WO2018060916A1 - Process for the preparation of brexpiprazole and intermediates thereof - Google Patents

Process for the preparation of brexpiprazole and intermediates thereof Download PDF

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Publication number
WO2018060916A1
WO2018060916A1 PCT/IB2017/055958 IB2017055958W WO2018060916A1 WO 2018060916 A1 WO2018060916 A1 WO 2018060916A1 IB 2017055958 W IB2017055958 W IB 2017055958W WO 2018060916 A1 WO2018060916 A1 WO 2018060916A1
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Prior art keywords
brexpiprazole
acid
formula
preparation
sodium
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PCT/IB2017/055958
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French (fr)
Inventor
Maitreyee RAWAT
Ketan Patel
Mitul Patwa
Dinesh Panchasara
Mahender Rao Siripragada
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Alembic Pharmaceuticals Limited
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Publication of WO2018060916A1 publication Critical patent/WO2018060916A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention is directed to process for preparation of Brexpiprazole of formula-l and intermediates thereof.
  • the present invention further relates to process for the preparation of Brexpiprazole, pharmaceutical composition containing them.
  • Brexpiprazole is a partial dopamine D2 agonist, which also has activity at several other receptors. Brexpiprazole is marketed as REXULTITM by Otsuka Pharmaceutical Co Ltd as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) and for the treatment of schizophrenia.
  • MDD major depressive disorder
  • Brexpiprazole is chemically known as 7- ⁇ 4-[4-(1 -Benzothiophen-4- yl)piperazin-1 -yl]butoxy ⁇ quinolin-2(1 H)-one which is disclosed in WO20061 12464A1 . It also discloses process for synthesis of Brexpiprazole as shown below:
  • WO2013015456A1 discloses process for the preparation of Brexpiprazole.
  • WO2013162046A1 discloses dihydrate of Brexpiprazole and process for the preparation thereof.
  • Chinese applications CN104447723A, CN104829602A, CN104844585A, CN105061414A, CN105175401 A, CN105399736A, CN105440026A, CN105461704A, CN105461703A, CN105541819A and CN105732572A disclose process for the preparation of Brexpiprazole.
  • Another Chinese application CN104844586A discloses amorphous form of Brexpiprazole and process for the preparation thereof.
  • Brexpiprazole prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process.
  • the present invention relates to a process for preparation of Brexpiprazole with high purity.
  • the present invention relates to novel intermediates useful in preparation of Brexpiprazole, process for preparing such intermediates and process for the synthesis of Brexpiprazole utilizing these novel intermediates.
  • the present invention relates to crystalline form of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8°, 9.6°, 14.4°, 19.2° and 29.0 ° + 0.2° 2 ⁇ .
  • PTSA p-toluene sulphonate
  • the present invention relates to crystalline form of
  • PTSA Brexpiprazole p-toluene sulphonate
  • the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
  • the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of: i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
  • the present invention provides anhydrous form of Brexpiprazole having particle size D go ⁇ 200pm; preferably, D go ⁇ 50pm, more preferably D 90 ⁇ 20 ⁇ .
  • the present invention provides Brexpiprazole which is substantially free from impurity A to F.
  • the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.
  • Figure 1 is an illustration of a PXRD pattern of anhydrous form of Brexpiprazole
  • FIG. 2 is an illustration of a PXRD pattern of Brexpiprazole p- toluene sulphonate (PTSA) salt
  • Figure 3 is an illustration of a PXRD pattern of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt
  • the present invention relates to a process for preparation of Brexpiprazole with improved yields making it suitable for large scale production as described below:
  • X is a leaving group selected from chloro, bromo, iodo and X' is a leaving group selected from chloro, bromo, iodo, mesylate or tosylate.
  • 4-X-benzo[b]thiophene (II) and piperazine are reacted in presence of Pd on carbon and BINAP (2,2 ! -bis(diphenylphosphino ⁇ -1 ,1 '-binaphthyl) to obtain benzo[b]thiophene-4-yl-piprazine (MIA) which is treated with acid obtain salt of 1 -benzo[b]thiophene-4-yl-piprazine (III).
  • MIA benzo[b]thiophene-4-yl-piprazine
  • leaving group X is bromo.
  • Solvents that used for the reaction is toluene or xylene or the like. The reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer.
