PROCESS FOR PREPARATION OF VILAZODONE AND ITS NOVEL

INTERMEDIATES

FIELD OF INVENTION

The invention relates to a process for preparation of Vilazodone. The invention also relates to novel intermediates for synthesis of Vilazodone.

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-XI as shown below-

Formula-XI

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:

Seheme-l 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 rocess for Vilazodone as shown in below Scheme-2:

eduction

Sciiem -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:

Scheme-3

Org. Process Res. Dev. 2012, 16, 1552-1557 discloses a process for Vilazodone as shown in below Scheme-4:

Scheme-4

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

Wherein X = halogen F, CI, Br, I; preferably Br

Scheme-5 US Publication 20130225818 describes a process for Vilazodone free base and subsequent converted to Vilazodone HCl as 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.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for preparation of Vilazodone and novel intermediates for synthesis of Vilazodone.

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

(a) treating compound of Formula-I

7

Formula-I

with a suitable reagent in presence of a suitable catalyst and solvent to give intermediate compound of Formula-II;

Formula-II

(b) coupling Formula-II obtained in above step-(a) with a compound of Formula- III

Formula-Ill

in presence of a suitable solvent and/or suitable bases and/or activating agents to give a compound of Formula- IV;

Formula-IV (c) amidation of the compound of Formula-IV (when R ₃ is not NH ₂ ) by treating with a suitable amidation agent in presence of suitable solvent to give a compound of Formula-V

Formula-V

(d) deprotection of the compound of Formula-V with an suitable reagent/catalyst in presence of a suitable solvent to give a compound of Formula- VI;

Formula- VI

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

Formula- VII

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

XI

wherein, in all the above steps,

Z represents an amino protecting group -S(=0) ₂ Ri , 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.

Y is either oxygen (O) or sulfur (S); preferably Y is O.

When Y is O, for acyclic ketals; R ₂ is selected from CI to C5 alkyl chain or substituted derivatives like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R ₂ is selected from CI to C5 alkyl chain individually or its substituted derivatives like 4-bromomethyl-l,3-dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane, trans- 1,2-cyclohexanediol ketal, trans- 4,6-dimethyl- 1 ,3-dioxolane, 4,5-dimethoxymethyl- 1 ,3-dioxolane, 5-methylene- 1,3-dioxanes, 5,5-dibromol,3-dioxanes, 5-(2'-pyridyl)-l,3-dioxanes, 5- trimethylsilyl-l,3-dioxanes etc; preferably when Y is O, R ₂ is CI to C5 alkyl chain, more preferably methyl or ethyl.

When Y is S, for acyclic thioketals R ₂ is selected from CI to C5 alkyl chain or substituted derivatives like diphenyl, dibenzyl, diacetyl etc, and for cyclic thioketals R ₂ is selected from CI to C5 alkyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepin.

R ₃ represents either NH ₂ or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R ₃ is methoxy (-OMe) or ethoxy (-OEt).

When Y is O, the suitable reagents used in step-(a) may be selected from Trialkylorthoformates , alkyl which includes C 1 to C5 alkyl chain or branched like isopropyl, CC1 ₃ CH ₂ 0H, ((MeO) ₄ Si, montimorillonite clay, ammonium chloride, allyl bromide/Sb(OEt) ₃ , Sc(OTf) ₃ /HC(OCH ₃ ) ₃ , CeCl ₃ .7H ₂ 0, Ac ₂ 0/lewis acids/PCl ₃ /zeolite/Iodine, amberlyst, SmCl ₃ , HOCH ₂ C(CH ₃ ) ₂ CH ₂ OH/Sc(NTf ₂ ) ₃ /N-4- methoxybenzyl-2-cyanopyridinium hexafluoroantimonate/sulphated zarconica, CH ₂ =C(CH ₂ OH) _2, Br ₂ C(CH ₂ OH) ₂ , 2-(2-pyridyl)-l,3-propanediol, 2-trimethylsilyl-l,3- propanediol, HO(CH) _n OH (n=2-5)/lewis acids/Me ₃ SiCl/Al ₂ 0 ₃ /CuCl ₂ /Me ₃ SiOTf/Se0 ₂ / ZrOCl ₂ /MgS0 ₄ , 2-ethoxy-l,3-dioxolane, 2-methoxy-l,3-dioxolane, 2-ethyl-2-methyl- 1,3-dioxolane/pyridinium tosylate, HOCH ₂ CHOHCH ₂ Br,

CH ₂ =CHCH ₂ CH ₂ CHOHCH ₂ OH, TMS protected l-(4- methoxyphenyl)ethyleneglycol/TMSI, TMS protected glycerol, trans- 1,2- cyclohexanediol/z ^' -prOTMS, 2,4-pentane diol/Sc(OTf) ₃ and 4,5-dimethoxymethyl-l,3- diol; preferably when Y is O, the suitable reagents are trimethylorthoformate or Triethyl Orthoformate. When Y is S, suitable reagents used in above step (a) may be selected from R ₂ SH/mineral acid, R ₂ SiMe ₃ /ZnI ₂ , R ₂ SH/TMSC1, (BSR ₂ ) ₃ , PhSH/lewis acid, R ₂ SH/S0 ₂ , EtSiH/TiCl ₄ , R ₂ SSR ₂ , MeCOSH, HS(CH ₂ )„SH,n=2-5/lewis acid/SOCl ₂ - Si0 ₂ /TiCl ₄ /Zn(OTf) ₂ /Mg(OTf) ₂ /FeCl ₃ -Si0 ₂ /SnCl ₂ /MgI ₂ /ZrCl ₄ -silica and TMSSCH ₂ CH ₂ STMS; preferably when Y is S, the suitable reagents is ethanethiol.

Step-(a) is performed with or without presence of catalyst.

