FIELD OF THE INVENTION
The present invention relates to the process for the preparation of Brexpiprazole (1), hydrochloride salt of Brexpiprazole (2) and tartrate salt of Brexpiprazole (3). Further, the present invention also provides solid forms of Brexpiprazole and the process for the preparation thereof.
BACKGROUND OF INVENTION
Brexpiprazole is an atypical antipsychotic drug, having dopamine D2 receptor partial agonist activity. Chemically, it is known as 7-[4-[4-(l-benzothiophen-4-yl) piperazin-1-yl] butoxy] quinolin-2(lH)-one. The USFDA approved Brexpiprazole on July 13, 2015 for the treatment of schizophrenia, and as an adjunctive treatment for depression. The drug was developed by Otsuka and Lundbeck, sold under the brand name REXULTI.
The synthesis of Brexpiprazole was reported in many patents, the contents of which are hereby incorporated as reference in their entirety.
US8618109 patent disclosed the process for the preparation of Brexpiprazole by reacting 7- (4-chlorobutoxy) -IH- quinolin-2-one with 1-benzo [b] thiophene-4-yl-piperazine hydrochloride in presence of a base potassium carbonate and sodium iodide. The residue was purified by silica gel column chromatography and recrystallized from ethanol but does not disclose the purity of Brexpiprazole.
US9499525 patent discloses Brexpiprazole anhydride, hydrate and dihydrate crystal forms of Brexpiprazole.
WO2017106641 application discloses crystalline form G and form J of Brexpiprazole.
Polymorphism is a property of some molecules which exists in different crystalline forms. A single molecule may give rise to a variety of polymorphs having distinct

crystal structures and are distinct in physical properties like melting point, thermal behaviors, X-ray diffraction pattern, infrared absorption fingerprint, and solid state (13C-) NMR spectrum. The variation in such a physical property of different forms may provide a basis for improving formulation and the final dosage form, for example, changing the dissolution profile in a favorable direction, by facilitating better processing or handling characteristics, or improving stability, shelf-life and for instance, if they serve to improve bioavailability. Moreover, modification in the various physical properties of active pharmaceutical ingredient which is to a large extent influenced by its solid state. Solid state may include crystalline or amorphous forms of the API.
The prior art methods do not clearly disclose the purity and yield of the Brexpiprazole synthesized. Hence, the present inventors also disclose solid forms of Brexpiprazole and process thereof. It further discloses an improved process for the preparation of Brexpiprazole (1).
OBJECTIVE OF THE INVENTION
In one object the present invention provides an improved process for the preparation of Brexpiprazole (1) or its salt.
In another object the present invention provides process for the purification of Brexpiprazole (1) or its salt.
In another object the present invention provides solid dispersions of Brexpiprazole (1) and the process for preparing the same.
In another object the present invention provides amorphous form of Brexpiprazole (1) and processes for the preparation thereof.

Yet, in another object, the present invention provides crystalline form of Brexpiprazole (1) and process for the preparation thereof.
SUMMARY OF THE INVENTION
In one aspect the present invention provides an improved process for the preparation of Brexpiprazole (1) or its salts comprising the following steps:
a) reacting 7-hydroxy-lH-quinolin-2-one with l-bromo-4-chlorobutane in presence of base to form 7-(4-chlorobutoxy)-lH-quinolin-2-one;
b) reacting 7-(4-chlorobutoxy)-lH-quinolin-2-one with Tert-butyl piperazinel-carboxylate to form tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate in-situ;
c) treating tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate with a suitable base to form 7-(4-(piperazin-l-yl) butoxy) quinolin-2( 1 H)-one;
d) reacting 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one with 4 bromo-benzo (b) thiophene in presence of a suitable base and catalyst to form Brexpiprazole (1); and
e) purifying Brexpiprazole (1).
In another aspect the present invention provides a process for the purification of Brexpiprazole (1) or its salts comprising the following steps:
a) providing Brexpiprazole (1) in a suitable solvent or mixture of solvents;
b) heating to a temperature of about 60-100 °C;
c) treating reaction mixture with neutral charcoal and filtering;
d) cooling the filtrate and isolating solid;
e) adding another suitable solvent to the solid of step d); and
f) isolating pure Brexpiprazole (1).

