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WO2012000308A1 - Procédé de résolution de tétrabénazine - Google Patents

Procédé de résolution de tétrabénazine Download PDF

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Publication number
WO2012000308A1
WO2012000308A1 PCT/CN2011/001060 CN2011001060W WO2012000308A1 WO 2012000308 A1 WO2012000308 A1 WO 2012000308A1 CN 2011001060 W CN2011001060 W CN 2011001060W WO 2012000308 A1 WO2012000308 A1 WO 2012000308A1
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WO
WIPO (PCT)
Prior art keywords
tetrabenazine
acid
llbr
salt
solvent
Prior art date
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Ceased
Application number
PCT/CN2011/001060
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English (en)
Chinese (zh)
Inventor
孙宏斌
姚彰彧
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.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
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Filing date
Publication date
Priority claimed from CN 201010222617 external-priority patent/CN101985447A/zh
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Publication of WO2012000308A1 publication Critical patent/WO2012000308A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Definitions

  • the invention relates to the field of chemistry, and in particular to a method for resolution of tetrabenazine. Background technique
  • Tetrabenazine is a benzoquinazine derivative whose chemical name is 2-oxo-3-isobutyl-9, 10-dimethoxy-1, 2, 3, 4, 6, 7-Hexahydrobenzo[ ⁇ ]quinolizine (see Formula 1).
  • Terfenazin was marketed in Switzerland in the late 1950s and was originally used for the treatment of schizophrenia. After a period of clinical use, it was found that tetrabenazine is a dopamine receptor blocker. It has been tested and found that tetrabenazine has a wider range of uses, especially in terms of hyperkinesia. In 2008, tetrabenazine became the first drug in the United States to be approved by the FDA for the treatment of Huntington's disease. Tetrabenazine mainly reduces the supply of monoamines such as serotonin, dopamine and norepinephrine by reversibly inhibiting the monoamine transporter 2 (VMAT 2) of the central nervous system to produce pharmacological activity.
  • VMAT 2 monoamine transporter 2
  • tetrabenazine In addition to inhibiting VMAT 2, tetrabenazine also has some antagonistic effects on presynaptic and postsynaptic dopamine receptors. Tebuconazine is a safe and effective drug for the treatment of various motor hyperactivity disorders. It does not cause tardive dyskinesia compared with traditional antipsychotics. However, tetrabenazine also causes some dose-related side effects such as sedation, Parkinson's syndrome, depression, insomnia, and meditation. All side effects are reversible. Although tetrabenazine may cause some side reactions, it is generally relatively safe, with a small chance of serious side effects and good tolerance. Terfenazin has 2 chiral centers: 3 and lib.
  • the listed tetrabenazine is (3R, llbR)-tetrabenazine (see formula 2) and (3S, llbS)-butylbenzene.
  • a racemic mixture of naazine see formula 3).
  • Tebuconazine is rapidly metabolized in the human body to dihydrotetrabenazine (DHTBZ), which is also its main active form. Because tetrabenazine is a racemic mixture of the RR configuration and the SS configuration, dihydrotetrabenazine is also available in four forms: (+)-dihydrotetrabenazine (2R, 3R, llbR) See formula 4), (-) - dihydrotetrabenazine (2S, 3S, llbS) (see formula 5), (+) - ⁇ -dihydrotetrabenazine (2S, 3R, llbR) (see Formula 6) and (-) - ⁇ -dihydrotetrabenazine (2R, 3S, llbS) (see formula 7).
  • (+)-dihydrotetrabenazine (2R, 3R, llbR) See formula 4
  • (+) _-dihydrotetrabenazine (2R, 3R, llbR) has the highest binding affinity to VMAT 2 and is much stronger in vivo than the other three isomers.
  • Pharmacological activity (Mol. Pharmacol. 1987, 33, 72-77; Eur. J. Pharmacol. 1995, 278, 249-252; Appl. Radiat. Isot. 1993, 44, 1487-1489)o corresponding, optically pure (3R, llbR) -
  • the activity of tetrabenazine (formula 2) is also stronger than that of (3S, llbS)-tetrabenazine (formula 3). Since the enantiomers of chiral drugs generally have significant differences in efficacy and safety, preparation of optically pure (3R, llbR)-tetrabenazine has important practical significance.
  • the existing methods for preparing optically active tetrabenazine are mainly by chiral column splitting method (W0 2008058261) or asymmetric synthesis method (W0 2008154243; US 20080306267; US 20080306269; J. Org. Chem. 2009, 74, 4001-4004). Both of the above methods for preparing optically active tetrabenazine are not suitable for industrial production. Therefore, there is an urgent need to establish an economical and simple method for preparing optically active tetrabenazine. Summary of the invention
  • the present invention provides a method for resolution of tetrabenazine.
  • the method uses the racemic tetrabenazine as a raw material to form a salt with a right-handed or a left-handed chiral acid, and obtains the corresponding chiral acid salt of tetrabenazine according to the difference in solubility, and further dissociates to obtain a corresponding configuration.
  • Tebufenazide as shown below:
  • HX represents a right-handed or left-handed chiral acid.
  • the present invention provides chiral acid salts of (3R, llbR)-tetrabenazine (see formula 8) or (3S, l lbS)-tetrabenazine (see formula 9). And its preparation method.
  • the invention provides a preparation method of (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine, comprising: dissolving the racemic tetrabenazine and the dextrorotatory or levodomic acid in a solvent.
  • the salt is formed, then cooled and crystallized, and filtered to obtain a chiral acid salt of (3R, llbR)-tetrabenazine or a chiral acid salt of (3S, llbS)-tetrabenazine, which is further recrystallized with a solvent to obtain pure
  • the product is adjusted to basic with an aqueous alkaline solution to form (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine.
  • the chiral acid used may be selected from camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, 2'-nitroaniline tartaric acid, mandelic acid, malic acid, camphoric acid or phenoxypropionic acid. Camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyltartaric acid is preferred.
  • the molar ratio of the racemic tetrabenazine to the right-handed or left-handed chiral acid is 1: 0.2 to 1.8, and the preferred molar ratio is 1: 0.4 to 1.2.
  • the solvent used for the salt formation with the chiral acid may be selected from the group consisting of water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene, A mixture of one or more of R 2 0R3, R 2 0H or dioxane. among them,!
  • R 2 , R 3 independently represent a straight or branched alkyl group having 5 carbon atoms, preferably water, methanol, ethanol, acetonitrile, A mixture of one or more of acetone or ethyl acetate is used as a resolving solvent, and more preferably ethyl acetate, methanol, acetonitrile or acetone is used as a resolving solvent.
  • the ratio of the racemate tetrabenazine to the resolution solvent is 1 g : 3 ml TlOO mL, preferably in a ratio of 1 g : 10 mL to 50 mLo
  • the salt formation temperature of the racemic tetrabenazine and the chiral acid is from 0 °C to 150 °C, and the preferred salt formation temperature is from 20 °C to 100 °C.
  • the crystallization temperature is - 20 °C ⁇ 50. C, a preferred crystallization temperature is 5 ° C to 35 ° C.
  • the high purity (3R, llbR)-tetrabenazine or the chiral acid salt of (3S, llbS)-tetrabenazine precipitated during the above resolution can be directly dissociated (3R, llbR). - tetrabenazine or (3S, llbS) - tetrabenazine.
  • the crude (3R,llbR)-tetrabenazine or (3S,llbS)-tetrabenazine salt precipitated in the above resolution may be subjected to one or more times in a suitable solvent.
  • the solvent used for recrystallization and recrystallization may be selected from the group consisting of water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene,
  • R 2 0R 3 , R 2 0H or dioxane ⁇ a linear or branched fluorenyl group representing a hydrogen atom or a broad 5 carbon atoms
  • R 2 , R 3 independently represent a straight or branched 'fluorenyl group having 5 carbon atoms, preferably water, methanol, ethanol, acetonitrile, a mixture of one or more of acetone or ethyl acetate as a recrystallization solvent Ethyl acetate, methanol, acetonitrile or acetone was selected as the recrystallization solvent.
  • the method of the invention has the advantages of simple operation, low cost, high purity of the product obtained by the separation, is advantageous for large-scale industrial production, and has great application value.
  • TMS internal standard nuclear magnetic resonance apparatus
  • racemate tetrabenazine 0.3 g, 0.95 ⁇ ol
  • (+)-camphorsulfonic acid 0.11 g, 0.48 mmol
  • racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.37 g, 1.6 mmol) were dissolved in 6 mL ethyl acetate, refluxed for 30 min, cooled to 5 ° crystallization, filtered A white crystal was obtained.
  • the crude salt was recrystallized from acetone three times (5 mL per acetone, heated to reflux to dissolve the solid, and then cooled and crystallized) to give a white solid (3R, llbR) - tetrabenazine (-)-camphorsulfonic acid salt.
  • racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.19 g, 0.8 mmol) were dissolved in 3 mL of acetonitrile, refluxed for 30 minutes, cooled to 5 ° crystallization, filtered to give white Crystal.
  • the crude salt was recrystallized two times in C (3 mL per acetone, heated to reflux to dissolve the solid, and then cooled and crystallized) to give a white solid (3R, llbR) - tetrabenazine (+)-camphor Sulfonate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de résolution de tétrabénazine. De la tétrabénazine racémique est utilisée comme matière première et salifiée à l'aide d'acide chiral D ou L pour former le sel d'acide chiral énantiomère?de tétrabénazine en fonction de la distinction de dissolubilité. Le sel d'acide chiral énantiomère de tétrabénazine est en outre dissocié pour obtenir de la (3R,1 lbR)-tétrabénazine ou de la (3S,1 lbS)-tétrabénazine à haute pureté optique.
PCT/CN2011/001060 2010-06-29 2011-06-27 Procédé de résolution de tétrabénazine Ceased WO2012000308A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010222617.X 2010-06-29
CN 201010222617 CN101985447A (zh) 2009-07-15 2010-06-29 丁苯那嗪的拆分方法

