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WO2017216661A1 - Procédé pour la préparation de brexpiprazole à partir de 7-(4-chlorobutoxy)quinolin-2(1h)-one et du 1-(benzo[b]thiophen-4-yl)piperazine - Google Patents

Procédé pour la préparation de brexpiprazole à partir de 7-(4-chlorobutoxy)quinolin-2(1h)-one et du 1-(benzo[b]thiophen-4-yl)piperazine Download PDF

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Publication number
WO2017216661A1
WO2017216661A1 PCT/IB2017/053018 IB2017053018W WO2017216661A1 WO 2017216661 A1 WO2017216661 A1 WO 2017216661A1 IB 2017053018 W IB2017053018 W IB 2017053018W WO 2017216661 A1 WO2017216661 A1 WO 2017216661A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
brexpiprazole
quinolin
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/053018
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English (en)
Inventor
Deepak Bansal
Himanchal MISHRA
Vaibhav MISHRA
Alka Srivastava
Dharam Vir
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jubilant Generics Ltd
Original Assignee
Jubilant Generics Ltd
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Filing date
Publication date
Application filed by Jubilant Generics Ltd filed Critical Jubilant Generics Ltd
Publication of WO2017216661A1 publication Critical patent/WO2017216661A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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 relates to process for the preparation of benzo[b]thiophene compound used for the treatment of schizophrenia and as an adjunct for major depressive disorder. More particularly, the present invention is directed to the process for the preparation of 7- ⁇ 4-[4-(l-benzothiophen-4-yl) piperazin-l-yl] butoxy ⁇ quinolin-2 (1H)- one (Brexpiprazole) and its intermediates thereof.
  • Brexpiprazole is a D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM). Brexpiprazole is chemically known as 7- ⁇ 4-[4-(l-benzothiophen-4- yl) piperazin-l-yl] butoxy ⁇ quinolin-2 (lH)-one. It is known from US 7,888,362 and is represented by Formula I.
  • Brexpiprazole is sold in USA under the proprietary name of "REXULTI” and is indicated for the treatment of schizophrenia and also as an adjunctive therapy to antidepressants in adults having major depressive disorder.
  • Another intermediate 1- benzo[b]thiophene-4-yl-piperazine hydrochloride compound of Formula V is prepared by reacting compound of Formula IV with anhydrous piperazine using (R) (+)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl(BINAP), dipalladiumtris (dibenzylidene acetone) in presence of sodium i-butoxide by heating under reflux.
  • Impurity D (Dimer impurity)
  • the main drawback of the said process is the use of expensive palladium carbene complex on commercial scale, which makes the process costly and needs special handling equipment for industrial scale production.
  • Another disadvantage of this process is the formation of impurity A and impurity B during the reaction of compound of Formula V with compound of Formula III which is difficult to separate from the final product and requires multiple purifications, thus in order to attain the purity of final compound, it leads to undue operational steps for removal of impurities, thus makes the process expensive and tedious on commercial scale.
  • CN 105175401A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with 1 -chlorine-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III, which then reacts with N-Boc piperazine to obtain 7-(l-piperazine) butoxy-lH-quinolin-2-one dihydrochloride of Formula VIII followed by reaction with compound of Formula IV and isopropyl magnesium chloride in THF to obtain brexpiprazole compound of Formula I according to Scheme-Ill.
  • Scheme-Ill CN 105440026A discloses the synthesis of Brexpiprazole wherein 7-hydroxyl-lH- quinolin-2-one of Formula II reacts with l-chloro-4-bromobutane to obtain 7-(4- chlorobutoxy)-lH-quinolin-2-one of Formula III which reacts with piperazine monohydrochloride to obtain 7-(4-(piperazin-l-yl)butoxy)quinolin-2(lH)-one hydrochloride compound of formula VHP.
  • the resulting compound of Formula VHP then reacts with 4-chlorobenzo [b] thiophene in presence of a base and palladium triphenyl complex to give Brexpiprazole compound of Formula I according to Scheme - IV.
  • the principal object of the present invention is to provide a process for the preparation of Brexpiprazole of Formula I, which alleviates one or more drawbacks of prior art processes.
  • a process for the preparation of Brexpiprazole of Formula I comprising the steps of: AA) reacting compound of Formula II with compound of Formula X in presence of a base and solvent at temperature below 45°C to obtain compound of Formula XIII;
  • Impurity D (Dimer impurity) DETAIL DESCRIPTION OF THE INVENTION:
  • the present invention is directed to a process of preparing brexpiprazole that is simple, convenient, environment friendly and economical for industrial application.
  • the method utilizes a careful reaction condition and reagent for reducing the formation of known and unknown impurities while at the reaction stage itself, avoids the additional requirements of purifying intermediates at various stages and accordingly reduces the use of solvents and reagents. This in turn results in decrease in costs attributed to a more efficient use of reagents and solvents and at the same time becomes more environment friendly and cost effective.
  • a process for the preparation of Brexpiprazole of Formula I comprising the steps of: AA) reacting compound of formula II with compound of formula X in the presence of a base and solvent at temperature below 45°C to obtain compound of formula XIII;
  • reaction of compound of formula II with compound of formula X in step AA) is carried out in presence of a base and solvent wherein the base is selected from the group comprising of inorganic or organic base.
  • the organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N- methylpyrrolidine, N-methylmorpholine and the like; aromatic amines such as pyridine, lutidine, ⁇ , ⁇ -dimethylaniline and the like.
  • the inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like.
  • the solvent is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-buty ⁇ ether, and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, or mixture thereof.
  • ethers such as dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-buty ⁇ ether, and the
  • reaction of compound of formula II with compound of formula X in step AA) is carried out at a temperature of about 20 to 45°C, preferably 35 to 45°C for about 2 to 8 hours, more preferably 6-8 hours.
