CLIAMS:We Claim:
1. A process for preparation of Vilazodone comprising the steps of:

(a) treating a compound of Formula-I

Formula-I
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;

Formula-II
(b) coupling the compound of Formula-II with a compound of Formula-III

Formula-III
in presence of a suitable solvent and/or suitable acid binding agents and with or without suitable activating agents to give a compound of Formula-IV;

Formula-IV
(c) amidation of the compound of Formula-IV by treating with a suitable amidation agent in presence of suitable solvent to give a compound of Formula-V;

Formula-V
(d) reduction of the compound of Formula-V with suitable reducing agent(s) in presence of suitable solvent to give a compound of Formula-VI;

Formula-VI
(e) deprotection of the compound of Formula-VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula-VII.

Formula-VII
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).

- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably Cl.

- Et represents ethyl (-C2H5).

2. The process as claimed in claim 1, wherein the suitable reducing agent in step-(a) may be selected from sodiumborohydride, lithium borohydride, NaBH3CN, DIBAL-H, lithium aluminiumhydride, vitride, borane-THF, sodiumborohydride/ iodine, 9-BBN.

3. The process as claimed in claim 2, wherein the suitable reducing agent used in step-(a) is sodiumborohydride.

4. The process as claimed in claim 1, wherein the suitable solvent in step-(a) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like.

5. The process as claimed in claim 4, wherein the suitable solvent used in step-(a) is methanol or ethanol.

6. The process as claimed in claim 1, wherein the coupling of Formula-II with Formula-III in step-(b) is performed in presence of suitable solvents and or suitable acid binding agents and with or without suitable activating agents.

7. The process as claimed in claim 6, wherein the solvent may be selected from triethylamine (TEA), disiopropylethyl amine, toluene, diglyme, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran (THF), dioxane, water, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, acetonitrile or mixtures thereof.

8. The process as claimed in claim 7, wherein the solvent is triethylamine (TEA).

9. The process as claimed in claim 6, wherein the acid binding agents may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal or alkali earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid, preferably a potassium, sodium or calcium salt, or an organic bases such as triethylamine, disiopropylethyl amine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof.

10. The process as claimed in claim 9, wherein the acid binding agent is triethylamine.

11. The process as claimed in claim 6, wherein the activating agents may be metal halides and/or phase transfer catalysts.

12. The process as claimed in claim 11, wherein the metal halides may be selected from iodide and bromide of alkali metals or alkali earth metals.

13. The process as claimed in claim 12, wherein the metal is sodium iodide or potassium iodide.

14. The process as claimed in claim 11, wherein the phase transfer catalyst may be selected from 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.

15. The process as claimed in claim 14, wherein the phase transfer catalyst is TBAB.

16. The process as claimed in claim 1, wherein the suitable amidation agent in step-(c) may be 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 tartarate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate, alkyl or aryl amines, magnesium nitride; mixtures such as magnesium methoxide/ammonium chloride, magnesium methoxide/ammonia, calcium chloride/ammonium chloride and calcium chloride/ ammonia.

17. The process as claimed in claim 16, wherein the amidation agent is ammonia gas.

18. The process as claimed in claim 1, wherein the suitable solvent in step-(c) may be selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, N,N-dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane.

19. The process as claimed in claim 18, wherein the solvent is methanol or ethanol.

20. The process as claimed in claim 1, wherein the suitable reducing agent in step-(d) may be used alone or in combination of suitable reagents; selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH3CN, sodium borohydride/BF3-etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, trifluoroacetic acid (TFA)/sodiumborohydride(SBH), Et3SiH/TFA.

21. The process as claimed in claim 20, wherein the reducing agent is a combination of trifluoroacetic acid with sodiumborohydride.

22. The process as claimed in claim 1, wherein the suitable solvent in step-(d) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like.

23. The process as claimed in claim 22, wherein the solvent is methylene dichloride (DCM).

24. The process as claimed in claim 1, wherein the suitable base in step-(e) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof.

