 2 cm^"1 as illustrated in figure- 10.

The eighteenth aspect of the present invention provides a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of;

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide in formic acid,

b) adding water to the reaction mixture,

c) filtering the reaction mixture,

d) adding a suitable hydrochloric acid source to the reaction mixture,

e) stirring the reaction mixture at a suitable temperature,

f) filtering the precipitated solid and drying the compound to provide crystalline form-R of

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

Wherein, in step-d) the suitable hydrochloride source is selected from HC1 gas, aqueous HC1, dry HCl, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.

in step-e) the suitable temperature is ranging from 0°C to 100°C, preferably 25°C to

40°C. The preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of;

b) adding water to the reaction mixture,

c) filtering the reaction mixture,

d) adding isopropyl alcohol hydrochloride to the reaction mixture,

e) stirring the reaction mixture at 25°C-30°C,

f) filtering the precipitated solid and drying the compound to provide crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

US7834020 discloses crystalline vilazodone dihydrochloride form-XIII characterized by its powder X-ray diffractogram having peaks at about 13.4, 14.4, 16.3, 17.5, 18.1, 20.4, 20.63, 21.2, 26,0, and 28.3± 0.2 degrees of two theta.

Whereas, the present invention provides crystalline form-R of vilazodone dihydrochloride monohydrate characterized by its powder X-ray diffractogram having peaks at about 5.6, 7.6, 10.8, 11.2 15.0, 15.3, 15.6, 16.0, 21.5, 22.3, 22.6, 23.2, 24.7, 25.1, 25.8, 26.8, 27.2, 29.2, 29.9, 30.6 and 34.0 ± 0.2 degrees of two theta.

The data provided in the following tables illustrates the stability of Vilazodone dihydrochloride monohydrate obtained by the process of the present invention.

Accelerated Stability data of Vilazodone dihydrochloride monohydrate

Long Term Stability data of Vilazodone dihvdrochloride monohvdrate

The compound of formula- la produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

PXRD analysis of compound of formula- 1 and its salts were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

HPLC Method of Analysis:

5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-1 and its hydrochloride salt:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry CI 8, 150 x 4.6mm, 3.5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Column Temperature: 40°C; Injection volume: 5 μί; Run time: 35 min; Diluent: Water : Isopropyl alcohol (1 : 1) v/v; Needle wash: Water : Isopropyl alcohol (1 : 1) v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30) v/v; Buffer: 2.72 grams of potassium dihydrogen phosphate and 3.0 grams of 1 -Octane sulphonic acid in 1000 ml of water. Adjust pH to 2.0 with diluted orthophosphoric acid and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it.

The process of the present invention is schematically represented as below:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples: Example-1: Preparation of l-Tosyl-lH-indoIe-5-carbonitrile (Formula-3)

To a mixture of 5-cyanoindole (10 g) and dichloromethane (80 ml) added dimethylamino pyridine (25.8 g) at 25-30°C. Cooled the reaction mixture to 10 -15°C. Para toluene sulfonyl chloride (33.58 g) was added to the reaction mixture at 10 -15°C and the reaction mixture was stirred for 2 hours at 10-15°C. After completion of the reaction, quenched the reaction mixture with water. Separated the both aqueous layer and organic layer. Aqueous layer was extracted with dichloromethane. Both the organic layers were combined and washed with 2% hydrochloric acid solution and followed by water. Distilled off the solvent completely from organic layer. Co- distilled the crude with methanol. Methanol (40 ml) was added to the obtained compound at 25- 30°C and stirred for 2 hour at 25-30°C. Filtered the solid and washed with methanol and dried to get the title compound. Yield: 16.6 gm; Melting point: 122- 12_.7°C.

ExampIe-2: Preparation of 3-(4-chIorobutanoyl)-l-tosyl-lH-indole-5-carbonitrile (FormuIa-5)

4-chloro butyryl chloride compound of formula-4 (28.6 g) was added to a mixture of dichloromethane (100 ml) and aluminium chloride (54.1 g) at 25-30°C and stirred the reaction mixture for 30 minutes at same temperature. Solution of l-tosyl-lH-indole-5-carbonitrile (10 g) in dichloromethane (100 ml) was added to the above reaction mixture at 25-30°C. Stirred the reaction mixture for 3 hours at 25-30°C. After completion of the reaction, the reaction mixture was slowly added to chilled water and stirred for 15 minutes. Separated both the organic and aqueous layers. Organic layer was washed with 5% sodium bicarbonate solution and followed by water. Distilled off the solvent completely from organic layer and distilled with methanol. Methanol (50 ml) was added to the obtained compound at 25-30°C and stirred for 2 hour at 25- 30°C. Filtered the solid and washed with methanol and dried to get the title compound. Yield: 9.3 gm. Melting point: 152-155°C.

Example-3: 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile (Formula-6) Trifluoroacetic acid (100 ml) was added to a mixture of dichloromethane (50 ml) and 3- (4-chlorobutanoyl)-l-tosyl-lH-indole-5-carbonitrile (10 g) at 25-30°C. The reaction mixture was cooled to 0 - 10°C and sodium borohydride (5.54 g) was added to the reaction mixture at 0-5°C. Stirred the reaction mixture at 10 - 15°C for 5 hours. After completion of the reaction, quenched the reaction mixture with hydrochloric acid solution. Stirred the reaction mixture for 1 hour at 30-35°C. Filtered the precipitated solid and washed with water and dried to get the title compound. Yield: 9.1 gm; Melting point: 96-100°C.

