FIELD OF INVENTION:
The present invention reports Improved Processes for the preparation of Brexpiprazole and its Acid salt. It also reports an improved process for the purification of Brexpiprazole.
BACKGROUD OF INVENTION:
Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin-dopamine activity modulator" (SDAM). The drug was approved by the U.S. Food and Drug Administration (FDA) on July 10, 2015, for the treatment of schizophrenia, and as an adjunctive treatment for depression. It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).
The drug was developed by Otsuka and Lundbeck, and is considered to be a successor of Otsuka's top-selling atypical antipsychotic aripiprazole (Abilify). Otsuka's U.S. patent on aripiprazole expired on October 20, 2014; and a generic was approved in April 2015.
Brexpiprazole is used in the treatment of schizophrenia and as an adjunct for major depressive disorder. Based on information given on the consent forms, it seems

Brexpiprazole is a substrate of CYP2D6 and CYP3A4, like its predecessor aripiprazole. Participants in the clinical trials are advised to avoid grapefruit, Seville oranges and related citruses.
Brexpiprazole is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). Brexpiprazole is chemically known as 7-{4-[4-(l-benzothiophen-4- yl) piperazin-1-yl] butoxy} quinolin-2 (lH)-one. It is known from US 7,888,362 and is represented by Formula I.
H
Formula I Brexpiprazole is sold in USA under the proprietary name of "REXULTI" and is indicated
for the treatment of schizophrenia and also as an adjunctive therapy to antidepressants in
adults having major depressive disorder.
US 7,888,362 describes a process for the preparation of Brexpiprazole compound of Formula I wherein compound of Formula II reacts with l-bromo-4-chlorobutane using potassium hydroxide as base in methanol at 50°C to obtain compound of Formula III which was purified by silica gel column chromatography (dichlorome thane: methanol= 100:3) to

obtain pure compound of Formula III. Another intermediate 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V is prepared by reacting compound of Formula IV with anhydrous piperazine using (R) (+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl(BINAP), dipalladiumtris (dibenzylidene acetone) in presence of sodium i-butoxide by heating under reflux. The resulting 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V then reacts with compound of Formula III to obtain Brexpiprazole compound of Formula I as residue which was purified by silica gel column chromatography (dichlorome thane: methanol=100:3) followed by recrystallization with ethanol to obtain pure compound of Formula I as shown in Scheme-I.
! jl i l-tiromo-4-chlorobiJtane ' jl
O^/^OH ^^Z ~cA/^S:
|_| KQH.PiieOH H
50°C
Formula II Forniula III
H

Sodium-i-butoxide
dipalladiurr Iris [d ibenzyl ideneacetone}
Formula W [RM+)-2.2'-bis(diphenylphosphino)-1,1 '-binaphtiyl Formula V
HCI

K;COs . IMal/UMh j?
i HCI fTl
O r *
.
C,H6OH ^^IJ^| ^ "-'-■ :■
H
Formula V Formula III
Formula I
Stheme-I

The main drawback of this process is the use of expensive and laborious column chromatographic purification at various stages, which not only require handling of large volume of solvent at commercial scale but also makes the process expensive and time consuming. Another drawback of the process is the formation of by-product mainly Impurity D (dimer impurity) during the reaction of compound of Formula II with 1- bromo-4-chlorobutane, which is difficult to separate, thus require multiple purification which in turn decreases the yield and increases the cost of the final product.

Impurity D (Dimer impurity)
US 9,206,169 describes an improved process for the preparation of 4-(l-piperazinyl)benzo[b]thiophene compound of Formula V which involves reaction of compound of Formula VII with piperazine in presence of (a) a palladium compound and a tertiary phosphine or (b) a palladium carbene complex, in an inert solvent or without a solvent to obtain compound of Formula V which further reacts with compound of Formula III to obtain Brexpiprazole of Formula I as shown in (Scheme II)


CI
DMI
DBU 160 to 195" C
MCI toluene

i
Formula VII

Pd(QAcfc
(CH3)3CaNa xylene
120-130°C HCI


ISL H-CI
V
Formula V

-.AX
H Formula III

O Formula I

Cl-

l-K2COs
Kl
2-C2l l5OI I CH5COOH H20
XXX
N ^O
H

Scheme-I I
The main drawback of the said process is the use of expensive palladium carbene complex on commercial scale, which makes the process costly and needs special handling equipment for industrial scale production. Another disadvantage of this process is the formation of impurity A and impurity B during the reaction of compound of Formula V with compound of Formula III which is difficult to separate from the final product and requires multiple purifications, thus in order to attain the purity of final compound, it leads to undue operational steps for removal of impurities, thus makes the process expensive and tedious on
commercial scale.


