DESC:Field of the invention
The present invention is directed to process for preparation of Brexpiprazole of formula-I and intermediates thereof. The present invention further relates to process for the preparation of Brexpiprazole, pharmaceutical compositions containing them.

Formula-I

Background of the invention
Brexpiprazole is a partial dopamine D2 agonist, which also has activity at several other receptors. Brexpiprazole is marketed as Rexulti™ by Otsuka Pharmaceutical Co Ltd as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) and for the treatment of schizophrenia.
Brexpiprazole is chemically known as 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin­2(1H)-one which is disclosed in WO2006112464A1. It also discloses process for synthesis of Brexpiprazole as shown below:

However the above process step of preparation of Brexpiprazole is not satisfactory from commercial point of view as it involves use of costly catalysts, like Pd2(dba)3. Accordingly, the disclosed process is commercially not viable.
WO2013015456A1 discloses process for the preparation of Brexpiprazole.
WO2013162046A1 discloses dihydrate of Brexpiprazole and process for the preparation thereof.
PCT applications WO2015054976A1 and WO2016124144A1 disclose process for the preparation of Brexpiprazole.
Chinese applications CN104447723A, CN104829602A, CN104844585A, CN105061414A, CN105175401A, CN105399736A, CN105440026A, CN105461704A, CN105461703A, CN105541819A and CN105732572A disclose process for the preparation of Brexpiprazole.
Another Chinese application CN104844586A discloses amorphous form of Brexpiprazole and process for the preparation thereof.
However the prior art processes described above for the preparation of Brexpiprazole have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; use of column chromatography and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associates with prior art process for preparation of Brexpiprazole.
Brexpiprazole prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process.

Object of the invention
In one aspect, the present invention relates to a process for preparation of Brexpiprazole with high purity.
In another aspect, the present invention relates to novel intermediates useful in preparation of Brexpiprazole, process for preparing such intermediates and process for the synthesis of Brexpiprazole which utilize these intermediates.
In one aspect, the present invention relates to crystalline form of 1-benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8o, 9.6o, 14.4o, 19.2o and 29.0 o + 0.2o 2?.
In one aspect, the present invention relates to crystalline form of Brexpiprazole p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 6.3o, 9.4o, 15.6o, 18.7o and 28.1 + 0.2o 2?.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) providing Brexpiprazole acid addition salt;
ii) hydrolyzing the Brexpiprazole acid addition salt with one or
more base;
iii) isolating the crystal of anhydrous form of Brexpiprazole by conventional techniques.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent;
iii) isolating the crystal of anhydrous form of Brexpiprazole by conventional techniques.
In yet one aspect, the present invention provides anhydrous form of Brexpiprazole having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
In yet one aspect, the present invention provides Brexpiprazole which is substantially free from impurity A to F.
In another aspect, the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.

Brief description of the Drawings
Figure 1 is an illustration of a PXRD pattern of anhydrous form of Brexpiprazole
Figure 2 is an illustration of a PXRD pattern of Brexpiprazole p-toluene sulphonate (PTSA) salt
Figure 3 is an illustration of a PXRD pattern of 1-benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt

Detailed description of the invention
The present invention relates to a process for preparation of Brexpiprazole with improved yields making it suitable for large scale production as described below:

wherein X is a leaving group selected from chloro, bromo, iodo and X’ is a leaving group selected from chloro, bromo, iodo, mesylate or tosylate.
4-X-benzo[b]thiophene (II) and piperazine are reacted in presence of Pd on carbon or Pd catalyst complex and ligand to obtain benzo[b]thiophene-4-yl-piprazine (IIIA) which is treated with acid obtain salt of 1-benzo[b]thiophene-4-yl-piprazine (III). Preferably, BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) is used as ligand. Preferably, leaving group X is bromo. Solvents that used for the reaction is toluene or xylene or the like. The reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer.
Applicant found that the prior art process of isolation of 1-benzo[b]thiophene-4-yl-piprazine as a free base resulted with either impure 1-benzo[b]thiophene-4-yl-piprazine and its use in the preparation of Brexpiprazole resulted with impure Brexpiprazole. Hence the said prior art process is not suitable for commercial manufacturing. Applicant found isolation of 1-benzo[b]thiophene-4-yl-piprazine as a acid addition salt and / or isolation of Brexpiprazole as a acid addition salt resulted with Brexpiprazole with purity greater than 99.5% by HPLC. Thus present process provides robust commercial manufacturing process for the preparation of Brexpiprazole.
Acid addition salt of 1-benzo[b]thiophene-4-yl-piprazine (III) is reacted with 7-(4-X’-butoxyquinolin-2(1H)-one to obtain Brexpiprazole. Preferably, leaving group X’ is chloro. Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamnie or tert-butyl amine or the like are used as base. The reaction is carried out in solvents such as dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like. The reaction may be carried out for time periods ranging from about 1hour to about 4 hours, or longer. The reaction is carried out at 50 to 120 ºC preferably at 70 to 90 ºC.
Brexpiprazole is treated with acid to produce acid addition salt of Brexpiprazole. p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, maleic acid or hydrochloric acid, hydrobromic acid or the like are used as acid. The reaction is carried out in solvents such as acetone or dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like.
Brexpiprazole acid addition salt is hydrolysed with one or more base to obtain Brexpiprazole. Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamnie or tert-butyl amine or the like are used as base. The reaction is carried out in solvents such as methanol, ethanol, isopropanol or the like.
In one aspect, the present invention relates to crystalline form of 1-benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8o, 9.6o, 14.4o, 19.2o and 29.0 o + 0.2o 2?.
In one aspect, the present invention relates to crystalline form of Brexpiprazole p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 6.3o, 9.4o, 15.6o, 18.7o and 28.1 + 0.2o 2?.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) providing Brexpiprazole acid addition salt;
ii) hydrolysing the Brexpiprazole acid addition salt with one or
more base;
iii) isolating the crystal of anhydrous form of Brexpiprazole by conventional techniques..
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent;
iii) isolating the crystal of anhydrous form of Brexpiprazole by conventional techniques..
In yet one aspect, the present invention provides anhydrous form of Brexpiprazole having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
In yet one aspect, the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.
Further the present invention provides a process of preparing a pharmaceutical composition of Brexpiprazole which process comprises the step of mixing of Brexpiprazole together with a pharmaceutically acceptable carrier. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.
Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of Brexpiprazole.
In yet one aspect, the present invention provides Brexpiprazole which is substantially free from impurity A to F.
i) Impurity-A:

i) Impurity-B:

ii) Impurity-C:

iii) Impurity-D:

iv) Impurity-E:

v) Impurity-F:

vi) Impurity-G:

vii) Impurity-H:

Brexpiprazole as obtained by present invention is stable and not contaminated with any crystalline form.
The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-anti solvent, spray drying, lyophilization or freeze drying.
The term “organic solvent” or “solvent” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol.
Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
The “acid addition salts” as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, followed by isolation of salt by conventional techniques, if required. A salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to, acetic, benzoic, p-toluene sulphonic, benzenesulfonic, hydrobromic, hydrochloric, citric, gluconic, glucuronic, glutamic, tartaric, lactic, malic, maleic, oxalic, camphorsulphonic, methanesulfonic, palmoic, salicylic, stearic, succinic, sulfuric, and the like. The class of acids suitable for formation of pharmaceutically acceptable salts is well known to person having ordinary skills in the art, and are described, for example in Stahl, P. H., et al., “Handbook of Pharmaceutical Salts”, Wiley-VCH, Weinheim: Germany (2002), the contents of which are hereby incorporated herein by reference.
Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, p-toluene sulphonate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, tartarate, citrate, maleate, fumarate, succinate, camphor-sulphonate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like. Pharmaceutically acceptable salts are well known to person having ordinary skills in the art, and are described, for example in Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19, 1977, the contents of which are hereby incorporated herein by reference.
The tem “base” as used herein includes but not limited to inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine. The base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
The term “palladium catalyst complex” as used herein includes but not limited to complexes of palladium such as sodium hexachloro
palladate(IV)tetrahydrate, potassium hexachloropalladate(IV), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetyl
acetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)
palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichloro
tetraamminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex, or tetrakis(triphenylphosphine)palladium (0) or the like.
The term “ligand” used herein (±)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), Diacetato[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) Ru(OAc)2(BINAP), dichloro[(S)-(-)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl][(2S)-(+)-1,1-bis(4-methoxy
phenyl)-3-methyl-1,2-butanediamine]ruthenium(II) RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN], diacetato[(S)-(-)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl]ruthenium(II) (S)-Ru(OAc)2(T-BINAP),
The term “substantially free from impurity A to F” as used herein relates Brexpiprazole which is about 99.9% pure and the amount of impurity A to F present is not more than 0.05%.
To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermograms, thermal gravimetric analyzers thermograms, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