25. The process as claimed in claim 24, wherein the base used in is sodium hydroxide (NaOH).

26. The process as claimed in claim 1, wherein the solvent in step-(e) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, 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, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like.

27. The process as claimed in claim 26, wherein the solvent is methanol or ethanol.

28. A process for preparation of Vilazodone comprising the steps of:

(a) treating a compound of Formula-Ia

Formula-Ia
with sodiumborohydride (SBH) in presence of solvent methanol to give a compound of Formula-IIa;

Formula-IIa
(b) coupling the compound of Formula-IIa with a compound of Formula-III

Formula-III
in presence of acid binding agent TEA, potassium iodide (KI) and TBAB in solvent TEA to give a compound of Formula-IVa;

Formula-IVa
(c) amidation of the compound of Formula-IVa by treating with ammonia gas in presence of solvent ethanol to give a compound of Formula-Va;

Formula-Va
(d) reduction of the compound of Formula-Va with reducing agents TFA/SBH in presence of solvent DCM to give a compound of Formula-VIa;

Formula-VIa
(e) deprotection of the compound of Formula-VIa by treating with base NaOH in presence of solvent methanol to obtain Vilazodone of Formula-VII.

Formula-VII

wherein -Et represents ethyl.

29. A compound of Formula-II

Formula-II
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).
- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and O-trifluoromethane sulfonyl with the exception that when Z is Ts (tosyl), X is not Cl and when X is Cl, Z is not Ts (tosyl).

30. A compound of Formula-IV

Formula-IV

wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).
- Et represents ethyl (-C2H5).

31. A compound of Formula-V

Formula-V
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).

32. A compound of Formula-IVa:

Formula-IVa

wherein Ts represents tosyl and Et represents ethyl.

33. A compound of Formula-Va:

Formula-Va

wherein Ts represents tosyl.

34. A novel crystalline form of Vilazodone hydrochloride of Formula VIII

Formula-VIII
characterized by X-ray powder diffraction (XRPD) spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values.

35. A process for preparation of crystalline form of Vilazodone hydrochloride of Formula VIII characterized by X-ray powder diffraction (XRPD) spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values, comprising the steps of:

(a) preparing a suspension of Vilazodone free base of Formula-VII in isopropanol;

Formula-VII

(b) to the above suspension drop wise adding conc. hydrochloric acid (HCl) at about 45 0C for about 30 min followed by stirring for about 1 hr at same temperature;

(c) cooling to about 00C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HCl of Formula VIII.

Formula-VIII
(Vilazodone HCl)

36. A novel crystalline form of Vilazodone hydrochloride of Formula VIII

Formula-VIII
characterized by X-ray powder diffraction (XRPD) spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values obtained by the process as claimed in claim 35.
,TagSPECI:FIELD OF INVENTION
The invention relates to a process for preparation of vilazodone, novel intermediates thereof and novel crystalline form thereof. More particularly, the invention relates to a process for preparation of Vilazodone. Invention also relates to novel intermediates for synthesis of Vilazodone. The invention also relates to novel crystalline form of Vilazodone hydrochloride and a process for preparation of the same.

BACKGROUND OF THE INVENTION
Vilazodone is a benzofuran-2-carboxamide derivative, chemically known as 5-(4-[4-(5-cyano-lH-indol- 3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide. It is represented by the structure of Formula-VII as shown below-

Formula-VII

Vilazodone and its acid addition salts were first disclosed in US Patent No. US 5532241 (EP 0648767). Various routes for synthesis of benzofuran-2-carboxamide derivatives have been described in US 5532241. In one route Vilazodone is prepared by condensation of 5-(1-piperazin-l-yl) benzofuran-2-carboxamide with 3-(4-chlorobutyl)-1H-indole-carbonitrile. In another route Vilazodone is prepared 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 presence of N-methylpyrrolidine and dried NH3 gas. Scheme-1 below represents above said synthetic routes:

Scheme-1

J. Med. Chem., 2004, 47 (19), pp 4684–4692 also describes a similar process for Vilazodone wherein (5-(4-[4-(5-cyano-lH-indol- 3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxylic acid reacts with 2-chloro-1-methylpyridinium iodide in presence of N-methylpyrrolidone to produce a reaction mass, followed by drop wise addition of ethyldiisopropyl amine while introducing ammonia gas and subsequent work up to give Vilazodone.