OvO *-
^s^

Impurity -A

Impurity - B

CN 105175401A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with 1 -chlorine-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III, which then reacts with N-Boc piperazine to obtain 7-(l-piperazine) butoxy-lH-quinolin-2-one dihydrochloride of Formula VIII followed by reaction with compound of Formula IV and isopropyl magnesium chloride in THF to obtain
Brexpiprazole compound of Formula I according to Scheme-Ill

XXX

CI 1 ■6,3ro4-tMoro3 Jtaie

H

1- HN NBOC
'Cl i nr, "X '
H

NKJ .ZHCI

Formula II

I r; ~i„ ii |

FgcrriMa VIII

B-

THF (CHJ)aCHUgCI

Fsmnula V


0XHX^XC

a ■

Scheme-Ill

For", a I

CN 105440026A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with l-chloro-4-bromobutane to obtain 7-(4- chlorobutoxy)4H-quinolin-2-one of Formula III which reacts with piperazine monohydrochloride to obtain 7-(4-(piperazin4-yl) butoxy) quinolin-2(lH)-one hydrochloride compound of formula VHP. The resulting compound of Formula VHP then reacts with 4-chlorobenzo [b] thiophene in presence of a base and palladium triphenyl complex to give Brexpiprazole compound of Formula I according to Scheme - IV.

1 -Droirio-4-cfiloroLiLlane

■i Fsrmjla I

duane j ]
CjH^OH.NaDH
Formula ill

1- H*f HM.HCI
pipeline *i/drost"knidc
-ci inc. ;XHAA,.,-..^-^- ■ ™
Formula V II'


Pd(OAjc)2 (rlpierylphMphlr-t
Fornula VII

XXX


a w

hcdi.ui;i ■
Schcmc-IV
The main drawback of the processes disclosed in Scheme-Ill & IV is the formation of di-benzo[b] thiophene impurity (Impurity C) during the reaction of compound of Formula VIII or VHP with compound of Formula IV or VII using isopropyl magnesium chloride or
palladium triphenylphosphine complex used as a catalyst which once formed, is difficult to

remove and gets carried forward to the final step and affects the yield and purity of the final product.
Impurity C.
Brexpiprazole can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO 2006/1 12464 Al discloses Brexpiprazole and its use for the treatment of schizophrenia and other central nervous system disorders. Brexpiprazole is described in example 1 as a crystalline material obtained as a white powder by recrystallization from ethanol.
WO 2013/162046 Al characterizes the crystalline Brexpiprazole obtained from example 1 of WO 2006/1 12464 Al as an "anhydride", more properly to be understood as an "anhydrate" form of Brexpiprazole. Brexpiprazole anhydrate, herein referred to as form I, shows characteristic PXRD reflections at 2 Theta angles of 14.4°, 19.1 °, 20.2°, 21.3° and 23.2°. WO 2013/162046 Al also discloses a crystalline hydrate of Brexpiprazole which is