Example-4: Preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (Formula-7)

3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile (10 g) was dissolved in tetrahydrofuran (100 ml) at 25-30°C. Cesium carbonate (16.9 g) and methanol (50 ml) were added to the reaction mixture at 25-30°C. Stirred the reaction mixture for 3 hours at 25-30°C. After completion of the reaction, distilled off the solvent completely. Added water (70 ml) to the crude compound and stirred for 1 hour at 25-30°C. Filtered the precipitated solid and washed with water. Cyclohexane (70 ml) was added to the wet compound and heated to reflux temperature and stirred for 1 hour. Cooled the reaction mixture to 30-35°C and stirred for 1 hour. Filtered the precipitated solid and washed with cyclohexane and dried to get the title compound. Yield: 4.5 gm; Melting point: 78-84°C.

Example-5: Preparation of 3-(4-chIorobutyl)-lH-indole-5-carbonitrile (Formula-7)

A mixture of methanol (82.5 ml) and sodium methoxide (21.8 ml) were added to 3-(4- chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile (32.0 g) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and added water (82.5 ml) to the reaction mixture. Stirred the reaction mixture for 30 minutes at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 17.0 gms; Melting point: 78-84°C. Purity by HPLC: 95%.

ExampIe-6: Preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (Formula-7)

Potassium carbonate (0.36 g) was added to a mixture of 3-(4-chlorobutyl)-l-tosyl-lH- indole-5-carbonitrile (1 g), methanol (5 ml) and tetrahydrofuran (10 ml) and heated to 50-55°C. The reaction mixture was stirred for 3 hours at 50-55°C. The reaction mixture was cooled to 25- 35°C and water was added to it. The reaction mixture was stirred further about 45 minutes at 25- 35°C. Filtered the precipitated solid and then dried to get title compound. Yield: 0.5 g

Example-7: Preparation of ethyl 5-(piperazin-l-yI)benzofuran-2-carboxylate hydrochloride (Formula-10)

To a mixture of n-butanol (400 ml) and ethyl 5-aminobenzofuran-2-carboxylate (50 g) was added potassium carbonate (33.7 g) at 25-30°C. Bis(2-chloroethyl)amine hydrochloride (43 g) was added to the reaction mixture. The reaction mixture was heated to 110-120°C and stirred for 48 hours. The reaction mixture was cooled to 25-30°C and stirred for 1 hour. Filtered the reaction mixture and washed with methanol. The obtained wet compound was dissolved in methanol (500 ml) at 25-30°C and heated to reflux temperature and then stirred for 45 minutes. Filtered the reaction mixture and washed with methanol. Dissolved the wet compound in methanol at 25-30°C and heated to reflux temperature and then stirred for 45 minutes. Filtered the reaction mixture and then combined both n-butanol filtrate and methanol filtrates. Distilled ^; off the solvent completely under reduced pressure. The obtained compound was dissolved in methanol (100 ml), cooled the reaction mixture to 0 - 10°C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled methanol and dried to get the title compound. Yield: 37.5 gm; Melting point: 236-240°C.

Example-8: Preparation of ethyl 5-(4-(4-(5-cyano-lH-indoI-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride (Formula-lla)

Potassium carbonate (22.2 g) was added to a mixture of acetonitrile (600 ml) and ethyl 5-

(piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (50 g) at 30-35°C and stirred for 15 minutes. Potassium iodide (5.3 g), tetrabutyl ammonium bromide (5.2 g) and triethyl amine (16.3 g) were added to the reaction mixture at 25-30°C. 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7 (34 g) was added to the reaction mixture and the reaction mixture was heated to reflux temperature. Stirred the reaction mixture for 48 hours. Distilled off the solvent and water was added to the obtained residue. Extracted the product with ethyl acetate and washed the ethyl acetate layer with 10% sodium bicarbonate solution. Further washed the organic layer with 0.5% aqueous hydrochloric acid solution and distilled off the solvent completely from organic layer. The obtained compound was dissolved in acetone (250 ml). pH of the reaction mixture was adjusted to 2 by using 2N aqueous hydrochloric acid solution and water was added to the reaction mixture. Stirred the reaction mixture for 1 hour and then filtered the precipitated solid and washed with water. The obtained compound was dissolved in dimethylformamide (125 ml) by heating and then cooled to 25-30°C. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with dimethylformamide and dried to get the title compound. Yield: 35 gm. Example-9: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l-piperazinyl]-2- benzofuran carboxamide (Formula-1)

Mixture of dimethylformamide (450 ml) and ethyl 5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (30.0 g) was cooled to 0-5°C and stirred for 20 minutes. Formamide (48.7 g) and followed by sodium methoxide in methanol (51.6 g) was added to reaction mixture at 0-5 °C and stirred the reaction mixture for 1 hour at same temperature. After completion of the reaction, water (900 ml) was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound as crystalline solid. Yield: 25.7 gm; Melting point: 203- 209°C. Purity by HPLC: 99.5%.

The PXRD of the obtained compound is shown in figure- 1.

Example-10: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l-piperazinyI]-2- benzofuran carboxamide hydrochloride (Formula-la)

Mixture of dioxane (50 ml) and 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (2.0 g) was heated to 80-90°C and stirred for 30 minutes. 20% aqueous hydrochloric acid solution (4 ml) was added to the reaction mixture at 80-90°C and stirred for 30 minutes at the same temperature, Reaction mixture was cooled to 50-55 °C, filtered the precipitated solid, washed with 1,4-dioxane and dried to get the title compound. Yield: 1.8 gm; Melting point: 280-284°C. Purity by HPLC: 99.95%.

The PXRD of the obtained compound is shown in figure-3.

Example-11: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butylJ-l-piperazinyI]-2- benzofuran carboxamide hydrochloride (Formula-la)

20% hydrochloric acid (5 ml) was added to a mixture of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (1 gm) and water (20 ml) at 25-30°C. The reaction mixture was heated to 80-90°C and stirred for 20 minutes. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes. Filtered the solid and washed with water and then dried to get the title compound. Purity by HPLC: 99.0%.