  • Applicant found that the prior art process of isolation of 1 - benzo[b]thiophene-4-yl-piprazine as a free base resulted with either impure 1 -benzo[b]thiophene-4-yl-piprazine and its use in the preparation of Brexpiprazole resulted with impure Brexpiprazole. Hence the said prior art process is not suitable for commercial manufacturing. Applicant found isolation of 1 -benzo[b]thiophene-4-yl-piprazine as an acid addition salt and / or isolation of Brexpiprazole as an acid addition salt resulted with Brexpiprazole with purity greater than 99.5% by HPLC. Thus present process provides robust commercial manufacturing process for the preparation of Brexpiprazole.
  • Acid addition salt of 1 -benzo[b]thiophene-4-yl-piprazine (III) is reacted with 7-(4-X -butoxyquinolin-2(1 H)-one to obtain Brexpiprazole.
  • leaving group X is chloro.
  • Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamine or tert-butyl amine or the like are used as base.
  • the reaction is carried out in solvents such as dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like.
  • the reaction may be carried out for time periods ranging from about 1 hour to about 4 hours, or longer.
  • the reaction is carried out at 50 to 120 Q C preferably at 70 to 90 Q C.
  • Brexpiprazole is treated with acid to produce acid addition salt of Brexpiprazole.
  • p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, maleic acid, sulphuric acid or hydrochloric acid, hydrobromic acid or the like are used as acid.
  • the reaction is carried out in solvents such as acetone or dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like.
  • Brexpiprazole acid addition salt is hydrolysed with one or more base to obtain Brexpiprazole.
  • Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t- butoxide, sodium carbonate, sodium bicarbonate, triethylamnie or tert- butyl amine or the like are used as base.
  • the reaction is carried out in solvents such as methanol, ethanol, isopropanol or the like.
  • the present invention relates to crystalline form of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8°, 9.6°, 14.4°, 19.2° and 29.0 ° + 0.2° 2 ⁇ .
  • PTSA p-toluene sulphonate
  • the present invention relates to crystalline form of Brexpiprazole p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 6.3°, 9.4°, 15.6°, 18.7° and 28.1 + 0.2° 2 ⁇ .
  • PTSA Brexpiprazole p-toluene sulphonate
  • the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
  • the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
  • the present invention provides anhydrous form of Brexpiprazole having particle size D go ⁇ 200pm; preferably, D go ⁇ 50pm, more preferably D 90 ⁇ 20pm.
  • the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.
  • the present invention provides a process of preparing a pharmaceutical composition of Brexpiprazole which process comprises the step of mixing of Brexpiprazole together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.
  • Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol.
  • the said polymers/agents are used to facilitate the presence of Brexpiprazole.
  • the present invention provides Brexpiprazole which is substantially free from impurity A to F.
  • Brexpiprazole obtained by present invention is stable and not contaminated with any crystalline form.
  • distillation distillation under reduced pressure or vacuum, evaporation, solvent-anti solvent, spray drying, lyophilization or freeze drying.
  • organic solvent(s) or “solvent(s)” or “anti-solvent(s)” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), THF, pyridine, phenol, dimethylacetamide (DMA), carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
  • polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), THF, pyridine, phenol, dimethylacetamide (DMA), carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
  • Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
  • Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
  • Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1 , 2-propane diol and S (+)-1 , 2- propane diol.
  • Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1 ,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
  • Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1 , 2-dichloro ethane.
  • Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
  • the "acid addition salts" as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, followed by isolation of salt by conventional techniques, if required.
  • a salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to, acetic, benzoic, p-toluene sulphonic, benzenesulfonic, hydrobromic, hydrochloric, citric, gluconic, glucuronic, glutamic, tartaric, lactic, malic, maleic, oxalic, camphorsulphonic, methanesulfonic, palmoic, salicylic, stearic, succinic, sulfuric, and the like.
  • the class of acids suitable for formation of pharmaceutically acceptable salts is well known to person having ordinary skills in the art, and are described, for example in Stahl, P. H., et al., "Handbook of Pharmaceutical Salts", Wiley-VCH, Weinheim: Germany (2002), the contents of which are hereby incorporated herein by reference.
  • Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, p-toluene sulphonate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, tartarate, citrate, sulphate, maleate, fumarate, succinate, camphor-sulphonate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like.
  • base includes but not limited to inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine.
  • inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine.