Example-1: Preparation of 1-benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate
A mixture of 100 g 4-bromobenzo[b]thiophene, 190 g of Piperazine anhydride, 60 g of Sodium t-butoxide, 3.4 g of rac-BINAP, 4.2 g of Palladium carbon and 1200 ml xylene was refluxed till completion of reaction. After completion of reaction palladium carbon was removed by filtration and to filtrate, p-toluenesulfonic acid in xylene was added. Precipitated crystals were separated by filtration to get 92 g of 1-benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate.

Example-2: Preparation of 1-benzo[b]thiophene-4-yl-piperazine dihydrochloride
A mixture of 100 g 4-bromobenzo[b]thiophene, 206 g of Piperazine anhydride, 65.35 g of Sodium t-butoxide, 3.9 g of rac-BINAP, 3.9 g of Palladium carbon and 1500 ml Toluene was refluxed for 4 hrs. Palladium carbon was removed by filtration and dihydrochloride was isolated by reaction with concentrated hydrochloric acid in acetone. Precipitated crystals were separated by filtration to get 88 g of 1-benzo[b]thiophene-4-yl-piperazine dihydrochloride.

Exmaple-3: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-)butoxy]-1H-quinolin-2-one (Brexpiprazole)
A mixtue of 100 g of 7-(4-chlorobutoxy)-1H-quinolin-2-one, 110 g of 1-benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate, 214 g of sodium bicarbonate, sodium iodide and 650 ml of dimethyl sulfoxide (DMSO) were stirred at 85-95°C. After completion of the reaction, water was added to reaction mixture and precipitated crystals were separated by filtration. Wet solid was dried at 60°C to get 155 g of Brexpiprazole. Purity: 98.7%

Exmaple-4: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-)butoxy]-1H-quinolin-2-one (Brexpiprazole)
A mixtue of 100 g of 7-(4-chlorobutoxy)-1H-quinolin-2-one, 115.70 g of 1-benzo[b]thiophene-4-yl-piperazine dihydrochloride, 210 g of potassium carbonate, sodium iodide and 700 ml of dimethylformamide were stirred at 80-90°C. After completion of the reaction, water was added to reaction mixture and precipitated crystals were separated by filtration. Wet solid was dried at 60°C to get 160 g of Brexpiprazole. Purity: 98.5%

Exmaple-5: Preparation of Brexpiprazole p-toluenesulfonate
A mixture of 100 g Brexpiprazole was dissolved in 2000 mL of dichloromethane at 30 to 40 °C. Dichloromethane (1000 mL) was recovered under atmospheric pressure at 40-50°C. p-toluenesulfonic acid solution (48.26 g in Acetone) was added at 40-50°C. Reaction mass was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were dissolved in mixture of acetone :water (12 : 6). Reaction mixture was cooled to room temperature. Precipitated crystals were separated by filtration. Solid was dried at 60-70°C to get 120 g of Brexpiprazole p-toluenesulfonic acid salt.