Yield: 1 g; Melting point: 272-275°C.

Particle size distribution before micronization: D(0.1): 8.406 μπι; D(0.5): 19.775 μηι; D(0.9): 41.199 μηι; ϋ[4,3]: 22.533 μιη.

Particle size distribution after micronization: D(0.1): 1.206 μπι; D(0.5): 4.266 μηι; D(0.9): 11.005 μm; D[4,3]: 5.316 μm.

Example-12: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride: (Formula-la)

A mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (4 gms), 1,4-dioxane (50 ml) and ethanol (50 ml) was heated to 55-60°C and stirred for 30 minutes at the same temperature. Hydrochloride acid (8.8 ml) was added to the reaction mixture at the same temperature and stirred for 20 minutes. Filtered the precipitated solid and dried to get the title compound.

Yield: 3.6 gms; Melting point: 274-276°C. Purity by HPLC: 99.0%.

The PXRD of the obtained compound is shown in figure-3.

Example-13: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide methanesulfonate (Formula-lb)

Mixture of tetrahydrofiiran (24 ml) and 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (2 g) was heated to 60-65°C and stirred for 30 minutes. Methane sulfonic acid (0.4 ml) was added to the reaction mixture at 60-65 °C and then cooled the reaction mixture to 25-30°C. Stirred the reaction mixture for 3 hours at same temperature. Filtered the precipitated solid and washed with tetrahydrofiiran and dried to get the title compound. Yield: 1.8 gms. Purity by HPLC: 99.93%.

The PXRD of the obtained compound is shown in figure-4.

Example-14: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (Formula-1)

Mixture of dimethylformamide (450 ml) and ethyl 5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin-l-yl)benzofiiran-2-carboxylate hydrochloride (30.0 g) was cooled to 0-10°C ,

WO 2014/049612

and stirred for 20 minutes at the same temperature. Formamide (48.7 g) and followed by sodium methoxide in methanol (51.6 g) was added to reaction mixture at 0-10°C and stirred the reaction mixture for 45 minutes at same temperature. After completion of the reaction, water (900 ml) was added to the reaction mixture and stirred for 1 hour at 25-30°C. Filtered the precipitated solid and washed with water to get the title compound. Yield: 25.7 gms. Melting point: 203- 209°C. Purity by HPLC: 99.5%.

The PXRD of the obtained compound is shown in figure- 1.

Example-15: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (Formula-1)

Acetonitrile (300 ml) was added to the wet compound obtained in example- 14 and heated to 80-85°C and stirred for 1 hour. Filtered the reaction mixture and washed with acetonitrile at the same temperature. Distilled off the solvent completely from the filtrate to obtain the crude compound. Acetonitrile (30 ml) was added to the crude compound and stirred for 2 hours at 25- 30°C. Filtered the solid and washed with acetonitrile. Water (300 ml) was added to the wet compound and was heated to 90-95°C. Stirred the reaction mixture for 30 minutes at 90-95°C. Cooled the reaction mixture to 30-35°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the crystalline form-M.

The PXRD of the crystalline form-M is shown in figure-5.

Example-16: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride (Formula-la)

20% hydrochloric acid (5 ml) was added to a mixture of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (1 gm) and water (20 ml) at 25-30°C. The reaction mixture was heated to 80-90°C and stirred for 20 minutes. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes. Filtered the precipitated solid and washed with water and then dried to get the title compound.

Yield: 1 g; MR: 272-275°C; Purity by HPLC: 99.0%.

Particle size distribution before micronization: D(0.1): 14.922 μιη; D(0.5): 51.330 μηι; D(0.9): 100.400 μι^η; D[4,3]: 55.250 μπι.

Particle size distribution after micronization: D(0.1): 1.206 μπι; D(0.5): 4.266 μιη; D(0.9): 11.005 μι^η; 0[4,3]: 5.316 μηι. Example-17: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride (Formula-la)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride obtained from example- 16 (2.0 g) was dissolved in formic acid (2.0 ml) at 25- 30°C. Slowly ethyl acetate (4.0 ml) was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with ethyl acetate to get the title compound. Yield: 1.6 g;

The PXRD of the obtained compound is shown in figure-7. Example-18: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yI)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydro bromide (formula-12b)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (3.0 g) was dissolved in acetone (225 ml) at 55-60°C. Aqueous hydrobromic acid (0.81 g) was added to the reaction mixture at 55-60°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 2.90 g; MR: 264-269°C; Purity by HPLC: 98.76%.

Example-19: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l-piperazinyl]-2- benzofuran carboxamide hydro bromide (formula-12b)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (3.0 g) was dissolved in acetone (225 ml) at 55-60°C. Slowly added hydrogen bromide in glacial acetic acid (0.54 g) to the reaction mixture at 55-60°C. Reaction mixture was cooled to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 3. 0 g; MR: 264-269°C;

Example-20: Preparation of 5-[4-[4-(5-cyano-lH-indoI-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide phosphate (formula-12c)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (1.0 g) was dissolved in tetrahydrofuran (10 ml) at 47-52°C. Slowly added ortho phosphoric acid (0.266 g) to the reaction mixture at 47-52°C and stirred for 15 minutes at the same temperature. Reaction mixture was cooled to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried to get the title compound.

Yield: 1.1 g; MR: 208-212°C. Example-21: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyI]-2- benzofuran carboxamide benzene sulfonate (formula-12d)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (1.0 g) was dissolved in tetrahydrofuran at 47-52°C. Slowly added benzene sulfonic acid (0.42 g) to the reaction mixture at 47-52°C and stirred for 20 minutes at the same temperature. Reaction mixture was cooled to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried to get the title compound.

Yield: 1.0 gm. MR: 205-209°C.