CN 103304547 A discloses a process for Vilazodone as shown in below Scheme-2:

Scheme-2

CN103570697 discloses various routes for synthesis of Vilazodone. In one route, 5-(piperazin-1-yl) benzofuran-2-carboxamide reacts with 4-bromo-1-butene to give an intermediate 5- (4- (3- butenyl) piperazin-1-yl) benzofuran-2-carboxamide, which further reacts with 3- iodo-1-tosyl-indole-5- carbonitrile to give 5- (4- (4- (5-cyano-1-tosyl-indol-3-yl) -3-butenyl) piperazin -1- yl) benzofuran -2-carboxamide. The resultant product is then reduced to give 5- (4- (4- (5-cyano-1-tosyl-indol-3-yl) -3-butyl) piperazin -1- yl) benzofuran -2-carboxamide and then detosylated to produce Vilazodone as shown in Scheme-3 below:

Scheme-3
Org. Process Res. Dev. 2012, 16, 1552-1557 (HU et. al.) discloses a process for Vilazodone as shown in below Scheme-4:

HU et. al. describes varieties of process for preparation of above intermediate compound 3, starting from reduction of intermediate compound 2.

Another Chinese publication CN 102180868A discloses a process as shown in Scheme-5 below:

Wherein X = halogen F, Cl, Br, I; preferably Br
Scheme-5

US Patent 8802851 B2 describes a process for preparation of Vilazodone free base and subsequent conversion to Vilazodone HCl comprising the steps of: (a) reacting 3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile of formula (I) with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride of formula (II) to give 5-{4-[4-(5-cyano-1H-indol-3-yl)-4-hydroxybutyl]-piperazin-1-yl}benzofuran-2-carboxylate methyl of formula (III); (b) treating the compound of formula (III), obtained from step (a), with an acidification agent to obtain 5-{4-[4-(5-cyano-1H-indol-3-yl)-4-hydroxy-butyl]-piperazin-1-yl}benzofuran-2-carboxylate methyl of formula (IV); (c) hydrogenating the compound of formula (IV) with H2 to obtain 5-{4-[4-(5-cyano-1H-indol-3-yl)-4-hydroxy-butyl]-piperazin-1-yl}benzo-furan-2-carboxylate methyl of formula (V); (d) treating the compound of formula (V) obtained from step (c) with ammonia to obtain 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzo-furan-2-carboxamide of formula (VI); (e) optionally treating the compound of formula (VI) with hydrochloride acid to obtain vilazodone hydrochloride of formula (VII).
Wherein, in the above process, compound of Formula (I) is obtained by reduction of 3-(4-chlorobutynoyl)1-H-indol-5-carbonitrile in presence of Sodium Borohydride.

The above said process is shown in below Scheme-6:

Scheme-6
Many other patent publications have also been disclosed so far. Still there is a need of a process which is industrially viable and economical. None of the above prior arts teaches about the present process. The present process of the invention uses novel intermediates for the preparation of Vilazodone free base in a good yield making the process industrially viable process.

OBJECTS OF THE INVENTION
The primary object of the invention is to provide a novel process for the preparation of Vilazodone.

Another object of the invention is to provide novel intermediates for the synthesis of Vilazodone.

Another object of the invention is to provide a novel crystalline form of Vilazodone hydrochloride.

A further object of the invention is to provide a process for preparing novel crystalline form of Vilazodone hydrochloride.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone. The invention also provides novel crystalline form of Vilazodone hydrochloride and process for preparing the same.

In one aspect the invention provides a process for preparation of Vilazodone comprising the steps of:

(a) treating a compound of Formula-I

Formula-I
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;

Formula-II
(b) coupling the compound of Formula-II with a compound of Formula-III

Formula-III
in presence of a suitable solvent and/or suitable acid binding agents and with or without suitable activating agents to give a compound of Formula-IV;

Formula-IV
(c) amidation of the compound of Formula-IV by treating with a suitable amidation agent in presence of suitable solvent to give a compound of Formula-V;

Formula-V
(d) reduction of the compound of Formula-V with suitable reducing agent(s) in presence of suitable solvent to give a compound of Formula-VI;

Formula-VI
(e) deprotection of the compound of Formula-VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula-VII.