  • step AA crude compound of formula XIII obtained in step AA) contains high amount of dimer impurity.
  • the inventors of present invention observed the presence of dimer impurity of formula D in an amount higher than regulatory recommendations, in brexpiprazole obtained by prior art process. Also, the inventors of present invention observed that removal of dimer impurity of formula D is not possible by general purification techniques and is difficult to remove once formed. Accordingly, the present invention provides a simple and efficient process for removal of dimer impurity of formula D at the intermediate stage by treating the 7-(4-halobutoxy) quinolin- 2(lH)-one compound of formula XIII using resin in suitable solvent.
  • the resin is selected from the group comprising of polystyrene-divinylbenzene, acrylic resins, crosslinked organic monomer preferably AMBER LITE IR 120 H brand of resins, silica and the like.
  • the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol and the like.
  • the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is carried out in presence of a base and solvent, wherein the base is selected from the organic or inorganic base.
  • the organic base is selected from triethylamine, diisopropylethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine and the like; aromatic amines such as pyridine, lutidine, N,N- dimethylaniline and the like.
  • the inorganic base is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, hydride and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, cesium, calcium, magnesium and the like.
  • the solvent used for the reaction of compound of formula XIII with compound of formula V or its salt in step BB) is selected from the group comprising of ethers such as dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-buty ⁇ ether, diethylene glycol, ethylene glycol and the like; esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene, xylene chloroxylene, and the like; polar solvents such as DMF, DMSO, DMA, sulfolane, hexamethylphosphoric triamide, water or mixture thereof.
  • ethers such as dioxane,
  • reaction of compound of formula XIII with compound of formula V or its salt is optionally carried out in presence of reaction accelerator selected from sodium iodide, potassium iodide and the like at a suitable temperature selected from 80 to 120°C, preferably 90-100°C to obtain Brexpiprazole compound of Formula I.
  • reaction accelerator selected from sodium iodide, potassium iodide and the like at a suitable temperature selected from 80 to 120°C, preferably 90-100°C to obtain Brexpiprazole compound of Formula I.
  • Brexpiprazole obtained from above process is optionally further purified by techniques already known in prior art technique such as crystallization, solvent anti-solvent method etc.
  • the solvent used for purification is selected from the group comprising of alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like; chlorinated solvent such as dichloromethane and the like; esters such as ethyl acetate, propyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; water or mixture thereof.
  • Brexpiprazole obtained by the process of the present invention is in fact substantially pure, and in particular substantially free from the dimer impurity of Formula D, wherein the dimer impurity is less than 0.1%.
  • the expression "substantially pure” means having a purity degree equal to or higher than 99%.
  • Table no. 1 Comparative data for dimer impurity of Formula D of prior art vis-avis present invention:
  • reaction conditions are very simple and do not involve stringent critical operating parameters.
  • the resulting wet material was taken in methanol (1000 ml) at 25-30°C and heated to reflux till complete dissolution. Cooled the solution to 10-15°C. Filtered the resulting solid, wash with methanol (100 ml) and dried at 60-65 °C for 12-15 hours under vacuum to obtain title compound.
  • wet material 40g.
  • the resulting wet material was taken in a mixture of ethanol (400 ml) and acetic acid (50 ml) at 30-35°C and heated to reflux at 80°C. Cooled the resulting solution to 30- 35°C and filter, washed the wet material with ethanol. Charged the wet material to a mixture of ethanol (400 ml) and water (100 ml) at 30-35°C, heated to 75-80°C for complete dissolution. Added activated charcoal (1 g), stirred the resulting mixture for 30- 40 minutes filter at 75-80 °C.
  • the resulting wet material was taken in a mixture of ethanol (3200 ml) and acetic acid (240 ml) and heated to reflux at 75-80°C. Cone HC1 (36 ml) was added and stirred for 30-40 minutes. Cooled the resulting solution and then heated to 75-80°C under stirring for 1-2 hours. Cooled, filtered and the resulting wet material was washed with ethanol. The resulting wet material was taken in ethanol (3200 ml) and water (100 ml) and heated to 75-80°C for complete dissolution. Added activated charcoal (16 g), stirred the resulting mixture for 1-2 hours, filtered through hyflow.
  • the resulting filtrate was heated to 75-80°, and to this added aqueous solution of sodium bicarbonate (40 g in 800 ml water) under stirring. Added water (480 ml) at 75-80°C. Cooled the resulting mass to 35-40°C, filtered, washed with water. The resulting wet material was taken in ethanol (348 ml) and stirred for 1-2 hours. Filtered the material, washed the wet cake with ethanol and dried at 60-70°C for 12-16 hours to obtain title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de 7-{4-[4-(1-benzothiophen-4-yl)piperazine-1-yl]butoxy} quinolin-2(1H)-one (brexpiprazole) à partir de 7-(4-chlorobutoxy)quinolin-2(1H)-one et du 1-(benzo[b]thiophen-4-yl)piperazine. L'intermédiaire 7-(4-chlorobutoxy)quinolin-2(1H)-one est préparé à partir de 7-hydroxy-quinolin-2(1H)-one et de 1-bromo-4-chloro-butane à une température inférieure à 45 °C. L'intermédiaire brut 7-(4-chlorobutoxy)quinolin-2(1H)-one est ensuite traité avec une résine (par exemple, AMBER LITE IR 120 h) dans un solvant alcoolique (par exemple, le méthanol) par lequel le dimère D est éliminé. Le brexpiprazole obtenu par ce procédé est considérablement sans impureté dimère D. Le brexpiprazole est un agoniste partiel de la dopamine D2 appelé modulateur de l'activité de la sérotonine-dopamine (SDAM) utilisé pour le traitement de la schizophrénie et comme adjuvant pour les troubles dépressifs majeurs.
PCT/IB2017/053018 2016-06-17 2017-05-23 Procédé pour la préparation de brexpiprazole à partir de 7-(4-chlorobutoxy)quinolin-2(1h)-one et du 1-(benzo[b]thiophen-4-yl)piperazine Ceased WO2017216661A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201611020752 2016-06-17
IN201611020752 2016-06-17

