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WO2018172463A1 - Procédé de préparation de brexpiprazole - Google Patents

Procédé de préparation de brexpiprazole Download PDF

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Publication number
WO2018172463A1
WO2018172463A1 PCT/EP2018/057305 EP2018057305W WO2018172463A1 WO 2018172463 A1 WO2018172463 A1 WO 2018172463A1 EP 2018057305 W EP2018057305 W EP 2018057305W WO 2018172463 A1 WO2018172463 A1 WO 2018172463A1
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sodium
potassium
lithium
formula
carbonate
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Inventor
Bhushan Nimba JAGTAP
Narendra Dattatray BADGUJAR
Abhay Subodhbhai MAHETA
Pankaj Chhaganbhai BUTANI
Paragkumar Vrujlal AJUDIA
Joseph Prabahar Koilpillai
Virendra Kumar Agarwal
Kalpesh Ratilal HEDAPARA
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Amneal Pharmaceuticals Co GmbH
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Amneal Pharmaceuticals Co GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates to a process for preparation of Brexpiprazole (I).
  • Brexpiprazole is an atypical antipsychotic and indicated for adjunctive treatment of major depressive disorder (MDD).
  • MDD major depressive disorder
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides processes for preparation of brexpiprazole or salts thereof, which involve novel intermediates.
  • a rocess for preparation of brexpiprazole (I) or salt thereof is a rocess for preparation of brexpiprazole (I) or salt thereof:
  • H (I) comprises,
  • a rocess for preparation of brexpiprazole (I) or salt thereof in second aspect, a rocess for preparation of brexpiprazole (I) or salt thereof:
  • X is halogen CI, Br, I, F;
  • 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).
  • Pg amino protecting group
  • X is halogen CI, Br, I, F
  • a rocess for preparation of brexpiprazole (I) or salt thereof is a rocess for preparation of brexpiprazole (I) or salt thereof
  • G is X, OH or L;
  • X is halogen CI, Br, I, F; and L is leaving group;
  • X is halogen CI, Br, I, F
  • novel intermediates used in preparation of brexpiprazole comprise one ore of the following structures.
  • 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° 2 ⁇ .
  • Differential Scanning Calorimetry (DSC) thermogram having endothermic peaks at about 95.03°C, 107.82°C and at about 181.33°C.
  • a process for preparation of Brexpiprazole chlorobenzene solvate Form R comprises :
  • 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;
  • FIG. 3 Thermogravimetric analysis (TGA) curve of brexpiprazole chlorobenzene solvate form R. Detail Description
  • 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.
  • halogen refers to an atom selected from the group consisting of F, CI, Br and I.
  • Pg represents an amino protecting group.
  • 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
  • amino protecting reagent refers to a compound that reacts with the amino functionality to give a protected amino group.
  • amino protecting reagent refers to a compound that reacts with the amino functionality to give a protected amino group.
  • tert-butyloxycarbonyl protection can be prepared by a process reported in Bioorganic & Medicinal Chemistry, 18(3), 1135-1142, 2010.
  • 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.
  • 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.
  • the amino- protecting reagent can be used.
  • the reaction can be accomplished in the presence of an organic or inorganic base.
  • 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 .
  • 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, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ -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 hexa
  • 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),
  • 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.
  • leaching refers to mixing or stirring a compound with solvent either at ambient temperature or elevated temperature so as to remove impurities.
  • 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.
  • TLC thin layer chromatography
  • GC gas chromatography
  • 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.
  • brexpiprazole has impact on dissolution properties. It is important to control size of particles of brexpiprazole during its preparation.
  • brexpiprazole has average particle size of particles between 1 to 100 ⁇ , less than 90 ⁇ , less than 80 ⁇ , less than 60 ⁇ , less than 50 ⁇ , less than 40 ⁇ , less than 30 ⁇ , less than 20 ⁇ , less than 10 ⁇ , less than 5 ⁇ or any other suitable particle sizes.