  • the base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
  • palladium catalyst complex includes but not limited to complexes of palladium such as sodium hexachloro palladate(IV)tetrahydrate, potassium hexachloropalladate(IV), palladium(ll) chloride, palladium(ll) bromide, palladium(ll) acetate, palladium(ll) acetyl acetonate, dichlorobis(benzonitrile)palladium(ll), dichlorobis(acetonitrile) palladium(ll), dichlorobis(triphenylphosphine)palladium(ll), dichloro tetraamminepalladium(ll), dichloro(cycloocta-1 ,5-diene)palladium(ll), palladium(ll) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex, or
  • ligand used herein ( ⁇ )-2,2'-Bis(diphenylphosphino)- 1 , 1 '-binaphthalene (BINAP), Diacetato[2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl]ruthenium(ll) Ru(OAc) 2 (BINAP), dichloro[(S)-(-)-2,2'- bis[di(3,5-xylyl)phosphino]-1 ,1 '-binaphthyl][(2S)-(+)-1 ,1 -bis(4-methoxy phenyl)-3-methyl-1 ,2-butanediamine]ruthenium(ll) RuCI 2 [(S)-(DM- BINAP)][(S)-DAIPEN], diacetato[(S)-(-)-2,2'-bis(di-p-tolylphosphino)-1 ,
  • substantially free from impurity A to F relates Brexpiprazole which is about 99.9% pure and the amount of impurity A to F present is not more than 0.05%.
  • a mixtue of 100 g of 7-(4-chlorobutoxy)-1 H-quinolin-2-one, 1 10 g of 1 - benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate, 214 g of sodium bicarbonate, sodium iodide and 650 ml of dimethyl sulfoxide (DMSO) were stirred at 85-95°C. After completion of the reaction, water was added to reaction mixture and precipitated crystals were separated by filtration. Wet solid was dried at 60°C to get 155 g of Brexpiprazole.
  • Brexpiprazole p-toluenesulfonic acid salt was dissolved in mixture of acetone : water (12 : 6). 20% NaOH solution was added till alkaline pH was achieved. Reaction mixture was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were washed with water till neutral pH was achieved. Solid was dried at 60-70°C to get 85 g of Brexpiprazole. Purity: 99.9%

Abstract

The present invention relates to process for preparation of Brexpiprazole of formula-l and intermediates thereof. The present invention is further directed to process for the preparation of anhydrous form of Brexpiprazole, pharmaceutical compositions containing them.

Description

TITLE: PROCESS FOR THE PREPARATION OF BREXPIPRAZOLE AND INTERMEDIATES THEREOF RELATED APPLICATIONS
This application claims the benefit of priority of our Indian patent application number 201621033048 filed on 28th September 2016, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention is directed to process for preparation of Brexpiprazole of formula-l and intermediates thereof. The present invention further relates to process for the preparation of Brexpiprazole, pharmaceutical composition containing them.
Figure imgf000002_0001
Formula-I
BACKGROUND OF THE INVENTION
Brexpiprazole is a partial dopamine D2 agonist, which also has activity at several other receptors. Brexpiprazole is marketed as REXULTI™ by Otsuka Pharmaceutical Co Ltd as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) and for the treatment of schizophrenia.
Brexpiprazole is chemically known as 7-{4-[4-(1 -Benzothiophen-4- yl)piperazin-1 -yl]butoxy}quinolin-2(1 H)-one which is disclosed in WO20061 12464A1 . It also discloses process for synthesis of Brexpiprazole as shown below:
Figure imgf000003_0001
However the above process step of preparation of Brexpiprazole is not satisfactory from commercial point of view as it involves use of costly catalysts, like Pd2(dba)3. Accordingly, the disclosed process is commercially not viable.
WO2013015456A1 discloses process for the preparation of Brexpiprazole.
WO2013162046A1 discloses dihydrate of Brexpiprazole and process for the preparation thereof.
PCT applications WO2015054976A1 and WO2016124144A1 disclose process for the preparation of Brexpiprazole.
Chinese applications CN104447723A, CN104829602A, CN104844585A, CN105061414A, CN105175401 A, CN105399736A, CN105440026A, CN105461704A, CN105461703A, CN105541819A and CN105732572A disclose process for the preparation of Brexpiprazole.
Another Chinese application CN104844586A discloses amorphous form of Brexpiprazole and process for the preparation thereof.
