FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Brexpiprazole.
The present invention particular relates to an improved process for the preparation of Brexpiprazole using polymorphic Form-S of Brexpiprazole phosphate salt which is highly cost effective, commercially feasible & industrially advantageous.
The present invention further relates to an improved process for the preparation of polymorphic Form-S of Brexpiprazole phosphate salt which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Brexpiprazole, an atypical antipsychotic, the chemical name of Brexpiprazole
is 7-{4-[4-( 1 -Benzothiophen-4-yl)piperazin-1 -yl]butoxy }quinolin2( 1 H)-one.
Brexpiprazole is achiral and has the following structural formula:

The empirical formula is C25H27N3O2S and a molecular weight of 433.57. Brexpiprazole is non-hygroscopic, with white to off white crystals or crystalline powders. Brexpiprazole is a weakly basic compound with a pKa of 7.8. It is practically insoluble in water, and the solubility of the drug substance at pH 2 is 0.56 mg/mL, at pH 4 is 0.13 mg/mL, and at pH 6 is 0.0020 mg/mL.
Brexpiprazole and process for its preparation is first disclosed in US 7,888,362 B2. The process as disclosed in the said patent is shown in the scheme given below:

The process disclosed in the said patent involves the use of silica gel column chromatography for the purification of Brexpiprazole; the said process is not feasible at plant/industrial level. To overcome the said issues and also to achieve the highest purity, the inventors of the present invention have developed an improved process which involves the preparation of Brexpiprazole phosphate salt which is further converted to Brexpiprazole free base to achieve the highest purity.
The process of the present invention using Brexpiprazole phosphate salt for the preparation of highly purified Brexpiprazole is efficient, industrially feasible and economically viable which substantially eliminate the problems associated with the prior art, and that will be suitable for large-scale preparation such that the process will be safe to handle, simple and easy to carry out with high yield and purity of the product.

OBJECT OF THE INVENTION
The main object of the invention is to provide an improved process for the purification of Brexpiprazole which is simple and cost effective.
The further object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of highly pure Brexpiprazole using crystalline Form-S of Brexpiprazole phosphate salt which yields pure Brexpiprazole at a high yield with high purity without formation of undesired impurities.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the purification of Brexpiprazole of Formula I

which comprises
a) treating crude Brexpiprazole with phosphoric acid in a solvent to give crystalline Brexpiprazole phosphate Form-S, wherein crystalline Brexpiprazole phosphate Form-S is characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83 ±0.2° 29.
b) treating crystalline Brexpiprazole phosphate Form-S with a base in a solvent to give highly pure Brexpiprazole, wherein the solvent used in step a) is selected from polar protic or polar aprotic solvent or their mixture.
In a preferred aspect, the present invention provides an improved process for the purification of Brexpiprazole of Formula I
'EMT OFFICE CH|Njf AI 0 5 / 8 3/ '2 0 1-9 1.6 s 3 0

Formula I which comprises
a) dissolving crude Brexpiprazole in polar protic or aprotic or mixture of polar protic & aprotic solvents,
b) reaction mass was heated to 60-90°C,
c) phosphoric acid was added to reaction mass of step b),

c) optionally isolating Brexpiprazole phosphate salt,
d) treating step c) reaction mass with a base in a solvent to give highly pure Brexpiprazole.
In another preferred aspect, the present invention provides an improved process for the purification of Brexpiprazole of Formula I
which comprises
a) dissolving crude Brexpiprazole in isopropanol or dimethyl acetamide or mixture,
b) phosphoric acid was added to step a) solution,
c) optionally isolating Brexpiprazole phosphate salt,
d) treating step c) reaction mass with a base in a solvent to give highly pure Brexpiprazole.
In yet another preferred aspect, the present invention provides an improved process for the preparation of Brexpiprazole phosphate, which comprises
a) dissolving crude Brexpiprazole in polar protic or aprotic or mixture of polar protic & aprotic solvents,
b) phosphoric acid was added to step a) solution,
c) isolating Brexpiprazole phosphate salt.
.'1
In yet another preferred aspect, the present invention provides an improved

process for the preparation of crystalline Form-S of Brexpiprazole phosphate characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83 ±0.2° 20, which comprises
a) dissolving crude Brexpiprazole in polar protic or aprotic or mixture of polar protic & aprotic solvents,
b) phosphoric acid was added to step a) solution,
c) isolating crystalline Form-S of Brexpiprazole phosphate.
In yet another preferred aspect, the present invention provides the use of crystalline Brexpiprazole phosphate Form-S characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83. ±0.2° 20 in the preparation of highly pure Brexpiprazole.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1: Illustrates the characteristic powder X-ray diffraction (XRD) pattern of crystalline Form-S of Brexpiprazole phosphate Form-S.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of highly pure Brexpiprazole of Formula I