In another aspect, the present invention provides an alternate process for the purification of Brexpiprazole (1) or its salts.
a) providing Brexpiprazole (1) in an aprotic solvent;
b) filtering the reaction mixture; and
c) isolating the pure Brexpiprazole (1).
In another aspect Brexpiprazole (1) obtained in the above process after purification is having purity greater than 99.0% by HPLC.
In another aspect, the present invention provides solid dispersions of Brexpiprazole (1) with at least one pharmaceutically acceptable excipient.
In another aspect the present invention provides process for the preparation of amorphous solid dispersions of Brexpiprazole (1), comprising the steps of:
a) providing solution of Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture thereof;
b) providing at least one pharmaceutically acceptable excipient;
c) removing the solvent from the solution obtained in step b); and
d) isolating amorphous solid dispersion of Brexpiprazole (1).
In some aspect the present invention provides an amorphous form of Brexpiprazole (1) and an alternative process for the preparation of same, comprising the steps of:
a) providing Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture
thereof;
b) optionally, treating the solution of step a) with an anti-solvent; and
c) isolating the amorphous form of Brexpiprazole (1).

Yet, in another aspect the present invention provides crystalline form of Brexpiprazole (1) and the process for its preparation, comprising the steps of:
a) providing Brexpiprazole (1) in a suitable aprotic solvent;
b) heating to a suitable temperature;
c) cooling the reaction solution to a suitable temperature; and
d) isolating the crystalline Brexpiprazole (1).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates X-Ray powder diffraction (XPRD) pattern of crystalline
Brexpiprazole (1).
Figure 2: illustrates Differential scanning calorimetry (DSC) of Brexpiprazole (1).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of Brexpiprazole (1) or its salts as illustrated in scheme 1.

In another embodiment the present invention provides a process for the preparation of Brexpiprazole (1) or its salts comprising:
a) reacting 7-hydroxy-lH-quinolin-2-one (8) with l-bromo-4-chlorobutane (7) in presence of base and suitable solvent to form 7-(4-chlorobutoxy)-lH-quinolin-2-one (6);
b) reacting 7-(4-chlorobutoxy)-lH-quinolin-2-one (6) with tert-butyl piperazinel-carboxylate (5) to form tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate (4) in-situ;
c) treating tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate (4) with a suitable base to form 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3); and
d) reacting 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3) with 4 bromo-
benzo (b) thiophene (2) in presence of a suitable base and catalyst to form
Brexpiprazole (1); and
e) purifying Brexpiprazole (1).
In some embodiment the step a) proceeds with reacting 7-hydroxy-lH-quinolin-2-one (8) with l-bromo-4-chlorobutane (7) to form 7-(4-chlorobutoxy)-lH-quinolin-2-one (4). 7-hydroxy-lH-quinolin-2-one (8) may be reacted with l-bromo-4-chlorobutane (7) in presence of a base and reagent, preferably sodium iodide to form -(4-chlorobutoxy)-lH-quinolin-2-one (6).The said reaction may be heated at a temperature of 40-60 °C, preferably 50-55 °C.
Step b) involves reacting 7-(4-chlorobutoxy)-lH-quinolin-2-one (6) with tert-butyl piperazine 1-carboxylate (5) to form tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1 -carboxylate (4) in presence of a base and reagent, preferably sodium iodide. On completion of reaction, the product was isolated from different protic and aprotic solvents and acid to yield tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-

