Process for the preparation of Brexpiprazole

Field

The present disclosure relates to a process for preparation of Brexpiprazole (I).

Background

Brexpiprazole is an atypical antipsychotic and indicated for adjunctive treatment of major depressive disorder (MDD). Brexpiprazole is known by chemical name 7-{4-[4-(l- Benzothiophen-4-yl) piperazin-l-yl]butoxy}quinolin-2(l/7)-one. Brexpiprazole is marketed in USA by Otsuka Pharmaceutical Co Ltd. under trade name Rexulti* in the form of oral tablet of 0.25mg, 0.5mg, lmg, 2mg, 3mg and 4mg dosage form. It is represented by following structure.

US 7,888,362 discloses brexpiprazole and process for its preparation. Referen example 30 and example 1 of US 7,888,362 disclose a method for producing benzo[b]thiophene compound and brexpiprazole as shown in following scheme.

Brexpiprazole

In reference example 30, 4-(l-piperazinyl)benzo[b]thiophene is produced by heating under reflux, a mixture comprising bromonbenzo[b]thiophene, anhydrous piperazine, sodium tert-butoxide, (R)-(+)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) of tris (dibenzylideneacetone)dipalladium(O) and toluene. However, this step produces a relatively large amount of by-product that can hardly be separated and the purity of the compound 4a is inevitably reduced. Moreover, although column purification is performed to increase the purity of the compound 4a, it is very difficult to completely remove by-products. Compound 4a is condensed with 7-(4-chlorobutoxy) quinolin-2(l/7)-one to give Brexpiprazole. By-product contained in the compound 4a, reduces the purity of the Brexpiprazole (I). The process requires purification by column chromatography to get desired purity. This method is not suitable for the industrial scale preparation.

US 9,206,169 discloses process for the preparation of brexpiprazole as shown in following scheme.

Brexpiprazole

In this process, decarbxylation reaction of 2-carboxy-4-chlorobenzo[b]thiophene is conducted in presence of l,3-dimethyl-2-imidazolidinone and l,8-diazabicyclo[5.4.0]-undec-7- ene at 160 to 195°C to give 4-chlorobenzo[b]thiophene. This intermediate is condensed with pipearzine in presence of palladium catalyst and phosphine ligand and in presence of base and solvent at 130°C to give 4-(l-piperazinyl)benzo[b]thiophene. This is further condensed with 7- (4-chlorobutoxy)quinolin-2(l/7)-one to give brexpiprazole. In this process, the reactions are carried out at very high temperature, which possibly leads to degradation of product and forms impurities.

The above synthetic processes suffer one or more drawbacks. For this reason, there is need for the development of novel methods for producing brexpiprazole. The present application covers novel processes for preparation of brexpiprazole involving novel intermediates.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecule in the crystal lattice." Discovering new polymorphic forms of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, dissolution rate, ease of purification. Such properties may significantly influence the processing, shelf life, and commercial acceptance of a polymorph. The present application also covers novel polymorphic form of brexpiprazole.

Summary

The present invention provides processes for preparation of brexpiprazole or salts thereof, which involve novel intermediates.

In one aspect, a rocess for preparation of brexpiprazole (I) or salt thereof:

H (I) comprises,

a) reacting 7-(4-halobutoxy) quinoline-2(lH)-one (II) with compound of formula (III) to give compound of formula (IV),

H (IV) wherein G is X, OH or L; X is halogen CI, Br, I or F; and L is leaving group; and

b) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In second aspect, a rocess for preparation of brexpiprazole (I) or salt thereof:

comprises,

a) reacting 7-hydroxy quinolone-2-one (VI) with 4-halo-n-butanol (VII) to give 7-(4- h droxybutoxy) quinoline-2(lH)-one (VIII)

wherein X is halogen CI, Br, I, F;

b) converting compound of formula (VIII) to its reactive derivative (Villa) wherein L is Leaving group;

c) reacting compound of formula (Villa) with compound of formula (I II) to give compound of formu

wherein G is X, OH or L; wherein X is halogen CI, Br, I, F; and L is leaving group; and d) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In third aspect, a rocess for preparation of brexpiprazole (I) or salt thereof

comprises:

a) reacting N-protected 3-amino phenol (IX) with 1,4-dihalo butane (X) to give compound of formula (XI)

(IX) (X) (XI) wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

reacting compound of formula (XI) with l-(l-benzothiophen-4-yl) piperazine (XII) or its salt to give compound of formula (XIII);

c) deprotecting compound of formula XIII) to give compound of formula (XIV);

reacting compound of formula (XIV) with cinnamoyi halide (XV) to give compound of formula (XVI); and

e) cyclizing compound of formula (XVI) to give brexpiprazole (I). In fourth aspect, a rocess for preparation of brexpiprazole (I) or salt thereof,

comprises:

a) reacting monoprotected piperazine (XVII) with 1,4-dihalo butane (X) to give compound of formula (XVIII)

wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

b) reacting compound of formula (XVIII) with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (XIX);

c) deprotecting compound of formula XIX) to give compound of formula (XX); and d) reacting compound of formula (XX) with compound of formula (XXI) to give brexpiprazole (I)

wherein L is leaving group.

In fifth aspect, a rocess for preparation of brexpiprazole (I) or salt thereof,

comprises:

a) reacting compound of formula (III) with 1, 4-dihalo butane (X) to give compound of formula (XXII)

wherein G is X, OH or L; X is halogen CI, Br, I, F; and L is leaving group;

b) reacting compound of formula (XXII) with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (IV); and c) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In sixth aspect, a process for preparation of Brexpiprazole (I) or salt thereof,

comprises:

a) reacting 7-hydroxyquinolin-2(lH)-one (VI) with compound of formula (XXIII) to give com ound of formula (XXIV);

H

(VI) (XXIII) wherein Pg is amino protecting group; X is halogen CI, Br, I, F; b) deprotecting compound of formula (XXIV) to give 7-(4-aminobutoxy) quinolin-2(lH)-one (XXV); c) reacting compound of formula (XXV) with compound of formula (XXVI) or (XXVIa) to give compound of formula (IV) wherein G is X, OH or L ; X is halogen CI, Br, I, F; and L is leaving group; and

d) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In seventh aspect, a rocess for preparation of brexpiprazole (I) or salt thereof:

comprises,

a) reacting 7-(4-halobutoxy) quinoline-2(lH)-one (II) with monoprotected piperazine (XVII) to give compound of formula (XIX)

(XIX) wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

b) deprotecting compound of formula XIX) to give compound of formula (XX); and c) reacting compound of formula (XX) with compound of formula (XXI) to give brexpiprazole (I),

wherein L is leaving group.

In eighth aspect, a process for reparation of brexpiprazole (I) or salt thereof,

a) reacting 3-amino phenol (XXII) with cinnamoyi halide (XV) to give compound of formula (X

X is halogen CI, Br, I, F;

b) reacting compound of formula (XXIII) with 1,4-dihalobutane (X) to give compound of formula XXIV);

d) cyclizing compound of formula (XVI) to give brexpiprazole (I).

In ninth aspect, novel intermediates used in preparation of brexpiprazole comprise one ore of the following structures.

wherein G=X, OH, L; X=halogen CI, Br, I, F; L=leaving group; Pg= amino protecting group.

In tenth aspect, novel polymorphic forms of brexpiprazole are provided.

Brexpiprazole chlorobenzene solvate Form R can be characterized by any one of x-ray reflections at about 6.12, 9.43, 11.35, 13.44, 16.75, 17.23, 18.36, 19.92, 21.47, 22.70, 24.74 and 25.34 +0.2° 2Θ. Differential Scanning Calorimetry (DSC) thermogram having endothermic peaks at about 95.03°C, 107.82°C and at about 181.33°C. Thermogravimetric analysis (TGA) with loss on drying (LOD) of about 7.60% and 2.98%.

A process for preparation of Brexpiprazole chlorobenzene solvate Form R comprises :

(a) providing a solution of Brexpiprazole in chlorobenzene; and

(b) crystallizing Brexpiprazole Form R. Brief description of the drawings

FIG. 1: X-ray powder diffractogram (XRPD) of brexpiprazole chlorobenzene solvate form R;

FIG. 2: Differential Scanning Calorimetry (DSC) thermogram of brexpiprazole chlorobenzene solvate form R; and

FIG. 3: Thermogravimetric analysis (TGA) curve of brexpiprazole chlorobenzene solvate form R. Detail Description

As used herein, the term "leaving group" can be defined as part of a substrate that cleaved by the action of a nucleophile. In different embodiments , L represents a leaving group which includes, halo (CI, Br, I, F); hydroxy; alkoxy; aryloxy; alkanoate; aryloate; alkyl sulphonate; arylsulphonate; a substituted or unsubstituted or cyclic or acyclic amino that can form amide bond.

As used herein, the term "halogen" refers to an atom selected from the group consisting of F, CI, Br and I.

