WO2016170542A1 - Process for preparation of vilazodone, novel intermediates thereof and novel crystalline form thereof - Google Patents

Process for preparation of vilazodone, novel intermediates thereof and novel crystalline form thereof Download PDF

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WO2016170542A1
WO2016170542A1 PCT/IN2015/050044 IN2015050044W WO2016170542A1 WO 2016170542 A1 WO2016170542 A1 WO 2016170542A1 IN 2015050044 W IN2015050044 W IN 2015050044W WO 2016170542 A1 WO2016170542 A1 WO 2016170542A1
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formula
ammonium
solvents
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solvent
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Satyanarayana Reddy BHEMIREDDY
Venkat Reddy YARAPATHI
V. Vara Prasada Reddy Paidimarla
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Nosch Labs Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • 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.
  • CN 103304547 A discloses a process for Vilazodone as shown in below Scheme- 2:
  • Scheme-2 CN103570697 discloses various routes for synthesis of Vilazodone.
  • 5-(piperazin-l-yl) benzofuran-2-carboxamide reacts with 4-bromo-l-butene to give an intermediate 5- (4- (3- butenyl) piperazin-l-yl) benzofuran-2- carboxamide, which further reacts with 3- iodo-l-tosyl-indole-5- carbonitrile to give 5- (4- (4- (5-cyano-l-tosyl-indol-3-yl) -3-butenyl) piperazin -1- yl) benzofuran -2-carboxamide.
  • X halogen F, CI, Br, I; preferably Br
  • US Patent 8802851 B2 describes a process for preparation of Vilazodone free base and subsequent conversion to Vilazodone HC1 comprising the steps of: (a) reacting 3-(4-chloro-l-hydroxy-butyl)-lH-indol-5-carbonitrile of formula (I) with 5-piperazin-l-yl-benzofuran-2-carboxylate methyl hydrochloride of formula (II) to give 5- ⁇ 4-[4-(5-cyano-lH-indol-3-yl)-4-hydroxybutyl]-piperazin-l- 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-lH-indol-3-yl)-4-hydroxy-butyl]-piperazin-l-yl ⁇ benzofuran-2- carboxylate methyl of formula (IV);
  • 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.
  • 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.
  • the invention provides a process for preparation of Vilazodone comprising the steps of:
  • Ts Tosyl
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
  • Et represents ethyl (-C 2 Hs).
  • the suitable reducing agent in step-(a) may be selected from sodiumborohydride, lithium borohydride, NaBH 3 CN, DIBAL-H, lithium aluminiumhydride, vitride, borane-THF, sodiumborohydride/ iodine, 9-BBN; preferably sodiumborohydride.
  • 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 tet
  • 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).
  • TFA triethylamine
  • 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.
  • TBAB tetra butyl ammonium bromide
  • 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
  • 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, ⁇ , ⁇ -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, NaBH 3 CN, sodium borohydride/BF 3 - etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, trifluoroacetic acid (TFA)/sodiumborohydride(SBH), Et 3 SiH/TFA; preferably combination of trifluoroacetic acid with sodiumborohydride is used.
  • suitable reagents selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 - etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, tri
  • 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 tet
  • 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
  • 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 tetrach
  • the invention provides a process for preparation of Vilazodone comprising the steps of:
  • the invention provides novel intermediate compounds of general Formula-II, Formula-IV and Formula-V as follows:
  • Ts Tosyl
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and 0-trifluoromethane sulfonyl with the exception that when Z is Ts (tosyl), X is not CI and when X is CI, Z is not
  • Et represents ethyl (-C 2 H 5 ).
  • 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.
  • the invention provides a process for preparation of novel crystalline form of Vilazodone hydrochloride of Formula VIII comprising the step of:
  • novel crystalline form of Vilazodone HCl of Formula VIII is obtained by the above described process for Vilazodone hydrochloride.
  • 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.
  • the present invention provides a process for preparation of Vilazodone of Formula- VII.
  • the invention provides a process for preparation Vilazodone as shown in below Scheme- A:
  • Ts Tosyl
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
  • Et represents ethyl (-C 2 H 5 ).
  • the invention provides a process for preparation Vilazodone comprising the steps of:
  • 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
  • the suitable reducing agent in step-(a) may be selected from sodiumborohydride, lithium borohydride, NaBH 3 CN, DIBAL-H, lithium aluminiumhydride, vitride, borane-THF, sodiumborohydride/ iodine, 9-BBN; preferably sodiumborohydride.
  • 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 tet
  • Z is tosyl (Ts) and X is chlorine (- CI).
  • Ts tosyl
  • X chlorine
  • the compound of Formula- la reacts with the reducing agent sodiumborohydride in presence of solvent methanol to give intermediate com ound of Formula-IIa as shown below:
  • 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 ste -(a) with a compound of Formula-Ill as shown below:
  • 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.
  • 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
  • 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.
  • TBAB tetra butyl ammonium bromide
  • the compound of Formula- Ila reacts with the compound of Formula-Ill 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) 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
  • 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, ⁇ , ⁇ -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.
  • 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, NaBH 3 CN, sodium borohydride/BF 3 - etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, trifluoroacetic acid (TFA)/sodiumborohydride(SBH), Et 3 SiH/TFA; preferably combination of trifluoroacetic acid with sodiumborohydride is used.
  • suitable reagents selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithium borohydride, NaBH 3 CN, sodium borohydride/BF 3 - etherate, vitride, sodiumborohydride/aluminium chloride, borane/aluminium chloride, sodiumborohydride/iodine, 9-BBN, tri
  • 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 tet
  • 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.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide
  • alkali metal or alkaline earth metal carbonate or bicarbonate salts such as sodium carbonate, potassium carbonate and calcium carbonate
  • alkali metal or alkaline earth salt of weak acid preferably a potassium, sodium or calcium salt
  • 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 tetrach
  • the invention provides novel intermediates for the preparation of Vilazodone.
  • Ts Tosyl
  • X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and 0-trifluoromethane sulfonyl with the exception that when Z is Ts, X is not CI and when X is CI, Z is not Ts.
  • Et represents ethyl (-C 2 H 5 ).
  • 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 de rees 2 ⁇ values.
  • the invention provides a process for preparation of novel crystalline form of Vilazodone hydrochloride of Formula VIII comprising the step of:
  • XRPD x-ray powder diffraction
  • 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-Ill (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 80-85°C for 8hrs. Reaction was monitored by the HPLC. After completion of the reaction, the triethylamine was distilled out completely under reduced pressure.
  • 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-HC1 was added drop wise at 60 °C 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 °C and stirred for 1 hr. The solid was filtered and washed with chilled isopropanol. The wet material was dried for 10 hrs at 60 °C to get the constant weight. Weight: 100 g, yield: 92.5%, purity by HPLC: 99.6%.
  • XRPD x-ray powder diffraction