yloxy) butyl) piperazine-1-carboxylate (4) in situ , which may be directly used in the next step.
Step c) involves treating tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate (4) with a suitable base to form 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3). The intermediate (4) obtained in situ in step b) may be cooled, and dissolved in a suitable solvent and pH adjusted to 11.0-12.0 by using 30% sodium hydroxide, precipitating the 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3) and drying.
Step d) proceeds with reacting 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3) with 4 bromo-benzo (b) thiophene (2) in presence of a suitable base and catalyst to form Brexpiprazole (1). 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3) was added to a suitable solvent in presence of a suitable base, catalyst and ligand, preferable Palladium acetate-II and Phosphine ligand (S-Phos) were used. 4 bromo-benzo (b) thiophene (2) was then further added and reaction heated to 80-120 °C, preferably 100-110 °C. On completion of reaction, reaction mass was treated with suitable solvents and the organic layer separated and reacted with a suitable acid to form a solid. The solid formed was isolated to yield Brexpiprazole (1).
In another embodiment the suitable bases used in the preparation of Brexpiprazole (1) or its salts may be selected from a group comprising organic or inorganic bases. The inorganic base were used in the present invention was selected from potassium tertiary butoxide, potassium ethoxide, potassium isopropoxide, sodium methoxide, sodium tertiary methoxide , sodium isopropoxide, lithium tertiary butoxide, magnesium isopropoxide, calcium isopropoxide , lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide , sodium carbonate, potassium carbonate, magnesium carbonate , sodium bicarbonate, potassium bicarbonate or the like. Suitable organic base may be selected from the group comprising of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl

morpholine, pyridine, ammonia, or the like. Preferably, potassium carbonate, sodium hydroxide, sodium tertiary methoxide was used in the present invention.
The acid used in the preparation of Brexpiprazole (1), may be selected from a group comprising of with organic or inorganic acids. The organic acid may be selected form the group consisting of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. More preferably aqueous hydrochloric acid or methanol hydrochloric acid was used in the present invention.
In another embodiment, step e) proceeds with purification of Brexpiprazole (1) or its salts comprising:
a) providing the Brexpiprazole (1) in an aprotic solvent;
b) heating to a temperature of about 60 -100 °C;
c) filtering the reaction mixture;
d) treating reaction mixture with activated carbon at about 60-100 °C in an aprotic solvent;
e) filtering the reaction mixture;
f) treating with an aprotic solvent at about -10 °C to 20 °C; and
g) isolating the pure Brexpiprazole (1).
In another embodiment, the present invention provides an alternate process for the purification of Brexpiprazole (1) or its salts.
a) Providing the Brexpiprazole (1) in an aprotic solvent;
b) filtering the reaction mixture; and
c) isolating the pure Brexpiprazole (1).

The solvents used in the purification processes of Brexpiprazole (1) may be selected from the group comprising of protic or aprotic solvents. Protic solvents may be selected from but not limited to alcohols and water. The alcoholic solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, ethylene glycol or the like. Preferably, methanol and isopropyl alcohol, were used in the present invention. The suitable aprotic solvent used in the present invention for the purification of Brexpiprazole (1) may be selected from but not limited to ethers, ketones, acetates, hydrocarbons, halogenated solvents, amides or the like. Preferably, dichloromethane, dimethylformamide, acetone, toulene was used in the present invention.
In some embodiment the present invention provides amorphous solid dispersions of Brexpiprazole (1) together with at least one pharmaceutically acceptable excipient.
In another embodiment the present invention provides process for the preparation of solid dispersions of Brexpiprazole (1), comprising the steps of:
a) providing solution of Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture thereof;
b) providing at least one pharmaceutically acceptable excipient;
c) removing the solvent obtained in step b); and
d) isolating amorphous solid dispersion of Brexpiprazole (1).
In another embodiment, the present invention provides a process for the preparation of amorphous form of Brexpiprazole (1), comprising the steps of:
a) providing Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture
thereof;
b) optionally treating the solution of step, a) with another solvent/ anti-solvent and
c) isolating the amorphous form of Brexpiprazole (1).