In different embodiments , Pg represents an amino protecting group. The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures. N-protecting group includes, aryloxycarbonyl such as benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc); alkoxycarbonyl such as methyloxycarbonyl, acetoxycarbonyl, propoxycarbonyl, tert- butyloxycarbonyl (Boc); acyl such as acetyl, propanoyl, iso-butyryl, tert-butyryl, t-butylacetyl, pivaloyl; aroyl groups such as benzoyl; trityl; silyl such as trimethylsilyl, ter-butyldimethylsilyl; sulphonyl such as methanesulphonyl, p-tolylsulphonyl; sulphenyl such as 2-nitorphenylsulfenyl; urea; urethane; nitroso; nitro and the like. A thorough discussion of amino-protecting groups disclosed in Protective Groups in Organic Synthesis, Fourth edition, Wiley, New York 2006 by T. W. Greene and P. G. M. Wuts, which is incorporated herein by reference.

Pg protected compound can be prepared using amino protecting reagent. The term "amino protecting reagent" as used herein refers to a compound that reacts with the amino functionality to give a protected amino group. For example, tert-butyloxycarbonyl protection can be prepared by a process reported in Bioorganic & Medicinal Chemistry, 18(3), 1135-1142, 2010. Similarly other amino protecting group can incorporated using amino-protecting reagents such as acylating reagents, sulfonylating reagents, sulfenylating reagents, urea and urethane- type reagents, nitroso derivatives, nitro derivatives, or silyl reagents. Various amino-protecting reagents have been described by Greene & Wuts in Protective Groups in Organic Synthesis. Person skilled in the art can choose individual reagent or reagent combinations based on desired protecting group. The reaction conditions for incorporation of protecting group can be optimized depending upon factors as the solubility of reagents, reactivity of reagents, preferred temperature ranges and suitable conditions for removing excess protecting reagent. The amount of the amino-protecting reagent can vary depending on which amino-protecting reagent is used. Typically, the reaction can be accomplished with from about 1.0 to about 4.0 molar equivalents of the amino-protecting reagent relative to one molar equivalent of unprotected amine. Preferably, about 1.0 to about 1.5 molar equivalents of the amino- protecting reagent can be used. The reaction can be accomplished in the presence of an organic or inorganic base. When required, deprotection of the amino protecting group can be carried out using methods known to persons skilled in the art. Based on the sensitivity of protecting group to pH, the pH of the reaction mixture can be adjusted for removal of protecting group. Various methods for deprotection of an amino protecting have been described in Chem. Rev. 2009, 2455-2504; which is incorporated herein by reference. For example, when protecting group is alkoxycarbonyl, deprotection can be carried out using acid, lewis acid or water. The acid that can be used includes trifluoacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or aqueous phosphoric acid. The lewis acid that can be used includes, BF ₃ .OEt ₂ , TMSI, TMSOTf, TiCI ₄ , SnCI ₄ , AICI ₃ , Sn(OTf) ₂ , ZnBr ₂ , FeCI ₃ , lnBr ₃ , Sc(OTf) ₃ , InCIs, Yb(OTf) ₃ , or ZnCI ₂ .

As referred herein, the term "base" used in any reaction step is includes a single base or bases any combination or in aqueous form depending upon the kind and nature of the reaction. Bases can be inorganic or organic base. Inorganic bases may be alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal. Inorganic bases may be selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic bases may be selected from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, pyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, Ν,Ν-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.

As referred herein, "organic solvent" used in any reaction step is a single solvent or mixtures of solvents. The selection of solvent depends upon the nature of the reaction. Organic solvents may be selected from chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like; water or mixtures thereof.

As referred herein, the term 'salt' includes pharmaceutically acceptable acid addition salts formed with organic or inorganic acids. Inorganic salts is selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; or organic salts is selected from maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-toulenesulfonic acid, p- aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids.

The term leaching refers to mixing or stirring a compound with solvent either at ambient temperature or elevated temperature so as to remove impurities.

The term "about" when used herein preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .

In all the embodiments, the progress of the reaction is monitored by thin layer chromatography (TLC) or by gas chromatography (GC) or any customary method known in the art of chemistry.

Customary work up includes quenching of the reaction generally by means of addition of water, extraction of the product in organic solvent, optionally washing of the organic phase containing product with water to remove impurities or inorganic salts soluble in water. Finally, the product is isolated by means of removal of solvent from organic phase or adding anti- solvent to solution containing product so as to induce precipitation or crystallization. In other method wherein reaction solvent is polar solvent miscible in water, the reaction is quenched with water so as to precipitation of product in water.

Particle size of brexpiprazole has impact on dissolution properties. It is important to control size of particles of brexpiprazole during its preparation. In an embodiment, brexpiprazole has average particle size of particles between 1 to 100 μπι, less than 90 μπι, less than 80 μπι, less than 60 μπι, less than 50 μπι, less than 40 μπι, less than 30 μπι, less than 20 μΓΠ, less than 10 μπι, less than 5 μπι or any other suitable particle sizes. In another embodiment, brexpiprazole may have particle size distribution: Di ₀ of particles smaller than 20 μΓΠ, smaller than 15 μπι, smaller than 10 μπι, or smaller than 5 μπι; D ₅₀ of particles smaller than 100 μΓΠ, smaller than 90 μπι, smaller than 80 μπι, smaller than 70 μπι, smaller than 60 μπι, smaller than 50 μπι, smaller than 40 μπι, smaller than 30 μπι, smaller than 20 μπι, smaller than 10 μπι; Dg ₀ of particles smaller than 200 μπι, smaller than 175 μπι, smaller than 150 μπι, smaller than 140 μπι, smaller than 130 μπι, smaller than 120 μπι, smaller than 110 μπι, smaller than 100 μΓΠ, smaller than 90 μπι, smaller than 80 μπι, smaller than 70 μπι, smaller than 60 μπι, smaller than 50 μπι, smaller than 40 μπι, smaller than 30 μπι, smaller than 20 μπι, smaller than 10 μΓη. Particle size distributions of brexpiprazole particles may be measured using any techniques known in the art. For example, particle size distributions of brexpiprazole particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term "Dio" is 10% of the particles by volume are smaller than the Dio value and 90% particles by volume are larger than the Di ₀ value. "D ₅₀ " as used herein is 50% of the particles by volume are smaller than the D ₅₀ value and 50% particles by volume are larger than the D ₅₀ value. "Dg ₀ " as used herein is 90% of the particles by volume are smaller than the Dg ₀ value and 10% particles by volume are larger than the D ₉₀ value.

Accordingly, in first embodiment, a process for preparation of brexpiprazole (I) or salt thereof:

H (I) comprises,

a) reacting 7-(4-halobutoxy) quinoline-2(lH)-one (II) with compound of formula (III) to give compound of formula (IV),

(I I I)

H (IV) wherein G is X, OH or L; X is halogen CI, Br, I or F; and L is leaving group; and

b) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In step a) 7-(4-halobutoxy) quinoline-2(lH)-one (II) is reacted with compound of formula (III) to give compound of formula (IV). When G=X or L, the reaction is carried out in presence of base and solvent. When G=OH, then OH group is first converted to its reactive derivative such as mesyloxy, tosyloxy or nosyloxy, that is, G=L and then it is reacted with compound (II). Base is selected from organic base or inorganic base as mentioned in the beginning of the detailed description. Preferred base is selected from carbonate, bicarbonate, hydroxide, hydride or metal alkoxide of alkali or alkaline earth metal such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydride, potassium hydride, lithium hydride, and sodium amide. Organic base is selected from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, N,N-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and mixtures thereof. An aqueous solution of base can be used in the reaction. Solvent can be selected from solvent or mixture thereof as mentioned in the beginning of detailed description. Preferred solvent include polar aprotic solvents such as Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP) or mixture of solvent with water. The other suitable solvents include methylene dichloride, ethylene dichloride, carbon tetrachloride, toluene, xylene, nitrobenzene, cyclohexane, chlorobenzene, bromobenzene, ethylacetate, isopropylacetate, tetrahydrofuran (THF), methanol, ethanol, isopropanol, butanol, acetonitrile, acetone, methylethyl ketone and the like. In preferred embodiment, the reaction is carried out at 80-100°C for about 5-8h.

In step b) compound of formula (IV) is reacted with l-benzothiophen-4-amine (V) to give brexpiprazole (I). The reaction is carried out in presence of base, solvent and metal halide. Base is selected from organic base or inorganic base as mentioned in the beginning of detailed description. Inorganic base is selected from alkoxide, carbonate, bicarbonate or hydroxide or hydride of alkali or alkaline earth metal such as sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium hydride, potassium hydride and lithium hydride. Organic base is selected from from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and mixtures thereof. The solvent used include chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, chlorobenzene; aromatic hydrocarbon such as toluene, xylene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. Metal halide used is selected from sodium halide, potassium halide and the like. In preferred embodiment, residue is triturated with alcohol such as isopropanol or methanol to give solid compound brexpiprazole.