characterized by means of PXRD. Brexpiprazole hydrate is described as showing characteristic PXRD reflections at 2 Theta angles of 7.7°, 9.4°, 1 1 .8°, 18.9° and 24.0°. WO 2013/162046 Al also discloses a crystalline dihydrate of Brexpiprazole which is characterized by means of PXRD, Infrared spectroscopy, Raman-spectroscopy, and 1 H-NMR. Brexpiprazole dihydrate is described as showing characteristic PXRD reflections at 2 Theta angles of 8.1°, 8.9°, 15.1°, 15.6° and 24.4°. An advantage of Brexpiprazole dihydrate is described to be that when injected intramuscularly into rats, the dihydrate crystals can still be detected at the injection site, while the anhydrate form (form I) was no longer detectable 56 days after the injection. The Brexpiprazole dihydrate crystals are thus suggested for injectable preparations of Brexpiprazole with sustained release properties.
WO 2013/161830 Al discloses an aqueous suspension comprising secondary particles formed by aggregation of Brexpiprazole having a mean secondary particle diameter of 1 to 50 urn. A bulk powder is to be produced wherein Brexpiprazole dihydrate should have a defined primary particle size. Milling and grinding are mentioned as methods for the preparation of the bulk powder.
WO 2017208251A1 discloses a new crystalline polymorph of Brexpiprazole. More specifically, the invention relates to novel Form M of Brexpiprazole, process for preparing the novel form of Brexpiprazole and pharmaceutical formulations comprising the novel form

of Brexpiprazole. The present invention also relates to an improved process for the preparation of l-(benzo[b]thiophen-4-yl) piperazine and its further use for the preparation of Brexpiprazole
WO2017106641A1 provides solid state forms of Brexpiprazole, and pharmaceutical compositions thereof namely Form J & G. The present disclosure also encompasses uses of the solidstate forms of Brexpiprazole of the present disclosure for the preparation of pharmaceutical compositions and/or formulations of Brexpiprazole.
The invention in WO2018172463 relates to processes for preparation of 7-{4-[4-(l-benzothiophen-4-yl) piperazin-1-yl] butoxy} quinolin-2(lH)-one (Brexpiprazole), intermediates used during preparation, and polymorphs of Brexpiprazole. Brexpiprazole is an atypical antipsychotic and indicated for adjunctive treatment of major depressive disorder (MDD).
WO2018015354 is related to a method for the manufacture of Brexpiprazole (I) comprising: (a) reaction of 4-[(2-oxo-l,2-dihydroquinolin-7-yl) oxy] butanal or a solvate thereof with 1-(l-benzothiophen-4-yl) piperazine or a salt thereof in a solvent, optionally in the presence of a catalyst, and (b) reduction of the iminium salt formed in step (a) using a reducing agent in a solvent, optionally in the presence of a catalyst in the form of tetraalkylammonium

halogen. The invention is also related to the intermediates used for the manufacture of brexpiprazole, and the method for manufacture of these intermediates. A method for manufacture of compounds II [Rl, R2 = independently CI-5 alkyl or Rl and R2 together with the- (CH2) n- group [n = 2-3] form a ring] by reaction of 7-hydroxyquinolin-2(lH)-one with X(CH2)3(0R1) (OR2) [X = a leaving group] in the presence of a solvent and a base, and optionally in the presence of a catalyst. The invention allows manufacture of I in a very pure form and in high yield without the need for performing complex purification procedures.
As none of the above reported processes is not able to provide Brexpiprazole of high purity qualifying stringent ICH grade specifications, therefore, there was a need to develop economical process for the preparation and purification of Brexpiprazole and its Acid salts to remove all critical impurities to get highly pure Brexpiprazole and easy to handle at commercial scale.
After careful study of the available literature, keeping in view the Target of developing Improved cost-effective processes for the preparation of highly pure Brexpiprazole & its acid salts which can be used at commercial scale for production of Brexpiprazole in plant, the development work was started in the lab. The exact details of the invention are disclosed in the next section of this patent application.

SUMMARY OF INVENTION:
The present invention relates to the Improved processes for the preparation of Brexpiprazole and its acid salts using l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride as the key starting material. Under improved conditions of reaction, the key raw material is coupled with 7-(4-Chlorobutoxy)-lH-quinoline-2-one to give Brexpiprazole initially which is further converted to its respective hydrochloride salt in acetone-water.
Also disclosed is a process for purification of Brexpiprazole which involves conversion of Brexpiprazole Acid salt into Brexpiprazole followed by its purification in presence of NaOH in acetone- water.
The details of invention are disclosed in the next section of this patent application
Advantages of the process disclosed herein are given below:
1) The present invention results Brexpiprazole Acid salt of improved purity which ultimately results almost impurity free Brexpiprazole which otherwise can not be achieved by prior art processes.
2) The present invention results almost impurity free Brexpiprazole of very low Residual solvents and sulphated ash.

