Technical field of the Invention:

The present invention relates to 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 1-(benzo[b]thiophen-4-yl)piperazine and its further use for the preparation of brexpiprazole.

Background of the invention

Brexpiprazole, is a serotonin- dopamine activity modulator (SDA M) for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder and chemically known as 7-[4-(4-(Benzo[b]thien-4-yl)-piperazin-1-yl)butoxy]-1 H-quinolin-2-one.

US7888362 patent disclosed brexpiprazole which has following structure of Formula I;

Formula I

WO2013015456 discloses a dihydrate of a benzothiophene compound or a salt thereof, and a process for producing the same. C N 104829603 discloses a crystalline form A of brexpiprazole hydrochloride and a process for preparing the same.

Polymorphism is a typical property of some molecules, wherein the occurrence of different crystal forms is noticed.

A single molecule may give rise to diverse polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravi metric analysis - "TGA", or differential scanning calorimetry - "DSC"), X -ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.

One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Identifying new polymorphic forms and solvates of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.

New polymorphic forms and solvates of a pharmaceutical useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.

For one or more of these reasons, there is an inherent need for identifying new polymorphs of brexpiprazole.

Obj ectives of the invention

A primary object of the present invention is to provide new stable crystalline polymorph of brexpiprazole. Another object of the present invention is to provide processes for preparation of new stable polymorph of brexpiprazole.

Another object of the present invention is to provide a new stable polymorph of brexpiprazole which is suitable for use on a commercial scale.

Another object of the present invention is to provide an improved process for the preparation of tert-butyl 4-(benzo[b]thiophen-4-yl)piperazine-1-carboxylate.

Another object of the present invention is to provide an improved process for the preparation of brexpiprazole using 1-(benzo[b]thiophen-4-yl)piperazine prepared by the present invention.

Brief description of drawings

Figure 1 : X -ray diffraction spectrum of brexpiprazole Form M.

Figure 2: Differential Scanning calorimetric (DSC) curve of brexpiprazole Form M.

SU M MA RY OF T H E INV E NTION:

The present invention comprises a new stable polymorph of brexpiprazole. The new polymorph of brexpiprazole is hereafter designated as ^' brexpiprazole Form M _.

According to a first aspect of the present invention, there is provided crystalline Form M characterized by having an X -ray powder diffraction pattern that comprises peaks with 2 : :values (+ 0.2) of 4.19, 8.43, 9.47, 14.62, 16.91, 18.08, 19.05, 19.80, 21.33, 22.56, 24.51, 28.30 and 30.79. According to a second aspect of the present invention, there is provided an improved process for the synthesis of 1-(benzo[b]thiophen-4-yl)piperazine or its salt (II)

(II)

by reacting a compound of formula (III)

(HI) a compound represented by formula (IV )

(IV) in the presence of palladium compound and a tertiary phosphine, with or without solvent. According to a third aspect of the present invention, there is provided an improved process for the preparation of b la (I) comprising;

Formula I by reacting 1-(benzo[b]thiophen-4~yl)piperazine (II) or its salt prepared by the present invention,

with compound of formula V)

Formula (V)

in the presence of suitable base and solvent.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention comprises a new stable polymorph of brexpiprazole. The new polymorph of brexpiprazole is hereafter designated as ^' brexpiprazole Form M_. The term ^' stable _, with respect to this application refers to brexpiprazole Form M which does not change on storage and does not require any special conditions for storage.

Brexpiprazole Form M of the present invention is non- solvated crystalline form and is characterized by means of its characteristic X -ray diffraction pattern and DSC pattern.

According to a first aspect of the present invention, there is provided crystalline Form M of brexpiprazole.

As polymorphic forms are reliably characterized by peak positions in the X -ray diffractogram, the crystalline Form M of the present invention have been characterized by powder X -ray diffraction spectroscopy which produces a fingerprint of the particular

crystalline form. Measurements of 2 : :values are accurate to within e 0.2 degrees. All the

powder diffraction patterns were measured on a Rigaku Dmax 2200 advanced X - ray

powder diffractometer with a cu-K radiation source.

In an embodiment brexpiprazole Form M in accordance with the present invention is characterized by having an X -ray powder diffraction pattern that comprises peaks with 2 : :values (+ 0.2) of 4.19, 8.43, 9.47, 14.62, 16.91, 18.08, 19.05, 19.80, 21.33, 22.56, 24.51, 28.30 and 30.79.

In an embodiment, the crystalline polymorph Form M of brexpiprazole has an X RD pattern with peaks at 2 rvalues as shown in Table 1.