A process according to an embodiment is given in following Scheme 1

Scheme 1

Wherein G is X, OH or L wherein X is halogen CI, Br, I, F and L is leaving group.

In second embodiment, a rocess for preparation of brexpiprazole (I) or salt thereof:

H (I) comprises,

a) reacting 7-hydroxy quinolone-2-one (VI) with 4-halo-n-butanol (VII) to give 7-(4- hydroxybutoxy) quinoline-2(lH)-one (VIII)

(VII) (VI I I) wherein X is halogen CI, Br, I, F;

b) converting compound of formula (VIII) to its reactive derivative (Villa) wherein L is Leaving group;

c) reacting compound of formula (Villa) with compound of formula (III) to give compound of formu

(H i) H (IV) wherein G is X, OH or L; wherein X is halogen CI, Br, I, F; and L is leaving group; and d) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In step a) 7-hydroxy quinolone-2-one (VI) is reacted with 4-halo-n-butanol (VII) in presence of base and a solvent to give 7-(4-hydroxybutoxy) quinoline-2(lH)-one (VIII). Base is selected from organic base or inorganic base as mentioned in the beginning of detailed description. Inorganic base is selected from alkoxide, carbonate, bicarbonate or hydroxide or hydride of alkali or alkaline earth metal such as sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, lithium hydride and mixtures thereof. Organic base is selected from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N- methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N- dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and mixtures thereof.

Preferred solvent includes polar aprotic solvents such as Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP) or mixture of solvent or mixture with water. Solvent used for this step also includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, chlorobenzene; aromatic hydrocarbon such as toluene, xylene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 40-50°C for about 4-6h.

In step b) compound of formula (VIII) is converted to its reactive derivative (Villa). The hydroxyl group is converted to its reactive derivative such as mesyloxy, tosyloxy, nosyloxy, OS0 ₂ CF ₃ , group by reacting it with respective reagents such as mesyl chloride, tosyl chloride, nosyl chloride and trifluoromethanesulfonic anhydride. The hydroxyl group can be converted to suitable leaving group such as halogen L=X. The reaction takes place in the presence of base and a solvent. Base can be selected from organic or inorganic base. Organic base is selected from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) and the like; inorganic base is selected from carbonate, bicarbonate or hydroxide of alkali or alkaline earth metal such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide. Solvent can be selected from solvent or mixture thereof mentioned in the beginning of detailed description. Preferred solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, bromobenzene; aromatic hydrocarbon such as toluene, xylene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic solvents such as Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixture thereof. In preferred embodiment, the reaction is carried out at 0-10°C for about l-3h. In another preferred embodiment, the residue is triturated with aromatic hydrocarbon such as cyclohexane to give solid.

In step c) compound of formula (Villa) is reacted with compound of formula (III) to give compound of formula (IV). The reaction is carried out in presence of base and a solvent. The base is selected from organic or inorganic base. The preferred base is selected from alkoxide, hydroxide, carbonate, bicarbonate, hydride of alkali and alkaline earth metal such as sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride and the like or mixture thereof. Organic base is selected from triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixture thereof. Organic solvent is selected from chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixture thereof.

In step d) compound of formula (IV) is reacted with l-benzothiophen-4-amine (V) to give brexpiprazole (I). The details of this condensation reaction are given in first embodiment in step b).

A processes according to an embodiment is given in following Scheme 2

H (I)

Scheme 2

In third embodiment, a process for preparation of brexpiprazole (I) or salt thereof comprises:

a) reacting N-protected 3-amino phenol (IX) with 1,4-dihalo butane (X) to give compound of formula (XI)

(IX) (X) (XI) wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

reacting compound of formula (XI) with l-(l-benzothiophen-4-yl) piperazine (XII) or its salt to give com ound of formula (XIII);

c) deprotecting compound of formula XIII) to give compound of formula (XIV);

reacting compound of formula (XIV) with cinnamoyi halide (XV) to give compound of formula (XVI); and

e) cyclizing compound of formula (XVI) to give brexpiprazole (I).

In step a) N-protected 3-amino phenol (IX) is reacted with 1,4-dihalo butane (X) to give compound of formula (XI). The protection of amino group is any group that protects amino group as defined above. Preferably, the protecting group is selected from tertbutyloxycarbonyl (boc), triphenylmethyl (trityl), benzyloxycarbonyl (cbz), benzyl, trifluoroacetyl (COCF ₃ ), acetyl, and silyl. Halogen in 1,4-dihalo butane can be same or different and selected from CI, Br, I, and F. The reaction can be carried in the presence of base and a solvent. The base used can be selected from organic or inorganic base. Inorganic base includes carbonate, bicarbonate, hydroxide, alkoxide, hydride of alkali or alkaline earth metal such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium amide, sodium hydride, potassium hydride, lithium hydride, and the like. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. In an embodiment, an aqueous solution of the base can be used in the reaction. Solvent can be selected from any solvent or mixture thereof as mentioned in the beginning of detailed description. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like; water or mixtures thereof. In preferred embodiment, the reaction is carried out at 40-50°C for 6-10h and after completion of the reaction; water is added to quench reaction.

In step b), compound of formula (XI) is reacted with l-(l-benzothiophen-4-yl) piperazine (XII) or its salt to give compound of formula (XIII). The reaction can be carried out in the presence of base, solvent and metal halide. The base used in this reaction can be selected from organic or inorganic base as mentioned in the beginning of detailed description. Inorganic base includes carbonate, bicarbonate, hydroxide, alkoxide, hydride of alkali or alkaline earth metal such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium amide, sodium hydride, potassium hydride, lithium hydride, and the like. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA), 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. Solvent can be selected from any solvent or mixture thereof as mentioned in the beginning of detail description. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like; or mixtures thereof. The metal halide which acts as initiator can be selected potassium iodide, sodium iodide and the like. In preferred embodiment, the reaction is carried out at 80-100°C for 6-10h.

In step c), the deprotection of Pg group from compound of formula (XIII) is carried out to give compound of formula (XIV). Deprotection of the amino protecting group can be carried out using methods known to persons skilled in the art. General procedure for deprotection is mentioned in the beginning of detail description. In preferred embodiment, depending upon the protecting group, deprotection is carried out by hydrolysis in presence of acid or base or hydrogenolysis. If protecting group Pg is boc or trityl, then it can be deprotected by acid. If protecting group Pg is benzyl or cbz, then it can be removed by hydrogenation. Deprotection can be effected in a solvent. The solvent can be selected from any solvent or mixture thereof as mentioned in the beginning of detail description. Preferred solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like; water or mixtures thereof or mixture of solvent with water can also be used. Acid used may be organic or mineral acid such as HCI, HBr, sulfuric acid, phosphoric acid, nitric acid, methane sulfonic acid, p-toluene sulfonic acid (PTSA), trifluorosulfonic acid (TFA). In more preferred embodiment, Pg is Boc.

In step d), compound of formula (XIV) is reacted with cinnamoyl halide (XV) to give compound of formula (XVI). The reaction is carried out in presence of base and solvent. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal such as sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA), 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. An aqueous solution of base can be used. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like; water or mixtures thereof. In preferred embodiment, the reaction is carried out at low to ambient temperature from 0 to 20°C for about 1-4 h. In step e), compound of formula (XVI) is cyclized using cyclizing agent to give brexpiprazole (I). The cyclizing agent is selected from polyphosphoric acid, phosphoric acid and phosphorous pentoxide, phosphorous pentachloride, phosphorous oxychloride, sulphuric acid, lewis acid such as aluminum chloride, aluminum bromide, zinc chloride, boronetrifluoride etherate, trifluoromethanesulfonic acid, trifluoroacetic acid, BiCI ₃ , and the like. The reaction is carried out in the presence of solvent at room temperature to reflux temperature of the reaction. The solvent used in this reaction includes chlorinated hydrocarbon such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or chlorobenzene; aromatic hydrocarbon such as toluene, xylene; polar aprotic solvent such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP) and the like or mixtures thereof. In preferred embodiment, high boiling solvents are utilized when reaction is carried out at elevated temperature in the range of 100-135°C.

A process according to an embodiment is given in following Scheme 3

Scheme 3

In fourth embodiment, a process for preparation of Brexpiprazole (I) or salt thereof comprises:

a) reacting monoprotected piperazine (XVII) with 1,4-dihalo butane (X) to give compound of formula (XVIII)

wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

b) reacting compound of formula (XVIII) with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (XIX); c) deprotecting compound of formula XIX) to give compound of formula (XX); and d) reacting compound of formula (XX) with compound of formula (XXI) to give brexpiprazole (I)

wherein L is leaving group. In step a), monoprotected piperazine (XVII) is reacted with 1,4-dihalo butane (X) to give compound of formula (XVIII). In monoprotected piperazine, the protection of nitrogen can be using group specified in the starting of the detailed description. In preferred embodiment, amino protecting group is selected from tertbutyloxycarbonyl (boc), triphenylmethyl (trityl), benzyloxycarbonyl (cbz), benzyl, trifluoroacetyl (COCF ₃ ), acetyl, silyl and the like. The reaction is carried out in the presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 70-100°C for about 8-12h.