Formula-VII
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).

- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably Cl.

- Et represents ethyl (-C2H5).

The suitable reducing agent in step-(a) may be selected from sodiumborohydride, lithium borohydride, NaBH3CN, DIBAL-H, lithium aluminiumhydride, vitride, borane-THF, sodiumborohydride/ iodine, 9-BBN; preferably sodiumborohydride. In one preferred embodiment the suitable reducing agent used in step-(a) is sodiumborohydride.

The solvent used in step-(a) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably the solvent used is methanol or ethanol.

Step-(b) proceeds in presence of suitable solvents and or suitable acid binding agents and with or without suitable activating agents. The solvent used in step-(b) may be selected from triethylamine (TEA), disiopropylethyl amine, toluene, diglyme, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran (THF), dioxane, water, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, acetonitrile or mixtures thereof; preferably triethylamine (TEA).

The suitable acid binding agents in step-(b) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal or alkali earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid, preferably a potassium, sodium or calcium salt, or an organic bases such as triethylamine, disiopropylethyl amine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof; preferably triethylamine.

The suitable activating agents in step-(b) may be metal halides and/or phase transfer catalysts. Step-(b) is performed with or without presence of metal halides and with or without presence of phase transfer catalyst.

The metal halides in step-(b) may be selected from iodide and bromide of alkali metal or alkali earth metal; preferably sodium iodide or potassium iodide.

The phase transfer catalyst in step-(b) may be selected from 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; preferably TBAB.

The suitable amidation agent in step-(c) may be 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 tartarate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate, alkyl or aryl amines, magnesium nitride; mixtures such as magnesium methoxide/ammonium chloride, magnesium methoxide/ammonia, calcium chloride/ammonium chloride and calcium chloride/ ammonia; preferably the suitable amidation agent used is ammonia gas under pressure of about 1 Kg/Cm² to about 10 Kg/ Cm²; preferably about 3 Kg/ Cm².

The suitable solvent in step-(c) may be selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, N,N-dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane; preferably the solvent selected from methanol or ethanol.

The suitable reducing agent in step-(d) may be used alone or in combination of suitable reagents; selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH3CN, sodium borohydride/BF3-etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, trifluoroacetic acid (TFA)/sodiumborohydride(SBH), Et3SiH/TFA; preferably combination of trifluoroacetic acid with sodiumborohydride is used.

The solvent used in step-(d) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably the solvent used is methylene dichloride (DCM).

The suitable base used in step-(e) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof; preferably the base is sodium hydroxide (NaOH) and potassium hydroxide (KOH); more preferably the base used is NaOH.

The suitable solvent used in step-(e) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, 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, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably alcoholic solvent such as methanol or ethanol are used.

In another aspect, the invention provides a process for preparation of Vilazodone comprising the steps of:

(a) treating a compound of Formula-Ia

Formula-Ia
with sodiumborohydride (SBH) in presence of solvent methanol to give a compound of Formula-IIa;

Formula-IIa
(b) coupling the compound of Formula-IIa with a compound of Formula-III

Formula-III
in presence of acid binding agent TEA, potassium iodide (KI) and TBAB in solvent TEA to give a compound of Formula-IVa;

Formula-IVa
(c) amidation of the compound of Formula-IVa by treating with ammonia gas in presence of solvent ethanol to give a compound of Formula-Va;

Formula-Va
(d) reduction of the compound of Formula-Va with reducing agents TFA/SBH in presence of solvent DCM to give a compound of Formula-VIa;

Formula-VIa
(e) deprotection of the compound of Formula-VIa by treating with base NaOH in presence of solvent methanol to obtain Vilazodone of Formula-VII.