The solvents used in the preparation of solid dispersions and amorphous forms may be selected from a group comprising of pro tic and aprotic solvents. The suitable protic solvent used in the present invention may be selected from but not limited to alcohols, acids and water. The alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, ethylene glycol or the like. Acid solvents may be selected from the group comprising of acetic acid, formic acid or the like. Preferably, methanol was used in the present invention. The suitable aprotic solvent used in the present invention for the preparation of amorphous form as well as amorphous solid dispersions may be selected from but not limited to ethers, ketones, acetates, hydrocarbons, halogenated solvents, amides or the like. Preferably, halogenated solvent, particularly dichloromethane was used in the present invention.
The said processes for the preparation of amorphous form as well as amorphous solid dispersions were conducted at a temperature of about 10 -70 °C, preferably at about 20-50 °C, more preferably at about 25 -40 °C.
The suitable pharmaceutical^ acceptable excipients may be selected from but not
limited to maltodextrin, hydroxypropyl methyl cellulose (HPMC), sulfobutylether-(3-
cyclodextrin (SBECD), Hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone,
povidone K-30, povidone K-60, povidone K-90, Hydroxypropyl-beta-cyclodextrin
(HPBCD), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether,
polyethyene glycol, hydroxypropylmethyl cellulose phthalate, Soluplus® (polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-
PEG)), gelucire 44/14, cyclodextrins, gelatins, D-alpha-tocopheryl polyethylene glycol
1000 succinate, Polyvinylacetal diethylamino acetate or the like. Preferably
maltodextrin, hydroxypropyl methyl cellulose (HPMC), sulfobutylether-(3-cyclodextrin
(SBECD), Hydroxypropyl cellulose (HPC), povidone K-30, Hydroxypropyl-beta-
cyclodextrin (HPBCD) were used in the present invention.

Yet, in another specific aspect the present invention provides crystalline form of Brexpiprazole (1) and the process for the preparation of crystalline Brexpiprazole, comprising the steps of:
a) providing Brexpiprazole (1) in a suitable aprotic solvent;
b) heating to a suitable temperature;
c) cooling the reaction solution to a suitable temperature; and
d) isolating the crystalline Brexpiprazole (1).
Brexpiprazole (1) may be added to a suitable aprotic solvent and heated to 60-100 °C, preferably 90-100 °C and then cooled 20-40 °C, preferably 25 -30 °C and isolated to yield crystalline Brexpiprazole (l).The suitable aprotic solvent used in the preparation of crystalline Brexpiprazole (1) may be selected from but not limited to ethers, ketones, acetates, hydrocarbons, halogenated solvents, amides or the like. Preferably, toulene was used in the present invention.
Brexpiprazole (1) obtained by the above process was having purity greater than 99.0% by HPLC
In another aspect, the present invention provides a purification process to produce of Brexpiprazole (1) having total impurity levels less than 1.0% (w/w) preferably less than 0.5% (w/w).
In another aspect of the embodiment, the crystalline Brexpiprazole (1) may produce an X-ray diffraction (XRD) pattern comprising of 2(0) theta values ± 0.2 degrees as illustrated in figure 1 and tabulated in table 1.

Table 1: X-Ray diffraction data of Brexpiprazole (1)

2 theta 2(9) Relative Intensity %
6.78 23.0
10.8 19.4
12.29 30.2
13.89 19.5
14.46 40.4
14.93 27.1
15.81 7.1
16.52 §M
17.08 17.6
17.45 33.5
19.19 100
20.24 50.9
20.78 16.4
21.37 34.8
23.26 37.8
24.57 20.0
25.77 13.4
26.4 13.7
26.84 15.1
27.98 12.4
28.62 7.40
29.35 14.8
30.66 6.60
31.69 7.30
33.6 10.1

In another aspect, the pure crystalline Brexpiprazole (1) may produce Differential scanning calorimetry (DSC) thermogram having an endothermic peak at 184.19 °C as shown in Figure 8.
In another aspect, the pure crystalline Brexpiprazole (1) may produce a melting point at a range of 180.0 to 182 °C.
In another aspect, the present invention provides pure Brexpiprazole (1) having heavy metal content less than 20ppm, preferably less than % (w/w).
In another aspect, the present invention provides pure Brexpiprazole (1) having water content by Karl Fischer method, not more than 1.0% (w/w), preferably less than 0.54 % (w/w).
The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.
EXAMPLES
Example-1: Preparation of 7-(4-chIorobutoxy)-lH-quinolin-2-one (6)
250g of potassium carbonate was dissolved in 800mL methanol and 9.0g of sodium iodide added. To this reaction mixture 100 g of 7-hydroxy-lH-quinolin-2-one (8) and 320g of l-bromo-4-chlorobutane (7) were added and the total reaction mixture heated to 60-65 °C. On completion of reaction, the reaction mass was cooled to 0-5 °C and filtered under vacuum. 1000 mL of water was added to the wet solid, filtered through vacuum and washed with methanol at 0-5 °C. The solid was then dissolved in methanol, heated to 60-65 °C and then cooled to 5-10 °C. The solid formed was filtered and again washed with chilled methanol at 5-10 °C and dried to yield 7-(4-chlorobutoxy)-lH-quinolin-2-one (6). Yield: 58%; Purity: 98.8%.