In step b), compound of formula (XVIII) is reacted with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (XIX). The reaction is carried out in the presence of base, solvent and metal halide. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, N,N-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. The metal halide used are selected from potassium iodide, sodium iodide and the like which act as initiator. In preferred embodiment, the reaction is carried out at temperature from ambient temperature to reflux, preferably at 80-90°C for about 6-10h.

In step c), deprotection of Pg group from compound of formula (XIX) is done to give compound of formula (XX). Deprotection of the amino protecting group can be carried out using methods known to persons skilled in the art. General procedure for deprotection is mentioned in the beginning of detail description. In preferred embodiment, depending upon the protecting group, deprotection is carried out by hydrolysis in presence of acid or base or hydrogenolysis. If protecting group Pg is boc or trityl, then it can be deprotected by acid. If protecting group Pg is benzyl or cbz, then it can be removed by hydrogenation. Deprotection can be effected in a solvent. The solvent can be selected from any solvent or mixture thereof as mentioned in the beginning of detail description.

In step d), compound of formula (XX) is reacted with compound of formula (XXI) to give Brexpiprazole (I). Compound of formula (XXI) wherein L is leaving group such as halogen or B(OH) ₂ , mesyloxy, tosyloxy, nosyloxy, benzenesulfonyloxy, and the like. The reaction is carried out in presence of base, solvent and catalyst. The base used is selected from organic or inorganic base mentioned in the beginning of detail description. The preferred base includes organic base such as triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and the like or mixtures thereof. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. Catalyst used is copper catalyst such as copper (II) acetate, copper (II) bromide, copper (II) iodide, copper oxide, Copper(ll)triflate, Nickel (II) chloride, Nickel based catalyst, Rhodium based catalyst. In preferred embodiment, the reaction is carried out at ambient temperature 25-35°C for about 24-30h.

In alternate embodiment, the above reaction alternatively can be carried out using base, solvent and catalyst. The base includes inorganic base such as alkoxide, carbonate, bicarbonate or hydroxide of alkali or alkaline earth metal such as sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide or mixtures thereof. The catalyst used is combination of two component. One is palladium complex and the other is phosphine ligand. For example (Tris(dibenzylideneacetone)dipalladium(O) and (Oxydi-2,1- phenylene)bis(diphenylphosphine) is used in combination as catalyst. The catalyst used is selected from Palladium acetate, triphenylphosphine in 5,5dimethyl-l,3-cyclohexadiene, tris- (dibenzylidieneacetone)dipalladium, (+/-)-2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl (Rac- BINAP), (R)-(+)-2 2'-bis(diphenylphosphino)-l l'-binaphthyl (R(+)-BINAP), (S)-(-)-2 2'- bis(diphenylphosphino)-l l'-binaphthyl (S(-)-BINAP), Tri-tert-butylphosphonium tetrafluoroborate, l-phenyl-2-(di-tertbutylphosphino)-lH-indene, X-PHOS [2- (dicyclohexylphosphino)-2'4'6'-tri-i-propyl-l,l'-bi phenyl], Bis(dibenzylideneacetone) palladium(O), RuPhos [2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl], [1,1'-

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane, [1,1'- Bis(di phenyl phosphino)ferrocene]dichloropalladium(l I),

Tetrakis(triphenylphosphine)palladium(0) and the like. Solvent can be selected from any solvent or mixture thereof as mentioned in the beginning of detail description. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 140-150°C for about 2-4h.

In other embodiment step c) and step d) can be carried out insitu to give Brexpiprazole which is optionally converted to its hydrochloride salt. The salt is purified and converted to Brexpiprazole. Brexpiprazole hydrochloride can be purified by various methods such as crystallization or leaching with solvent or solvent mixture either at elevated temperature or ambient temperature.

Process for purification of Brexpiprazole hydrochloride comprising :

i) leaching Brexpiprazole hydrochloride in in N-Methyl-2-pyrrolidone; and

ii) leaching Brexpiprazole hydrochloride obtained in above step in toluene

wherein (i) and (ii) can be performed in any order.

The Brexpiprazole hydrochloride salt is charcoalized and then converted to Brexpiprazole using base. Brexpiprazole is purified by crystallization or leaching with ethanol.

A process according to an embodiment is given in following Scheme 4

Scheme 4

In fifth embodiment, a process for preparation of Brexpiprazole (I) or salt thereof

wherein G is X, OH or L; X is halogen CI, Br, I, F; and L is leaving group;

b) reacting compound of formula (XXII) with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (IV); and

In step a), compound of formula (III) is reacted with 1, 4-dihalo butane (X) to give compound of formula (XXII). Wherein X is halogen CI, Br, I, F; G is X, OH or L and L is leaving group. The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. An aqueous solution of base can be used in the reaction. The solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol, water and the like or mixtures thereof. In preferred embodiment, the reaction is carried out 30-40°C for about 5 to 7h.

In step b), compound of formula (XXII) is reacted with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (IV). Wherein G and X has the meaning defined above. The reaction is carried out in presence of base and solvent. The base can be selected from organic or inorganic base. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, N,N-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out from ambient temperature to reflux temperature; preferably at 70-80°C for about 20-24h.

In step c), compound of formula (IV) is reacted with l-benzothiophen-4-amine (V) to give Brexpiprazole (I). In compound of formula (IV) wherein G is OH, the OH group is converted to leaving group or its reactive derivative such as mesyloxy, tosyloxy, nosyloxy or benzenesulfonyloxy by reacting hydroxyl compound (IV) with mesyl chloride, tosyl chloride, nosyl chloride or benzenesulfonyl chloride. The reaction is carried out in presence of base and solvent. Base can be selected from organic or inorganic base. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. The solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 0° to ambient temperature; preferably 0-10°C for about l-4h.

In step (c), the compound (IV) wherein G is X, OH or L is reacted with 1-benzothiophen- 4-amine (V) to give Brexpiprazole (I). The reaction is carried out in presence of base and solvent. The details of this condensation reaction are similar to step b) of first embodiment. A process according to an embodiment is given in following Scheme 5

Scheme 5

In sixth embodiment, a rocess for preparation of Brexpiprazole (I) or salt thereof

mprises:

a) reacting 7-hydroxyquinolin-2(lH)-one (VI) with compound of formula (XXIII) to give com ound of formula (XXIV);

wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

b) deprotecting compound of formula (XXIV) to give 7-(4-aminobutoxy) quinolin-2(lH)-one (XXV); c) reacting compound of formula (XXV) with compound of formula (XXVI) or (XXVIa) to give compound of formula (IV) (XXVI) (XXVIa)

wherein G is X, OH or L ; X is halogen CI, Br, I, F; and L is leaving group; and

d) reacting compound of formula (IV) with l-benzothiophen-4-amine (V) to give brexpiprazole (I).

In step a), 7-hydroxyquinolin-2(lH)-one (VI) is reacted with compound of formula (XXIII) to give compound of formula (XXIV). The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. An aqueous solution of base can be used in the reaction. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent used includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol, water and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 45-55°C for about 4-6h.

In step b), Pg group is deprotected from compound of formula (XXIV) to give 7-(4- aminobutoxy) quinolin-2(lH)-one (XXV). The details of deprotection reaction are given in third embodiment in step c).

In step c), compound of formula (XXV) is reacted with compound of formula (XXVI) or (XXVIa) to give compound of formula (IV). When compound of formula (XXV) is reacted with compound (XXVI), then compound of formula (IV) obtained has G=OH; and when compound of formula (XXV) is reacted with compound (XXVIa), then compound of formula (IV) obtained has G=X wherein X is halogen. Compound of formula (IV; G=OH) is converted to its reactive derivative by reacting the hydroxyl compound with mesyl chloride, tosyl chloride or nosyl chloride to convert it to mesyloxy, tosyloxy or nosyloxy group respectively. The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal. Inorganic base includes sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. Organic solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. The customary work up provides reactive derivative of compound of formula (IV; G=OH) which is compound of formula (IV; G=L); L is leaving group such as mesyloxy, tosyloxy or nosyloxy.

In step d), the compound of formula (IV; G=L or G=X) is reacted with l-benzothiophen-4- amine (V) to give Brexpiprazole (I). The details of this condensation reaction are given in first embodiment in step b).

A process according to an embodiment is given in following Scheme 6

Scheme 6

In seventh embodiment a process for preparation of Brexpiprazole (I) or salt thereof:

comprises,

a) reacting 7-(4-halobutoxy) quinoline-2(lH)-one (II) with monoprotected piperazine (XVI I) to give compou

wherein Pg is amino protecting group; X is halogen CI, Br, I, F;

b) deprotecting compound of formula (XIX) to give compound of formula (XX); and

H (XX) c) reacting compound of formula (XX) with compound of formula (XXI) to give brexpiprazole (I),

wherein L is leaving group.

