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WO2018015354A1 - Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé - Google Patents

Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé Download PDF

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Publication number
WO2018015354A1
WO2018015354A1 PCT/EP2017/068058 EP2017068058W WO2018015354A1 WO 2018015354 A1 WO2018015354 A1 WO 2018015354A1 EP 2017068058 W EP2017068058 W EP 2017068058W WO 2018015354 A1 WO2018015354 A1 WO 2018015354A1
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WIPO (PCT)
Prior art keywords
reaction
catalyst
solvent
conducted
brexpiprazole
Prior art date
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Ceased
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PCT/EP2017/068058
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English (en)
Inventor
Rafał RUSIECKI
Marcin ŚNIEŻEK
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Adamed Sp zoo
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Adamed Sp zoo
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Priority to EP17740021.5A priority Critical patent/EP3487854A1/fr
Publication of WO2018015354A1 publication Critical patent/WO2018015354A1/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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • 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 invention relates to the method for manufacture of brexpiprazole, intermediates used in this method, and the method for manufacture thereof.
  • Brexpiprazole and its synthesis was disclosed for the first time in WO2006112464.
  • the synthesis consisted in a construction of a brexpiprazole molecule from two fragments 3 and 4 by nucleophilic substitution reaction between the leaving group X 1 in the form of a halogen and a secondary amine group of a piperidine ring.
  • the main problem associated with the methods known in the prior art is primarily the formation of hardly removable impurities which are formed via uncontrolled nucleophilic substitution reactions.
  • the main side reaction is a secondary alkylation reaction of compound 3 with another molecule of compound 1.
  • the separation of reactivities of groups X 1 and X 2 through the use of various leaving groups with different reactivities produces no satisfactory results.
  • the present invention relates to the method for manufacture of brexpiprazole, comprising the following steps: (a) reaction of 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal 5 or a solvate thereof with l-(l-benzothiophen-4-yl)piperazine 4 or a salt thereof in a solvent, optionally in the presence of a catalyst;
  • step (b) reduction of the iminium salt formed in step (a) using a reducing agent in a solvent, optionally in the presence of a catalyst.
  • a reducing agent in a solvent, optionally in the presence of a catalyst.
  • l-(l-Benzothiophen-4-yl)piperazine 4 used in this process, is a known compound, and it may be obtained according to the procedures known in the prior art. For example, a procedure described in Reference Example 30 included in WO2006112464A1 may be applied.
  • a base catalyst is used in step (a).
  • the base catalyst is sodium acetate.
  • an acid catalyst is used in step (a).
  • the acid catalyst is acetic acid.
  • step (a) the reaction is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile. More preferably, the solvent is either methanol or 2-propanol. Particularly preferably, the solvent is 2-propanol.
  • step (a) l-(l-benzothiophen-4-yl)piperazine is used in the form of a hydrochloride salt, and 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal is used in the form of a hydrate.
  • a base catalyst is used in step (b).
  • the base catalyst is sodium acetate.
  • an acid catalyst is used in step (b).
  • the acid catalyst is acetic acid.
  • step (a) and step (b) Good results were obtained where acetic acid is used as a catalyst in step (a) and step (b). Good yields of the final products were obtained using acetic acid at an amount of 1-3 equivalents, particularly preferably 1.2 equivalent in relation to the amount of the aldehyde used.
  • the reducing agent is selected from a group consisting of NaBH(OAc)3, NaBH 3 CN, NaBH 4 , and H 2 /Pd.
  • a particularly preferable reducing agent is NaBH(OAc) 3 .
  • the reduction reaction in step (b) is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile. More preferably, the solvent is either methanol or 2-propanol. Particularly preferably, the solvent is 2-propanol.
  • the method of the invention comprising the generation of an iminium ion and the reduction thereof, is performed in one vessel.
  • Iminium salts are relatively unstable intermediates, therefore preferably no separation or purification thereof is conducted. This enables the maximization of the yield of the entire process while maintaining high purity of the final product.
  • Aldehyde 5 used in the reaction may be obtained by using alkylation of 7- hydroxyquinolin-2(lH)-one 1 with an appropriate n-butanal derivative 7, protected in the form of an acetal, which comprises a leaving group at the opposite end in relation to the protected aldehyde group, and then by hydrolyzing the obtained product 8, under acidic conditions, according to the following scheme:
  • both groups R 1 , and R 2 are methyl or ethyl group, particularly preferably both groups are ethyl groups.
  • Said alkylation reaction is preferably conducted in an appropriate solvent such as DMSO, DMF, acetonitrile, acetone, toluene, THF, water, or mixtures thereof.
  • DMSO DMSO
  • DMF acetonitrile
  • acetone acetone
  • toluene THF
  • water or mixtures thereof.
  • either DMSO or a mixture of water and DMF is used.
  • a 1 :1 ratio (v/v) mixture of water and DMF, or DMSO is used. Most preferably, DMSO is used.
  • Said alkylation relation is conducted in the presence of a base.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, DMAP, and DBU, and inorganic bases such as KOH, NaOH, K2CO3, and CS2CO3 may be used as the base. Reactions with organic bases proceed with a much lower yield.
  • KOH and NaOH leads to the formation of large amounts of impurities.
  • K2CO3 or Na 2 C03 is used.
  • a catalyst can be used in this process.
  • a quaternary ammonium salt such as tetraalkylammonium halide, and preferably tetrabutylammonium bromide, can be used.
  • the obtained 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal acetal is then hydrolyzed using an acid to yield 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal.