Example-22: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide nitrate (formuIa-12e)

5-[4-[4-(5-cyano H-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (1.0 g) was dissolved in tetrahydrofuran (10 ml) at 47-52°C. Slowly added nitric acid (0.17 g) to the reaction mixture at 47-52°C. Reaction mixture was cooled to 25-30°C and stirred for 2 hour at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried to get the title compound. Yield: 1.0 g. MR: 212-217°C.

Example-23: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide para toluene sulfonate (formula-12f)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (1.0 g) was dissolved in tetrahydrofuran (12 ml) at 60-65°C and stirred for 10 minutes. Slowly added para toluene sulfonic acid (0.4 g) to the reaction mixture at 60-65 °C and stirred for 1 hour at the same temperature. Reaction mixture was cooled to 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried to get the title compound. Yield: 0.8 g. MR: 204-207°C.

Example-24: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l- piperazinyl]-2-benzofuran carboxamide from isopropanol (Formula-1) 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (2.0 g) was dissolved in isopropanol (100 ml) at 80-85°C. Slowly cooled the reaction mixture to 25-30°C and then further cooled to 5-10°C. Stirred the reaction mixture for 2 hours at 5-10°C. Filtered the precipitated solid, washed with chilled isopropanol and dried to get the title compound. Yield: 1.7 g.

The PXRD of the crystalline form-M is shown in figure-5. Example-25: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyI]-2-benzofuran carboxamide from tetrahydrofuran (Formula-l)

5-[4-[4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide obtained from example-14 (10 g) was dissolved in tetrahydrofuran (50 ml) at 50-55°C. Slowly cooled the reaction mixture to 25-30°C and then further cooled the reaction mixture to 5-10°C. Stirred the reaction mixture for 2 hours at 5-10°C. Filtered the precipitated solid, washed with chilled tetrahydrofuran and dried to get the title compound. Yield: 5.2 gm; MR: 185-190°C.

Example-26: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yI)butyI]-l- piperazinyl]-2-benzofuran carboxamide from ethyl acetate (Formula-l)

Mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example-14 (2.0 g) and ethyl acetate (50 ml) was heated to 75-80°C and stirred for 1 hour. Cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 1.2 gm.

Example-27: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indoI-3-yl)butyI]-l- piperazinyl]-2-benzofuran carboxamide (Formula-l)

Mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example-14 (33 g) and acetone (1950 ml) was heated to 50-55°C and stirred for 1 hour. Filtered the reaction mixture and washed with acetone (66 ml). Distilled off the 70% solvent from the reaction mixture and cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the precipitated solid and washed with acetone (66 ml). To the obtained wet compound water (300 ml) was added and heated to 85-95°C- Stirred the reaction mixture for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 27.5 gm. Example-28: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide by anti-solvent addition (Formula-1)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example-14 (2.0 g) was dissolved in tetrahydrofuran (14.0 ml) at 40-45°C. Filtered the reaction mixture and washed with tetrahydrofuran (2.0 ml). Distilled off the filtrate at to obtain residue. Cyclohexane (11.0 ml) was added to the residue. Stirred the reaction mixture for 45 minutes at 25-30°C. Filtered the precipitated solid and dried to get the title compound. Yield: 1.6 gm.

Example-29: Preparation of crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (Formula-1)

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example-14 (1.0 g) was dissolved in methylene dichloride (5.0 ml) at 35-40°C and stirred for 20 minutes. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes. Filtered the precipitated solid, washed with methylene chloride and dried to get the title compound. Yield: 0.7 g;

The PXRD of crystalline form-N is shown in figure-6.

Example-30: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyI]-2- benzofuran carboxamide (Formula-1).

5-[4-[4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrobromide (5 gm) and methanol (30 ml) were charged into a clean and dry RBF at 25-30°C. Basifying the reaction mixture with aqueous sodium hydroxide solution. Filtered the precipitated solid, washed with methanol and then dried to get the title compound.

Yield: 4.3 gm; Purity by HPLC: 99.9%.

Example-31: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (Formula-1). 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide Para toluene sulfonate (5 gm) and acetone (30 ml) were charged into a clean and dry RBF at 25-30°C. Basifying the reaction mixture with aqueous sodium carbonate solution. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.

Yield: 4.2 gm; Purity by HPLC: 99.9%.

ExampIe-32: Preparation of crystalline forni-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide from acetone (Formula-1).

A mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (2 gm) and acetone (200 ml) was heated to 50-55°C and stirred for 10 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Distilled off 90% of the solvent from the reaction mixture. The reaction mixture was cooled to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 1.3 gm.

Example-33: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide from tetrahydrofuran (Formula-1).

A mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (2 gm) and tetrahydrofuran (18 ml) was heated to 40- 45 °C and stirred for 10 min at the same temperature. Distilled off 50% of the solvent from the reaction mixture. The reaction mixture was cooled to 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried to get the title compound. Yield: 1.4 gm.

Example-34: Preparation of crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyI]-2-benzofuran carboxamide from water (Formula-1).

A mixture of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide obtained from example- 14 (2 gm) and water (100 ml) was heated to reflux and stirred for 40 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 1.1 gm. Example-35: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l-piperazinyl]-2- benzofuran carboxamide (Formula-1)

Mixture of dimethylformamide (450 ml) and ethyl 5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (30.0 g) was cooled to 0-10°C and stirred for 20 minutes at the same temperature. Formamide (48.7 g) and followed by sodium methoxide in methanol (51.6 g) was added to reaction mixture at 0-10°C and stirred the reaction mixture for 45 minutes at same temperature. After completion of the reaction, water (900 ml) was added to the reaction mixture and stirred for 1 hour at 25-30°C. Filtered the precipitated solid and washed with water. Acetonitrile (300 ml) was added to the obtained wet compound and heated to 80-85°C and stirred for 1 hour. Filtered the reaction mixture and washed with acetonitrile at the same temperature. Distilled off the solvent completely from the filtrate to obtain the crude compound. Acetonitrile (30 ml) was added to the crude compound and stirred for 2 hours at 25-30°C. Filtered the solid and washed with acetonitrile. Water (300 ml) was added to the wet compound and was heated to 90-95°C. Stirred the reaction mixture for 30 minutes at 90-95°C. Cooled the reaction mixture to 30-35°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound; Yield: 21 gms.