However the prior art processes described above for the preparation of Brexpiprazole have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; use of column chromatography and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associates with prior art process for preparation of Brexpiprazole.
Brexpiprazole prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process.
OBJECT OF THE INVENTION
In one aspect, the present invention relates to a process for preparation of Brexpiprazole with high purity.
In another aspect, the present invention relates to novel intermediates useful in preparation of Brexpiprazole, process for preparing such intermediates and process for the synthesis of Brexpiprazole utilizing these novel intermediates.
In one aspect, the present invention relates to crystalline form of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8°, 9.6°, 14.4°, 19.2° and 29.0 ° + 0.2° 2Θ.
In one aspect, the present invention relates to crystalline form of
Brexpiprazole p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 6.3°, 9.4°, 15.6°, 18.7° and 28.1 + 0.2° 2Θ.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) providing Brexpiprazole acid addition salt;
ii) treating Brexpiprazole acid addition salt with one or
more base; and
iii) isolating anhydrous form of Brexpiprazole.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of: i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent; and
iii) isolating anhydrous form of Brexpiprazole.
In yet one aspect, the present invention provides anhydrous form of Brexpiprazole having particle size Dgo <200pm; preferably, Dgo ≤50pm, more preferably D90≤20μιη.
In yet one aspect, the present invention provides Brexpiprazole which is substantially free from impurity A to F.
In another aspect, the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of anhydrous form of Brexpiprazole
Figure 2 is an illustration of a PXRD pattern of Brexpiprazole p- toluene sulphonate (PTSA) salt
Figure 3 is an illustration of a PXRD pattern of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparation of Brexpiprazole with improved yields making it suitable for large scale production as described below:
Figure imgf000006_0001
wherein X is a leaving group selected from chloro, bromo, iodo and X' is a leaving group selected from chloro, bromo, iodo, mesylate or tosylate.
4-X-benzo[b]thiophene (II) and piperazine are reacted in presence of Pd on carbon and BINAP (2,2!-bis(diphenylphosphino}-1 ,1 '-binaphthyl) to obtain benzo[b]thiophene-4-yl-piprazine (MIA) which is treated with acid obtain salt of 1 -benzo[b]thiophene-4-yl-piprazine (III). Preferably, leaving group X is bromo. Solvents that used for the reaction is toluene or xylene or the like. The reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer.
Applicant found that the prior art process of isolation of 1 - benzo[b]thiophene-4-yl-piprazine as a free base resulted with either impure 1 -benzo[b]thiophene-4-yl-piprazine and its use in the preparation of Brexpiprazole resulted with impure Brexpiprazole. Hence the said prior art process is not suitable for commercial manufacturing. Applicant found isolation of 1 -benzo[b]thiophene-4-yl-piprazine as an acid addition salt and / or isolation of Brexpiprazole as an acid addition salt resulted with Brexpiprazole with purity greater than 99.5% by HPLC. Thus present process provides robust commercial manufacturing process for the preparation of Brexpiprazole.
Acid addition salt of 1 -benzo[b]thiophene-4-yl-piprazine (III) is reacted with 7-(4-X -butoxyquinolin-2(1 H)-one to obtain Brexpiprazole. Preferably, leaving group X is chloro. Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamine or tert-butyl amine or the like are used as base. The reaction is carried out in solvents such as dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like. The reaction may be carried out for time periods ranging from about 1 hour to about 4 hours, or longer. The reaction is carried out at 50 to 120 QC preferably at 70 to 90 QC.
Brexpiprazole is treated with acid to produce acid addition salt of Brexpiprazole. p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, tartaric acid, oxalic acid, maleic acid, sulphuric acid or hydrochloric acid, hydrobromic acid or the like are used as acid. The reaction is carried out in solvents such as acetone or dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or the like.
Brexpiprazole acid addition salt is hydrolysed with one or more base to obtain Brexpiprazole. Ammonia, sodium iodide, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t- butoxide, sodium carbonate, sodium bicarbonate, triethylamnie or tert- butyl amine or the like are used as base. The reaction is carried out in solvents such as methanol, ethanol, isopropanol or the like.
In one aspect, the present invention relates to crystalline form of 1 - benzo[b]thiophene-4-yl-piprazine p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 4.8°, 9.6°, 14.4°, 19.2° and 29.0 ° + 0.2° 2Θ.