Table 1 : X RD peaks of crystalline Form M of Brexpiprazole. Position d-spacing (Al) Relative

(2 : values) Intensity (%)

4.19 21.04 14.26

8.43 10.48 5.66

9.47 9.33 21.51

14.62 6.05 19.40

16.91 5.23 35.81

18.08 4.90 72.10

19.05 4.65 35.42

19.80 4.47 43.89

21.33 4.16 100.00

22.56 3.93 29.15

24.51 3.62 63.67

28.30 3.15 19.91

30.79 2.90 17.18

In another embodiment, crystalline Form M of brexpiprazole is characterized by havi ng an X R D pattern as shown i n F igure 1.

In an embodiment, crystalline Form M of brexpiprazole of the present invention is characterized as having a DSC, exhibiting a significant peak at around 184eC.

In another embodiment crystalline Form M of brexpiprazole of the present invention is characterized as having a DSC as shown in Figure 2.

It will be appreciated that other conventional analytical methods including, but not limited to, intrinsic dissolution profiles, IR, solid state NM R, Thermogravi metric analysis (TGA), Dynamic Vapour Sorption analysis (DV S) and Raman spectroscopy may also be employed to characterize the crystalline Form M of the present invention. According to another aspect of the present invention, there is provided a process for preparing crystalline Form M of brexpiprazole.

The brexpiprazole base used in preparing the polymorph may be obtained by methods described in the prior art which are herein incorporated by reference in their entirety. The brexpiprazole used as a starting material can be in any form, e.g. it can be in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.

Crystalline Form M of brexpiprazole, may be prepared by dissolving brexpiprazole of any form or mixture of any form in a suitable solvent or solvent mixture thereof and then precipitating crystalline Form M of brexpiprazole from the solution.

The suitable solvent is selected form alcohols such as methanol, ethanol, isopropyl alcohol, tert- butyl alcohol or n- butyl alcohol; ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as methylene di chloride, chloroform, carbon tetrachloride and ethylene di chloride; tetrahydrofuran, methyl tert-butyl ether, di isopropyl ether, toluene, xylene and a mixture thereof. Preferable solvents used are mixture of alcoholic solvents and chlorinated solvents. In a most preferred embodiment the solvents used are methanol and MDC.

The ratio of polar to non- polar solvent may vary from 10:1 to 1 :10, preferably 1 :10. The reaction mass may be stirred for about 30 minutes to about 5 hours at a temperature of about 25eC to 80eC to get clear solution. The reaction is preferably sti rred at a temperature rangi ng from about 25eC to about 50eC .

Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti -solvent or a combination thereof. Optionally, seeds of brexpiprazole Form M may be used during the isolation.

In a preferred embodiment, the reaction mixture containing the product was cooled down to a temperature of 5-151C. To this anti -solvent was added followed by stirring for prolong period of time.

Preferable anti-solvents are n-heptane, cyclohexane, diisopropyl ether, petroleum ether and n-hexane; n-heptane being more preferable.

In an embodiment, the prolonged period is from about 1 hour to about days, preferably from about 1 hour to about 1 day, more preferably from about 1 hour to about 5 hours.

The precipitated Form M may be isolated by filtration, for example by either gravity or

suction. The precipitate may be dried at 25-60eC and/or in vacuum to obtain crystalline

Form M of brexpiprazole.

The process of the present invention affords crystalline Form M of brexpiprazole in high purity and high yield.

The novel crystalline Form M of brexpiprazole obtained according to the present invention is substantially free from other crystal and non-crystal forms of brexpiprazole. ^' Substantially free_ from other forms of brexpiprazole shall be understood to mean that the polymorphs of brexpiprazole contain less than 10%, preferably less than 5%, of any other forms of brexpiprazole and less than 1 % of other impurities, water or solvates. Thus, the brexpiprazole Form M prepared according to the present invention contains less than 11 % total impurities, preferably less than 6% total impurities. In a particularly preferred embodiment, the brexpiprazole Form M prepared according to the present invention contains less than 1 % total impurities.

The process of the present invention affords crystalline Form M of brexpiprazole having moisture content less than 2%.

Advantageously, the novel form is environmentally friendly and suitable for use on a commercial scale. The process of invention may be used as a method for purifying any form of brexpiprazole, as well as for the preparation of the new polymorphic form M.

According to another aspect, the crystalline Form M of brexpiprazole obtained by the processes disclosed in the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.