Example-36: Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (5 g) obtained in example-35 was dissolved in formic acid (21 ml) at 25-30°C. Filter the reaction mixture through hyflow bed and isopropanolic hydrochloric acid (11 ml) was added to the obtained filtrate. The reaction mixture was stirred for 1 hour at room temperature. Isopropanol (40 ml) was added to the reaction mixture and stirred for 1 hour. Filtered the precipitated solid and washed with isopropanol and dried to get the title compound. Yield: 5.3 gms;

Purity by HPLC: 99.9%; Water content: 3.45% w/w; Chloride content: 13.98% w/w.

Example-37: Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (10.5 g) obtained in example-36 was dissolved in formic acid (42 ml) at 25-30°C. Filter the reaction mixture through hyflow bed and isopropanolic hydrochloric acid (22 ml) was added to the obtained filtrate. The reaction mixture was stirred for 1 hour at room temperature. Isopropanol (85 ml) was added to the reaction mixture and stirred for 1 hour. Filtered the precipitated solid and washed with isopropanol and dried to get the title compound. Yield: 10.8 gms. M.R: 284- 288°C.

The PXRD of the obtained compound is shown in figure-8.

Example-38: Preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (10.5 g) obtained in example-36 was dissolved in formic acid (42 ml) at 25-30°C. Filter the reaction mixture through hiflow bed and ethyl acetate hydrochloric acid (22 ml) was added to the obtained filtrate. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate (85 ml) was added to the reaction mixture and stirred for 1 hour. Filtered the precipitated solid and washed with ethyl acetate and dried to get the title compound. Yield: 10.2 gms.

Purity by HPLC: 99.85%; Water content: 4.15% w/w; Chloride content: 13.55% w/w

Particle size distribution before micronization: D(1.0): 3.034 μιη; D(0.5): 10.780 μηι; D(0.9): 34.164 μπι; D[4,3]: 15.796 μιη.

Particle size distribution after micronization: D(1.0): 1.297 μιη; D(0.5): 3.230 μηι; D(0.9): 6.875

Purity by HPLC: 99.9%; Water content: 3.59% w/w; Chloride content: 14.25% w/w.

The PXRD of the obtained compound is shown in figure-8.

Example-39: Preparation of l-tosyI-lH-indole-5-carbonitrile (Formula-3)

Dichloromethane (300 ml) was added to lH-indole-5-carbonitrile (100 gms) at 25-30°C.

Dimethyl amino pyridine (21.4 gms) and triethyl amine (106.3 gms) were added to the reaction mixture at 25-30°C. Para toluene sulfonyl chloride solution {200.2 gms of Para toluene sulfonyl chloride in 400 ml of dichloromethane} was slowly added to the reaction mixture at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated and aqueous layer is extracted with dichloromethane. Combined both the ' organic layers. Dilute hydrochloric acid was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed twice with water. The organic layer containing l-tosyl-lH-indole-5- carbonitrile compound of formula-7 was utilized in the next step without isolation. ExampIe-40: Preparation of 3-(4-Chlorobutanoyl)-l-tosyl-lH-indole-5-carbonitrile (Formula-5)

Aluminium chloride (235 gms) was slowly added to dichloromethane (1000 ml) under nitrogen atmosphere at 25-30°C. 4-chlorobutanoyl chloride (149 gms) was added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. The organic layer obtained in example-39 was added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. After completion of the reaction, reaction mixture was slowly added to water and stirred for 15 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined both the organic layers. Aqueous sodium bi carbonate solution was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. The organic layer was washed with sodium chloride solution. Distilled off the solvent from the organic layer and co-distilled with methanol. Cooled the obtained crude compound to 25-30°C. Methanol (800 ml) was added to the crude compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 282.0 gms; Melting point: 152-155°C.

Example-41: Preparation of 3-(4-Chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile(Formula-6)

Dichloromethane (700 ml) was added to 3-(4-chlorobutanoyl)-l-tosyl-lH-indole-5- carbonitrile (100 gms ) at 25-30°C. Cooled the reaction mixture to 0-5°C. Titanium tetrachloride {titanium tetrachloride (59.18 gms) dissolved in dichloromethane (300 ml)} solution was slowly added to the reaction mixture at 0-5°C. Triethyl silane (145 gms) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 8 hours at the same temperature. After completion of the reaction, reaction mixture was added to chilled water (1000 ml) at 0-5°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer is extracted with dichloromethane. Combined both the organic layers and washed with water and then followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Methanol (300 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with methanol to get the title compound.

Example-42: Preparation of 3-(4-Chlorobutyl)-lH-indole-5-carbonitrile (Formula-7)

Methanol (1000 ml), potassium carbonate (51.08 gms) were added to the wet compound obtained in example-41 at 25-30°C. Heated the reaction mixture to 50-60°C and stirred for 8 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the obtained filtrate. Water (500 ml), toluene (300 ml) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was cooled to 25-30°C. Cyclohexane (300 ml) was added to the organic layer at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with cyclohexane and dried to get the title compound.

Yield: 69.11 gms; Melting point: 86-94°C.