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WO2017216661A1 true WO2017216661A1 (fr) 2017-12-21

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PCT/IB2017/053018 Ceased WO2017216661A1 (fr) 2016-06-17 2017-05-23 Procédé pour la préparation de brexpiprazole à partir de 7-(4-chlorobutoxy)quinolin-2(1h)-one et du 1-(benzo[b]thiophen-4-yl)piperazine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909159A (zh) * 2019-05-08 2020-11-10 成都弘达药业有限公司 一种依匹哌唑有关物质及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7888362B2 (en) 2005-04-14 2011-02-15 Otsuka Pharmaceutical Co., Ltd. Piperazine-substituted benzothiophenes for treatment of mental disorders
US9206169B2 (en) 2011-07-28 2015-12-08 Otsuka Pharmaceutical Co., Ltd. Method for producing benzo[b]thiophene compound
CN105175401A (zh) 2015-10-16 2015-12-23 北京康立生医药技术开发有限公司 一种依匹哌唑的制备方法
CN105440026A (zh) 2015-12-04 2016-03-30 上海勋和医药科技有限公司 依匹哌唑的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7888362B2 (en) 2005-04-14 2011-02-15 Otsuka Pharmaceutical Co., Ltd. Piperazine-substituted benzothiophenes for treatment of mental disorders
US9206169B2 (en) 2011-07-28 2015-12-08 Otsuka Pharmaceutical Co., Ltd. Method for producing benzo[b]thiophene compound
CN105175401A (zh) 2015-10-16 2015-12-23 北京康立生医药技术开发有限公司 一种依匹哌唑的制备方法
CN105440026A (zh) 2015-12-04 2016-03-30 上海勋和医药科技有限公司 依匹哌唑的制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909159A (zh) * 2019-05-08 2020-11-10 成都弘达药业有限公司 一种依匹哌唑有关物质及其制备方法

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