Example-2: Preparation of tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate (4)
lOOg of 7-(4-chlorobutoxy)-lH-quinolin-2-one (6) was added to 800mL of dimethylformamide. 165g of potassium carbonate, 42g of sodium iodide and 75g of tert-butyl piperazine-1-carboxylate were further added to the reaction mass at 25-30 °C. The reaction mass was heated to 90-95 °C. On completion of reaction, the reaction mass was cooled to 25-30 °C and quenched with water. The product formed was extracted with different volumes of dichloromethane and the organic layer washed with sodium chloride solution. The reaction mixture was filtered, and the filtrate distilled under vacuum to yield tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate (4) in situ, which was directly used in the next step.
Example-3: Preparation of 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3)
300 mL of methanol and 300mL of methanol hydrochloride were added to the residue containing intermediate (4), heated to 60-65 °C and cooled to 5-10 °C. The solid formed was filtered under vacuum and dried. Water was added to the dried solid and pH adjusted to 11.0-12.0 using 30% sodium hydroxide. The solid formed was filtered under vacuum and washed with chilled water. The solid was then isolated from acetone and dried under vacuum to yield 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3). Yield: 55.0%; Purity: 98.9%.
Example-4: Preparation of Brexpiprazole (1)
100 g of 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (3) and 95g of sodium t-butoxide was added to 2000mL of toulene at 25-30 °C and stirred under nitrogen pressure.0.75g of palladium acetate-II ,3.5g of phosphine ligand and 70g of 4-bromo-benzo (b) thiophene (2) dissolved in 500mL of toulene were added to the reaction mass. The reaction mass was heated to 100-110 °C. On completion of reaction, reaction mass was cooled and treated with 200mL of methanol, 600mL of water and layers separated. The organic layer was then treated with aqueous hydrochloric acid and the solid formed

was filtered, washed with water and ethyl acetate and dried. The dried solid so obtained was treated with ethanol and water and heated to 85-90 °C. The filtrate was again cooled, filtered and solid obtained was washed with isopropyl alcohol and dried under tray dryer. The solid so obtained was added to toulene, heated to 90-100 °C and 10% sodium hydroxide added. The reaction mass was cooled to 25-30 °C, filtered and washed with toulene to yield Brexpiprazole (1). Yield: 75%; Purity: 99.5%
Example-5: Purification of Brexpiprazole (1)
Brexpiprazole (1) was dissolved in toulene and heated to 90-100 °C and neutral charcoal added. The reaction mass was cooled and filtered through Hyflo, the filtrate so obtained was again filtered through 0.2 mm micron filter at 85-90 °C. The filtrate was cooled to 25-30 °C and the solid filtered and washed with toulene. The solid so obtained was dissolved in methanol and heated to 60-65 °C. The reaction mass was then cooled to 10-15 °C and filtered under vacuum. The solid obtained was washed with isopropyl alcohol and dried under vacuum to yield pure Brexpiprazole (1). Yield: 50%; Purity: 99.8%.
Example-6: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one hydrochloride salt (2)
1.49g of palladium acetate [Pd (OAc)2] and 4g of (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) [BINAP] were charged into a solution of toluene under nitrogen atmosphere. To this solution lOOg of 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one (5), 95.4g of sodium tert-butoxide and 70.6g of 4-bromobenzo[b]thiophene were added under nitrogen atmosphere at 25-30 °C. The reaction mixture was heated to 110 °C for 16 hours and then cooled to 25 °C. 300mL of methanol was added to the reaction mixture and stirred for 10-20 minutes at 55 °C. The reaction mixture was filtered through Hyflo bed. The obtained filtrate was diluted with water and the layers were separated. The aqueous layer was washed with toluene twice. Dilute hydrochloric acid was added to the combined organic layers and the reaction mass was maintained for 1