In one aspect, the present invention relates to crystalline form of Brexpiprazole p-toluene sulphonate (PTSA) salt characterized by X-ray diffraction pattern having characteristic peaks at about 6.3°, 9.4°, 15.6°, 18.7° and 28.1 + 0.2° 2Θ.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) providing Brexpiprazole acid addition salt;
ii) treating Brexpiprazole acid addition salt with one or
more base; and
iii) isolating anhydrous form of Brexpiprazole.
In another aspect, the present invention relates to process for the preparation of anhydrous form of Brexpiprazole comprising steps of:
i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent(s); and
iii) isolating anhydrous form of Brexpiprazole.
In yet one aspect, the present invention provides anhydrous form of Brexpiprazole having particle size Dgo <200pm; preferably, Dgo ≤50pm, more preferably D90≤20pm.
In yet one aspect, the present invention provides pharmaceutical compositions comprising anhydrous form of Brexpiprazole.
Further the present invention provides a process of preparing a pharmaceutical composition of Brexpiprazole which process comprises the step of mixing of Brexpiprazole together with a pharmaceutically acceptable carrier. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.
Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of Brexpiprazole.
In yet one aspect, the present invention provides Brexpiprazole which is substantially free from impurity A to F.
i) Impurity-A
Figure imgf000009_0001
i) Impurity-B:
Figure imgf000009_0002
ii) Impurity-C:
Figure imgf000010_0001
iii) Impurity-D:
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000010_0004
vi) Impurity-G: vii) Impurity-H:
Figure imgf000011_0001
Brexpiprazole obtained by present invention is stable and not contaminated with any crystalline form.
The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-anti solvent, spray drying, lyophilization or freeze drying.
The term "organic solvent(s)" or "solvent(s)" or "anti-solvent(s)" as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), THF, pyridine, phenol, dimethylacetamide (DMA), carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1 , 2-propane diol and S (+)-1 , 2- propane diol. Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1 ,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1 , 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
The "acid addition salts" as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, followed by isolation of salt by conventional techniques, if required. A salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to, acetic, benzoic, p-toluene sulphonic, benzenesulfonic, hydrobromic, hydrochloric, citric, gluconic, glucuronic, glutamic, tartaric, lactic, malic, maleic, oxalic, camphorsulphonic, methanesulfonic, palmoic, salicylic, stearic, succinic, sulfuric, and the like. The class of acids suitable for formation of pharmaceutically acceptable salts is well known to person having ordinary skills in the art, and are described, for example in Stahl, P. H., et al., "Handbook of Pharmaceutical Salts", Wiley-VCH, Weinheim: Germany (2002), the contents of which are hereby incorporated herein by reference.
Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, p-toluene sulphonate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, tartarate, citrate, sulphate, maleate, fumarate, succinate, camphor-sulphonate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like. Pharmaceutically acceptable salts are well known to person having ordinary skills in the art, and are described, for example in Berge S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1 -19, 1977, the contents of which are hereby incorporated herein by reference.
The tern "base" as used herein includes but not limited to inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine. The base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
The term "palladium catalyst complex" as used herein includes but not limited to complexes of palladium such as sodium hexachloro palladate(IV)tetrahydrate, potassium hexachloropalladate(IV), palladium(ll) chloride, palladium(ll) bromide, palladium(ll) acetate, palladium(ll) acetyl acetonate, dichlorobis(benzonitrile)palladium(ll), dichlorobis(acetonitrile) palladium(ll), dichlorobis(triphenylphosphine)palladium(ll), dichloro tetraamminepalladium(ll), dichloro(cycloocta-1 ,5-diene)palladium(ll), palladium(ll) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex, or tetrakis(triphenylphosphine)palladium (0) or the like.
The term "ligand" used herein (±)-2,2'-Bis(diphenylphosphino)- 1 , 1 '-binaphthalene (BINAP), Diacetato[2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl]ruthenium(ll) Ru(OAc)2(BINAP), dichloro[(S)-(-)-2,2'- bis[di(3,5-xylyl)phosphino]-1 ,1 '-binaphthyl][(2S)-(+)-1 ,1 -bis(4-methoxy phenyl)-3-methyl-1 ,2-butanediamine]ruthenium(ll) RuCI2[(S)-(DM- BINAP)][(S)-DAIPEN], diacetato[(S)-(-)-2,2'-bis(di-p-tolylphosphino)-1 , 1 '- binaphthyl]ruthenium(ll) (S)-Ru(OAc)2(T-BINAP),
The term "substantially free from impurity A to F" as used herein relates Brexpiprazole which is about 99.9% pure and the amount of impurity A to F present is not more than 0.05%.