In step a), 7-(4-halobutoxy) quinoline-2(lH)-one (II) is reacted with monoprotected piperazine (XVII) to give compound of formula (XIX). The reaction is carried out in presence of base, solvent and metal halide. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent used includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. The metal halide used are potassium iodide, sodium iodide and the like which act as initiator. In preferred embodiment, the reaction is carried out at elevated temperature preferably at 80-100°C for about 6-10h.

In step b), deprotection of Pg group from compound of formula (XIX) gives compound of formula (XX). The details of deprotection reaction are given in third embodiment in step c).

In step c), compound of formula (XX) is reacted with compound of formula (XXI) to give Brexpiprazole (I). The details of this condensation reaction are given in fourth embodiment in step d).

In other embodiment step b) and step c) can be carried out insitu to give Brexpiprazole which is optionally converted to its hydrochloride salt. The salt is purified and converted to Brexpiprazole. Brexpiprazole hydrochloride can be purified by various methods such as crystallization or leaching with solvent or solvent mixture either at elevated temperature or ambient temperature.

Process for purification of Brexpiprazole hydrochloride comprising :

i) leaching Brexpiprazole hydrochloride in in N-Methyl-2-pyrrolidone; and

ii) leaching Brexpiprazole hydrochloride obtained in above step in toluene

wherein (i) and (ii) can be performed in any order.

The Brexpiprazole hydrochloride salt is charcoalized and then converted to Brexpiprazole using base. Brexpiprazole is purified by crystallization or leaching with ethanol.

A process according to an embodiment is given in following Scheme 7

L=leaving group such as halo, B(OH) ₂

Scheme 7

In eighth embodiment a process for preparation of Brexpiprazole (I) or salt thereof

mprises:

a) reacting 3-amino phenol (XXII) with cinnamoyi halide (XV) to give compound of formula (XXIII

X is halogen CI, Br, I, F;

reacting compound of formula (XXIII) with 1,4-dihalobutane (X) to give compound of formula (XXIV ;

reacting compound of formula (XXIV) with l-(l-benzothiophen-4-yl) piperazine (XII) its salt to give compound of formula (XVI); and

cyclizing compound of formula (XVI) to give brexpiprazole (I).

In step a), 3-amino phenol (XXII) is reacted with cinnamoyl halide (XV) to give compound of formula (XXIII). The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. An aqueous solution of base can be used in the reaction. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent used includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol, water and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at ambient temperature for about 2-4h.

In step b), compound of formula (XXIII) is reacted with 1,4-dihalobutane (X) to give compound of formula (XXIV). The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. An aqueous solution of base can be used in the reaction. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropyl ethylamine (DIPEA) and 1,4- diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, N,N-dimethyl amino pyridine (DMAP), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent used includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N- methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol, water and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 40-50°C for about 6-10h.

In step c), compound of formula (XXIV) is reacted with l-(l-benzothiophen-4-yl) piperazine (XII) or its salt to give compound of formula (XVI). The reaction is carried out in presence of base and solvent. Base is selected from any organic base or inorganic base as mentioned in the beginning of detail description. Inorganic base includes alkoxide, hydroxide, carbonate, bicarbonate or hydride of alkali or alkaline earth metal are selected from sodium tert butoxide, potassium tert butoxide, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium amide, sodium hydride, potassium hydride, lithium hydride, potassium phosphate, sodium phosphate and the like or mixtures thereof. Organic base includes triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N- Ethyldiisopropyl amine, dimethyl aniline, N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), diisopropyl ethylamine (DIPEA) and l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole, Ν,Ν-dimethyl aniline, pyridine, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The solvent includes chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene; ether such as dioxan, tetrahydrofuran (THF), methyl tertbutyl ether (MTBE), ethyleneglycol dimethylether, diethyleglycol dimethylether; nitrile such as acetonitrile; ester such as ethylacetate, isopropyl acetate; ketone such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); polar aprotic such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ ₆ linear or branched alcohol such as methanol, ethanol, isopropanol, propanol, butanol and the like or mixtures thereof. In preferred embodiment, the reaction is carried out at 80-100°C for about 6-10h.

In step d), cyclization of compound of formula (XVI) gives Brexpiprazole (I). The details of this cyclization reaction are given in third embodiment in step e).

A process according to an embodiment is given in following Scheme 8

Scheme 8

In ninth embodiment, novel intermediates used in preparation of brexpiprazole comprise one or more of the following structures.

wherein G=X, OH, L; X=halogen CI, Br, I, F; L=leaving group; Pg= amino protecting group.

In tenth embodiment, novel polymorphic form of Brexpiprazole are provided. Analytical methods

Characterization by Powder X-ray Diffraction

Analytical method: Powder X-ray Diffraction can be performed using PANALYTICAL Empyrean DY666, the powder X-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45kV, 40 mA) as the X- ray source with a wide-angle goniometer, a 1/2° scattering slit, an programable divergence slit, and a x'celerator detector [1]. Data collection was done in 2Θ continuous scan mode at a scan speed of 0.047747/s in step size of 0.0083556° in the range of 3° to 45°. Cu radiation of λ=1.54 A° was used.

Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms presented herein were obtained by methods known in the art. Differential scanning calorimetric (DSC) analysis was performed with a Shimadzu DSC 60 calorimeter. Samples of about 2 to about 4 milligrams, held in aluminum crucible, were analyzed at a heating rate of 10°C per minute in closed pan under nitrogen atmosphere.

Thermogravimetric analysis (TGA) was performed using a Shimadzu DTG60 thermobalance. TGA traces reflect transitions that involve either a loss or gain of mass. Samples of about 3 to about 6 milligrams were analyzed at a heating rate of 10°C per minute in nitrogen atmosphere.

Brexpiprazole chlorobenzene solvate Form R can be characterized by XRPD reflections (peaks) at about 6.12, 9.43, 11.35, 13.44, 16.75, 17.23, 18.36, 19.92, 21.47, 22.70, 24.74 and 25.34 +0.2° 2Θ. Brexpiprazole chlorobenzene solvate Form R can be further characterized by XRPD reflections (peaks) at about 9.87, 11.98, 12.51, 18.03, 18.89, 20.10, 21.26, 22.13, 24.27, 26.15, 26.60, 27.62, 30.61, 31.00+0.2° 2Θ. A typical XRPD of Brexpiprazole Form R as chlorobenzene solvate is shown in FIG. 1.

The DSC thermogram of Brexpiprazole chlorobenzene solvate Form R is shown in FIG. 2. The DSC thermogram of Brexpiprazole chlorobenzene solvate Form R is characterized by endothermic peaks at about 95.03°C, 107.82°C and at about 181.33°C. Brexpiprazole chlorobenzene solvate Form R shows loss on drying (LOD) of about 7.60% and 2.98%. in TGA in the temperature range of between 85°C and about 120°C. TGA for Brexpiprazole Form R as chlorobenzene solvate is shown in FIG. 3

A further aspect is a process for preparation of Brexpiprazole chlorobenzene solvate Form R comprising :

(a) providing a solution of Brexpiprazole in chlorobenzene; and

(b) crystallizing Brexpiprazole Form R

Other further aspect is a process for preparation of chlorobenzene solvate Form R of brexpiprazole. Brexpiprazole or its any polymorphic form or amorphous form is stirred in chlorobenzene at 120-130°C to get clear solution. The solution is filtered to remove undissolved particles. The filtrate again heated at 120-130°C and stirred for 60 minutes at same temperature. The reaction mixture is cooled at 25-35°C and stirred for lh at same temperature. The reaction mixture is further cooled to 5-15°C and stirred for 2h at same temperature. The solid obtained is filtered and wash with chlorobenzene, dried at 40-50°C to give chlorobenzene solvate form R of brexpiprazole as off white solid.

The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

Example 1

Preparation of 7-(4-chlorobutoxy)quinolin-2(lH)-one

A mixture of 4-chlorobromobutane (20.2 g 0.117 mol), 7-hydroxy quinoline-2-one (10.0 g, 0.062 mol), Dimethylformamide (50 ml) and aq. potassium carbonate solution (10.0 g, 0.072 mol in 20 ml water) was heated at 35-45°C for 8 to lOh. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (100 ml) was added to it. The precipitated solid was filtered. The solid obtained was washed with water (2 X 50 ml), dried to give the title product as off-white solid (11 g).