Publications (1)

Publication Number Publication Date
WO2012000308A1 true WO2012000308A1 (fr) 2012-01-05

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PCT/CN2011/001060 Ceased WO2012000308A1 (fr) 2010-06-29 2011-06-27 Procédé de résolution de tétrabénazine

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WO (1) WO2012000308A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018067945A1 (fr) 2016-10-06 2018-04-12 Assia Chemical Industries Ltd. Formes à l'état solide de valbénazine
CN111285867A (zh) * 2018-12-10 2020-06-16 江苏威凯尔医药科技有限公司 一种苯并喹嗪类衍生物的制备方法
US11654142B2 (en) 2017-10-10 2023-05-23 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058261A1 (fr) * 2006-11-08 2008-05-15 Neurocrine Biosciences, Inc. Composés 3-isobutyl-9, 10-diméthoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol substitués et procédés associés
WO2008154243A1 (fr) * 2007-06-08 2008-12-18 General Electric Company Procédé de fabrication de composés tétrabénazine
CN101985447A (zh) * 2009-07-15 2011-03-16 中国药科大学 丁苯那嗪的拆分方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058261A1 (fr) * 2006-11-08 2008-05-15 Neurocrine Biosciences, Inc. Composés 3-isobutyl-9, 10-diméthoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol substitués et procédés associés
WO2008154243A1 (fr) * 2007-06-08 2008-12-18 General Electric Company Procédé de fabrication de composés tétrabénazine
CN101985447A (zh) * 2009-07-15 2011-03-16 中国药科大学 丁苯那嗪的拆分方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANGYU YAO ET AL.: "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 5, May 2011 (2011-05-01), pages 1841 - 1848, XP028370954, DOI: doi:10.1016/j.ejmech.2011.02.046 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018067945A1 (fr) 2016-10-06 2018-04-12 Assia Chemical Industries Ltd. Formes à l'état solide de valbénazine
EP3523300A1 (fr) * 2016-10-06 2019-08-14 Assia Chemical Industries Ltd. Formes à l'état solide de valbénazine
US11242341B2 (en) 2016-10-06 2022-02-08 Assia Chemical Industries Ltd. Solid state forms of valbenazine
US11654142B2 (en) 2017-10-10 2023-05-23 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
CN111285867A (zh) * 2018-12-10 2020-06-16 江苏威凯尔医药科技有限公司 一种苯并喹嗪类衍生物的制备方法
CN111285867B (zh) * 2018-12-10 2022-06-03 江苏威凯尔医药科技有限公司 一种苯并喹嗪类衍生物的制备方法

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