To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X- ray diffraction patterns, differential scanning calorimeter, thermograms, thermal gravimetric analyzers thermograms, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.
Example-1 : Preparation of 1-benzo[b]thiophene-4-yl-piperazine p- toluenesulfonate
A mixture of 100 g 4-bromobenzo[b]thiophene, 190 g of Piperazine anhydrous, 60 g of Sodium t-butoxide, 3.4 g of rac-BINAP, 4.2 g of Palladium carbon and 1 200 ml xylene was refluxed till completion of reaction. After completion of reaction palladium carbon was removed by filtration and to filtrate, p-toluenesulfonic acid in xylene was added. Precipitated crystals were separated by filtration to get 92 g of 1 - benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate.
Example-2: Preparation of 1 -benzo[b]thiophene-4-yl-piperazine dihydrochloride
A mixture of 100 g 4-bromobenzo[b]thiophene, 206 g of Piperazine anhydrous, 65.35 g of Sodium t-butoxide, 3.9 g of rac-BINAP, 3.9 g of Palladium carbon and 1500 ml Toluene was refluxed for 4 hrs. Palladium carbon was removed by filtration and dihydrochloride was isolated by reaction with concentrated hydrochloric acid in acetone. Precipitated crystals were separated by filtration to get 88 g of 1 -benzo[b]thiophene-4- yl-piperazine dihydrochloride. Example-3: Preparation of 1 -benzo[b]thiophene-4-yl-piperazine sulphate
A mixture of 100 g 4-bromobenzo[b]thiophene, 161 .56 g of Piperazine anhydrous, 1 12.63 g of Sodium t-butoxide, 3 g of rac-BINAP, 4 g of Palladium carbon and 1700 ml xylene was refluxed for 4 hrs. After completion of reaction, add process water and filter the reaction mixture to remove palladium. Add sulfuric acid to filtrate and stir reaction mixture. Filter reaction mass and wash with xylene and dry to get 90 g of 1 - benzo[b]thiophene-4-yl-piperazine sulphate.
Exmaple-4: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1- yl-)butoxy]-1 H-quinolin-2-one (Brexpiprazole)
A mixtue of 75.5 g of 7-(4-chlorobutoxy)-1 H-quinolin-2-one, 100 g of 1 - benzo[b]thiophene-4-yl-piperazine sulphate, 92.9 g of sodium bicarbonate, 52 g of sodium iodide and 400-450 ml of dimethyl sulfoxide (DMSO) were stirred at 85-95°C. After completion of the reaction, methanol and water was added to reaction mixture and crude product were separated by filtration. To this crude product 900 ml acetone and 600 ml water was charged followed by addition of p-toluene sulphonic acid monohydrate in 100 ml acetone. Stirr reaction mass for about hour at 60°C. Cool the reaction mass and filter the solid and wash with acetone and water and dry at 60°C to get 100 g of p-toluene sulphonic acid salt.