ExampIe-43: Preparation of Crystalline Form-R of Vilazodone Dihydrochloride Monohydrate

Formic acid (100 ml) was added to 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]- 2- benzofuran carboxamide (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Water (4.0 ml) was added to the reaction mixture at 25-30°C. Filtered the reaction mixture and washed with formic acid. To the obtained filtrated isopropanolic hydrochloric acid (206.61 ml), followed by isopropanol (800 ml) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 120.60 gms; Melting point: 284-288°C. Diamide impurity: 0.04%; Condensed acid impurity: 0.03%; Condensed ester impurity: Not detectable;

Particle size distribution before micronization: D(1.0): 2.579 μπι; D(0.5): 8.555 μιη; D(0.9): 27.159 μηι; D[4,3]: 12.672 μιη.

Particle size distribution after micronization: D(1.0): 1.297 μιη; D(0.5): 3.230 μιη; D(0.9): 6.875 μιη; D[4,3]: 3.755 μηι. Purity by HPLC: 99.9%; Water content: 3.59% w/w; Chloride content: 14.25% w/w. The PXRD of the obtained compound is shown in figure-8. Example-44: Preparation of 3-(4-(4-(2-carbamoylbenzofuran-5-yl)piperazin-l-yl)butyI)- lH-indole-5-carboxamide [Di-amide Impurity]

Acetone (1500 ml) and dimethyl sulfoxide (400 ml) were added to 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide (100 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and hydrogen peroxide (61.6 gms) was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 14 hours at 50-60°C. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water (3000 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. The obtained compound was purified by column chromatography.

Example-45: Preparation of 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzo furan-2-carboxyIic acid [Acid impurity]

Methnaol (160ml) was added to ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloride (20 gms) at 25-30°C. Sodium hydroxide (11.65 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and water was added to it and further cooled to 10-15°C. The pH of the reaction mixture was adjusted to 5.5 by using dilute hydrochloric acid at 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 12 gms.

Example-46: Purification of ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yI)benzofuran-2-carboxy!ate hydrochloride (Formula-lla)

A mixture of ethyl acetate (500 ml) and ethyl 5-(4-(4-(5-cyano-lH-indol-3-

9

yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (120 gms) obtained from example-8 were heated to 65-70°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 1 15 gms; Melting point: 218-222°C. Purity by HPLC: 96.5 %.

Example-47: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride (Form-IV)

Dimethyl formamide (25.0 ml) was added to 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2- benzofuran carboxamide (5.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with dimethyl formamide. Isopropanolic hydrochloric acid (0.413 gms), followed by isopropanol (60.0 ml) were added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 3.7 gms.

Particle size distribution before micronization: D(1.0): 5.341 μπι; D(0.5): 33.308 μιη; D(0.9): 58.770 μιη; D[4,3]: 33.627 μιη.

Particle size distribution after micronization: D(1.0): 1.122 μπι; D(0.5): 3.649 μηι; D(0.9): 8.672 μΓ^η; ϋ[4,3]: 4.512μιη.

Example-48: Preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyI]-2- benzofuran carboxamide hydrochloride (Form-IV)

Formic acid (15.0 ml) was added to 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2- benzofuran carboxamide (5.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with formic acid. Isopropanolic hydrochloric acid (0.496 gms) was added to the filtrate and stirred for 10 minutes. The reaction mixture was added to isopropanol (80.0 ml) were added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound.

Yield: 3.7 gms.

Particle size distribution before micronization: D(1.0): 4.045 μηι; D(0.5): 29.700 μηι; D(0.9): 66.124 μιη; D[4,3]: 32.374 μιη.

Particle size distribution after micronization: D(1.0): 1.122 μηι; D(0.5): 3.649 μηι; D(0.9): 8.672

ExampIe-49: Preparation of Amorphous 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyI]-2-benzofuran carboxamide hydrochloride

Dimethyl formamide (0.25 ml) was added to a mixture of acetonitrile (120 ml), water (60 ml) and 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (2 gms) at 25-30°C. Hydrochloric acid (0.54 ml) was slowly added to the reaction mixture at 25- 30°C. Filtered the reaction mixture through hi-flow bed and distilled off the solvent completely from the reaction mixture to get the title compound. Yield: 1.7 gms.

Example-50: Preparation of Amorphous 5-[4-[4-(5-cyano-lH-indol-3-yI)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride

Ethyl alcohol (60.0 ml) was added to a mixture of methanol (60.0 ml), water (60.0 ml) and 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (2.0 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Hydrochloric acid (0.54 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and distilled off the solvent completely from the reaction mixture to get the title compound. Yield: 1.6 gms.

Example-51: Preparation of . Amorphous 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride

A mixture of acetonitrile (120.0 ml) and water (60 ml) was added to 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride (2.0 gms) at 25- 30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and distilled off the solvent completely form the reaction mixture to get the title compound. Yield: 1.7 gms. Example-52: Preparation of Ethyl 5-(piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (Formula-lOa)

Diethylene glycol monoethyl ether (500 ml) was added to ethyl 5-aminobenzofuran-2- carboxylate (100 gms) at 25-30°C. Bis-(2-chloroethyl)amine hydrochloride (87.2 gms), potassium iodide (8.1 gms) followed by tetrabutyl ammonium bromide (7.85 gms) was slowly added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 130- 135°C and stirred for 30 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Acetone (300 ml) to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hour at the same temperature. Filtered the precipitated solid, washed with acetone. To the obtained wet compound, diethylene glycol mono ethyl ether (300 ml) was added at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 151.44 gms; Melting point: 238-242°C.