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for the 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one acid salt or Brexpiprazole acid salt is disclosed which comprises:
1. Dissolving l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (III) in an aliphatic amide such as N,N- Dimethylformamide followed by addition of 7-(4-Chlorobutoxy)-lH-quinoline-2-one.
2. Adding potassium carbonate & Sodium or potassium iodide at 25-30°C.
3. Heating the reaction mass to 70-80°C & stirring till reaction completion.
4. Cooling the reaction mass to 40-50°C & adding water to it
5. Stirring further to ensure proper crystallization
6. Cooling the mass to 20-30°C and stirring for 1-2 hours.
7. Isolation of material as wet cake by routine filtration and drying at 60-70°C for 10-20 hours under vacuum to get Brexpiprazole.

8. Brexpiprazole as obtained above, stirred in mixture of an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and water at 10-40°C in any different ratio.
9. Adding an acid which is selected from hydrochloric acid or Mandelic acid or p-toluene sulphonic acid or benzoic acid to the suspension formed above
10. Heating to 60-80°C & stirring for 60 minutes.
11. Adding water to reaction mass above
12. Stirring till complete crystallization.
13. Cooling the mass to 10-20°C and stirring for 1-2 hours.
14. Isolation of material as wet cake by routine filtration and drying at 60-70°C for 10-20 hours under vacuum to get 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one acid salt or Brexpiprazole acid salt of improved purity.
According to the second embodiment of the present invention, an improved process for the preparation of 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole is disclosed which comprises:

1. Stirring Brexpiprazole hydrochloride salt or mandelate salt or p-Toluene sulphonic acid salt or benzoate salt in mixture of an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and water at 10-40°C in different ratio.
2. Heating the suspension as obtained in step 1) above to 60-80°C.
3. Adding aq. Sodium or potassium hydroxide solution at 60-80°C.
4. Cooling the mass to 10-20°C and stirring for 1-2 hours.
5. Isolating material as wet cake by routine filtration and drying at 60-70°C for 10-20
hours under vacuum to get pure 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-
quinolin-2-one or Brexpiprazole.
According to the Third embodiment of the present invention, an improved process for the purification of 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole is disclosed, which comprises:
1. Stirring 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole in mixture of an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and water at 10-40°C in different ratio.

2. Heating the suspension as obtained in step 1) above to 60-80°C.
3. Adding aq. Sodium or potassium hydroxide solution at 60-80°C.
4. Cooling the mass to 10-20°C and stirring for 1-2 hours.
5. Isolating material as wet cake by routine filtration and drying at 60-70°C for 10-20
hours under vacuum to get almost impurity free 7-[4-(4-Benzo[b]thiophen-4-yl-
piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole.
The above-mentioned invention is supported by the following non limiting examples.
xample 1: Process for the preparation of Brexpiprazole Hydrochloride
To a solution of l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (100g) in N,N-Dimethylformamide (500ml), 7-(4-Chlorobutoxy)-lH-quinoline-2-one (1 lOg) , Potassium carbonate (140 g) and Sodium Iodide (60 g) are added at ambient temperature and the reaction mixture was heated at 70-80°C with stirring. After reaction completion, the reaction mixture was cooled to 40-50°C and DI- Water was added with stirring. The resulting mass was further cooled to 20-30°C. The product was filtered, washed with Dl-water and dried at 60-70°C to get Brexpiprazole (HPLC purity 92%).
To a suspension of lOOg of Brexpiprazole (HPLC purity 93%) in Acetone (500 ml), Dl-water (400 ml) was added at 10-40°C followed by addition of aq Hydrochloric Acid (80 ml).