Yield: 70.5%

Example la Preparation of 7-(4-chlorobutoxy)quinolin-2(lH)-one

A mixture of 4-chlorobromobutane (212.8 g), 7-hydroxy quinoline-2-one (100 g), Dimethyl Sulfoxide (800 ml) and aq. potassium carbonate solution (102.9 g in 100 ml water) was stirred at 20-25°C for 15h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (800 ml) was slowly added to it. The precipitated solid was filtered. The wet solid was added to methanol (1000 ml) and heated to 60-70°C for lh. The reaction mixture was cooled to 25-35°C and then to 0-10°C and stirred for 2h. The solid was filtered and washed with chilled Methanol (50 ml X 2). The solid was dried in air dryer 60- 70°C for 12h to give the title product (130.0 g)

Yield: 83.2%

Example 2

Preparation of 7-(4-(bis(2-chloroethyl)amino)butoxy)quinolin-2(lH)-one (where G=CI)

Bis (2-chloroethyl)amine hydrochloride (8.4 g, 0.047 mol) was added to a solution of 7-(4- chlorobutoxy)quinolin-2(lH)-one (10.0 g, 0.040 mol) in Dimethylformamide (40 ml) at 25-35°C. Aq. potassium carbonate solution (11.04 g, 0.08 in water (22 ml)) was added to the reaction mixture. The reaction mixture was heated at 80-90°C for 5 to 7h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C, water (60 ml) and ethyl acetate (180 ml) was added to it and extracted. The organic phase was separated and washed with water (70 ml x 2). The organic phase was evaporated up to thick residue. The cyclohexane (100 ml) was added to the residue at 25-35°C and stirred for 1 to 2h. The solid obtained was filtered, washed with cyclohexane (2 X 10 ml) and dried to give the title product as white solid (10.8g)

Yield: 76%

Example 3

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e. Brexpiprazole)

A mixture of 7-(4-(bis(2-chloroethyl)amino)butoxy)quinolin-2(lH)-one (10 g, 0.028 mol), 1- benzothiophen-4-amine (5g, 0.034), potassium carbonate (5.0 g, 0.036 mol) and potassium iodide (1.0 g) in xylene (100 ml) was heated at 130-140°C. Completion of reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (50 ml) was added to it and extracted. The organic phase was separated and evaporated under vacuum to obtain residue. The IPA (100 ml) was added to the residue and stirred for 2 hr at 25-35°C. The solid obtained was filtered and wash with IPA (20 ml), dried to give the title product as off white solid (9.5 g).

Yield: 78.5 %

Example 4

Preparation of 7-(4-hydroxybutoxy)quinolin-2(lH)-one

A mixture of 4-bromobutanol (12.3 g 0.080 mole), 7-Hydroxy quinoline-2-one (10.0 g, 0.0620 mol), aq. potassium carbonate solution (8.0 g, 0.058 mol in 16 ml water) and Dimethylformamide (40 ml) was heated at 40-50°C for 4 to 6 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added to the reaction mixture and it was cooled at 25-35°C andstirred for 1 hr. The solid precipitate out was filtered and washed with water (2 X 50 ml), dried to give the title product as off-white solid (11.8 g).

Yield: 81.4%

Example 5

Preparation of 4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl methanesulfonate (where L= mesyl)

A mixture of 7-(4-hydroxybutoxy)quinolin-2(lH)-one (10.0 g, 0.043 mol), dichloromethane (50 ml), Triethylamine (6.09 g, 0.060 mol) was cooled at 0-5°C and methane sulphonyl chloride (5.91 g, 0.052 mol) was added slowly to it. The reaction mixture was stirred at 0-5°C for 1 to 2h. Completion of reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (40 ml) was added to reaction mixture and extracted. Organic phase was separated, dried over sodium sulfate and evaporated to give the residue. Cyclohexane (50 ml) was added to the residue and stirred for 1 h at 25-35°C. The solid precipitate out was filtered, washed with cyclohexane (20 ml) and dried to give title product as light yellow solid (10.3 g). Yield: 76.8%

Example 6 Preparation of 7-(4-(bis(2-chloroethyl)amino)butoxy)quinolin-2(lH)-one (where G= CI)

A mixture of 4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl methanesulfonate (10 g, 0.032 mol), bis(2-chloroethyl)amine hydrochloride (6.85 g, 0.038 mol) and toluene (70 ml) was cooled to 0- 5°C. Potassium tertiary butoxide (8.9 g, 0.079 mol) was added to it. The reaction mixture was heated to 100-110°C for 4-6 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (50 ml) was added to the reaction mixture and extracted. Organic phase was separated and evaporated to give the residue. Cyclohexane (40 ml) was added to the residue and stir for 2 h at 25-35°C. Obtained solid was filtered, washed with cyclohexane (20 ml) and dried to give title product as off-white solid (8.6 g).

Yield: 75.4%

Example 7

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one

The compound is prepared according to the example 3.

Example 8

Preparation of tert-butyl (3-(4-chlorobutoxy)phenyl)carbamate (where Pg=Boc)

A mixture of tert-butyl (3-hydroxyphenyl)carbamate (10.0 g, 0.048 mol), dimethylformamide (50 ml), 4-chlorobromobutane (9.83 g 0.057 mol) and aq. potassium carbonate solution (9.32 g, 0.067 mol in water (20 ml)) was heated at 40-50°C for 6 to 8h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added to the reaction mixture. The reaction mixture was cooled at 25-35°C and obtained solid was filtered. The solid was washed with water (2 X 50 ml) and dried to give the title product as off-white solid (11.5 g).

Yield: 80.4%

Example 9

Preparation of tert-butyl (3-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)phenyl ) carbamate (where Pg=Boc)

A mixture of tert-butyl (3-(4-chlorobutoxy)phenyl)carbamate (10.0 g, 0.033 mol), dimethylformamide (50 ml), l-(benzothiophen-4-yl)piperazine hydrochloride (9.3 g, 0.036 mol), potassium carbonate (11.5 g, 0.083 mol) and potassium iodide (6.0 g, 0.036 mol) was heated at 80-90°C for 6 to 8h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (140 ml) was added to it and stirred for 2h. The precipitated solid was filtered, washed with water (2 X 20 ml) and dried to give the title product as light brown solid (12.8g)

Yield: 80%

Example 10

Preparation of 3-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)aniline

To a stirred solution of tert-butyl (3-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)phenyl)carbamate (10 g, 0.021 mol) in ethylacetate (60 ml) was added 35% hydrochloric acid (5.41 g, 0.052 mol) over 20-30 minutes at 50-60°C. The reaction mixture was stirred at 50-60°C for 1 to 2h. The reaction progress was monitored on thin layer chromatography (TLC). After completion of the reaction, water (40 ml) was added to it and then basified with 10N sodium hydroxide solution and extracted. The organic phase was separated and evaporated to obtain residue. Cyclohexane (50 ml) was added to the residue and stirred for 3h at 25-35°C. The solid was filtered, washed with cyclohexane (2 X 10 ml), suck dried and dried to give the title product (6.5 g).

Yield: 82.27%

Example 11

Preparation of N-(3-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)phen yl) cinnamamide

A solution of 3-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)aniline (10.0 g, 0.026 mol) in acetone (80 ml) was cooled to 0-10°C and aq. Potassium carbonate solution (5.0 g, 0.0362 mol in water (20 ml)) was added to it. Cinnamoyl chloride (5.0 g, 0.030 mol) was added to the reaction mixture at 0-10°C and stirred for 1 to 2h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added to the reaction mixture and stirred for lh at 0-10°C. The solid obtained was filtered, washed with water (2 X 50 ml) and dried to give the title product as off-white solid (12.1 g). Yield: 90.4%

Example 12 Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e Brexpiprazole)

Aluminum chloride (10 g, 0.075) was added to a precooled at 0-10°C solution of N-(3-(4-(4- (benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)phenyl)cinnamam ide (10.0 g, 0.020 mol) in chlorobenzene (100 ml) and stirred for 30 m. The reaction mixture was heated at 125-135°C for 4 to 6h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture cooled to 0-5°C and 2N hydrochloric acid (80 ml) was added slowly to the reaction mixture. The solid obtained was filtered, washed with water (2 X 50 ml) and dried. The solid was purified by column chromatography to give the title product as off-white solid (6.0 g).

Yield: 70.8%

Example 13

Preparation of tert-butyl 4-(4-chlorobutyl)piperazine-l-carboxylate (XVIII where Pg=Boc)

A mixture of 4-chlorobromobutane (15.0 g 0.874 mol), tert-butyl piperazine-l-carboxylate (10.0 g, 0.054 mol), acetonitrile (70 ml) and potassium carbonate (11.1 g, 0.080) was heated at 70- 80°C for 8 to lOh. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (120 ml) was added; the reaction mixture was cooled at 25-35°C and precipitated solid was filtered. The solid obtained was washed with acetonitrile (2 X 20 ml) and dried to give the title product as off-white solid (11.2 g).