Reference Example:

Preparation of crystalline Form-S 5-{4-[4-(5-cyano-3-indolyl)butyl]-l- piperazinyl}benzofuran-2-carboxamide according to US7799916 B2 (Formula-1)

5-(l-piperazinyl)benzofuran-2-carboxamide (1.7 gms) and sodium cyanoborohydride (1.1 gms) are dissolved in 200 ml of methanol at 20-25°C and stirred for the reaction mixture for 2 hours at te same temperature. A solution of 3-(4-oxobutyl)-lH-indole-5-carbonitrile (2.4 gms in 50 ml of methanol (50 ml) was added to the reaction mixture and stirred for 18 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 5-10°C and stirred for 6 hours at the same temperature. Filtered the precipitated solid, washed with methanol and water and dried to get the title compound.

Claims

We Claim:

1. A process for the preparation of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- la, comprising of the following steps;

a) Reacting lH-indole-5-carbonitrile c la-2,

Formula-2

with para toluene sulfonyl chloride in the presence of dimethylaminopyridine in methylene chloride to provide 1 -tosy - lH-indole-5-carbonitrile compound of formula-3,

b) reacting the compound of formula-3 with 4-chlorobutanoyl chloride compound of formula-4

Formula-4

in the presence of aluminium chloride in methylene chloride to provide 3-(4- chlorobutanoyl)- 1 -tosyl- 1 H- d of formula-5,

Formula-5

c) reducing the compound of formula-5 with sodium borohydride in the presence of trifluoroacetic acid in methylene chloride to provide 3-(4-chlorobutyl)-l-tosyl-lH-indole- 5-carbonitrile compound of formula-6,

Formula-6 d) treating the compound of formula-6 with potassium carbonate in a mixture of tetrahydrofuran and methanol to provide 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7,

Formula-7

e) treating ethyl 5-(piperazin-l-yl)benzofuran-2-carboxylate hydrochloride compound of formula- 10a,

Formula- 10a

with potassium carbonate in acetonitrile to provide free base of formula- 10, which on in- situ condensation with compound of formula-7 in the presence of triethylamine and potassium iodide in the presence or absence of tetrabutylammonium bromide to provide ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate compound of formula- 11,

f) treating the compound of formula- 1 1 with aqueous hydrochloric acid in acetone to provide ethyl 5-(4-(4-(5-cyano- 1 H-indol-3-yl)butyl)piperazin- 1 -yl)benzofuran-2- carboxylate hydrochloride of compound formula- 11a,

g) amidating the compound of formula-l la with formamide in the presence of sodium methoxide in a mixture of dimethyl formamide and methanol at a suitable temperature to provide 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula-

h) optionally, isolating the compound of formula- 1 as a solid,

i) treating the compound of formula- 1 with hydrochloric acid in a suitable solvent or mixture of solvents to provide 5-4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- la.

2. A process for the preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of,

a) adding a suitable solvent to the 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6,

b) adding a suitable base and a suitable solvent, to the reaction mixture,

c) stirring the reaction mixture at a suitable temperature,

d) distilling off the solvent from the reaction mixture and cooling to a suitable temperature,

e) adding water to the reaction mixture and stirring,

f) filtering the precipitated solid and adding suitable solvent to the solid,

g) heating the reaction mixture to the reflux temperature and stirring,

h) cooling the reaction mixture to a suitable temperature,

3. The process of claim-2, wherein, the suitable base is selected from inorganic base or organic base and the suitable solvent is selected from ether solvents, alcoholic solvents, chloro solvents and mixture thereof.

4. A process for the preparation of 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6, comprising of reducing the compound of formula-5 with triethylsilane in presence of titanium tetrachloride in methylene chloride provides 3-(4- chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6.

5. Crystalline 1,4-dioxane solvate form-M of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride characterized by its powder X-ray diffractogram having peaks at 2.7, 10.6, 13.5, 13.8, 14.6, 16.2, 17.2, 18.0, 19.1, 19.7, 20.3,

21.1, 21.8, 22.2, 22.8, 26.5, 27.3, 28.0 and 31.3 ± 0.2 degrees of two-theta as illustrated in figure-3.

6. Crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb characterized by its powder X-ray diffractogram having peaks at 5.6, 6.3, 7.0, 7.4, 9.5, 10.3, 11.7, 12.6, 13.7, 14.2, 14.7, 15.0,

15.2, 16.3, 16.7, 17.1, 17.9, 18.4, 18.7, 19.1, 19.5, 19.8, 20.4, 20.8, 21.8, 22.4, 22.8, 23:7,

24.3, 24.6, 25.0, 25.8, 26.2, 26.5, 27.7, 28.5, 29.0, 30.9, 31.5, 32.3, 34.3, 35.3 and 42.5 ± 0.2 degrees of two-theta as illustrated in figure-4.

7. A process for the preparation of crystalline form-N of 5-[4_:[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide methanesulfonate compound of formula- lb, comprising of:

b) adding methane sulfonic acid to the above reaction mixture,

c) cooling the reaction mixture and stirring,

d) filtering the precipitated solid and drying to get the crystalline form-N of compound of formula- lb.

8. Crystalline acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide compound of general formula- 12,

Formula- 12 wherein the acid is preferably selected from hydrobromic acid, phosphoric acid, benzene sulfonic acid, nitric acid and para toluene sulfonic acid.

9. Crystalline form-N of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 characterized by its X-ray powder diffraction pattern having peaks at 6.0, 7.6, 11.3, 14.0, 16.3, 17.5, 18.8, 20.3, 21.1, 21.8, 22.2, 24.6, 25.6, 28.2, 29.9 and 36.2 ± 0.2 degrees of two-theta as illustrated in figure-6.

10. Crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la characterized by its X-ray powder diffraction pattern having peaks at 4.9, 9.0, 10.6, 12.6, 12.8, 13.8, 14.4, 15.2, 16.2, 17.7, 18.8, 19.9, 20.7, 21.4, 22.3, 22.6, 23.9, 24.5, 25.8, 27.0, 27.4, 28.1, 28.6 and 30.0 ± 0.2 degrees of two-theta as illustrated in figure-7.