The resulting reaction mixture was heated at 60-80°C with stirring for 30-60 minutes. Then Dl-water (300 ml) was added to it with stirring. The resulting mass was cooled to 10-20°C. The product was filtered, washed with a mixture of Acetone-DI-Water (1:1) and dried at 60-70°C to obtain 1 lOg of Brexpiprazole Hydrochloride (HPLC purity= 97.67%). Example 2: Process for the preparation of Brexpiprazole
To a suspension of lOOg Brexpiprazole Hydrochloride (HPLC purity= 97.67%) in Acetone (500ml) and Dl-Water (400 ml) at 60-80°C, a solution of aqueous Sodium Hydroxide (35 g) in Dl-Water (100 ml) was added and the reaction mixture was stirred at 60-80°C. The resulting mass was cooled to 10-20°C and stirred for 1-2 hrs. The product was filtered and washed with water to get 85g of Brexpiprazole. (HPLC purity = 99.50%). with other individual impurities 0.20%, 0.16%, 0.14%).
Example 3: Process for the Purification of Brexpiprazole
A suspension of lOOg of Brexpiprazole (HPLC purity 99.50%) in Acetone (500ml) and DI-
water (400 ml) mixture was heated at 60-70°C followed by addition of aqueous sodium
hydroxide (35 g) solution in Dl-water (100 ml) and stirred for 1-2 hrs . The resulting mass
was cooled to 10-20°C. The product was filtered, washed with Dl-Water and dried at 60-
70°C to obtain impurity free Brexpiprazole having HPLC purity = 100%).

Example 4: Process for the Purification of Brexpiprazole
A suspension of lOOg of Brexpiprazole (HPLC purity 99.50%) in Acetone (500ml) and DI-
water (300 ml) mixture was heated at 60-70°C followed by addition of aqueous sodium
hydroxide (35 g) solution in Dl-water (100 ml) and stirred for 1-2 hrs . The resulting mass
was cooled to 10-20°C. The product was filtered, washed with Dl-Water and dried at 60-
70°C to obtain impurity free Brexpiprazole having HPLC purity = 99.97%.
Example 5: Process for the Purification of Brexpiprazole
A suspension of lOOg of Brexpiprazole (HPLC purity 99.50%) in Acetone (500ml) and DI-
water (250 ml) mixture was heated at 60-70°C followed by addition of aqueous sodium
hydroxide (35 g) solution in Dl-water (100 ml) and stirred for 1-2 hrs . The resulting mass
was cooled to 10-20°C. The product was filtered, washed with Dl-Water and dried at 60-
70°C to obtain impurity free Brexpiprazole having HPLC purity = 99.95%).
Example 6 : Process for the preparation of Brexpiprazole Mandelate
To a solution of l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (100g) in N,N-Dimethylformamide (500ml), 7-(4-Chlorobutoxy)-lH-quinoline-2-one (HOg) , Potassium carbonate (140 g) and Sodium Iodide (60 g) are added at ambient temperature and the reaction mixture was heated at 70-80°C with stirring. After reaction completion, the reaction mixture was cooled to 40-50°C and DI- Water was added with stirring. The resulting mass

was further cooled to 20-30°C. The product was filtered, washed with Dl-water and dried at 60-70°C to get Brexpiprazole (HPLC purity 92%).
To a suspension of lOOg of Brexpiprazole (HPLC purity 93%) in Acetone (500 ml), Dl-water (400 ml) was added at 10-40°C followed by addition of Mandelic acid (50g). The resulting reaction mixture was heated at 60-80°C with stirring for 30-60 minutes. Then Dl-water (300 ml) was added to it with stirring. The resulting mass was cooled to 10-20°C. The product was filtered, washed with a mixture of Acetone-DI-Water (1:1) and dried at 60-70°C to obtain 1 lOg of Brexpiprazole Mandelate (HPLC purity= 98.50%). Example 7: Process for the preparation of Brexpiprazole Benzoate salt
To a solution of l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (100g) in N, N-Dimethylformamide (500ml), 7-(4-Chlorobutoxy)-lH-quinoline-2-one (HOg), Potassium carbonate (140 g) and Sodium Iodide (60 g) are added at ambient temperature and the reaction mixture was heated at 70-80°C with stirring. After reaction completion, the reaction mixture was cooled to 40-50°C and DI- Water was added with stirring. The resulting mass was further cooled to 20-30°C. The product was filtered, washed with Dl-water and dried at 60-70°C to get Brexpiprazole (HPLC purity 92%).
To a suspension of lOOg of Brexpiprazole (HPLC purity 93%) in Acetone (500 ml), Dl-water (400 ml) was added at 10-40°C followed by addition of Benzoic acid (30g). The