Yield: 75.3%

Example 14

Preparation of tert-butyl 4-(4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-l - carboxylate (XIX where Pg=Boc)

A mixture of tert-butyl 4-(4-chlorobutyl)piperazine-l-carboxylate (10.0 g, 0.036 mol), dimethylformamide (40 ml), 7-hydroxyquinolin-2(lH)-one (6.3 g, 0.039 mol), potassium carbonate (7.5 g, 0.054 mol) and potassium iodide (6.0 g, 0.036 mol) was heated at 80-90°C for 6 to 8 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (80 ml) was added to it and stirred for 1 to 2h. The solid obtained was filtered, washed with water (2 X 20 ml) and dried to give the title product as white solid (12.2 g)

Yield: 84.1%

Example 15

Preparation of 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one

35% hydrochloric acid (2.27g, 0.062 mol) was added to a stirred solution of tert-butyl 4-(4-((2- oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-l-carboxyl ate (10 g, 0.025 mol) in isopropyl alcohol (50 ml) at 25-35°C. The reaction mixture was heated to 50-60°C for 2-4 h. Completion of reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was basified with 20N sodium hydroxide solution. The solvent was removed under vacuum completely at 50-60°C to obtain residue. The residue was dissolved in dichloromethane (100 ml), dried over sodium sulphate and evaporated under vacuum completely at 35-40°C to get residue. Cyclohexane (50 ml) was added to the residue and stirred for 2 h at 25-35°C. The solid obtained was filtered, washed with cyclohexane (20 ml) and dried to give the title product as off white solid (6.0 g).

Yield: 80 %

Example 16

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e. Brexpiprazole)

To a stirred solution of 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one (10.0 g, 0.033 mol) in dichloromethane (50 ml) was added benzo[b]thiophen-4-ylboronic acid (6.6 g, 0.037 mol) at 25- 35°C. The reaction mixture was cooled to 0-10°C and added copper acetate (7.3 g, 0.040 mol) and triethylamine (6.0 g, 0.036 mol) was slowly added to it at 0-10°C. The reaction mixture was stirred at 25-35°C for 24 to 30 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was filtered. Water (40 ml) was added to the filtrate, extracted and the organic phase was separated. The organic phase was evaporated under vacuum completely to get residue. Methanol (50 ml) was added to the residue stirred at 25-35°C for 1 to 2h. The solid obtained was filtered, washed with methanol (2 X 10 ml) and dried to give the title product as off-white solid (12.0 g). Yield: 83.3% Example 16a

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e. brexpiprazole)

To a mixture of 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one (10.0 g, 0.033 mol), dimethylsulphoxide (30 ml) and cesium carbonate (32.3 g, 0.099 mol), a solution of catalyst mixture (Tris(dibenzylideneacetone)dipalladium(O) (3.02 g, 0.003 mol) and (Oxydi-2,1- phenylene)bis(diphenylphosphine) (7.1 g, 0.013 mol) in dimethylsulfoxide (10 ml) was added under inert atmosphere at 25-35°C and stirred for 15 m. 4-bromobenzo[b]thiophene (7.7 g, 0.036 mol) was added to it. The reaction mixture was heated at 140-150°C for 2 to 4 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to 25-35°C, water (100 ml) and ethylacetate (100 ml) was added to it. The reaction mixture was filtered and organic phase was separated from filtrate. The organic phase was evaporated under vacuum completely to get residue. Methanol (50 ml) was charged to the residue and stirred at 25-35°C for 1 to 2h. The solid obtained was filtered, washed with methanol (2 X 10 ml) and dried to give the title product as off-white solid (11.2 g).

Yield: 77.8%

Example 17

Preparation of 2,2'-((4-chlorobutyl)azanediyl)bis(ethan-l-ol)

A mixture of 4-chlorobromobutane (24.1 g 0.140 mol), 2,2'-azanediylbis(ethan-l-ol) (10.0 g, 0.095 mol), dimethylformamide (40 ml), aq. potassium carbonate solution (20.0 g, 0.145 mol in water(40 ml)) was heated at 30-40°C for 5 to 7 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (20 ml) and ethylacetate (80 ml) was added to the reaction mixture then cooled at 25-35°C and extracted. The organic phase was separated and evaporated to give residue. The obtained residue was purified by column chromatography to obtain the title product (10.3 g).

Yield: 55.3%

Example 18 Preparation of 7-(4-(bis(2-hydroxyethyl)amino)butoxy)quinolin-2(lH)-one (compound IV where G=OH)

A mixture of 7-hydroxyquinolin-2(lH)-one (9.1 g 0.055 mol), 2,2'-((4- chlorobutyl)azanediyl)bis(ethan-l-ol) (10.0 g, 0.051 mol), acetonitrile (60 ml) and potassium carbonate (9.0 g, 0.065 mol) was heated at 70-80°C for 20 to 24h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added to the reaction mixture. The reaction mixture was cooled at 25-35°C and filtered the solid. The solid obtained was washed with water (2 X 20 ml) and dried to give the title product as off-white solid (12.0 g).

Yield: 73.6 %

Example 19

Preparation of ((4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)azanediyl)bis (ethane-2,l-diyl) dimethanesulfonate (compound IV where G= L i.e. mesyloxy)

A mixture of 7-(4-(bis(2-hydroxyethyl)amino)butoxy)quinolin-2(lH)-one (10.0 g, 0.031 mol), dichloromethane (60 ml) and triethylamine (7.9 g, 0.078 mol) was cooled to 0-10°C. Methanesulfonyl chloride (7.9 g, 0.069 mol) was added slowly to the reaction mixture at 0-10°C and stirred for 1-3 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (40 ml) was added slowly to the reaction mixture and brought to 25°C and extracted. The organic phase was separated, washed with water (30 ml x 2) and evaporated to give the title product (13.2 g).

Yield: 88.6%

Example 20

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e. Brexpiprazole)

l-Benzothiophen-4-amine (3.3g, 0.022 mol) was added to a stirred solution of ((4-((2-oxo-l,2- dihydroquinolin-7-yl)oxy)butyl)azanediyl)bis(ethane-2,l-diyl )dimethanesulfonate (10 g, 0.021 mol) in toluene (90 ml) at 25-35°C. Then potassium tertiary butoxide (7.1g, 0.063 mol) was added to the reaction mixture slowly. Completion of reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (50 ml) was added to reaction mixture and extracted. The organic phase was separated and evaporated under vacuum to obtain residue. Methanol (50 ml) was added to the residue and stirred for 2 h at 25-35°C. The solid obtained was filtered, washed with methanol (20 ml) then dried to obtain the title product as off white solid (10 g).

Yield: 78.5 %

Example 21

Preparation of tert-butyl (4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)carbamate (XXIV where Pg=Boc)

A mixture of tert-butyl(4-bromobutyl)carbamate (17.2g 0.068 mol), 7-Hydroxy quinoline-2-one (10.0 g, 0.062 mol), dimethylformamide (50 ml) and aq. potassium carbonate solution (10.0 g, 0.072 mol in 20 ml water) was heated at 45-55°C for 4 to 6 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added. The reaction mixture was cooled at 25-35°C and filtered the solid. The solid obtained was washed with water (2 X 20 ml) and dried to give the title product as off-white solid (18 g).

Yield: 87.4%

Example 22

Preparation of 7-(4-aminobutoxy)quinolin-2(lH)-one

To a stirred solution of tert-butyl (4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)carbamate (lOg, 0.030 mol) in ethylacetate (50 ml) was added 35% Hydrochloric acid (2.7g, 0.074 mol) over 20- 30 minutes at 50-60°C. The reaction mixture was stirred at 50-60°C for 1 to 2h. The reaction progress was monitored on thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was charged with water (40 ml) and basified with 10N sodium hydroxide solution. The organic phase was separated and evaporated to obtain residue. Cyclohexane (40 ml) was charged to the residue and stirred for 2 hr at 25-35°C. The solid was filtered, washed with cyclohexane (2 X 10 ml), dried to give the title product (5.5 g).

Yield: 78.5 %

Example 23

Preparation of 7-(4-(bis(2-hydroxyethyl)amino)butoxy)quinolin-2(lH)-one A mixture of potassium carbonate (17.8 g, 0.129 mol), 7-(4-aminobutoxy) quinolin-2(lH)-one (10 g, 0.043 mol), Dimethylformamide (50 ml) and 2-chloroethan-l-ol (8.7g, 0.108) was heated at 50-60°C. Completion of reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (100 ml) was added it and stirred for 2-3 h. The solid obtained was filtered, washed with water (20 ml), dried to give the title product as off white solid (11 g).