  • brexpiprazole may have particle size distribution: Di 0 of particles smaller than 20 ⁇ , smaller than 15 ⁇ , smaller than 10 ⁇ , or smaller than 5 ⁇ ; D 50 of particles smaller than 100 ⁇ , smaller than 90 ⁇ , smaller than 80 ⁇ , smaller than 70 ⁇ , smaller than 60 ⁇ , smaller than 50 ⁇ , smaller than 40 ⁇ , smaller than 30 ⁇ , smaller than 20 ⁇ , smaller than 10 ⁇ ; Dg 0 of particles smaller than 200 ⁇ , smaller than 175 ⁇ , smaller than 150 ⁇ , smaller than 140 ⁇ , smaller than 130 ⁇ , smaller than 120 ⁇ , smaller than 110 ⁇ , smaller than 100 ⁇ , smaller than 90 ⁇ , smaller than 80 ⁇ , smaller than 70 ⁇ , smaller than 60 ⁇ , smaller than 50 ⁇ , smaller than 40 ⁇ , smaller than 30 ⁇ , smaller than 20 ⁇ , smaller than 10 ⁇ .
  • Particle size distributions of brexpiprazole particles may be measured using any techniques known in the art.
  • 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.
  • 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.
  • H (I) comprises,
  • step a) 7-(4-halobutoxy) quinoline-2(lH)-one (II) is reacted with compound of formula (III) to give compound of formula (IV).
  • 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 amide.
  • 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
  • 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, ⁇ , ⁇ -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
  • 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 ⁇ , ⁇ -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.
  • the reaction is carried out at 80-100°C for about 5-8h.
  • 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.
  • 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 hydrox
  • 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, ⁇ , ⁇ -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 he
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as alcoholic solvent Ci_ 6 linear
  • G is X, OH or L wherein X is halogen CI, Br, I, F and L is leaving group.
  • H (I) comprises,
  • 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.
  • 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
  • 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, ⁇ , ⁇ -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
  • Preferred solvent includes polar aprotic solvents such as ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methyl pyrrolidinone (NMP) or mixture of solvent or mixture with water.
  • polar aprotic solvents such as ⁇ , ⁇ -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.
  • the reaction is carried out at 40-50°C for
  • 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.
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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,
  • 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 ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (
  • 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, ⁇ , ⁇ -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 hex
  • 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
  • step d) compound of formula (IV) is reacted with l-benzothiophen-4-amine (V) to give brexpiprazole (I).
  • V l-benzothiophen-4-amine
  • a process for preparation of brexpiprazole (I) or salt thereof comprises:
  • 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.
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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 hexamethyl
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), di
  • 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.
  • 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 me
  • 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, ⁇ , ⁇ -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 hexamethyldisila
  • 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-
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • 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).
  • Pg is Boc.
  • 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, ⁇ , ⁇ -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 hexamethyld
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone
  • chlorinated hydrocarbons such as dich
  • the reaction is carried out at low to ambient temperature from 0 to 20°C for about 1-4 h.
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP) and the like or mixtures thereof.
  • high boiling solvents are utilized when reaction is carried out at elevated temperature in the range of 100-135°C.
  • a process for preparation of Brexpiprazole (I) or salt thereof comprises:
  • Pg amino protecting group
  • X is halogen CI, Br, I, F
  • step a monoprotected piperazine (XVII) is reacted with 1,4-dihalo butane (X) to give compound of formula (XVIII).
  • the protection of nitrogen can be using group specified in the starting of the detailed description.
  • amino protecting group is selected from tertbutyloxycarbonyl (boc), triphenylmethyl (trityl), benzyloxycarbonyl (cbz), benzyl, trifluoroacetyl (COCF 3 ), acetyl, silyl and the like.
  • 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.
  • 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
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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 hexa
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • 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, ⁇ , ⁇ -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 he
  • 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
  • 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.
  • step d compound of formula (XX) is reacted with compound of formula (XXI) to give Brexpiprazole (I).
  • 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, ⁇ , ⁇ -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 base such as triethylamine (TEA), diethylamine (DEA), tripropylamine, quinoline, piperidine, N-Ethyldiisopropyl
  • 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
  • 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.
  • the reaction is carried out at ambient temperature 25-35°C for about 24-30h.
  • 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.
  • 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-buty
  • 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 ⁇ , ⁇ -dimethylformamide (DMF),
  • chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride
  • aromatic hydrocarbon such
  • 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.