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Abstract

The invention relates to process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone. The invention also relates to novel crystalline form of Vilazodone hydrochloride and process for preparation thereof.

Description

PROCESS FOR PREPARATION OF VILAZODONE, NOVEL INTERMEDIATES THEREOF AND NOVEL CRYSTALLINE FORM
THEREOF 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-
Figure imgf000002_0001
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-(l -piperazin-l-yl) benzofuran-2- carboxamide with 3-(4-chlorobutyl)-lH-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 N¾ gas. Scheme- 1 below represents above said synthetic routes:
Figure imgf000003_0001
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-l-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:
Figure imgf000003_0002
Scheme-2 CN103570697 discloses various routes for synthesis of Vilazodone. In one route, 5-(piperazin-l-yl) benzofuran-2-carboxamide reacts with 4-bromo-l-butene to give an intermediate 5- (4- (3- butenyl) piperazin-l-yl) benzofuran-2- carboxamide, which further reacts with 3- iodo-l-tosyl-indole-5- carbonitrile to give 5- (4- (4- (5-cyano-l-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-l-tosyl-indol-3-yl) -3-butyl) piperazin -1- yl) benzofuran -2- carboxamide and then detosylated to produce Vilazodone as shown in Scheme-3 below:
Figure imgf000004_0001
Scheme-3
Org. Process Res. Dev. 2012, 16, 1552-1557 (HU et. al.) discloses a process for Vilazodone as shown in below Scheme-4:
Figure imgf000004_0002
Scheme-4
HU et. al. describes varieties of process for preparation of above intermediate compound 3, starting from reduction of intermediate compound 2.
Figure imgf000005_0001
Another Chinese publication CN 102180868A discloses a process as shown in Scheme-5 below:
Figure imgf000005_0002
Wherein X = halogen F, CI, Br, I; preferably Br
Scheme-5
US Patent 8802851 B2 describes a process for preparation of Vilazodone free base and subsequent conversion to Vilazodone HC1 comprising the steps of: (a) reacting 3-(4-chloro-l-hydroxy-butyl)-lH-indol-5-carbonitrile of formula (I) with 5-piperazin-l-yl-benzofuran-2-carboxylate methyl hydrochloride of formula (II) to give 5-{4-[4-(5-cyano-lH-indol-3-yl)-4-hydroxybutyl]-piperazin-l- 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-lH-indol-3-yl)-4-hydroxy-butyl]-piperazin-l-yl}benzofuran-2- carboxylate methyl of formula (IV); (c) hydro genating the compound of formula (IV) with H2 to obtain 5-{4-[4-(5-cyano-lH-indol-3-yl)-4-hydroxy-butyl]- piperazin-l-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-lH-indol-3-yl)butyl]piperazin-l-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)l-H-indol-5-carbonitrile in presence of Sodium Borohydride. The above said process is shown in below Scheme-6:
Figure imgf000007_0001
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
Figure imgf000008_0001
Z
Formula- 1
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;
Figure imgf000009_0001
Formula- II
(b) coupling the compound of Formula- II with a com ound of Formula-Ill
Figure imgf000009_0002
Formula-Ill
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;
Figure imgf000009_0003
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;
Figure imgf000009_0004
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;
Figure imgf000010_0001
Formula- VI
(e) deprotection of the compound of Formula- VI using suitable bases in presence of suitable sol ent to obtain Vilazodone of Formula- VII.
Figure imgf000010_0002
Formula- VII
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
Et represents ethyl (-C2Hs).
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, Ν,Ν-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- la
Figure imgf000014_0001
Ts
Formula- la
with sodiumborohydride (SBH) in presence of solvent methanol to give a compound of Formula-IIa;
Figure imgf000015_0001
Formula- Ila
(b) coupling the compound of Formula- Ila with a com ound of Formula- III
Figure imgf000015_0002
Formula-Ill
in presence of acid binding agent TEA, potassium iodide (KI) and TBAB in solvent TEA to give a compound of Formula- IVa;
Figure imgf000015_0003
Formula- IVa
(c) amidation of the compound of Formula- IVa by treating with ammonia in presence of solvent ethanol to give a compound of Formula- Va;
Figure imgf000015_0004
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;
Figure imgf000015_0005
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-
Figure imgf000016_0001
In another aspect, the invention provides novel intermediate compounds of general Formula-II, Formula-IV and Formula-V as follows:
Figure imgf000016_0002
Formula-II
Figure imgf000016_0003
Formula-IV
Figure imgf000016_0004
Formula-V
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and 0-trifluoromethane sulfonyl with the exception that when Z is Ts (tosyl), X is not CI and when X is CI, 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:
Figure imgf000017_0001
Formula- IVa
Figure imgf000017_0002
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 2Θ values as shown in Figure-1.
Figure imgf000018_0001
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) preparin a suspension of Vilazodone free base of Formula- VII in isopropanol;
Figure imgf000018_0002
Formula- VII
(b) to the above suspension drop wise adding cone, hydrochloric acid (HCl) at about 45 °C for about 30 min followed by stirring for about 1 hr at same temperature;