According to another aspect of the present invention, there is provided crystalline Form M of brexpiprazole as described above for use in medicine.

According to another aspect of the present invention, there is provided crystalline Form M of brexpiprazole as described above for use in treating schizophrenia, and as an adjunctive treatment for depression.

According to another aspect of the present invention, there is provided the use of crystalline M of brexpiprazole as described above for use in the manufacture of a medicament for treating schizophrenia, and as an adjunctive treatment for depression.

According to another aspect of the present invention, there is provided a method of treating schizophrenia, and as an adjunctive treatment for depression, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline M of brexpiprazole as described above.

According to a second aspect of the present invention, there is provided an improved process for the synthesis of 1-(benzo[b]thiophen-4~yl)piperazine (II) or a salt thereof, comprising

(ID

1) reacting a compound of formula (III)

(HI) with a compound represented by formula (IV )

(IV) in the presence of palladium compound

Tris(dibenzylideneacetone)dipalladium(0), a tertiary phosphine 2- Dicyclohexylphosphino-2 ₇ 4 ₇ €-triisopropylbi phenyl and a suitable base , in an i nert solvent or without a solvent,

2) deprotecting the compound obtained in step 1

3) isolating compound (II) in form of its salt.

As depicted in step (1), molar ratio of compound of formula (III) to palladium compound Tris(di benzyl ideneacetone)di pal I adium(0) is about 1 :0.01, preferably is about 1 :0.005, more preferably is about 1 :0.004.

As depicted in step (1), molar ratio of compound of formula (III) to tertiary phosphine 2-Dicyclohexylphosphino-2 ₇ 4 ₇ €-triisopropylbiphenyl is about 1 :0.02, preferably is about 1 :0.015, more preferably is about 1 :0.012.

As depicted in step (1), inert solvent may be selected from water; ethers such as dioxane, tetrahydrofuran, diethyl ether, di ethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as DM F, DM SO, hexamethy I phosphoric tri amide, and acetonitrile. A preferred inert solvent is toluene.

As depicted in step (1), suitable base may be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogen carbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and organic bases such as tri ethyl amine, tri propyl amine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethyl ami nopyri dine, tri methyl amine, dimethyl aniline, N-methylmorpholine, DBN, DBU, and 1 ,4-diazabi cyclo[2.2.2] octane ( D A B C 0). These basic compounds can be used singly or in combination of two or more. A preferred base is alkali metal alkoxide.

As depicted in step (1), the mixture is heated to reflux temperature.

As depicted in step (2), deprotection of the compound obtained in step (1) is carried out under acidic condition using cone HCI.

As depicted in step (3), isolating compound (II) in form of its salt is carried out using IPA. HCI.

According to a third aspect of the present invention, there is provided an improved process for the preparation of mula (I) comprising;

Formula I a) reacting 1-(benzo[b]thiophen-4~yl)piperazine (II) or its salt prepared by the present invention,

(ID

with compound of formula (V)

Formula (V)

in the presence of suitable base and suitable solvent

b) optionally purifying the compound obtained in step (a).

In an embodiment as depicted in step (a), suitable base may be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; inorganic bases such as sodium amide, sodium hydride, and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and organic bases such as tri ethyl amine, tri propyl amine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethyl ami nopyri dine, tri methyl amine, dimethyl aniline, N-methylmorpholine, DBN, DBU, and 1 ,4-diazabi cyclo[2.2.2] octane ( D A B C 0). These basic compounds can be used singly or in combination of two or more. A preferred base is alkali metal carbonates. In an embodiment as depicted in step (a), suitable solvent may be selected from polar solvents such as C 1-C4 alcohols; esters such as ethyl acetate; polar aprotic solvents such as sulfolane, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrol i done, dimethyl acetamide; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene di chloride, hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or mixture thereof.

In an embodiment as depicted in step (a), the dissolution temperatures may range from about 10tC to about reflux temperature of the solvent, depending on the solvent used for dissolution.

In an embodiment as depicted in step (b), optionally purifying the compound obtained in step (a) may be carried out using suitable solvent may be selected from polar solvents such as C1 -C4 alcohols; esters such as ethyl acetate; polar aprotic solvents such as sulfolane, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N- methyl pyrrol i done, dimethyl acetamide; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene di chloride, hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or mixture thereof.

In an embodiment as depicted in step (b), the dissolution temperatures may range from about 10tC to about reflux temperature of the solvent, depending on the solvent used for dissolution.