To flask containing 100 g of p-toluene sulphonic acid salt add 900 ml methanol and heat to about 60°C. Add cone. Hydrochloric acid followed by addition of 300 ml water. Raise temperature to about 75°C. Slowly add tert-butyl amine solution (60.98 ml in 600 ml water) in reaction mass. Further cool the reaction mass and filter followed by washing with methanol and water to get wet product. Dry the product to get anhydrous 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1 -yl-)butoxy]-1 H-quinolin-2-one (Brexpiprazole) 40 g. Exmaple-5: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1- yl-)butoxy]-1 H-quinolin-2-one (Brexpiprazole)
A mixtue of 100 g of 7-(4-chlorobutoxy)-1 H-quinolin-2-one, 1 10 g of 1 - benzo[b]thiophene-4-yl-piperazine p-toluenesulfonate, 214 g of sodium bicarbonate, sodium iodide and 650 ml of dimethyl sulfoxide (DMSO) were stirred at 85-95°C. After completion of the reaction, water was added to reaction mixture and precipitated crystals were separated by filtration. Wet solid was dried at 60°C to get 155 g of Brexpiprazole. Purity: 98.7% Exmaple-6: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1- yl-)butoxy]-1 H-quinolin-2-one (Brexpiprazole)
A mixtue of 100 g of 7-(4-chlorobutoxy)-1 H-quinolin-2-one, 1 15.70 g of 1 - benzo[b]thiophene-4-yl-piperazine dihydrochloride, 210 g of potassium carbonate, sodium iodide and 700 ml of dimethylformamide were stirred at 80-90°C. After completion of the reaction, water was added to reaction mixture and precipitated crystals were separated by filtration. Wet solid was dried at 60°C to get 160 g of Brexpiprazole. Purity: 98.5%
Exmaple-7: Preparation of Brexpiprazole p-toluenesulfonate
A mixture of 100 g Brexpiprazole was dissolved in 2000 imL of dichloromethane at 30 to 40 °C. Dichloromethane (1000 imL) was recovered under atmospheric pressure at 40-50°C. p-toluenesulfonic acid solution (48.26 g in Acetone) was added at 40-50°C. Reaction mass was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were dissolved in mixture of acetone: water (12:6). Reaction mixture was cooled to room temperature. Precipitated crystals were separated by filtration. Solid was dried at 60-70°C to get 120 g of Brexpiprazole p-toluenesulfonic acid salt. Example-8: Preparation of anhydrous form of 7-[4-(4-benzo[b] thiophen-4-yl-piperazin-1 -yl-)butoxy]-1 H-quinolin-2-one
(Brexpiprazole)
100 g of Brexpiprazole p-toluenesulfonic acid salt was dissolved in MeOH. 20 ml of cone. HCI was added and reaction mass was stirred for 30 minutes at 50-60°C. Activated carbon slurry was added and reaction was stirred for 10 min. The reaction mass was filtered and solution of tert-butyl amine was added to the filtrate till alkaline pH was achieved. Reaction mixture was cooled to room temperature. Precipitated compound was filtered and washed with MeOH. The obtained solid was suspended in water and heated at 70-80°C. The solid was filtered to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%
Example-9: Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1- yl-)butoxy]-1 H-quinolin-2-one (Brexpiprazole)
Brexpiprazole p-toluenesulfonic acid salt was dissolved in mixture of acetone : water (12 : 6). 20% NaOH solution was added till alkaline pH was achieved. Reaction mixture was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were washed with water till neutral pH was achieved. Solid was dried at 60-70°C to get 85 g of Brexpiprazole. Purity: 99.9%
Example-10: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dimethylformamide (600 imL) at 80-90°C. Water (1800 ml_) was added at 80-90°C. Reaction mixture was cooled to room temperature. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90g of anhydrous form of Brexpiprazole. Purity: 99.85% Example-11 : Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in methanol (400 mL). Crystals were precipitated and separated by filtration. Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9%
Example-12: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in methanol (400 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%
Example-13: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in acetone (500 mL) and water (1600 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.9%
Example-14: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in acetonitrile (600 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9% Example-15: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in tetrahydrofuran (500 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. . Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 96 g of anhydrous form of Brexpiprazole. Purity: 99.85% Example-16: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dichloromethane (700 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.85%
Example-17: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in toluene (400 mL). Crystals were precipitated and separated by filtration. Crystals were suspended in water and heated at 70-80°C. Solid was filtered and dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.8%
Example-18: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in dimethylacetamide (500 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 90 g of anhydrous form of Brexpiprazole. Purity: 99.8%
Example-19: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethanol (700 mL) and water (1500 mL) was added. Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.9% Example-20: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethanol (500 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 86 g of anhydrous form of Brexpiprazole. Purity: 99.9% Example-21 : Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in ethyl acetate (600 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 89 g of anhydrous form of Brexpiprazole. Purity: 99.8%
Example-22: Preparation of anhydrous form of Brexpiprazole
100 g of Brexpiprazole was dissolved in water (500 mL). Crystals were precipitated and separated by filtration. Crystals were washed with water. Solid was dried at 60-70°C to get 95 g of anhydrous form of Brexpiprazole. Purity: 99.9%

Claims

WE CLAIM:
1 . A process for the preparation of Brexpiprazole of formula (I)
Figure imgf000021_0001
comprising steps of:
a) reacting compound of formula
Figure imgf000021_0002
with piperazine in presence of a BINAP, Pd on carbon and organic solvent to obtain compound of formula (IMA)
Figure imgf000021_0003
( III A)
wherein X is a leaving group selected from chloro, bromo, iodo;
b) reacting compound of formula (III A) with acid selected from group consisting of p-toluene sulphonic acid, hydrobromic acid, tartaric acid, succinic acid, oxalic acid, sulphuric acid and maleic acid to obtain compound of formula (III) ; and
Figure imgf000021_0004
c) reacting compound of formula (III) obtained in step (b) with compound of formula (IV)
H
X' = chloro, bromo, iodo
mesylate, tosylate
Figure imgf000022_0001
in presence of base and organic solvent to obtain Brexpiprazole of formula (I).