Formula-VII

In another aspect, the invention provides novel intermediate compounds of general Formula-II, Formula-IV and Formula-V as follows:

Formula-II

Formula-IV

Formula-V
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).
- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and O-trifluoromethane sulfonyl with the exception that when Z is Ts (tosyl), X is not Cl and when X is Cl, Z is not Ts (tosyl).
- Et represents ethyl (-C2H5).

In a further aspect the invention provides novel intermediate compounds of Formula-IVa and Formula-Va as shown below:


Formula-IVa

Formula-Va
wherein Ts represents tosyl and Et represents ethyl.

A further aspect of the invention is to provide a novel crystalline form of Vilazodone hydrochloride of Formula VIII characterized by X-ray powder diffraction spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values as shown in Figure-1.

Formula-VIII

In a further aspect, the invention provides a process for preparation of novel crystalline form of Vilazodone hydrochloride of Formula VIII comprising the step of:

(a) preparing a suspension of Vilazodone free base of Formula-VII in isopropanol;

Formula-VII
(b) to the above suspension drop wise adding conc. hydrochloric acid (HCl) at about 45 0C for about 30 min followed by stirring for about 1 hr at same temperature;

(c) cooling to about 00C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HCl of Formula VIII.

Formula-VIII
(Vilazodone HCl)

In a further embodiment the novel crystalline form of Vilazodone HCl of Formula VIII is obtained by the above described process for Vilazodone hydrochloride.

BRIEF DESCRIPTION OF FIGURES:
Figure-1: XRPD spectrum of novel crystalline form of Vilazodone hydrochloride.
Figure-2: Table showing the list of XRPD peaks of novel crystalline form of Vilazodone hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of Vilazodone of Formula-VII.

Formula-VII
(Vilazodone)

In one embodiment, the invention provides a process for preparation of Vilazodone as shown in below Scheme-A:

Scheme-A
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).

- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably Cl.

- Et represents ethyl (-C2H5).

Various steps of above shown Scheme-A are described below.

In this embodiment, the invention provides a process for preparation of Vilazodone comprising the steps of:
(a) treating a compound of Formula-I

Formula-I
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;

Formula-II
(b) coupling the compound of Formula-II with a compound of Formula-III

Formula-III
in presence of a suitable solvent and/or suitable acid binding agents and with or without activating agents to give a compound of Formula-IV;

Formula-IV
(c) amidation of the compound of Formula-IV by treating with a suitable amidation agent in presence of suitable solvent to give a compound of Formula-V;

Formula-V
(d) reduction of the compound of Formula-V with suitable reducing agent in presence of suitable solvent to give a compound of Formula-VI;

Formula-VI
(e) deprotection of the compound of Formula-VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula-VII.

Formula-VII
wherein,
- Z, X and Et represent the same meanings as defined in Scheme-A above.

The above said general process is schematically represented in Scheme-A above and described in below paragraphs.

Step-(a): Reduction of Ketone:
Step-(a) of the process in Scheme-A comprises a process for the preparation of intermediate compound of Formula-II by reduction of starting compound of Formula-I as shown below:

Formula-I Formula-II
wherein, Z and X represent the same meanings as defined in above Scheme-A.

The above reduction reaction proceeds in presence of suitable reducing agent and suitable solvent.

The suitable reducing agent in step-(a) may be selected from sodiumborohydride, lithium borohydride, NaBH3CN, DIBAL-H, lithium aluminiumhydride, vitride, borane-THF, sodiumborohydride/ iodine, 9-BBN; preferably sodiumborohydride. In one preferred embodiment the suitable reducing agent used in step-(a) is sodiumborohydride.

The solvent used in step-(a) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably the solvent used is methanol or ethanol.

In one preferred embodiment of the invention Z is tosyl (Ts) and X is chlorine (-Cl). Thus when Z is Ts and X is –Cl, the compound of Formula-Ia reacts with the reducing agent sodiumborohydride in presence of solvent methanol to give intermediate compound of Formula-IIa as shown below:

Step-(b): Coupling
Step-(b) of the process in Scheme-A comprises a process for the preparation of novel intermediate compound of Formula-IV by coupling of the compound of Formula-II obtained in step-(a) with a compound of Formula-III as shown below:

wherein, Z, X and Et represent the same meanings as defined in above Scheme-A.