hour at 25-30 °C. The obtained solid was filtered, washed with water, acetone and dried at 50 °C to get titled compound. Yield: 77%
Purification of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one hydrochloride salt (2)
A mixture of 25g of compound of crude Brexpiprazole (1) and 250mL of dimethylformamide was stirred for 30 min at 25-30 °C. Heated the reaction mixture to 75-80 °C and stirred for 40 minutes, filtered the insoluble compound. To the filtrate 2g of neutral charcoal was added to the reaction mixture at 75-80 °C and stirred for 40 minutes. Filtered the reaction mixture through Hyflo to make it particle free and washed with dimethylformamide. The obtained filtrate was slowly added to acetone and cooled to 10 °C, stirred for 1 hour. Filtered the precipitated solid, washed with acetone. The obtained filtrate was distilled off completely, washed with water and dried to get the pure title compound. Yield: 80%; Purity: 96.5%
Example-7: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1) from 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin -1-yl) butoxy) quinolin-2(lH)-one hydrochloride salt (2)
Charge 17g of hydrochloride salt of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl)
butoxy) quinolin-2(lH)-one (1) into 200mL of water at 25-30 ° C. The pH of the
reaction mass was adjusted to 12.5 by adding 40mL of 30% sodium hydroxide solution.
To the reaction mixture 10% of methanol and dichloromethane were added. Separate
the immiscible layers, wash the organic layer with water and saturated sodium chloride
solution. The organic layer was dried over sodium sulphate, distilled off under reduced
pressure to get title compound. The obtained solid was suspended in ethanol and stirred
for one hour. The solution was filtered and washed with ethanol to get anhydrous 7-
(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1) having
moisture content less than 1.0%.
Yield: 82.8%

Purification of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1)
A mixture of 3g of Brexpiprazole (1) and lOOmL of methanol was stirred for 30 min at 25-30 °C. Heated the reaction mixture to 65 °C to get clear solution. To the filtrate 2g of neutral charcoal was added to the reaction mixture at 65 °C and stirred for 40 minutes. Filtered the reaction mixture through Hyflo to make it particle free and washed with methanol. The obtained filtrate was distilled off completely, filter, washed with methanol and dried the material to get the pure Brexpiprazole (1). Yield: 70.2%.
Example-8: Alternate process for Purification of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1)
25g of compound Brexpiprazole (1) was added to 400mL of dimethyl formamide at 250 °C and maintained for 30 minutes. The reaction mixture was filtered through Hyflo bed, washed with 50mL of dimethylformamide and dried at 50 °C to get pure Brexpiprazole (1).
Example-9: Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one tartrate salt (3)
lg of Brexpiprazole (1) was added to a solution of 20 volumes of isopropyl alcohol and heated to 65 °C for 30 minutes. To the reaction mixture lOmL of methanol, 0.34g of tartaric acid in 5mL of isopropyl alcohol was added and maintained for 4 hours. Cooled the reaction mixture to 25-30 °C, filtered the solid, washed with isopropyl alcohol and dried at 50 °C to get the title compound. Yield: 44.7%.

Example-10: Preparation of amorphous form of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1)
500mg of Brexpiprazole (1) was dissolved into a solvent mixture of 1:1 ratio of 1 OmL dichloromethane and methanol at 25 -35 °C. The reaction mass was stirred till it a clear solution was formed and filtered. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 55 -65 °C, dried at 45 -50 °C to get the amorphous form of 7-(4-(4-(benzo[b]thiophen-4-yl) piperazin-1-yl) butoxy) quinolin-2(lH)-one (1). Yield: 88%.
Example-11: Preparation of amorphous solid dispersion of Brexpiprazole and Hydroxypropyl- P-cyclodextrin (HPBCD)
250mg of Brexpiprazole (1) was dissolved in a mixture of 1:1 ratio of lOmL dichloromethane and methanol at 25-35 °C. To the reaction mass 750mg of Hydroxypropyl-P-cyclodextrin (HPBCD) was added, stirred for 30miutes to form a clear solution and filtered to make the solution particle free. The clear solution so obtained was taken into a Buchi flask, the solvent was evaporated completely under vacuum at 55 -65 °C and dried at 45-50 °C to get the title compound. Yield: 91%.
Example-12: Preparation of amorphous solid dispersion of Brexpiprazole and Polyvinylpyrrolidone K-30 (PVP K-30)
250mg of Brexpiprazole (1) was dissolved in a mixture of 1:1 ratio of lOmL dichloromethane and methanol at 25-35 °C. To the reaction mass 750mg of Polyvinyl pyrrolidone K-30 (PVP K-30) was added, stirred for 30miutes to form a clear solution and filtered to make the solution particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 55-65 °C, dried at 45 -50 °C to get the title compound. Yield: 90%.