The invention will now be illustrated further in relation to the following examples without restricting the scope of the invention in any way. E xamples

E xample 1 : Preparation of Form M

Brexpiprazole (5 gm) was stirred in a mixture of M DC and methanol (10 vol, 9:1) at 20-25eC. The reaction mass was heated at 35-38eC and stirred further for 10 min. The reaction mass was allowed to cool slowly to 5-10eC. 15 volumes of n- heptane was added at 5- 10eC . T he reacti on mass was further sti rred at 5- 10eC for 2-3 Hrs. The solid was isolated by filtration, washed with n-heptane (10mL x 2) and dried under vacuum at 45-50eC for 15-18 hrs. The isolated solid was identified as crystalline Form M by powder X -ray diffraction pattern (Fig 1) and DSC (Fig 2).

Y ield: 76%

E xample 2: Preparation of 1-(benzo[b]thiophen-4-yl)piperazine

To a slurry of (100 gm) Benzothiophene in (1000 mL) toluene was added Boc- Piperazine (131.10 gm) in single lot followed by NatBuO (63.12 gm) under stirring at 20eC to 25eC. To the mixture was added a slurry of Pd2(dba)3 (1.72gm) in 0.2 vol of toluene and X Phos (2.68gm) in 0.2 vol of toluene under inert atmosphere. The mixture was heated to reflux temperature. On completion of reaction (checked by T L C), cool the mixture to 20eC to 25eC gradually and then cooled to 10eC-20eC. To the cooled mixture was added slowly 10 vol of water under stirring by maintaining temp 25eC. After complete water addition, the mixture was sti rred at same temp for 10- 15 mi ns. T he mixture was f i Itered and the toluene layer was given washing of sat. brine solution (5 vol X 2). Toluene layer was separated and further distilled under vacuum at 45-50eC to get crude oil. To the obtained crude oil was added with 1.0 vol of methanol (100 mL) at room temperature followed by 8.0 vol of water under stirring and further cooled to 20eC. Dropwise addition of 200 mL of cone. HCI (2.0 vol) under stirring was carried out maintaining temperature below 30eC. (Slurry, Exothermic Addition, pH=1-2). On completion of addition, the mixture was heated to 50-55eC for 1 Hrs. On completion of hydrolysis, dropwise addition of liq.NH3 (-200 mL) under stirring by maintaining temperature below 25eC (Exothermic addition, pH=8-10) was carried out followed by addition of 10vol of toluene addition. The toluene layer was separated and subjected to addition of IPA.HCI maintaining temp below 25eC. On completion of addition, solid is obtained which is further maintained at 25eC for 2-3 Hrs. Further the solid obtained is subjected to filtration, washing with toluene (1 vol), drying in vacuum oven at 70eC for 12 to 16 Hrs. (K F > 1.0%) to obtain 90gm (75% yield) of 1-(benzo[b]thiophen-4-yl) piperazine HCI.

E xample 3: Preparation of Brexpiprazole.

To a slurry of 100 gm of Chi oroqui noli none and 10 vol of Sulfolane at 20-25eC, was added 116.40 gm of 1-(benzo[b]thiophen-4-yl) piperazine HCI followed by 87.84 gm K 2CO3 , 29.77 gm of Nal. The slurry was further heated at 92eC-97eC (Internal temperature) for 2-3hrs. On completion of reaction (checked by T LC), the mixture was gradually cooled to room temperature followed by addition of water (5vol). Solid obtained was filtered and washed with water (2vol). To the wet cake obtained was added water (10vol) and stirred at 45eC-50eC for 1-2 hrs. Hot filtration was carried out followed by washing of water (1 vol). The solid obtained was further dried in vacuum oven at 70eC under vacuum for 12 to 16 hrs. to obtain 125gm of brexpiprazole.

E xample 4: Purification of Brexpiprazole.

The slurry of 100gm of crude brexpiprazole and 10vol of methanol was heated to reflux. Dropwise addition of solution of 1.10 eq. of PTSA.Monohydrate solution in 1.0 vol of methanol was carried out. On completion of addition, the clear solution obtained was refluxed for 1 hr and further gradually cooled to room temperature. The solid obtained was further filtered and washed with methanol (1vol). To the wet cake along with 10vol of methanol was added dropwise aqueous 1 N NaOH solution maintaining temperature 55eC to 60eC. On completion of addition, the mixture was further stirred at room temperature for 1 hr. The solid obtained was further subjected to filtration, washed with methanol (1vol) and further dried in vacuum oven at 70eC for 12 to 16 hrs. to obtain 70gm of pure brex pi praz ol e ( 53% y i el d) .