  • aqueous solutions of organic acid such as formic acid, acetic acid, TFA, sulfonic acids, or mineral acids such as HC1, H2SO4, HCIO4, or acid resins such as Amberlyst 15 are used.
  • hydrochloric acid is used.
  • the solvent used in this step may be selected from water, THF, acetone, DCM, methanol, acetonitrile, diethyl ether, ethanol, 2-propanol, toluene, and mixtures thereof.
  • mixtures of water and the solvents mentioned are used.
  • the aldehyde is usually isolated in a form of a solvate.
  • the aldehyde when mixture with water is used as a solvent, the aldehyde is isolated as a hydrate.
  • the hydrate can be directly used in the next reaction or can be dried to obtain the anhydrous aldehyde. Preferably, it is used as the hydrate.
  • a further aspect of the present invention is an intermediate in the form of an iminium salt in which the cation is the iminium cation has the following formula:
  • Still a further aspect of the present invention is an intermediate of the following formula:
  • an additional aspect of the present invention is an intermediate of the following formula:
  • the intermediate is obtained by reaction of 7-hydroxyquinolin-2(lH)-one with a compound of the formula:
  • R 1 and R 2 are as defined above, and X is a leaving group.
  • the reaction is conducted in DMSO.
  • the reaction is conducted in the presence of Na 2 C03.
  • the reaction is conducted in the presence of a catalyst in the form of tetraalkylammonium halogen.
  • a catalyst in the form of tetraalkylammonium halogen.
  • the tetraalkylammonium halide is tetra-n- butylammonium bromide.
  • This compound is a particularly preferred intermediate in the synthesis of 4-[(2-oxo- 1 ,2- dihydroquinolin-7-yl)oxy]butanal, since when subjected to hydrolysis in the presence of an acid, it gives the aldehyde with very high, practically quantitative yields, and with high purity.
  • brexpiprazole is obtained with high yields and very high purities.
  • An additional advantage of the method of the invention is that both steps i.e. the step of iminium salt formation and the step of reduction of this salt to brexpiprazole may be conducted at room temperature.
  • a reactor was charged with 700 g (4.34 mol, 1.0 eq) 7-hydroxyquinolin-2(lH)-one, 920 g (8.68 mol, 2.0 eq) Na 2 C0 3 , 140 g (0.43 mol, 0.1 eq) TBAB, and 2170 mL DMSO.
  • the stirring was turned on, temperature of bath was set on 110°C.
  • temperature of reaction mixture reached 100°C
  • 1180 g (6.53 mol, 1.5 eq) 4-chloro-l,l-diethoxybutane was added. Reaction was conducted for 3 hours in 110°C. Next, 1075 mL 2-propanol was added, and reaction mixture was cooled to 40°C.
  • the dimethyl derivative was obtained analogously as in example I - Method 1-1 but using 4-chloro-l,l-dimethoxybutane instead of 4-chloro-l,l-diethoxybutane. 52% yield.
  • a reactor was charged with 956 g (3.13 mol, 1.00 eq) 7-(4,4-diethoxybutoxy)quinolin- 2(lH)-one, 2800 mL water and 3800 mL 2-propanol.
  • the stirring was turned on and 950 mL (11.4 mol, 3.64 eq) of 36%> hydrochloride acid was added.
  • the bath temperature was set to 20°C.
  • reactor was cooled down to 0°C and stirring was continued for 1 hour.
  • Precipitate was filtrated and washed with 3600 mL water, 3600 mL saturated sodium carbonate solution, and next again with 3600 mL water.
  • the solid was placed in the dryer for 18 hours at 60°C. 756 g (3.03 mol, 97% yield) 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal hydrate was obtained.
  • the product was crystallised twice. First, using 70%> ethanol, and next using 50%> ethanol with addition of 1.2 equivalent NaOH. A product with purity of 99.84%> and yield of 68.2% was obtained.
  • Step I Reactor was loaded with 756 g (3.03 mol, 1.00 eq) 4-[(2-oxo-l,2-dihydroquinolin-7- yl)oxy]butanal hydrate, 749 g (2.94 mol, 0.97 eq) l-(l-benzothiophen-4-yl)piperazine hydrochloride, 194 g (2.36 mol, 0.78 eq) sodium acetate and 7400 mL 2-propanol. The stirring was turned on and the bath was heated to 70°C.
  • Step II Crude brexpiprazole hydrochloride 1234 g (2.63 mol) was loaded to a reactor followed by 16300 mL methanol and 4100 mL water. The stirring was turned on and the bath was heated to 100°C. After the mixture was refluxed for 10 minutes at 70°C, 124 g of activated charcoal was added. 30 minutes after addition of coal, suspension was filtered through celite pad and filtrate was transferred to the reactor. Mixture was slowly cooled down to 0°C, suspension was filtered and precipitate was washed with 6800 mL methanol. The solid was placed in the air flow dryer for 18 hours at 60°C. 1028 g (2.19 mol) of brexpiprazole hydrochloride was obtained as a white solid.
  • Step III Next, a reactor was loaded with 1028 g (2.19 mol) brexpiprazole hydrochloride, 13900 mL ethanol 96% and 8400 mL water. The stirring was turned on and bath was heated to 130°C. Mixture was refluxed for 30 minutes at 80°C, than cooled to 75°C, and 525 g (3.28 mol, 1.5 eq) 25% sodium hydroxide solution was added. Temperature 70-75°C was kept for another 30 minutes. Next, 3200 mL water was added and mixture was cooled down to 0°C. This temperature was kept for 1 h. Next, the suspension was filtrated through a Buchner funnel with paper filter and washed with 13200 mL water. Light yellow solid was placed in the air flow dryer for 18 hours at 60°C. 886 g (2.04 mol, 67%> yield) of brexpiprazole as light yellow solid was obtained. HPLC Purity 99.81%.
  • Brexpiprazole was also obtained according to the procedure disclosed in WO 2006112464A1, Example 1. According to the procedure, workup of the reaction mixture consisted in pouring the mixture onto water, filtering off the product, and then crystallisation from 70% ethanol. The yield of the process was 52%. The HPLC purity of brexpiprazole was 93.91%.
  • brexpiprazole was obtained according to US Patent US9206169 (Step I - reference example 9, col. 27; Step II - example 4, col. 27) in a slightly larger scale.
  • the total yield after 2 stages and purification was 45%>, and the HPLC purity was 99.21%>.
  • brexpiprazole obtained in the above Method III- 1 was crystallized from 70% ethanol, and brexpiprazole was obtained in a total yield of 61% and with the HPLC purity of 99.70%.
  • brexpiprazole obtained in Method III-3 (large scale method) was analyzed. Total yield after 3 stages was 51%, and the HPLC purity was 99.81%).
  • Phase A 750 mL 10 mmol SDS solution, 250 mL ACN and 5 mL