Suitable catalyst in step-(a) may be selected from organic acids such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid; preferably hydrochloric acid or sulfuric acid.

Suitable 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, heptane, n- pentane and the like, "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimethylacetamide, dimethylsulfoxide 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 selected is alcoholic solvent; preferably methanol or ethanol. Step-(b) is performed in presence of suitable solvents and /or suitable bases/activating agents.

The suitable bases in step-(b) are acid binding agents, which 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 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 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/Cm ² to about 10 Kg/ Cm ² ; preferably about 3 Kg/ Cm ² .

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.

Step-(d) is performed in presence of suitable reagents/catalysts. The suitable reagents used in step-(d) for deprotection ketals may be selected from Si0 ₂ , TMSI,TIC1 ₄ , LiBF ₄ , Amberlyst, H ₂ 0 ₂ , BF ₃ Et ₂ 0/TEAI, SiH ₂ I ₂ , M0 ₂ (acac) ₂ , AcCl/SmCl ₃ , SnCl ₂ /graphite, DDQ, HM-zeolite, ISiCl ₃ , ZnCl ₂ /Me ₂ S, Na ₂ S ₂ 0 ₄ , montimorillonite, Me ₂ BBr, Zn, alumina/silica gel, pyridinium tosylate(PPTS), MgS0 ₄ , Ph3CBF ₄ , NaTeSH, CuS0 ₄ , DDQ, PPh ₃ /CBr ₄ , SmCl TMSCl, 2,4,6-triphenyl tetrafluoroborate, NaI/CeCl ₃ . 7H ₂ 0, Zn-Ag, Mel/base, LiBF4, NBS, Pd(OH) ₂ /H _2.

The suitable reagents used in step-(d) for deprotection of thioketals may be selected from AgN0 ₃ /Ag ₂ 0, AgC10 ₄ , HgCl ₂ /CdC0 ₃ /CaC0 ₃ , Me ₂ CH(CH ₂ ) ₂ ONO, T1(N0 ₃ ) ₃ , S0 ₂ Cl ₂ /Si0 ₂ , I2/NaHC0 ₃ , H ₂ 0 ₂ , NaI0 ₄ , CuCl/CuO, HgO, mCPBA, PhsCClCVPhsCOMe/NaHCOs, DDQ, GaCl ₃ , clay supported NH ₄ N0 ₃ , NaOMe/Si0 ₂ , Hg(C10 ₄ ) ₂ /CaC0 ₃ , NCS, Tl(OCOCF ₃ ) ₃ , p-MeC ₆ H ₄ S0 ₂ N(Cl)Na, (PhSeO) ₂ 0, Me ₂ (CH ₂ ) ₂ ONO, N-Chlorobezotrizole, Ce(NH ₄ ) ₂ (N0 ₃ ) ₆ , MeOS0 ₂ F, Mel, Et ₃ OBF ₄ , Ac ₂ 0/TEA, PyHBr/Br ₂ , TBAB, CuCl ₂ /Si0 ₂ , TMSOTf/0 ₂ NC ₆ H ₄ CHO, Se0 ₂ , H ₅ IO ₅ , DDQ, SbCls/N ₂ , GaCl ₃ , Amberlyst, Dowex 50W/paraformaldehyde, oxone/wetalumina, Fe(N0 ₃ ) _3.

The catalysts may be acid catalysts selected from organic acids such as trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid; preferably the acid used is hydrochloric acid (HC1), more preferably aqueous hydrochloric acid.

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, heptane, n- pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimetylacetamide, dimethyl sulfoxide 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. The suitable reducing agent in step-(e) 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, acetic acid /sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et ₃ SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone; preferably combination of trifluoroacetic acid with sodiumborohydride is used. The 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, dimethyl sulfoxide 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-(f) 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.

Suitable solvent used in step-(f) 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, dimethyl sulfoxide 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

Formula-la

with Triethyl Orthoformate in presence of sulfuric acid and ethanol to give a compound of Formula-IIa;

Formula-IIa

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

Formula-Ill

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

Formula-IVa

(c) amidation of the compound of Formula-IVa (when R ₃ is not NH ₂ ) by treating with ammonia gas in presence of solvent ethanol to give a compound of Formula-Va;

Formula-Va

(d) deprotection of ketone of the compound of Formula-Va with aqueous hydrochloric acid (aq. HC1) in presence of solvent methanol to give a compound of Formula- Via;

(e) reduction of the compound of Formula- Via with TFA/sodium borohydride in presence of solvent methylene dichloride (DCM) to give a compound of Formula- Vila;

Formula- Vila

(f) deprotection of the compound of Formula- Vila by treating with NaOH in presence of methanol to obtain Vilazodone. In another aspect the invention provides novel intermediate compounds of general Formula- II Formula- IV, Formula-V and Formula- VI:

II IV

wherein Z, X, Y, R ₂ and R ₃ represent the same meanings as defined above.

In a further aspect the present invention provides novel intermediate compounds of below shown Formula:

Ila IVa

Va Via

Formula- Villa Formula-IXa

Wherein, -Ts represents a tosyl group,

R ₃ represents either NH ₂ or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R ₃ is methoxy (-OMe) or ethoxy (-OEt) and, Et represents ethyl (-C ₂ Hs).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of Vilazodone of Formula- XL

Vilazodone base

Formula-XI

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

Scheme-A (Path-A)

wherein,

Z represents H or an amino protecting group selected from groups -S(=0) ₂ Ri , 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. In one preferred embodiment when Ri is p-toluene, Z is tosyl group (Ts). - X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O- mesyl, O-benzenesulfonyl, 0-trifluoromethane sulfonyl; preferably X is halogen, more preferably CI.

Y is either oxygen (O) or sulfur (S); preferably Y is O.