Step-(b) proceeds in presence of suitable solvents and or suitable bases/reagents.

The suitable solvent used in step-(b) may be selected from triethylamine (TEA), toluene, diglyme, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran (THF), dioxane, water, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, acetonitrile or mixtures thereof; preferably triethylamine (TEA).

The suitable acid binding agents in step-(b) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal or alkali earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate or calcium carbonate or alkali metal or alkaline earth metal salt of a week acid, preferably a potassium, sodium or calcium salt, or an organic bases such as triethylamine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof; preferably triethylamine.

The suitable activating agents in step-(b) may be metal halides and/or phase transfer catalysts. Step-(b) is performed with or without presence of metal halides and with or without presence of phase transfer catalyst.

The metal halides in step-(b) may be selected from iodide and bromide of alkali metal or alkali earth metal; preferably sodium iodide or potassium iodide.

The phase transfer catalyst in step-(b) may be selected from 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; preferably TBAB.

In a preferred embodiment of the invention, when Z is tosyl (Ts) and X is chlorine (-Cl), the compound of Formula-IIa reacts with the compound of Formula-III in presence of solvent triethyl amine (TEA) and acid binding agent TEA, optionally in presence of phase transfer catalyst TBAB and metal halide potassium iodide (KI) to give novel intermediate compound of Formula-IVa as shown below:

Step-(c): Amidation
Step-(c) of the process in Scheme-A comprises amidation of intermediate compound of Formula-IV obtained in above step-(b) by treating with an suitable amidation agent in presence of suitable solvent to give novel intermediate compound of Formula-V as shown below:

The suitable amidation agent in step-(c) may be 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 tartarate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate, alkyl or aryl amines, magnesium nitride; mixtures such as magnesium methoxide/ammonium chloride, magnesium methoxide/ammonia, calcium chloride/ammonium chloride and calcium chloride/ ammonia; preferably the suitable amidation agent used is ammonia gas under pressure of about 1 Kg/Cm² to about 10 Kg/ Cm²; preferably about 3 Kg/ Cm².

The suitable solvent in step-(c) may be selected from water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, N,N-dimethyl acetamide, PEG 300, propylene glycol; chloro solvents like methylene chloride, chloroform and ethylene chloride; hydrocarbon solvents like to toluene, xylene, heptane, cyclohexane and hexane; preferably the solvent selected from methanol or ethanol.

In a preferred embodiment of the invention, when Z is tosyl (Ts), compound of Formula-IVa reacts with ammonia gas in presence of solvent ethanol to give novel intermediate compound of Formula-Va as shown below:

Step-(d): Reduction of Hydroxy
Step-(d) of the process in Scheme-A comprises reduction of hydroxyl group of the compound of Formula-V obtained in step-(c) by treating with suitable reducing agent(s) in presence of suitable solvent to give a compound of Formula-VI as shown below:

The suitable reducing agent in step-(d) may be used alone or in combination of suitable reagents; selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH3CN, sodium borohydride/BF3-etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, trifluoroacetic acid (TFA)/sodiumborohydride(SBH), Et3SiH/TFA; preferably combination of trifluoroacetic acid with sodiumborohydride is used.

The solvent used in step-(d) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, n-pentane and the like; “chloro solvents” such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably the solvent used is methylene dichloride (DCM).

In a preferred embodiment of the invention, when Z is tosyl (Ts), compound of Formula-Va reacts with combination of reducing agents TFA/SBH in presence of solvent DCM to give intermediate compound of Formula-VIa as shown below:

Step-(e): Deprotection
Step-(e) of the process in Scheme-A comprises deprotection of the compound of Formula-VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula-VII.

The suitable base used in step-(e) may be selected from an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate; or alkali metal or alkaline earth salt of weak acid, preferably a potassium, sodium or calcium salt; or an organic base such as triethylamine, dimethylaniline, pyridine or quinoline and the like; ammonia or mixtures thereof; preferably the base is sodium hydroxide (NaOH) and potassium hydroxide (KOH); more preferably the base used is NaOH.