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

Abstract

L'invention concerne un procédé de fabrication du brexpiprazole comprenant l'étape (a) consistant à faire réagir le 4-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]butanal ou un solvate correspondant avec du 1-(1-benzothiophen-4-yl)pipérazine ou un sel correspondant dans un solvant, éventuellement en présence d'un catalyseur, et l'étape (b) consistant à réduire le sel d'iminium formé à l'étape (a) à l'aide d'un agent réducteur dans un solvant, éventuellement en présence d'un catalyseur. L'invention concerne également les intermédiaires utilisés pour la fabrication du brexpiprazole, et le procédé de fabrication de ces intermédiaires.
PCT/EP2017/068058 2016-07-19 2017-07-17 Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé Ceased WO2018015354A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP17740021.5A EP3487854A1 (fr) 2016-07-19 2017-07-17 Procédé de fabrication du brexpiprazole, intermédiaires utilisés dans ce procédé, et procédé de fabrication associé

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PL418019A PL233778B1 (pl) 2016-07-19 2016-07-19 Sposob wytwarzania brekspiprazolu oraz zastosowanie zwiazkow posrednich w sposobie wytwarzania brekspiprazolu
PLP.418019 2016-07-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112858524A (zh) * 2021-02-25 2021-05-28 丽珠集团新北江制药股份有限公司 一种依匹哌唑有关物质的检测方法和应用
WO2023068253A1 (fr) * 2021-10-18 2023-04-27 大塚製薬株式会社 Nouvelle forme cristalline de composé de benzothiophène et son procédé de production

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112858524A (zh) * 2021-02-25 2021-05-28 丽珠集团新北江制药股份有限公司 一种依匹哌唑有关物质的检测方法和应用
CN112858524B (zh) * 2021-02-25 2022-12-20 丽珠集团新北江制药股份有限公司 一种依匹哌唑有关物质的检测方法和应用
WO2023068253A1 (fr) * 2021-10-18 2023-04-27 大塚製薬株式会社 Nouvelle forme cristalline de composé de benzothiophène et son procédé de production

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EP3487854A1 (fr) 2019-05-29
PL418019A1 (pl) 2018-01-29

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