When Y is O, for acyclic ketals; R ₂ is selected from CI to C5 alkyl chain or substituted derivatives like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R ₂ is selected from CI to C5 alkyl chain individually or its substituted derivatives like 4-bro mo methyl- 1,3 -dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane, trans- 1,2-cyclohexanediol ketal, trans- 4,6-dimethyl- 1 ,3-dioxolane, 4,5-dimethoxymethyl- 1 ,3-dioxolane, 5-methylene- 1,3-dioxanes, 5,5-dibromol,3-dioxanes, 5-(2'-pyridyl)-l,3-dioxanes, 5- trimethylsilyl-l,3-dioxanes etc.; preferably when Y is O, R ₂ is CI to C5 alkyl chain, more preferably methyl or ethyl.

When Y is S, for acyclic ketals R ₂ is selected from CI to C5 akyl chain or substituted derivatives like diphenyl, dibenzyl, diacetyl etc, and for cyclic ketals R ₂ is selected from CI to C5 alkyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepinect; preferably when Y is S, R ₂ is CI to C5 alkyl chain, more preferably methyl or ethyl.

R ₃ represents either NH ₂ or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R ₃ is methoxy (-OMe) or ethoxy (-OEt).

Various steps of 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

z

Formula-I

with a suitable reagent in presence of a suitable catalyst and 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-Ill

in presence of a suitable solvent and/or suitable bases and/or activating agents and/or suitable phase transfer catalysts to give a compound of Formula- IV;

Formula-IV

(c) amidation of the compound of Formula-IV (when R ₃ is not NH ₂ ) by treating with an suitable amidation agent in presence of suitable solvent to give a compound of Formula- V

Formula-V

(d) deprotection of ketone of the compound of Formula-V with an suitable reagent/catalyst in presence of a suitable solvent to give a compound of Formula- VI;

Formula- VI

(e) reduction of the compound of Formula- VI by a suitable reducing agent in presence of a suitable solvent to give a compound of Formula- VII;

Formula- VII

(f) deprotection of the compound of Formula- VII using suitable bases in presence of suitable solvent to obtain Vilazodone of Formula XI. wherein,

Z, X, Y R ₂ and R ₃ are same as defined in Scheme-A (Path-A) above, wherein Z is not H and R ₃ may be NH ₂ or O-alkyl. The above said general process is schematically represented in Scheme-A (Path-A) above and described in below paragraphs.

Step-(a): Protection of Ketone:-

Step-(a) of the process in Scheme-A (Path-A) comprises a process for the preparation of a novel intermediate compound of Formula-II starting from a compound of Formula-I as shown below:

Fonnuia-I Fomiula-H

In the above compounds of Formula-I or Formula-II; Z, X, Y and R ₂ represent the same meanings as defined in above Scheme-A (Path-A).

The protection of ketone (C=0) group of Formula-I can be achieved by treating Formula-I with a suitable reagent which introduces protecting groups to give novel intermediate compound of Formula-II.

When Y is O, the suitable reagents for introducing protecting group may be selected from Trialkylorthoformates , alkyl which includes CI to C5 alkyl chain or branched like isopropyl, CC1 ₃ CH ₂ 0H, ((MeO) ₄ Si, montimorillonite clay, ammonium chloride, allyl bromide/Sb(OEt) ₃ ,Sc(OTf) ₃ /HC(OCH ₃ ) ₃ , CeCl ₃ .7H ₂ 0, Ac ₂ 0/lewis acids/PCl ₃ /zeolite/Iodine, amberlyst, SmCl ₃ , HOCH ₂ C(CH ₃ ) ₂ CH ₂ OH/Sc(NTf ₂ ) ₃ /N-4- methoxybenzyl-2-cyanopyridinium hexafluoroantimonate/sulphated zarconica, CH ₂ =C(CH ₂ OH) _2, Br ₂ C(CH ₂ OH) ₂ , 2-(2-pyridyl)-l,3-propanediol, 2-trimethylsilyl-l,3- propanediol, HO(CH) _n OH (n=2-5)/lewis acids/MesSiCl/A^Os/CuCyMesSiOTf/SeO^ ZrOCl ₂ /MgS0 ₄ , 2-ethoxy-l,3-dioxolane, 2-methoxy-l,3-dioxolane, 2-ethyl-2-methyl- 1,3-dioxolane/pyridinium tosylate, HOCH ₂ CHOHCH ₂ Br,

CH ₂ =CHCH ₂ CH ₂ CHOHCH ₂ OH, TMS protected l-(4- methoxyphenyl)ethyleneglycol/TMSI, TMS protected glycerol, trans- 1,2- cyclohexanediol/z ^' -prOTMS, 2,4-pentane diol/Sc(OTf) ₃ and 4,5-dimethoxymethyl-l,3- diol. In one preferred embodiment when Y is O, the suitable reagents are trimethylorthoformate or Triethyl Orthoformate.

When Y is S, suitable reagents for introducing protecting group may be selected from R ₂ SH/mineral acid, R ₂ SiMe ₃ /ZnI ₂ , R ₂ SH/TMSC1, (BSR ₂ ) ₃ , PhSH/lewis acid, R ₂ SH/S0 ₂ , EtSiH/TiCl ₄ , R ₂ SSR ₂ , MeCOSH, HS(CH ₂ ) _n SH,n=2-5/lewis acid/SOCl ₂ - Si0 ₂ /TiCl ₄ /Zn(OTf) ₂ /Mg(OTf) ₂ /FeCl ₃ -Si0 ₂ /SnCl ₂ /MgI ₂ /ZrCl ₄ -silica and TMSSCH ₂ CH ₂ STMS. In one preferred embodiment when Y is S, the suitable reagent is methane thiol or ethane thiol. The reaction of Formula-I with suitable reagent in above step-(a) is performed with or without suitable catalyst and/ or a suitable solvent.