2. The process as claimed in claim 1 , wherein organic solvent used in step (a) and (c) is selected from group comprising of benzene, toluene, xylene, acetone, methyl ethyl ketone, cyclohexanone, methyl isobutyl ketone, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA) and dimethylformamide (DMF).
3. The process as claimed in claim 1 , wherein base used in (c) is selected from group comprising of ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamine and tert-butyl amine.
4. A salt of 1 -benzo[b]thiophene-4-yl-piprazine of formula (III):
Figure imgf000022_0002
wherein salt is selected from group comprising of p-toluene sulphonate (PTSA), hydrobromide, tartrate, succinate, oxalate, sulfate and maleate.
5. A process for the preparation of Brexpiprazole according to claim 1 , further comprising steps of:
i) providing Brexpiprazole acid addition salt ;
ii) treating Brexpiprazole acid addition salt with one or more base; and iii) isolating anhydrous form of Brexpiprazole.
6. The process as claimed in claim 5, where in acid addition salt is selected from group comprising of p-toluene sulphonate , hydrobromide, tartrate, oxalate, succinate, maleate, hydrochloride, formate, acetate and sulfate.
7. The process as claimed in claim 5, where in base is selected from group comprising of ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamine and tert-butyl amine.
8. A process for the preparation of anhydrous form of Brexpiprazole according to claim 1 or 5, further comprising steps of:
i) dissolving Brexpiprazole in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent(s); and
iii) isolating anhydrous form of Brexpiprazole.
9. The process as claimed in claim 8, wherein suitable solvent(s) are selected from water, ethyl acetate, ethanol, methanol, dimethylacetamide, dimethylformamide (DMF), toluene, dichloromethane, THF, acetonitrile, acetone or mixture thereof.
10. The process as claimed in claim 8, wherein suitable anti-solvent(s) are selected from water, ethyl acetate, ethanol, methanol, dimethylacetamide, dimethylformamide (DMF), toluene, dichloromethane, THF, acetonitrile, acetone or mixture thereof.
xpiprazole of formula (I) prepared according to any of the proceeding claimubstantially free of following impurities:
i) Impurity-A:
Figure imgf000024_0001
ii) Impurity-B:
Figure imgf000024_0002
Figure imgf000024_0003
Figure imgf000024_0004
v) Impurity-E:
Figure imgf000025_0001
vi) Impurity-F:
Figure imgf000025_0002
vii) Impurity-G:
Figure imgf000025_0003
viii) Impurity-H:
Figure imgf000025_0004
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114044772A (en) * 2021-11-29 2022-02-15 浙江国邦药业有限公司 Epipiprazole synthesis method and intermediate thereof
CN114166960A (en) * 2021-11-10 2022-03-11 西安远大科创医药科技有限公司 Detection method of brexpiprazole related substance
CN115108981A (en) * 2022-08-29 2022-09-27 天津辰欣药物研究有限公司 Synthesis method of brexpiprazole impurity

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WO2006112464A1 (en) * 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Piperazine-substituted benzothiophenes for treatment of mental disorders

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2006112464A1 (en) * 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Piperazine-substituted benzothiophenes for treatment of mental disorders

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114166960A (en) * 2021-11-10 2022-03-11 西安远大科创医药科技有限公司 Detection method of brexpiprazole related substance
CN114166960B (en) * 2021-11-10 2023-09-29 西安远大科创医药科技有限公司 Method for detecting substances related to epipiprazole
CN114044772A (en) * 2021-11-29 2022-02-15 浙江国邦药业有限公司 Epipiprazole synthesis method and intermediate thereof
CN115108981A (en) * 2022-08-29 2022-09-27 天津辰欣药物研究有限公司 Synthesis method of brexpiprazole impurity

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