(c) cooling to about 0°C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HCl of Formula VIII.
Figure imgf000018_0003
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.
Figure imgf000019_0001
Formula-VII
(Vilazodone)
In one embodiment, the invention provides a process for preparation Vilazodone as shown in below Scheme- A:
Figure imgf000019_0002
Scheme-A
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.
Et represents ethyl (-C2H5).
Various steps of above shown Scheme-A are described below.
In this embodiment, the invention provides a process for preparation Vilazodone comprising the steps of:
(a) treating a compound of Formula-I
Figure imgf000020_0001
Z
Formula- 1
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;
Figure imgf000020_0002
Formula-II
(b) coupling the compound of Formula-II with a com ound of Formula-Ill
Figure imgf000020_0003
Formula-Ill
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;
Figure imgf000021_0001
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;
Figure imgf000021_0002
Formula-V
(d) reduction of the compound of Formula-V with suitable reducing agent in presence of suitable solvent to ive a compound of Formula- VI;
Figure imgf000021_0003
Formula- VI
(e) deprotection of the compound of Formula- VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula- VII.
Figure imgf000021_0004
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
Figure imgf000022_0001
Formula- 1 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 (- CI). Thus when Z is Ts and X is -CI, the compound of Formula- la reacts with the reducing agent sodiumborohydride in presence of solvent methanol to give intermediate com ound of Formula-IIa as shown below:
Figure imgf000023_0001
Formula-IIa
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 ste -(a) with a compound of Formula-Ill as shown below:
Figure imgf000023_0002
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 (-C1), the compound of Formula- Ila reacts with the compound of Formula-Ill 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:
Figure imgf000025_0001
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:
Figure imgf000025_0002
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, Ν,Ν-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:
Figure imgf000026_0001
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:
Figure imgf000027_0001
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:
Figure imgf000028_0001
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.
Figure imgf000028_0002
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 ive Vilazodone of Formula- VII as shown below:
Figure imgf000029_0001
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:
Figure imgf000029_0002
Formula-II
Figure imgf000030_0001
Formula- IV
Figure imgf000030_0002
Formula-V
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and 0-trifluoromethane sulfonyl with the exception that when Z is Ts, X is not CI and when X is CI, 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:
Figure imgf000030_0003
Formula- IVa
Figure imgf000031_0001
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 de rees 2Θ values.
Figure imgf000031_0002
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;
Figure imgf000031_0003
Formula- VII
(b) to the above suspension drop wise adding cone, hydrochloric acid (HC1) at about 45 °C for about 30 min followed by stirring for about 1 hr at same temperature; (c) cooling to about 0 C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HC1 of Formula VIII.
Figure imgf000032_0001
Formula- VIII
(Vilazodone HC1)
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- Ila (Step-(a))
To a suspension of Formula- la (100 g, 248 mmol) in 1000 mL of methanol, SBH was added portion wise at 10 °C 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 (2x750 mL). The combined organic layer was washed with water (2x200 mL) and saturated with brine (1x200 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-Ill (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 80-85°C 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 lhr at room temperature. The solid separated was filtered and washed with 25 mL of ethanol. The resultant solid was dried at 50 °C 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 °C 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 °C. 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 °C and stirred for 15 hrs at same temperature. After Completion of the reaction monitored by TLC, the reaction mixture was cooled to 10 °C and 300 mL of water was added drop wise and the solution P 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 (2x100 mL). The combined organic layer was washed with 200 mL of water and 200 mL of brine solution. The organic layer was dried with Na2S04 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 °C 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 °C 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-HC1 was added drop wise at 60 °C 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 °C and stirred for 1 hr. The solid was filtered and washed with chilled isopropanol. The wet material was dried for 10 hrs at 60 °C 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 2Θ values. The table in Figure-2 shows the list of XRPD peaks with peak intensity of novel crystalline form of Vilazodone hydrochloride.