The suitable catalyst used in the above step-(a) of the process may be selected from organic acids such as succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric aicd, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric aicd and phosphoric acid. In one preferred embodiment the catalyst used is hydrochloric acid or sulfuric acid.

The suitable solvent used in the above step-(a) of the process 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, heptane, n-pentane and the like, "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimethylacetamide, dimethylsulfoxide 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. In one preferred embodiment the solvent selected in step-(a) is alcoholic solvent, preferably methanol or ethanol.

Accordingly in one preferred embodiment of the invention, X is -CI; Ri is p-toluene, Y is O and R ₂ is ethyl (Et). When Ri is p-toluene, Z represents a tosyl group (Ts).

Thus when X is CI, Z is Ts, Y is O and R ₂ is ethyl, above mentioned Formula-I and Formula-II becomes below shown Formula- la and Formula- Ila respectively:

Formiiia-Ia

wherein Ts represents tosyl group.

According to one preferred embodiment of the invention, in step-(a) Formula-la is treated with Triethyl Orthoformate in presence of sulfuric acid and ethanol to give novel intermediate compound of Formula-IIa as shown below:

Foimnla-Ia Fermiila-IIa

Step-(b): Coupling

Step-(b) of the process in Scheme-A (Path-A) comprises a process for the preparation of novel intermediate of Formula- IV by coupling of the compound of Formula-II with a compound of Formula-Ill as shown below: wherein,

Z, X, Y _, R ₂ and R ₃ represent the same meanings as defined in above Scheme-A

(Path-A)

The coupling of Formula-II and Formula-Ill in step-(b) is performed in presence of suitable bases/reagents in suitable solvents.

The suitable bases in step-(b) are acid binding agents, which 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 base such as triethylamine, dimethylaniline, pyridine or quinoline and the like or the mixtures thereof. In one preferred embodiment of the invention, the acid binding agent selected is triethylamine.

The 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. In one preferred embodiment the solvent used in step- (b) is triethylamine (TEA).

The suitable reagents may be metal halides and phase transfer catalysts. The coupling reaction can be performed with or without metal halides. In one preferred embodiment of the present invention, in step-(b) Formula-II is condensed with Formula-Ill in presence of metal halides selected from iodide and bromide of alkali metal or alkali earth metal; preferably sodium iodide or potassium iodide. In one preferred embodiment of the invention, the metal halide used in step-(b) is potassium iodide (KI).

The coupling reaction can be performed with or without phase transfer catalysts. The phase transfer catalysts 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.

In one preferred embodiment of the invention, in step-(b) Formula-II is condensed with Formula-Ill in the presence of phase transfer catalyst tetra butyl ammonium bromide (TBAB).

Accordingly in one preferred embodiment of the invention, X is -CI; Ri is p-toluene, Y is O and R ₂ is ethyl (Et) and R ₃ is ethoxy (OEt). When Ri is p-toluene, Z represents a tosyl group (Ts).

Thus when X is CI, Z is Ts, Y is O, R ₂ is ethyl and R ₃ is ethoxy (OEt), above mentioned Formula- IV becomes Formula- IVa as shown below:

Formula-IVa wherein Ts represents tosyl group. According to one preferred embodiment of the present invention, in step-(b) Formula- Ila is condensed with Formula-IIIa (when R ₃ in Formula-Ill is ethoxy (OEt)) in presence of potassium iodide (KI) and catalyst TBAB in solvent TEA to give the novel intermediate compound of Formula- IVa as shown below:

When R ₃ in Formula- III is NH _2, coupling of Formula- Ila with Formula- III directly gives intermediate compound of Formula- V as shown below:

Step-(c): Amidation

Step-(c) of the process in Scheme-A (Path-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

wherein,

Z, Y, R ₂ and R ₃ represent the same meanings as defined in Scheme-A (Path-A). When R ₃ is NH ₂ this amidation step is not required and Formula- IV becomes Formula- V. In one preferred embodiment R ₃ is ethoxy (OEt).

The amidation agent is the source of ammonia. The suitable amidation agent used 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.

Source of ammonia is selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base; more preferably the source of ammonia is ammonia gas.

In one preferred embodiment, the amidation reaction in step-(c) is advantageously carried out using ammonia gas under pressure of about 1 Kg/Cm ² to about 10 Kg/ Cm ² , and specifically about 3 Kg/ Cm ² . 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 in step-(c) is alcohol; more preferably methanol (MeOH) or ethanol (EtOH).

Accordingly in one preferred embodiment of the invention, X is -CI; Ri is p-toluene, Y is O and R ₂ is ethyl (Et) and R ₃ is ethoxy (OEt). When Ri is p-toluene, Z represents a tosyl group (Ts).

Thus when X is CI, Z is Ts, Y is O, R ₂ is ethyl and R ₃ is ethoxy (OEt), above mentioned Formula-V becomes Formula- Va as shown below:

Formu! wherein Ts represents tosyl group.

According to one preferred embodiment of the present invention, in step-(c) Formula- IVa is treated with ammonia under pressure in presence of solvent ethanol to give a novel intermediate compound of Formula- Va as shown below:

Step-(d): Deprotection of Ketals or Thioketals

Step-(d) of the process in Scheme-A (Path-A) comprises deprotection of ketals or thioketals by treating intermediate compound of Formula-V with an suitable reagent in presence of a solvent to give intermediate compound of Formula- VI;

Formula-VI

wherein,

Z, Y & R ₂ represent the same meanings as defined above in Scheme-A (Path-

A).

Step-(d) is performed in presence of suitable reagents/catalysts.