Example-13: Preparation of amorphous solid dispersion of Brexpiprazole and Hydroxypropyl cellulose (HPC)
250mg of Brexpiprazole (1) was suspended in 5mL of dichloromethane, a solution of 750mg of Hydroxypropyl cellulose (HPC) in a mixture of 1:1 ratio of 40mL dichloromethane and methanol was added at 25 -35 °C and filtered to make the solution particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 55 -60 °C, dried at 55 -60 °C to get the title compound. Yield: 90% .
Example-14: Preparation of amorphous solid dispersion of Brexpiprazole and Sulfobutylether-p-cycIodextrin(SBECD)
250mg of Brexpiprazole was suspended in 5mL of dichloromethane, a solution of 750mg of sulfobutylether-(3-cyclodextrin (SBECD) in 40mL methanol was added at 25 -35 °C. Heat the reaction to about 60-65 °C for 30 minutes and filtered to make the solution particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 60-65 °C, dried at 60-65 °C to get the title compound. Yield: 90%.
Example-15: Preparation of amorphous solid dispersion of Brexpiprazole and Hydroxypropyl methyl cellulose (HPMC)
250mg of Brexpiprazole (1) was suspended in 5mL of dichloromethane, a solution of 750mg of Hydroxypropyl methyl cellulose (HPMC) in lOmL methanol was added at 25 -35 °C and filtered to make the solution particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 60 -65 °C, dried at 60 -65 °C to get the title compound. Yield: 98%.

Example-16: Preparation of amorphous solid dispersion of Brexpiprazole and Malto dextrin
250mg of Brexpiprazole (1) was suspended in 5mL of dichloromethane, a solution of 750mg of maltodextrin in a mixture of 1:1 ratio of 40mL methanol and dichloromethane was added at 25 -35 °C. Heat the reaction to about 35 -40 °C for 30 minutes and filtered to make the solution particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely at 40 - 45 °C, dried at 55 - 60 °C to get the title compound. Yield: 96%;
Example -17: Preparation of amorphous solid dispersion of Brexpiprazole and Hydroxypropyl-P-cycIodextrin (HPBCD) by spray drying method
8mg of Brexpiprazole (1) and 24mg of Hydroxypropyl-P-cyclodextrin (HPBCD) were dissolved in a mixture of 250mL dichloromethane and 150mL methanol at 25 -35 °C and filtered to make the solution particle free. The clear solution was then spray dried at below mentioned parameters to obtain the title compound.

Name of instrument:
Aspirator
Feed rate
Inlet temperature
Nitrogen Gas flow
Yield: 50%

Jay Instruments Mini Spray dryer
70%
10 mL/min
65 °C,
2kg/cm2

Example-18: Preparation of amorphous solid dispersion of Brexpiprazole and Hydroxypropyl-P-cyclodextrin (HPBCD) by Agitated Thin Film Drier method (ATFD)
8mg of Brexpiprazole (1) was dissolved in a mixture of 250mL dichloromethane and 150mL methanol at 25 °C-35 °C, 24mg of Hydroxypropyl-p-cyclodextrin (HPBCD) was added and filtered to make the solution particle free. The clear solution was then

dried by agitated thin film drier method (ATFD) method at below mentioned parameters to obtain the title compound. Operation parameters:

Vacuum 730 mm/Hg
Feed rate 15 mL/min
Inlet temperature 65 °C,
Condensed Temperature -5°C
Yield: 17.3%
Example -19: Preparation of crystalline Brexpiprazole (1)
lOOg Brexpiprazole o (1) was added to toluene at 25 °C-30 °C and stirred for 20-30 minutes. Then reaction was heated to 90 °C-100 °C for 1-2 hours. The reaction mixture was filtered to make it clear solution. The filtrate was again heated to 90 °C-100 °C for 1-2 hours and the reaction mass was cooled gradually to 25 °C-30 °C. Solid so obtained was filtered and dried under vacuum below 50 °C to get crystalline Brexpiprazole (1). Yield: 70%; XRD: Figure-1; DSC: Figure-2.