Claims

We Claim:
1. A process for preparation of Vilazodone comprising the steps of: (a) treating a compound of Formula-I
Figure imgf000036_0001
Z
Formula- 1
with suitable reducing agent in presence of a suitable solvent to give a compound of Formula-II;
Figure imgf000036_0002
Formula-II
(b) coupling the compound of Formula-II with a com ound of Formula-Ill
Figure imgf000036_0003
Formula-Ill
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;
Figure imgf000036_0004
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;
Figure imgf000037_0001
Formula-V
(d) reduction of the compound of Formula-V with suitable reducing agent(s) in presence of suitable solvent to ive a compound of Formula- VI;
Figure imgf000037_0002
Formula- VI
(e) deprotection of the compound of Formula- VI using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula- VII.
Figure imgf000037_0003
Formula- VII
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI. 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, NaBI¾CN, 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-Ill 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- la
Figure imgf000043_0001
Formula- la
with sodiumborohydride (SBH) in presence of solvent methanol to give a compound of Formula-IIa;
Figure imgf000043_0002
Ts
Formula-IIa
(b) coupling the compound of Formula-IIa with a com ound of Formula- III
Figure imgf000043_0003
Formula-Ill
in presence of acid binding agent TEA, potassium iodide (KI) and TBAB in solvent TEA to give a compound of Formula- IVa;
Figure imgf000043_0004
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;
Figure imgf000044_0001
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;
Figure imgf000044_0002
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.
Figure imgf000044_0003
Formula- VII wherein -Et represents ethyl.
29. A compound of Formula- II
Figure imgf000044_0004
Formula- II
wherein, Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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 (CI, Br and I), O-tosyl, O-mesyl, O-benzenesulfonyl and 0-trifluoromethane sulfonyl with the exception that when Z is Ts (tosyl), X is not CI and when X is CI, Z is not Ts (tosyl).
30. A compound of Formula- IV
Figure imgf000045_0001
Formula- IV wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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
Figure imgf000045_0002
Formula-V
wherein,
Z represents an amino protecting group -S(=0)2Ri , wherein Ri 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).
Figure imgf000046_0001
wherein Ts represents tosyl and Et represents ethyl.
Figure imgf000046_0002
wherein Ts represents tosyl.
34. A novel crystalline form of Vilazodone h drochloride of Formula VIII
Figure imgf000046_0003
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 2Θ 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 2Θ values, comprising the steps of:
(a) preparing a suspension of Vilazodone free base of Formula- VII in isoprop
Figure imgf000047_0001
Formula- VII
(b) to the above suspension drop wise adding cone, hydrochloric acid (HC1) at about 45 °C for about 30 min followed by stirring for about 1 hr at same temperature;
(c) cooling to about 0°C followed by stirring for about 1 hr to give novel crystalline form of Vilazodone HC1 of Formula VIII.
Figure imgf000047_0002
Formula- VIII
(Vilazodone HC1)
. A novel crystalline form of Vilazodone h drochloride of Formula VIII
Figure imgf000047_0003
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 2Θ values obtained by the process as claimed in claim 35.
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