The reagents used in step-(d) for deprotection of ketals may be selected from Si0 ₂ , TMSI,TIC1 ₄ , LiBF ₄ , Amberlyst, H ₂ 0 ₂ , BF ₃ Et ₂ 0/TEAI, SiH ₂ I ₂ , M0 ₂ (acac) ₂ , AcCl/SmCl ₃ , SnCl ₂ /graphite, DDQ, HM-zeolite, ISiCl ₃ , ZnCl ₂ /Me ₂ S, Na ₂ S ₂ 0 ₄ , montimorillonite, Me ₂ BBr, Zn, alumina/silica gel, pyridinium tosylate(PPTS), MgS0 ₄ , Ph3CBF ₄ , NaTeSH, CuS0 ₄ , DDQ, PPh ₃ /CBr ₄ , SmCl TMSCl, 2,4,6-triphenyl tetrafluoroborate, NaI/CeCl ₃ . 7H ₂ 0, Zn-Ag, Mel/base, LiBF4, NBS, Pd(OH) ₂ /H ₂ .

The reagents used for deprotection thioketals may be selected from AgN0 ₃ /Ag ₂ 0, AgC10 ₄ , HgCl ₂ /CdC0 ₃ /CaC0 ₃ , Me ₂ CH(CH ₂ ) ₂ ONO, T1(N0 ₃ ) ₃ , S0 ₂ Cl ₂ /Si0 ₂ , I2/NaHC0 ₃ , H ₂ 0 ₂ , NaI0 ₄ , CuCl/CuO, HgO, mCPBA, Ph ₃ CC10 ₄ /Ph ₃ COMe/NaHC0 ₃ , DDQ, GaCl ₃ , clay supported NH ₄ N0 ₃ , NaOMe/Si0 ₂ , Hg(C10 ₄ ) ₂ /CaC0 ₃ , NCS, Tl(OCOCF ₃ ) ₃ , p-MeC ₆ H ₄ S0 ₂ N(Cl)Na, (PhSeO) ₂ 0, Me ₂ (CH ₂ ) ₂ ONO, N-

Chlorobezotrizole, Ce(NH ₄ ) ₂ (N0 ₃ ) ₆ , MeOS0 ₂ F, Mel, Et ₃ OBF ₄ , Ac ₂ 0/TEA, PyHBr/Br ₂ , TBAB, CuCl ₂ /Si0 ₂ , TMSOTf/0 ₂ NC ₆ H ₄ CHO, Se0 ₂ , H ₅ IO ₅ , DDQ, SbCls/N ₂ , GaCl ₃ , Amberlyst, Dowex 50W/paraformaldehyde, oxone/wetalumina, Fe(N0 ₃ ) ₃ .

The catalyst used for deprotection of ketals in step-(d) is an acid, which may be selected from organic acids such as trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid. In one preferred embodiment of the invention, the acid used in step-(d) is hydrochloric acid (HCl), more preferably aqueous hydrochloric acid.

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, heptane, n- pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimetylacetamide, dimethyl sulfoxide 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. In one preferred embodiment of the invention the solvent used in step-(d) is alcoholic solvent, more preferably the solvent used is methanol (MeOH).

Accordingly in one preferred embodiment of the invention when Z is Ts, Y is O and R ₂ is ethyl, above mentioned Formula- VI becomes Formula- Via as shown below:

According to one preferred embodiment of the present invention, in step-(d) Formula- Va is treated with aqueous hydrochloric acid (aq. HCl) in presence of solvent methanol to give novel intermediate compound of Formula-VIa as shown below:

Step-(e): Reduction

Step-(e) of the process in Scheme-A (Path- A) comprises reduction of ketone group by treating Formula-VI with reducing agents in presence of suitable solvent to give intermediate compound of Formula- VII as shown below:

Formula-VI I

wherein,

Z represents the same meanings as defined above in Scheme-A (Path-A).

The reducing agents in step-(e) may be used alone or in combination of suitable reagent. The reducing agents used in step-(e) may be 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, acetic acid/sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et ₃ SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone. Preferably the reducing agent used is in combination with an acid. In a preferred embodiment of the invention the reducing agent used in step-(e) of the process is combination of trifluoroacetic acid with sodiumborohydride. 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, dimethyl sulfoxide 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 chloro solvent such as chloroform (CHCI ₃ ) and DCM. In one preferred embodiment of the invention the solvent used in step-(e) is methylene dichloride (DCM).

Accordingly in one preferred embodiment of the invention Z is Ts and above mentioned Formula-VII becomes Formula- Vila as shown below:

Accordingly in one preferred embodiment of the invention, in step-(e) the ketone group of Formula- Via is reduced to give intermediate compound of Formula- Vila by treating Formula- Via with reducing agents TFA/sodiumborohydride in presence of solvent methylene dichloride (DCM) as shown below:

Step-(f): Deprotection

Step-(f) of the process in Scheme-A (Path-A) comprises deprotection of protecting group (Z) of Formula-VII to provide Vilazodone free base as shown below:

Vilazodone base wherein,

Z represent the same meaning as defined above in Scheme-A (Path- A).

When Z is H, this deprotection step-(f) is not required and compound of Formula- VII becomes Vilazodone free base. In one preferred embodiment Z is Ts.

The deprotection of protecting group of nitrogen in step-(f) of the process involves basic hydrolysis of Formula- VII (when Z is not H) using bases. The suitable bases used in step-(f) 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 bases selected in step-(f) are alkali and alkaline earth metal hydroxides, more preferably NaOH and KOH. In one preferred embodiment the base used in step- (f) is NaOH.

The suitable solvent used in step-(f) 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, dimethyl sulfoxide 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 solvents like C1-C5 alkyl chain or branched alkyl chain is used. More preferably the solvent used in step-(f) is alcoholic solvent such as methanol or ethanol; more preferably methanol is used. Thus in a preferred embodiment when Z is Ts; in step-(f) compound of Formula- Vila is treated with NaOH in presence of solvent methanol to give Vilazodone free base as shown below:

Vilazodone base

In another aspect the invention provides a process for preparation of Vilazodone as shown below in general reaction scheme Scheme-B (Path-B):

DeBfotecfiOn

ilszsti -e base

Scheme-B (Path-B)

wherein Z, X, Y, R ₂ and R ₃ represent the same meanings as defined in above Scheme-A (Path-A).