Yield: 79.7 %

Example 24

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e Brexpiprazole)

The compound is prepared according to the Embodiment 5 example 19 &20. Example 25

Preparation of tert-butyl 4-(4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-l - carboxylate (where Pg=Boc)

A mixture of 7-(4-chlorobutoxy)quinolin-2(lH)-one (10.0 g, 0.040 mol), dimethylformamide (40 ml), tert-butyl piperazine-l-carboxylate (8.1 g, 0.043 mol), potassium carbonate (7.5 g, 0.054 mol) and potassium iodide (7.0 g, 0.042 mol) was heated at 80-90°C for 6 to 8 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (80 ml) was added to it and stirred for 1 to 2h. The solid obtained was filtered, washed with water (2 X 20 ml) and dried to give the title product as white solid (12.2 g)

Yield: 76.7%

Example 25a

Preparation of tert-butyl 4-(4-((2-oxo-l,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-l - carboxylate (where Pg=Boc)

A mixture of 7-(4-chlorobutoxy)quinolin-2(lH)-one (100 g), N-Methyl-2-Pyrrolidone (500 ml), tert-butyl piperazine-l-carboxylate (81.4 g), potassium carbonate (39.8 g) and potassium iodide (66 g) was heated at 80-90°C for 3h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the water (1000 ml) was added to the reaction mixture and then cooled to 25-35°C and stirred for 2h. The solid obtained was filtered, washed with water (100 ml X 2) and dried in air dryer at 60-70°C for 12h to give the title product (145.0 g)

Yield: 90.9%

Example 26

Preparation of 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one

The compound is prepared according to the Embodiment 4 example 15

Example 27

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e Brexpiprazole)

The compound is prepared according to the Embodiment 4 example 16 and 16a Example 27a

Preparation of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one hydrochloride (i.e. brexpiprazole HCI)

35% hydrochloric acid (103.9 g) was added to a stirred suspension of tert-butyl 4-(4-((2-oxo-l,2- dihydroquinolin-7-yl)oxy)butyl)piperazine-l-carboxylate (100 g) in isopropyl alcohol (700 ml) at 25-35°C. The reaction mixture was heated to 60-70°C for 3h. Completion of reaction was confirmed using thin layer chromatography (TLC). The reaction mixture was cooled to 25-35°C and filtered. The wet cake was added to toluene (500 ml) and heated to 105-115°C. The reaction mixture was cooled to 25-35°C. Under nitrogen atmosphere Sodium tert-butoxide (119.6 g), 4-bromobenzo[b]thiophene (58.4 g), Rac-BINAP (11.6 g) and Palladium (II) Acetate (2.8 g) were added to the reaction mixture and heated at 105-115°C for 5h. After completion of reaction, the mixture was cooled to 25-35°C. Water (1000 ml) and MDC (1000 ml) were added to it and extracted. The solution was filtered through hyflo bed. The filtrate was collected and separated the organic phase. The organic phase was washed with water (500 ml x 2) and solvent was distilled out below 50°C. The residue was stripped with ethanol (100 ml). Ethanol (500 ml) was added to the residue. Acetic Acid (100 ml) and hydrochloric acid (28.6 g) were added to it and heated to 70-80°C for 2h. The reaction mixture was cooled at 25-35°C for 2h. The solid was filtered and washed with ethanol (50 ml X 2). The solid was dried in air dryer at 60-70°C to give the title product (80.0 g)

Yield: 68.4%

Example 27b

Preparation of Brexpiprazole

A mixture of Brexpiprazole hydrochloride in N-Methyl-2-pyrrolidone (500 ml) was heated to 60- 70°C for lh. The solution was cooled to 25-35°C and stirred for lh. The precipitated solid was filtered and washed with N-methyl-2-pyrrolidone (50 ml X 2). The wet cake was added to Toluene (700 ml) and heated to 60-70°C for lh. The reaction mixture was cooled to 25-35°C and stirred for lh. The solid was filtered and washed with Toluene (50 ml X 2). The wet cake was added to dichloromethane (750 ml) and Methanol (750 ml) and heated to 35-45°C for 30m to make solution. Activated carbon (5g) was added to it and stirred for 2h. The reaction mixture was cooled to 25-35°C and filtered through hyflo bed. The bed was washed with mixture of Dichloromethane (50 ml): Methanol (50 ml). The filtrate was distilled out completely under vacuum Below 50°C to give residue. Ethanol (1000 ml) and water (600 ml) was added to the residue and heated to reflux 80-90°C to get clear solution. Aq. Sodium Hydroxide solution (12.8 g in 400 ml water) was added to the above reaction mixture and stirred at 80-90°C for lh. The reaction mixture was cooled to 25-35°C and solid was filtered. The solid was washed with mixture of ethanol (50 ml) and water (50 ml). The wet cake was slurry washed with water (500 ml) for lh at 25-35°C. The solid was filtered and washed with water (4 X 100 ml). The solid was dried in air dryer at 60-70°C for 12h to give the title product (65.0 g)

Yield: 70.5%

Example 27c

Purification of Brexpiprazole

A mixture of Brexpiprazole (100 g) and ethanol (500 ml) was heated to reflux 75-85°C for lh. The suspension was cooled to 25-35°C for lh. The solid was filtered and washed with ethanol (50 ml X 2). The solid was slurry washed with water (500 ml) for lh at 25-35°C. The solid was filtered and washed with water (100 ml X 4). The solid was dried in vacuum dryer at 60-70°C for 12h to give pure Brexpiprazole (96.0 g) Yield = 96.0%

Example 28

Preparation of N-(3-hydroxyphenyl)-3-phenylacrylamide

Potassium carbonate solution (15.2 g, 0.11 mole in water (50 ml) was added to a stirred solution of 3-aminophenol (10.0 g, 0.092 mol) in acetone (100 ml) at 25-35°C. The reaction mixture was cooled to 0-10°C. Cinnamoyl chloride (16.6 g 0.1 mol) was added to the reaction mixture at same temperature. The reaction mixture was stirred at 25-35°C for 2 to 3 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (200 ml) was added and stirred for 2 h at 25-35°C and filtered. The solid obtained was washed with water (2 X 20 ml) and dried to give the title product as off-white solid (18.0 g).

Yield: 82.2%

Example 29

Preparation of N-(3-(4-chlorobutoxy)phenyl)-3-phenylacrylamide

A mixture of N-(3-hydroxyphenyl)-3-phenylacrylamide (10.0 g, 0.042 mol), dimethylformamide (50 ml), l-bromo-4-chlorobutane (14.1 g, 0.082 mol) and aq. potassium carbonate solution (11.5 g, 0.083 mol in water (20 ml)) was heated at 40-50°C for 6 to 8h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled at 25-35°C and water (100 ml) was added to it and stirred for 2h. The solid obtained was filtered, washed with water (2 X 20 ml) and dried to give the title product as off-white solid (11.9)

Yield: 86.2%

Example 30

Preparation of N-(3-(4-(4-(benzo[b]thiophen-7-yl)piperazin-l-yl)butoxy)phen yl)-3- phenylacrylamide

A mixture of l-(benzo[b]thiophen-7-yl)piperazine hydrochloride (8.0g, 0.031 mol), N-(3-(4- chlorobutoxy)phenyl)-3-phenylacrylamide (10.0 g, 0.030 mol), dimethylformamide (50 ml) and potassium carbonate (8.3 g, 0.060 mol) was heated to 80-90°C for 6 to 8 h. Completion of the reaction was confirmed using thin layer chromatography (TLC). After completion of the reaction, water (100 ml) was added to the reaction mixture and cooled to 25-35°C and stirred for 2 h. The solid was filtered, washed with water (2 X 20 ml) and dried to give the title product as light brown solid (14.0 g).

Yield: 90.3%

Example 31

Preparation of 7-(4-(4-(benzo[b]thiophen-7-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (i.e. Brexpiprazole)

The compound is prepared according to the Embodiment 3 example 12 Example 32

Preparation of Polymorphic form R of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l- yl)butoxy)quinolin-2(lH)-one (Brexpiprazole Form R chlorobenzene solvate)

7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)butoxy)quinoli n-2(lH)-one (3.0 g, 0.007 mol) was added to chlorobenzene (30 ml) and heated to 120-130°C to get clear solution and further stirred for 30 m. The reaction mixture was filtered and filtrate was heated to 120-130°C and stirred for lh at same temperature. The reaction mixture was slowly cooled to 25-35°C and stirred for lh. The reaction mixture was slowly cooled to 5-15°C and stirred for 2h. The solid obtained was filtered, washed with chlorobenzene (6 ml) and dried at 40-50°C to give the title product as off white solid (2.5 g).

*H NMR(400MHz, DMSO-d ₆ ) : δ 11.59(s, 1H), 7.79-7.82(d, 1H), 7.69-7.70(d, 1H), 7.60-7.62(d, 1H), 7.54-7.57(t, 1H), 7.39-7.43(m, 3H), 7.34-7.37(m, 0.5H), 7.25-7.29(t, 1H), 6.87-6.89(d, 1H), 6.79-6.82 (m, 2H), 6.28-6.31(d, 1H), 4.04-4.07(t, 2H), 3.06(s, 4H), 2.62(s, 4H), 2.42-2.46(m, 2H), 1.77-1.82(m, 2H), 1.62-1.68(m, 2H).

XRD fig 1

DSC fig 2

TGA fig 3