The inventors of the present invention have developed an improved approach for the preparation of highly pure Brexpiprazole which involves the use of simple, commercially available and cost effective process.
The improved process according to the present invention does not yield any
T'E.Njmpufities^more^thah ^rfech^eS^evelsPlHirfhSr^tHe^prbeesk inVolvWlfess number of
solvent extractions and work up procedures which gives good yield and quality of the

product. Highly purified Brexpiprazole according to the present invention normally has the purity of above 99.5%, and the purity of said Brexpiprazole could be improved to 99.9% via optimization.
The present invention aims at providing a purification method of Brexpiprazole with the use of Brexpiprazole phosphate salt, which is based on the improvement of the purification disclosed in the prior art. In the large-scale industrial production, both the yield and quality (purity) of Brexpiprazole provided in the present invention are higher than those of the prior art such as US 7,888,362 B2. It is particularly surprising that purification method of Brexpiprazole provided in the present invention does not require operations (such as column chromatography) that are difficult for industrialization, which leads to a lowering in production cost in comparison with the purification procedure disclosed in US 7,888,362 B2, thus the present, invention is more suitable for industrialization. Moreover, due to the fact that the yield and purity of Brexpiprazole is relatively high and the conversion of Brexpiprazole phosphate salt to Brexpiprazole is as high as 99.0% under optimized conditions.
Brexpiprazole phosphate of the present invention may beisolated or carried out in-situ to Brexpiprazole free base. If Brexpiprazole phosphate salt is isolated it may be isolated as crystalline or isolated as an amorphous form or optionally recrystallized and used for further reactions.
According to this invention the polar protic solvents are selected from water, formic acid, nitromethane, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, acetic acid & polar aprotic solvents are selected from n-methyl pyrrolidine, tetrahydrofuran, ethyl acetate, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide, and dimethyl acetamide.
The term base used in the present invention is selected from organic base or r. j^inor^m^l^ase.-Ino^^anic^|^as^ jis selected, from, alkali carbonate and bicarbonate, ...,, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example

of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHC03s LiHC03, Na2C03, K2C03, Li2C03) CaC03, MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide, magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
The term solvent as used in the present invention is selected from water or acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or benzene, toluene, xylene, heptane, hexane and cyclohexane or acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or acetonitrile, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or formamide, DMF, DMSO, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, N-methyl morpholine, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone and/or mixtures thereof.
In a preferred embodiment, the present invention provides an improved process for the purification of Brexpiprazole of Formula I

which comprises, a) treating crude Brexpiprazole with phosphoric acid in a mixture of polar protic & = NT' Oa^rgtfc ^solvents^to7 ^iv(eActystailSie;-Br^xpiprazvGile jphosjpftafe ^Form-S, wherein •'•■ crystalline Brexpiprazole phosphate Form-S is characterized by its Powder X-ray

diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83 ±0.2° 26. b) treating crystalline Brexpiprazole phosphate Form-S with a base in a solvent to give highly pure Brexpiprazole.
In another preferred embodiment, the present invention provides an improved process for the purification of Brexpiprazole of Formula I
O-y'O K^J
Formula I which comprises
a) dissolving crude Brexpiprazole in a mixture of alcohols and DMF, DMSO or DMAC,
b) reaction mass was heated to 60-90°C,
c) phosphoric acid was added to reaction mass of step b),
d) optionally isolating Brexpiprazole phosphate salt,
e) treating step d) reaction mass with a base in a solvent to give highly pure Brexpiprazole.
In yet another preferred embodiment, the present invention provides an improved process for the purification of Brexpiprazole of Formula I

which comprises
a) dissolving crude Brexpiprazole in isopropanol or dimethyl acetamide or mixture,
b) phosphoric acid was added to step a) solution,
rENT OFFJCE LHE,NNAI,n OS / f)-& / Q n I q \ ft: ■* n
c) isolating crystallineTorm-S of Brexpiprazole phosphate salt,0 ou