The suitable solvent used in step-(e) may be selected from “alcoholic solvents” 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-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptanes, 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, dimetylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like; preferably alcoholic solvent such as methanol or ethanol are used.

In a preferred embodiment of the invention, when Z is tosyl (Ts), compound of Formula-VIa reacts with the base NaOH in presence of solvent methanol (MeOH) to give Vilazodone of Formula-VII as shown below:

In another aspect the invention provides novel intermediates for the preparation of Vilazodone.

In one embodiment of the invention, it provides novel intermediate compounds of general Formula-II, Formula-IV and Formula-V as follows:

Formula-II

Formula-IV

Formula-V
wherein,
- Z represents an amino protecting group -S(=O)2R1 , wherein R1 is selected from p-toluene, Phenyl, Methyl, n-propyl, n-butyl, Trifluoromethyl, benzyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-aminophenyl, 4-aminophenyl, 4-methylphenyl, 1-napthalene, 2-napthalene; preferably Z is Tosyl (Ts).
- X represents a leaving group selected from halogen (Cl, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and O-trifluoromethane sulfonyl with the exception that when Z is Ts, X is not Cl and when X is Cl, Z is not Ts.
- Et represents ethyl (-C2H5).

Thus in preferred embodiment when Z is Ts, the invention provides novel intermediate compounds of Formula-IVa and Formula-Va as shown below:

Formula-IVa

Formula-Va
wherein Ts represents tosyl and Et represents ethyl.

A further aspect of the invention is to provide a novel crystalline form of Vilazodone hydrochloride of Formula VIII characterized by X-ray powder diffraction spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values.

Formula-VIII

In a further aspect, the invention provides a process for preparation of novel crystalline form of Vilazodone hydrochloride of Formula VIII comprising the step of:

(a) preparing a suspension of Vilazodone free base of Formula-VII in isopropanol;

Formula-VII
(b) to the above suspension drop wise adding conc. hydrochloric acid (HCl) at about 45 0C for about 30 min followed by stirring for about 1 hr at same temperature;

(c) cooling to about 00C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HCl of Formula VIII.

Formula-VIII
(Vilazodone HCl)

The x-ray powder diffraction (XRPD) spectrum of novel crystalline form of Vilazodone hydrochloride showing the peaks is as shown in Figure-1. The table in Figure-2 shows the list of XRPD peaks with peak intensity of novel crystalline form of Vilazodone hydrochloride.

The present invention is further illustrated by the following examples:

EXAMPLES:

Example-1: Preparation of intermediate compound of Formula-IIa (Step-(a))

To a suspension of Formula-Ia (100 g, 248 mmol) in 1000 mL of methanol, SBH was added portion wise at 10 0C for 1 hr. Total reaction mixture was stirred for 1 hr at same temperature. After completion of the reaction monitored by TLC, 1000 mL of 10% ammonium chloride was added drop wise. Then the reaction mass temperature was raised to RT and the aqueous layer extracted DCM (2×750 mL). The combined organic layer was washed with water (2×200 mL) and saturated with brine (1×200 mL). The organic layer was dried with sodium sulphate and concentrated under reduced pressure to get the Formula-IIa as cream colour solid. Weight: 88 g, yield: 87.5%.

Example-2: Preparation of intermediate compound of Formula-IVa (Step-(b))

To a solution of Formula-IIa (60 g, 148 mmol) in 385 mL of triethyl amine, compound of Formula-III (43.2 g, 157 mmol), TBAB (33.6 g, 104 mmol) and KI (24.7 g, 148 mmol) were added at room temperature. The total reaction mixture was heated to 80-850C for 8hrs. Reaction was monitored by the HPLC. After completion of the reaction, the triethylamine was distilled out completely under reduced pressure. The residue was cooled to RT and dissolved in 300 mL of ethyl acetate and organic layer was washed with 100 mL of water fallowed by 100 mL of sutured NaCl solution. The organic layer was dried with sodium sulphate and distilled under reduced pressure to get the residue of the Formula-IVa. To the residue 100 mL of ethanol was added and stirred for 1hr at room temperature. The solid separated was filtered and washed with 25 mL of ethanol. The resultant solid was dried at 50 0C for 10 hrs to get the constant weight of formula-IVa, Weight: 66.7 gm, yield: 70%.