Thus in one aspect of the present invention provides a process for preparation of Vilazodone comprising the steps of:

(a) treating a compound of Formula-I

Formula-I

with a suitable reagent in presence of a suitable catalyst and solvent to g compound of Formula-II;

Formula-II

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

Formula-Ill

in presence of a suitable acid binding agent and suitable solvent to give a compound of Formula-IV;

Formula-IV

(c) deprotection of the compound of Formula-IV (when Z is not H) using suitable base in presence of suitable solvent to give a compound of Formula- VIII;

Formula- VIII

(d) amidation of the compound of Formula- VIII (when R ₃ is not NH ₂ ) by treating with an suitable amidation agent in presence of suitable solvent to give a compound of Formula-IX;

Formula-IX

(e) deprotection of the compound of Formula-IX with suitable acid in presence of a suitable solvent to give a compound of Formula-X;

Formula-X

(f) reduction of the compound of Formula-X with a suitable reducing agent in presence of suitable solvent to give Vilazodone (Formula- XI); wherein Z, X, Y, R ₂ and R ₃ represent the same meanings as defined in above Scheme-A

(Path-A)

When R ₃ is NH ₂ , the amidation step-(d) is not required and Formula- VIII becomes Formula-IX. In one preferred embodiment R ₃ is ethoxy (OEt) or Methoxy (-OMe). When Z is H, the deprotection step-(c) is not required. In one preferred embodiment Z is Ts (tosyl).

In the above Scheme-B (Path-B), process Step-(a) and Step-(b) starting from Formula-I to give compound of Formula- IV, are identical as described in Scheme-A (Path- A) for Step-(a) and Step-(b) above.

Step-(c): Deprotection:

Step-(c) of the process in Scheme-B (Path-B) involves deprotection of nitrogen protecting group (Z) of Formula- IV to give novel intermediate compound of Formula- VIII as shown in below:

When Z is H, this deprotection step is not required. In one preferred embodiment Z is Ts (tosyl).

When R ₃ is NH ₂ deprotection of Formula- IV directly gives the intermediate compound of Formula- IX as shown below:

The deprotection of protecting group of nitrogen in step-(c) of the process comprises basic hydrolysis of general Formula- IV (when Z is not H) using bases. The bases used in step-(c) 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 bases selected in step-(c) are alkali and alkaline earth metal hydroxides, more preferably NaOH and KOH. In one preferred embodiment the base used in step- (c) is NaOH. The suitable solvent used in step-(c) 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, dimethyl sulfoxide 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 solvents like C1-C5 alkyl chain or branched alkyl chain is used. More preferably the solvent used in step-(c) is ethanol.

Thus when Y is O, R ₂ is ethyl and R ₃ is ethoxy (OEt), above mentioned Formula- VIII becomes Formula- Villa as shown below:

Formula- Villa

Thus in a preferred embodiment when Z is Ts; in step-(c) compound of Formula- IVa is treated with NaOH in presence of solvent ethanol to give novel intermediate compound of Formula- Villa as shown below:

Step-(d): Amidation:

Step-(d) of present process in Scheme-B (Path-B) involves amidation of intermediate compound of Formula- VIII obtained in above step-(c) by treating with suitable amidation agent in presence of suitable solvent to give novel intermediate compound of Formula- IX as shown in below: Formcla-IX

When R ₃ is NH _2i this amidation step-(d) is not required and Formula- VIII becomes Formula-IX. In one preferred embodiment R ₃ is ethoxy (OEt). The amidation agent is the source of ammonia. The suitable amidation agent used in step-(d) 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.

Source of ammonia is selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base; more preferably the source of ammonia is ammonia gas.

In one preferred embodiment, the amidation reaction in step-(d) is advantageously carried out using ammonia gas under pressure of about 1 Kg/Cm ² to about 10 Kg/ Cm ² , and specifically about 3 Kg/ Cm ² .

Suitable solvent in step-(d) is 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 in step-(d) is alcohol; more preferably ethanol (EtOH) or Methanol (MeOH). Thus when Y is O and R ₂ is ethyl, above mentioned Formula- IX becomes Formula- IXa as shown below:

Formula-IXa

Thus in a preferred embodiment when R ₃ is not NH _2, compound of Formula- Villa is treated with ammonia under pressure in presence of solvent ethanol to give a novel intermediate compound of Formula-IXa as shown below:

Formula-IXa

Step-(e): Deprotection of Ketals or Thioketals:

Step-(e) of present process in Scheme-B (Path-B) comprises deprotection of ketals or thioketals of intermediate compound of Formula- IX obtained in above step-(d) with an suitable reagents which are selected from Scheme-A (path- A) step-d in presence of a suitable solvent to give intermediate compound of Formula-X as shown in below:

The acid used for deprotection of ketals in step-(e) may be selected from trifluoroacetic acid, formic acid, perchloric acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzene sulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid. In one preferred embodiment of the invention, the acid used in step-(e) is hydrochloric acid (HC1), more preferably aqueous hydrochloric acid. The 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, heptane, n- pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimetylacetamide, dimethyl sulfoxide 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. In one preferred embodiment of the invention the solvent used in step-(e) is alcoholic solvent, more preferably the solvent used is methanol (MeOH).