We claim:
1. A process for the preparation of Brexpiprazole (1) or its salts comprising the following steps:
a) reacting 7-hydroxy-lH-quinolin-2-one with l-bromo-4-chlorobutane in presence of base to form 7-(4-chlorobutoxy)-lH-quinolin-2-one;
b) reacting 7-(4-chlorobutoxy)-lH-quinolin-2-one with tert-butyl piperazinel-carboxylate to form tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate in-situ;
c) treating tert-butyl 4-(4-(2-oxo-l,2-dihydroquinolin-7-yloxy) butyl) piperazine-1-carboxylate with a suitable base to form 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one;
d) reacting 7-(4-(piperazin-l-yl) butoxy) quinolin-2(lH)-one with. 4-bromo-benzo (b) thiophene in presence of a suitable base and catalyst to form Brexpiprazole (1); and
e) purifying Brexpiprazole (1).
2. The process, as claimed in claim 1, wherein the suitable bases used in the preparation of Brexpiprazole or its salts may be selected from a group comprising organic or inorganic bases comprising of potassium tertiary butoxide, potassium ethoxide,, sodium methoxide, sodium tertiary methoxide , , lithium tertiary butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate , sodium bicarbonate, potassium bicarbonate, triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 3. The process, as claimed in claim 1, wherein the suitable acid used in the preparation of Brexpiprazole (1), may be selected from a group comprising of with organic or inorganic acids comprising of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic

acid, formic acid, tartaric acid and p-touenesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and mixtures thereof. The process, as claimed in claim 1, wherein the solvent used for the preparation of Brexpiprazole (1) is selected from the group comprising of protic or aprotic solvents comprising of water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, ethylene glycol, dicWororn.eth.ane, dimethylformamide, ethyl acetate acetone and toulene. A process for the purification of Brexpiprazole (1) or its salts comprising.
a) Providing the Brexpiprazole (1) in an aprotic solvent;
b) heating to a suitable temperature;
c) treating reaction mixture with activated carbon
d) filtering the reaction mixture;
e) treating with an aprotic solvent and cooling to a suitable; and
f) isolating pure Brexpiprazole (1).
The process, as claimed in claim 5, wherein the solvents used in the purification processes of Brexpiprazole (1) may be selected from the group comprising of protic or aprotic solvents comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, ethylene glycol , water, dichloromethane, dimethylformamide, acetone, toulene was used in the present invention.
A process for the preparation of solid dispersions of Brexpiprazole (1), comprising the steps of:
a) providing solution of Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture thereof;
b) providing at least one pharmaceutically acceptable excipient;
c) removing the solvent obtained in step b); and
d) isolating amorphous solid dispersion of Brexpiprazole (1).
. The process, as claimed in claim 7, wherein pharmaceutically acceptable excipients is selected from maltodextrin, hydroxypropyl methyl cellulose

(HPMC), sulfobutylether-(3-cyclodextrin (SBECD), Hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone, povidone K-30, povidone K-60, povidone K-90, Hydroxypropyl-beta-cyclodextrin (HPBCD), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, hydroxypropylmethyl cellulose phthalate, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, cyclodextrins, gelatins, D-alpha-tocopheryl polyethylene glycol 1000 succinate, Polyvinylacetal diethylamino acetate or the like. 9. The process, as claimed in claim 1, wherein Brexpiprazole obtained is amorphous form of Brexpiprazole (1), comprising the steps of:
a) providing Brexpiprazole (1) in a suitable protic or aprotic solvent or mixture thereof;
b) optionally treating the solution of step, a) with another solvent/ anti-solvent and
c) isolating the amorphous form of Brexpiprazole (1).
10. The process, as claimed in claim 1, wherein Brexpiprazole obtained is crystalline and the process for the preparation of crystalline Brexpiprazole, comprises:
a) providing Brexpiprazole (1) in a suitable aprotic solvent;
b) heating to a suitable temperature;
c) cooling the reaction solution to a suitable temperature; and
d) isolating the crystalline Brexpiprazole (1).