Example-6: Preparation of anhydrous form of 7-[4-(4-benzo[b] thiophen-4-yl-piperazin-1-yl-)butoxy]-1H-quinolin-2-one (Brexpiprazole)
100 g of Brexpiprazole p-toluenesulfonic acid salt was dissolved in MeOH. 20 ml of conc. HCl was added and reaction mass was stirred for 30 minutes at 50-60°C. Activated carbon slurry was added and reaction was stirred for 10 min. The reaction mass was filtered and solution of tert-butyl amine was added to the filtrate till alkaline pH was achieved. Reaction mixture was cooled to room temperature. Precipitated compound was filtered and washed with MeOH. The obtained solid was suspended in water and heated at 70-80°C. The solid was filtered to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-7: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-)butoxy]-1H-quinolin-2-one (Brexpiprazole)
Brexpiprazole p-toluenesulfonic acid salt was dissolved in mixture of acetone : water (12 : 6). 20% NaOH solution was added till alkaline pH was achieved. Reaction mixture was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were washed with water till neutral pH was achieved. Solid was dried at 60-70°C to get 85 g of Brexpiprazole. Purity: 99.9%

Example-8: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dimethylformamide (600 mL) at 80-90°C. Water (1800 mL) was added at 80-90°C. Reaction mixture was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90g of anhydrous form of Brexpiprazole. Purity: 99.85%

Example-9: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in methanol (400 mL). Crystals were precipitated and separated by filtration. Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-10: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in methanol (400 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-11: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in acetone (500 mL) and water (1600 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-12: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in acetonitrile (600 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-13: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in tetrahydrofuran (500 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. . Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 96 g of anhydrous form of Brexpiprazole. Purity: 99.85%

Example-14: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dichloromethane (700 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.85%

Example-15: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in toluene (400 mL). Crystals were precipitated and separated by filtration. Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.8%

Example-16: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dimethylacetamide (500 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.8%

Example-17: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethanol (700 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Example-18: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethanol (500 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 86 g of anhydrous form of Brexpiprazole.
Purity: 99.9%

Example-19: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethyl acetate (600 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.8%

Example-20: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in water (500 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Dated this 09th March 2017

,CLAIMS:1. A process for the preparation of Brexpiprazole of formula (I)

comprising steps of:
a) reacting compound of formula (II), with piperazine in presence of a ligand, Pd on carbon OR Pd carbon complex and organic solvent to obtain compound of formula (IIIA):
wherein X is a leaving group selected from chloro, bromo, iodo.
b) reacting compound of formula (III A) with acid selected from group comprising of p-toluene sulphonic acid, hydrobromic acid, tartaric acid, succinic acid, oxalic acid and maleic acid to obtain compound of formula (III)

c) reacting compound of formula (III) with compound of formula (IV), in presence of base and organic solvent to obtain Brexpiprazole of formula (I)

wherein X’ is a leaving group selected from chloro, bromo, iodo,
mesylate or tosylate.
2. The process as claimed in claim-1, wherein organic solvent used in (a) and (c) is selected from group comprising of: benzene, toluene, xylene, acetone, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF).
3. The process as claimed in claim-1, wherein base used in (c) is selected from group comprising of: ammonia, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamnie and tert-butyl amine.
4. A salt of 1-benzo[b]thiophene-4-yl-piprazine of formula (II):

wherein salt is selected from group comprising of p-toluene sulphonate (PTSA), hydrobromide, tartrate, succinate, oxalate and maleate.
5. A process for the preparation of Brexpiprazole, comprising steps of:
i) providing Brexpiprazole acid addition salt;
ii) hydrolysing the Brexpiprazole acid addition salt with one or
more base;
iii) isolating the crystal of anhydrous form of Brexpiprazole.
6. The process as claimed in claim-5, where in acid addition salt is selected from group comprising of p-toluene sulphonate , hydrobromide, tartrate, oxalate, succinate, maleate, hydrochloride, formate, acetate, sulfate.
7. The process as claimed in claim-5, where in base is selected from group comprising of ammonia, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamnie and tert-butyl amine.
8. A process for the preparation of anhydrous form of Brexpiparazole comprising steps of:
i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent;
iii) isolating anhydrous form of Brexpiprazole.
9. Brexpiprazole of formula (I) which is substantially free of following impurities:
i) Impurity-A:

ii) Impurity-B:

iii) Impurity-C:

iv) Impurity-D:

v) Impurity-E:

vi) Impurity-F:

vii) Impurity-G:

viii) Impurity-H:

Dated this 09th March 2017