According to one preferred embodiment of the present invention, in step-(e) Formula- IXa is treated with aqueous hydrochloric acid (aq. HC1) in presence of solvent methanol to give intermediate compound of Formula-X as shown below:

Fornmla-IXa

Step-(f): Reduction:

Step-(f) of the process in Scheme-B (Path-B) involves reduction of ketone group of Formula-X obtained in above step-(e) by treating with reducing agents in presence of suitable solvent to provide Vilazodone free base (Formula-XI) as shown in below:

Viiazodorse Sase

Formula-X

The reducing agents in step-(f) may be used alone or in combination of acids. The reducing agents used in step-(f) may be 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, acetic acid/sodiumborohydride, trifluoroacetic acid (TFA)/sodiumborohydride, Et ₃ SiH/TFA, Zn-Hg and sodiumborohydride/tosylhydrazone. Preferably the reducing agent used is in combination with an acid. In a preferred embodiment of the invention the reducing agent used in step-(f) of the process is combination of trifluoroacetic acid with sodiumborohydride.

The suitable solvent used in step-(f) 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, dimethyl sulfoxide 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 chloro solvent such as chloroform (CHC13) and DCM. In one preferred embodiment of the invention the solvent used in step-(f) is methylene dichloride (DCM).

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

In one embodiment the present invention provides novel intermediate compounds of general Formula- II Formula- IV, Formula- V and Formula- VI as shown below:

Formula-II Formula-IV

Formula-V Formula- VI

Wherein,

Z represents H or an amino protecting group selected from groups -S(=0) ₂ Ri , 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.

X represents a leaving group selected from halogen (CI, Br and I), O-tosyl, O- mesyl, O-benzenesulfonyl, O-trifluoromethane sulfonyl.

Y is either oxygen (O) or sulfur (S). when Y is O, for acyclic ketals; R ₂ is selected from CI to C5 akyl chain or substituted derivatieves like isopropyl, Bis(2,2,2-trichloroethyl), diacetyl etc; and for cyclic ketals R ₂ is selected from CI to C5 akyl chain individually or its substituted derivatieves like 4-bromomethyl-l,3-dioxolane, 4-(3-butenyl)- 1,3- dioxolane, 4-(4-methoxyphenyl)-l,3-dioxolane, 4-(2-nitrophenyl)-l,3- dioxolane, 4-trimethylsilylmethyl- 1 ,3-dioxolane, (4R,5R)-diphenyl- 1 ,3- dioxolane, 4,5-dimethyl-l,3-dioxolane, trans- 1,2-cyclohexanediol ketal, trans-

4,6-dimethyl- 1 ,3-dioxolane, 4,5-dimethoxymethyl- 1 ,3-dioxolane, 5-methylene- 1,3-dioxanes, 5,5-dibromol,3-dioxanes, 5-(2'-pyridyl)-l,3-dioxanes, 5- trimethylsilyl-l,3-dioxanes ect. preferably when Y is O, R ₂ is CI to C5 akyl chain, more preferably methyl or ethyl. when Y is S, for acyclic thioketals R ₂ is selected from CI to C5 akyl chain or substituted derivatives like diphenyl, Dibenzyl, Diacetyl etc, and for cyclic thioketals R ₂ is selected from CI to C5 akyl chain individually or its substituted derivatives like l,5-dihydro-3H-2,4-dibenzodithiepin. R ₃ represents either NH ₂ or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R ₃ is ethoxy (-OEt).

In a preferred embodiment, the present invention provides novel intermediate compounds of below shown Formula:

Formula-IIa Formula- IVa

Formula- Va Formula- Via

Formula- Villa Formula-IXa

wherein

-Ts represents a tosyl group,

- R ₃ represents either NH ₂ or C1-C4 alkoxy group selected from methoxy, ethoxy, propoxy and butoxy; preferably R ₃ is methoxy (-OMe) or ethoxy (-OEt) and;

- Et represents ethyl (-C ₂ H ₅ )

When R ₃ is -OEt, intermediate of Formula- IVa becomes below structure:

When R ₃ is NH _2, intermediate of Formula- IVa becomes Formula- Va as shown above.

The present invention is further illustrated by the following examples: EXAMPLES:

Example-1: Preparation of intermediate compound of Formula-IIa (Path-A, Step-(a)) To a solution of Formula-la (5 g, 12 mmol) and triethyl orthoformate (55g, 375 mmol) in 50 mL of Ethanol, Cone, sulfuric acid (2.15 g, 21 mmol) was added drop wise for 30 min at room temperature. The total reaction mixture was heated to 50-55°C for lhr. Reaction was monitored by the TLC. After completion of the reaction, the reaction mass cooled to RT, then poured in to the 35 mL of chilled saturated NaHC0 ₃ solution. Aqueous layer extracted with ethyl acetate (2x15 mL). Combined organic layer was washed with 30 mL of sutured NaCl solution followed by 30 mL of water. Dried the organic layer and distilled under vacuum to get the Formula-IIa. Weight: 5 gm, yield: 90%. Example-2: Preparation of intermediate compound of Formula-IVa (Path-A, Step-(b))

To a solution of Formula-IIa (5 g, 10.5 mmol) in 30 mL of triethyl amine, compound of Formula-IIIa (3.06 g, 11.5 mmol), TBAB (0.33 g, 1.05 mmol) and KI (1.74 g, 10.5 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, distil out the triethylamine completely under reduced pressure. The residue cooled to RT and dissolved in 50 mL of ethyl acetate and organic layer was washed with 30 mL of water fallowed by 30mL of sutured NaCl solution. Dried the organic layer with sodium sulphate and distilled under reduced pressure to get the residue of the Formula- IV. To the residue 30 mL of ethanol was added and stirred for lhr at room temperature. Solid separated was filtered and washed with 10 mL of ethanol. Solid dried at 50 °C for 10 hrs to get the constant weight of formula-IV, Weight: 6 gm, yield: 84%.