11. Process for the preparation of acid addition salts of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide compound of general formula- 12, comprises of treating the compound of formula- 1 with a suitable acid in a suitable solvent selected from chloro solvents, ketone solvents, ester solvents, alcohol solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

12. A process for the purification of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofurancarboxamide compound of formula- 1 , comprising of;

a) Converting the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- 1 into its acid-addition salt compound of general formula- 12 by treating it with a suitable acid in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents, polar aprotic solvents, nitrile solvents or mixtures thereof,

b) treating the acid-addition salt compound of general formula- 12 obtained in step-a) with a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents and/or their mixtures thereof to provide pure 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide compound of formula- 1.

13. Crystalline 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate

14. The crystalline compound according to claim 13, the 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate hereinafter designated as crystalline form-R, which is characterized by its X-ray powder diffractogram having peaks at 5.6, 7.6, 10.8, 11.2, 15.0, 15.3, 15.6, 21.3, 21.5, 22.3, 22.6,

23.2, and 29.2 ± 0.2 degrees of two-theta as illustrated in figure-8.

15. The crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide dihydrochloride monohydrate of claim- 13 is further characterized by its X-ray powder diffractogram having peaks at 5.6, 7.6, 10.8, 11.2, 14.0, 14.6, 15.0, 15.3,

15.6, 16.0, 16.6, 17.3, 18.0, 19.6, 20.5, 21.3, 21.5, 22.3, 22.6, 23.2, 24.7, 25.1, 25.8, 26.2, 26.8, 28.5, 29.2, 29.5, 29.9 and 34.0 ± 0.2 degrees of two-theta as illustrated in figure-8.

16. Crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate of claim- 13 is further characterized by its DSC thermogram showing endotherms as illustrated in figure-9.

17. Crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate of claim- 13 is further characterized by its IR spectrum having absorption bands at 1672, 1385, 1196, 1022, 934, 886, 873, 807 and 770 ±

2 cm^"l as illustrated in figure- 10.

18. A process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of:

b) adding water to the reaction mixture,

c) filtering the reaction mixture,

d) adding a suitable hydrochloric acid source to the reaction mixture,

e) stirring the reaction mixture at a suitable temperature,

f) filtering the precipitated solid and drying to provide crystalline form-R of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

19. The process according to claim- 18, wherein in step-d) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl, preferably IPA-HC1; and the suitable temperature in step-e) is ranging from 0°C to 100°C, preferably 25°C to 40°C.

20. A process for the preparation of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate, comprising of;

b) adding water to the reaction mixture,

c) filtering the reaction mixture,

d) adding isopropyl alcohol hydrochloride to the reaction mixture,

e) stirring the reaction mixture at 25°C-30°C,

f) filtering the precipitated solid and drying to provide crystalline form-R of 5-[4-[4-(5- cyano- 1 H-indol-3 -yl)butyl] - 1 -piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate.

21. Crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate of claim- 13 having water content of 3.0 weight-% to 5.0 weight-% and chloride content of 13.0 weight-% to 14.5 weight-%.

22. A process for the preparation of crystalline form-IV of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, comprising of

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide in a suitable solvent,

b) filtering the reaction mixture,

c) adding a suitable hydrochloride acid source in a suitable solvent to the reaction mixture, d) stirring the reaction mixture at a suitable temperature,

e) filtering the precipitated solid and drying to get the crystalline form-IV of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- 1 a.

23. A process for the preparation of crystalline form-IV of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, comprising of

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide in dimethyl formamide,

b) filtering the reaction mixture,

c) adding isopropyl alcohol hydrochloride in isopropanol to the reaction mixture, d) stirring the reaction mixture at 25°C to 40°C,

e) filtering the precipitated solid and drying to get the crystalline form-IV of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- 1 a.

24. A process for the preparation of crystalline form-IV of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la, comprising of

b) filtering the reaction mixture,

e) filtering the precipitated solid and drying to get the crystalline form-IV of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- la.

25. A process for the preparation of 3-(4-chlorobutyl)-lH-indole-5-carbonitrile compound of formula-7, comprising of,

a) adding a methanol to 3-(4-chlorobutyl)-l-tosyl-lH-indole-5-carbonitrile compound of formula-6,

b) adding sodium methoxide to the reaction mixture,

c) stirring the reaction mixture at 40-45°C,

d) cooling the reaction mixture to 25-30°C,

e) adding water to the reaction mixture,

f) filtering the precipitated sold and drying to provide 3-(4-chlorobutyl)-lH-indole-5- carbonitrile compound of formula-7.

26. Use of crystalline form-R of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide dihydrochloride monohydrate in the preparation of pharmaceutical composition.

27. Use of acid addition salts of claims 8, in the preparation of highly pure 5-[4-[4-(5-cyano- lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofurancarboxamide compound of formula- 1 as well as it's hydrochloride salt compound of formula- la.

28. Use of crystalline form-N or crystalline form-S of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofurancarboxamide for the preparation of highly pure 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- 1 a.

29. Particle size distribution of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide dihydrochloride monohydrate having D(0.1) less than 10 μηι, D(0.5) less than 50μηι, D(0.9) less than 100 μιη and D(3,4) less than 50 μιη.

30. Particle size distribution of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide dihydrochloride monohydrate after micronization having D(0.1) < 1.297 μηι, D(0.5) < 3.230 μm, D(0.9) < 6.875 μιη and D(3,4) < 18.04 μπι.

31. 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide dihydrochloride monohydrate obtained according to any of the preceding claims having purity more than 99% by HPLC, preferably more than 99.6 % by HPLC.