d) treating step c) reaction mass with a base in a solvent to give highly pure Brexpiprazole.
In yet another preferred embodiment, the present invention provides an improved process for the preparation of crystalline Form-S of Brexpiprazole phosphate salt, characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83 ±0.2° 29, which comprises which comprises
a) dissolving crude Brexpiprazole in a mixture of solvents selected from water, alcohols , DMF, DMSO or DMAC,
b) phosphoric acid was added to step a) solution,
c) isolating crystalline Form-S of Brexpiprazole phosphate salt.
In yet another preferred embodiment, the present invention provides the use of crystalline Brexpiprazole phosphate Form-S characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83. ±0.2° 20 in the preparation of highly pure Brexpiprazole.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example-1: Preparation of crystalline Form-S of Brexpiprazole phosphate salt:
100 gins of crude Brexpiprazole was dissolved in 800 mL of isopropyl alcohol and 600 mL of dimethyl acetamide at room temperature. Reaction mass was heated to 80-85°C, reaction mass was stirred for lhr. 20 gms of phosphoric acid was added slowly at 80-85°C, reaction.mass^was gradually .cooledUo 20-25°C and further cooled -

to 5-10°C. Reaction mass was filtered and washed with 100 mL of IP A, dried to
obtain crystalline Form-S Brexpiprazole phosphate salt.
Yield: 140 gms
Purity by HPLC: 99.5%
Example-2: Preparation of highly pure Brexpiprazole:
100 gms of crystalline Form-S of Brexpiprazole phosphate was dissolved in 600 mL of isopropyl alcohol and 400 mL of water at room temperature. Reaction mass was heated to 80-85°C, reaction mass was stirred for lhr. 30 gms of 10% NaOH solution was added at 80-85°C, reaction mass was gradually cooled to 20-25°C. Reaction mass was filtered and washed with 50 mL of water, dried at 65-70°C to obtain highly pure Brexpiprazole. Yield: 90 gms Purity by HPLC: 99.9%

We claim:
1. An improved process for the purification of Brexpiprazole of Formula I

which comprises,
a) treating crude Brexpiprazole with phosphoric acid in a mixture of polar protic & aprotic solvents to give crystalline Brexpiprazole phosphate Form-S, wherein crystalline Brexpiprazole phosphate Form-S is characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83 ±0.2° 26.
b) treating crystalline Brexpiprazole phosphate Form-S with a base in a solvent to give highly pure Brexpiprazole.
2. An improved process according to claim 1, wherein the polar protic and aprotic
solvents are selected from water, formic acid, liitromethane, alcohols such as
methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, acetic acid &
polar aprotic solvents are selected from n-methyl pyrrolidine, tetrahydrofuran,
ethyl acetate, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide, and
dimethyl acetamide.
3. An improved process for the purification of Brexpiprazole of Formula I

which comprises

a) dissolving crude Brexpiprazole in a mixture of alcohols and DMF, DMSO or DMAC,
b) reaction mass was heated to 60-90°C,
c) phosphoric acid was added to reaction mass of step b), optionally isolating Brexpiprazole phosphate salt,
d) treating step c) reaction mass with a base in a solvent to give highly pure Brexpiprazole.
4. An improved process for the purification of Brexpiprazole of Formula I
which comprises
a) dissolving crude Brexpiprazole in isopropanol or dimethyl acetamide or mixture,
b) phosphoric acid was added to step a) solution,
c) isolating crystalline Form-S of Brexpiprazole phosphate salt,
d) treating step c) reaction. mass with a base in a solvent to give highly pure Brexpiprazole.
5. An improved process as claimed in preceding claims, wherein crystalline Form-S
of Brexpiprazole phosphate salt is characterized by its Powder X-ray diffractogram
having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83
±0.2° 26, which comprises which comprises
a) dissolving crude Brexpiprazole in a mixture of solvents selected from water, alcohols , DMF, DMSO or DMAC,
b) phosphoric acid was added to step a) solution,
c) isolating crystalline Form-S of Brexpiprazole phosphate salt.

6. An improved process as claimed in any of the proceeding claims, wherein the solvent is selected from water or acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or benzene, toluene, xylene, heptane, hexane and cyclohexane or acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or acetonitrile, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofiiran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or formamide, DMF, DMSO, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, N-methyl morpholine, 2-pyrrolidone, l-ethenyl-2-pyrrolidone and/or mixtures thereof..
7. An improved process as claimed in any of the proceeding claims, wherein base is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base.
8. Use of crystalline Brexpiprazole phosphate Form-S of Formula-I

characterized by its Powder X-ray diffractogram having one or more peaks at about 4.8, 13.8, 15.30, 16.53, 17.43, 22.36 & 22.83. ± 0.2° 29 in the preparation of highly pure Brexpiprazole.