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

To a suspension of Formula-IVa (8 g, 11.2 mmol) in 80 mL of Ethanol was stirred for 24 hrs in sealed vessel under ammonia pressure (5kg) at 55-60°C. After completion of the reaction monitored by HPLC, distil out the excess ammonia and ethanol completely under reduced pressure then charged the 30 mL of methanol and stirred for 1 hr at same temperature. Solid separated was filtered and washed with 20 mL of methanol and dried the material at 50 °C to get the constant weight of Formula-V. Weight: 6.8 g, yield: 90 %. Example - 4: Preparation of intermediate compound of Formula- Via (Path-A, Step- id)):

To solution of Formula- Va (5 g, 7.3 mmol) in 50 ml of methanol, 5N aqueous HC1 (1.06 mL) was added drop wise at 0 °C for 30 min. after completion of the addition temperature was raised to 10-15 °C and stirred for 1 hr. completion of the reaction monitored by TLC, distilled the Methanol completely below 40 °C. To the residue 25 mL of water and 15 mL of DCM was added and solution P was adjusted to 10 using 10% K ₂ C0 ₃ at 10 °C. Now bottom organic layer was separated and aqueous layer again extracted with DCM (3x15 mL). Combined organic layer was washed with 25 mL of water and 25 mL of brine solution. Organic layer was dried with Na ₂ S0 ₄ and distil out completely under reduced pressure to get light yellow colour solid of Formula- Via. Weight 3.5 g, yield 80%.

Example-5: Preparation of intermediate compound of Formula- Vila (Path-A, Step-(e)): To a mixture of TFA (23.48 g, 206 mmol) and 50 mL of DCM, sodiumborohydride (2.6 g, 68.7 mmol) was added portion wise for 1 hr at 10-15 °C. After completion of the addition reaction mixture was stirred for additional 2 hrs at same temperature. Now the solution of Formula- Via (10 g, 16.4 mmol) in 100 mL of DCM was added drop wise to the above reaction mixture for 1 hr at same temperature. Now temperature was slowly raised to 40-45 °C and stirred for 15 hrs at same temperature. After Completion of the reaction monitored by TLC, reaction mixture cooled to 10 °C and 100 mL of water was added drop wise and solution P was adjusted to 10 using 10% K ₂ C0 ₃ at same temperature. Bottom organic layer was separated and aqueous layer again extracted with DCM (2x50 mL). Combined organic layer was washed with 50 mL of water and 50 mL of brine solution. Organic layer was dried with Na ₂ S0 ₄ and distil out completely under reduced pressure to get solid of Formula- Vila. Weight 6.8 g, yield 70%. Example-6: Preparation of crude Vilazodone free base (Path-A, Step-(f)):

To solution of formula- Vila (10 g, 16 mmol) in 100 mL of Methanol, solid NaOH (1.34 g, 33 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, cool the reaction mass to RT and 100 mL of water was added. 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: 6 g yield: 81%. Purity: 97%. Example-7: Preparation of intermediate compound of Formula- Villa (Path-B, Step- (c)):

To solution of formula-IVa (20 g, 28 mmol) in 200 mL of Methanol, solid NaOH (2.24 g, 56 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, cool the reaction mass to RT and 200 mL of cold water was added. Solid separated was filtered and washed with water and dried the material at 50 °C to get the constant weight of Formula- Villa. Weight: 15.2 g, yield: 97%.

Example-8: Preparation of intermediate compound of Formula-IXa (Path-B, Step-(d)):

To a suspension of Formula- Villa (18.5 g, 33 mmol) in 500 mL of Ethanol was stirred for 24 hrs in sealed vessel under ammonia pressure (5kg) at 55-60°C. After completion of the reaction monitored by HPLC, distil out the excess ammonia and ethanol completely under reduced pressure then charged the 90 mL of methanol and stirred for 1 hr at same temperature. Solid separated was filtered and washed with 30 mL of methanol and dried the material at 50 °C to get the constant weight of Formula-IXa. Weight: 16.6 g, yield: 95 %.

Example-9: Preparation of intermediate compound of Formula-X (Path-B, Step-(e)):

To solution of Formula-IXa (25 g, 47 mmol) in 250 ml of methanol, 5N aqueous HC1 (7 mL) was added drop wise at 0 °C for 30 min. after completion of the addition temperature was raised to 10-15 °C and stirred for 1 hr. completion of the reaction monitored by TLC, distilled the Methanol completely below 40 °C. To the residue 250 mL of water and 150 mL of DCM was added and solution P was adjusted to 10 using 10% K ₂ C0 ₃ at 10 °C. Now bottom organic layer was separated and aqueous layer again extracted with DCM (3x150 mL). Combined organic layer was washed with 200 mL of water and 200 mL of brine solution. Organic layer was dried with Na ₂ S0 ₄ and distil out completely under reduced pressure to get light yellow colour solid of Formula-X. Weight 19.56 g, yield 91%.

Example-10: Preparation of crude Vilazodone free base (Path-B, Step-(f)): To a mixture of TFA (33.9 g, 298 mmol) and 105 mL of DCM, sodiumborohydride (3.6 g, 96 mmol) was added portion wise for 1 hr at 10-15 °C. After completion of the addition reaction mixture was stirred for additional 2 hrs at same temperature. Now the solution of Formula-X (10.5 g, 23 mmol) in 100 mL of DCM was added drop wise to the above reaction mixture for 1 hr at same temperature. Now temperature was slowly raised to 40-45 °C and stirred for 15 hrs at same temperature. After Completion of the reaction monitored by TLC, reaction mixture cooled to 10 °C and 200 mL of water was added drop wise and solution P was adjusted to 10 using 10% K ₂ C0 ₃ at same temperature. Bottom organic layer was separated and aqueous layer again extracted with DCM (2x100 mL). Combined organic layer was washed with 50 mL of water and 100 mL of brine solution. Organic layer was dried with Na ₂ S0 ₄ and distil out completely under reduced pressure to get solid of crude Vilazodone base. Weight 8.3 g, yield 82.5%, purity by HPLC 95%.