Example-3: Preparation of intermediate compound of Formula-Va (Step-(c))

A suspension of Formula-IVa (30 g, 46.8 mmol) in 900 mL of Ethanol was stirred for 24 hrs in sealed vessel under ammonia pressure (3-5kg) at RT. After the completion of the reaction monitored by HPLC, the excess ammonia and ethanol were distilled out completely under reduced pressure and then charged with 150 mL of methanol and stirred for 1 hr at same temperature. The solid separated was filtered and washed with 50 mL of methanol and dried the material at 50 0C to get the constant weight of Formula-Va. Weight: 26 g, yield: 91 %.

Example-4: Preparation of intermediate compound of Formula-VIa (Step-(d))

To a mixture of TFA (60.39 g, 529 mmol) and 250 mL of DCM, sodiumborohydride (SBH) (6.49 g, 171 mmol) was added portion wise for 1 hr at 10-15 0C. After completion of the addition, the reaction mixture was stirred for additional 2 hrs at same temperature. Then the solution of Formula-Va (25 g, 40 mmol) in 100 mL of DCM was added drop wise to the above reaction mixture for 1 hr at same temperature. Then the temperature was slowly raised to 40-45 0C and stirred for 15 hrs at same temperature. After Completion of the reaction monitored by TLC, the reaction mixture was cooled to 10 0C and 300 mL of water was added drop wise and the solution PH was adjusted to 10 using 10% K2CO3 at same temperature. The bottom organic layer was separated and the aqueous layer was again extracted with DCM (2×100 mL). The combined organic layer was washed with 200 mL of water and 200 mL of brine solution. The organic layer was dried with Na2SO4 and distilled out completely under reduced pressure to get solid of Formula-VIa. Weight: 20 g, yield: 82%.

Example-5: Preparation of Vilazodone free base of Formula-VII (Step-(e))

To the solution of Formula-VIa (100 g, 160 mmol) in 1000 mL of Methanol, solid NaOH (13.4 g, 330 mmol) was added at RT. Total reaction mass temperature was increased to 60-65 0C and stirred for 2 hrs at same temperature. After completion of the reaction monitored by TLC, the reaction mass was cooled to RT and 1000 mL of water was added. The solid separated was filtered and washed with water and dried the material at 50 0C to get the constant weight of crude Vilazodone base. Weight: 70 g yield: 95%. Purity: 97.2%. Crude material was recrystallized from isopropyl alcohol to get the pure compound with 99.1% of purity by HPLC. Weight: 62 g. Yield: 84.1%.

Example-6: Preparation of crystalline form of Vilazodone hydrochloride of Formula-VIII

To a clear solution of Vilazodone free base (100 g, 226.5 mmol) in 4 Lit of isopropanol, 50 mL of IPA-HCl was added drop wise at 60 0C for 30 min. The total reaction mixture was stirred for 1 hr at same temperature. After short stirring the solid separated was cooled to RT, then cooled to 0 0C and stirred for 1 hr. The solid was filtered and washed with chilled isopropanol. The wet material was dried for 10 hrs at 60 0C to get the constant weight. Weight: 100 g, yield: 92.5%, purity by HPLC: 99.6%.

The x-ray powder diffraction (XRPD) spectrum of novel crystalline form of Vilazodone hydrochloride showing the peaks is as shown in Figure-1; which is characterized by X-ray powder diffraction spectrum having peaks at 8.98, 14.44, 18.75, 19.36, 20.01, 20.34, 20.97, 24.56 and 25.34 ± 0.2 degrees 2? values. The table in Figure-2 shows the list of XRPD peaks with peak intensity of novel crystalline form of Vilazodone hydrochloride.