resulting reaction mixture was heated at 60-80°C with stirring for 30-60 minutes. Then DI-water (300 ml) was added to it with stirring. The resulting mass was cooled to 10-20°C. The product was filtered, washed with a mixture of Acetone-DI-Water (1:1) and dried at 60-70°C to obtain 1 lOg of Brexpiprazole Benzoate (HPLC purity= 98.64%).
Example 8: Process for the preparation of Brexpiprazole Para-Toluene Sulphonate
To a solution of l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (100g) in N, N-Dimethylformamide (500ml), 7-(4-Chlorobutoxy)-lH-quinoline-2-one (HOg), Potassium carbonate (140 g) and Sodium Iodide (60 g) are added at ambient temperature and the reaction mixture was heated at 70-80°C with stirring. After reaction completion, the reaction mixture was cooled to 40-50°C and DI- Water was added with stirring. The resulting mass was further cooled to 20-30°C. The product was filtered, washed with Dl-water and dried at 60-70°C to get Brexpiprazole (HPLC purity 92%).
To a suspension of lOOg of Brexpiprazole (HPLC purity 93%) in Acetone (500 ml), Dl-water (400 ml) was added at 10-40°C followed by addition of para-Toluene Sulphonic acid (50g). The resulting reaction mixture was heated at 60-80°C with stirring for 30-60 minutes. Then Dl-water (300 ml) was added to it with stirring. The resulting mass was cooled to 10-20°C. The product was filtered, washed with a mixture of Acetone-DI-Water (1:1) and dried

at 60-70°C to obtain llOg of Brexpiprazole p-Toluenesulphonic acid salt. (HPLC purity= 98.00%).

WE CLAIM:

1.An improved process for the preparation of pure 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one acid salt or Brexpiprazole acid salt and its subsequent conversion to give highly pure 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole wherein the process comprises: -
i. dissolving l-Benzo[b]thiophene-4-yl-piperazine Hydrochloride (III) in N,N-Dimethylformamide followed by addition of 7-(4-Chlorobutoxy)-lH-quinoline-2-one;
ii. adding potassium carbonate & sodium or potassium iodide at 25-30°C;
iii. heating the reaction mass to 70-80°C & stirring till reaction completion;
iv. cooling the reaction mass to 40-50°C & adding water to reaction mass;
v. stirring;
vi. cooling the reaction mass to 20-30 °C and stirring further; and
vii. isolating the material as wet cake by filtration and drying it at 60-70°C to get crude Brexpiprazole.
2.The process as claimed in claim 1 further comprising:
stirring crude 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole of claim 2(vii) in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and water at 10-40°C;
adding a suitable acid selected from hydrochloric acid, mandelic acid, p-Toluene sulphonic acid or Benzoic acid;
heating the reaction mass for 1-2 hours at 60-80°C;
adding water & further stirring the reaction mass;
cooling the reaction mass at 10-20°C under stirring; and
isolating pure 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one acid salt or Brexpiprazole acid salt as per acid used in step 3(ii) by filtration and drying at 60-70°C for 10-20 hours.
3.The process as claimed in claim 1, further comprising:
stirring of 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one acid salt or Brexpiprazole acid salt of claim 3(vi) in an aliphatic ketone and water mixture as used in step 3(i) of claim 3 at 10-40°C;
heating the suspension to 60-80°C;
adding sodium hydroxide or potassium hydroxide at 60-80°C;
cooling the reaction mass to 10-20°C and continued stirring for 2 hours; and
isolating pure 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole by filtration and drying at 60-70°C for 1-2 hours.
4.The process as claimed in claim 3 wherein the process is repeated using pure Brexpiprazole of claim 4(v) as starting material to give highly pure, impurity free 7-[4-(4-Benzo[b]thiophen-4-yl-piper-azin-l-yl)-lH-quinolin-2-one or Brexpiprazole.