  • Brexpiprazole hydrochloride salt is charcoalized and then converted to Brexpiprazole using base.
  • Brexpiprazole is purified by crystallization or leaching with ethanol.
  • G is X, OH or L;
  • X is halogen CI, Br, I, F; and L is leaving group;
  • step a compound of formula (III) is reacted with 1, 4-dihalo butane (X) to give compound of formula (XXII).
  • X is halogen CI, Br, I, F; G is X, OH or L and L is leaving group.
  • 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.
  • 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
  • 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, ⁇ , ⁇ -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 hexamethyldisil
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrol
  • step b) compound of formula (XXII) is reacted with 7-hydroxyquinolin-2(lH)-one (VI) to give compound of formula (IV).
  • 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, ⁇ , ⁇ -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 he
  • 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
  • step c) compound of formula (IV) is reacted with l-benzothiophen-4-amine (V) to give Brexpiprazole (I).
  • G 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • 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
  • Pg amino protecting group
  • X is halogen CI, Br, I, F
  • G is X, OH or L ;
  • X is halogen CI, Br, I, F; and L is leaving group;
  • 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.
  • 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, ⁇ , ⁇ -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 (
  • 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
  • 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).
  • step c) compound of formula (XXV) is reacted with compound of formula (XXVI) or (XXVIa) to give compound of formula (IV).
  • compound of formula (XXV) is reacted with compound (XXVI)
  • compound of formula (XXV) is reacted with compound (XXVIa)
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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 hexamethyl
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • V l-benzothiophen-4- amine
  • Pg amino protecting group
  • X is halogen CI, Br, I, F
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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 hexa
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • 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).
  • step c compound of formula (XX) is reacted with compound of formula (XXI) to give Brexpiprazole (I).
  • step d The details of this condensation reaction are given in fourth embodiment in step d).
  • 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.
  • Brexpiprazole hydrochloride salt is charcoalized and then converted to Brexpiprazole using base.
  • Brexpiprazole is purified by crystallization or leaching with ethanol.
  • L leaving group such as halo, B(OH) 2
  • X is halogen CI, Br, I, F
  • 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.
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisil
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • 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.
  • 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, ⁇ , ⁇ -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 (
  • 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
  • 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, ⁇ , ⁇ -dimethyl aniline, pyridine, ⁇ , ⁇ -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 hexa
  • 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 ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP); polar protic such as
  • step d cyclization of compound of formula (XVI) gives Brexpiprazole (I).
  • step e cyclization of compound of formula (XVI) gives Brexpiprazole (I).
  • the details of this cyclization reaction are given in third embodiment in step e).
  • novel intermediates used in preparation of brexpiprazole comprise one or more of the following structures.
  • novel polymorphic form of Brexpiprazole are provided. Analytical methods
  • DSC Differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TGA Thermogravimetric analysis
  • 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° 2 ⁇ .
  • 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° 2 ⁇ .
  • 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 :
  • 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 compound is prepared according to the example 3.
  • Example 25 The compound is prepared according to the Embodiment 5 example 19 &20.
  • Example 25 The compound is prepared according to the Embodiment 5 example 19 &20.
  • the compound is prepared according to the Embodiment 4 example 15
  • 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).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des procédés de préparation de brexpiprazole, des intermédiaires utilisés au cours de la préparation, et des polymorphes de brexpiprazole.
PCT/EP2018/057305 2017-03-22 2018-03-22 Procédé de préparation de brexpiprazole Ceased WO2018172463A1 (fr)

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CN111269211A (zh) * 2018-12-05 2020-06-12 浙江京新药业股份有限公司 一种苯并噻吩衍生物的制备方法
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CN114181202A (zh) * 2021-12-17 2022-03-15 湖南省湘中制药有限公司 一种依匹哌唑的制备方法
CN114181145A (zh) * 2021-12-29 2022-03-15 湖南省湘中制药有限公司 一种依匹哌唑中间体的制备方法
CN114181145B (zh) * 2021-12-29 2024-03-29 湖南省湘中制药有限公司 一种依匹哌唑中间体的制备方法

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