WO2010099745A1 - Procédés de préparation de rivastigmine et de son intermédiaire - Google Patents

Procédés de préparation de rivastigmine et de son intermédiaire Download PDF

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Publication number
WO2010099745A1
WO2010099745A1 PCT/CN2010/070848 CN2010070848W WO2010099745A1 WO 2010099745 A1 WO2010099745 A1 WO 2010099745A1 CN 2010070848 W CN2010070848 W CN 2010070848W WO 2010099745 A1 WO2010099745 A1 WO 2010099745A1
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WIPO (PCT)
Prior art keywords
ethyl
dimethylamine
sodium
phenyl
reaction
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PCT/CN2010/070848
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English (en)
Chinese (zh)
Inventor
朱永超
张桂森
马彦琴
杨相平
周英珍
陈亮
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江苏恩华药业股份有限公司
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Publication of WO2010099745A1 publication Critical patent/WO2010099745A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method for preparing an anti-senile dementia drug rivastigmine tartrate and an intermediate thereof, and the intermediate. Background technique
  • Ribastatin tartrate chemical name (S)-N-ethyl-N-methylcarbamic acid-3-[(1-dimethylamino)ethyl] phenyl ester tartrate, an acetylcholinesterase inhibitor (AchEI), used to treat mild to moderate Alzheimer's disease, has been used clinically for many years at home and abroad.
  • AchEI acetylcholinesterase inhibitor
  • the first is to synthesize the rivastigmine racemate first, then the chiral separation to obtain the target; the second is asymmetric synthesis, which is the first step in the intermediate. Sexual resolution, and then the target is obtained by asymmetric synthesis.
  • the first type of synthesis generally involves the synthesis of the racemic rivastigmine via the important intermediate 3-(1-(dimethylamino)ethyl)phenol.
  • the existing synthetic intermediate 3-(1-(dimethylamino)ethyl)phenol has the following drawbacks: 3-(1-(Dimethylamino)ethyl)phenol Amphoteric compounds have a certain solubility in acidic or alkaline solutions, and the 3-(1-(dimethylamino)ethyl)phenol product obtained by the existing synthesis method needs to be freed under acidic conditions, free When the solution needs to be adjusted to the equivalent point of acid and alkali, it is very difficult to adjust the equivalence point in production, so the operation is difficult to carry out, and the production efficiency is not high.
  • the second type of method the asymmetric synthesis method, requires the use of relatively expensive catalysts, which also tend to exceed the heavy metal content of the final product. Therefore, there is still a need for a method for synthesizing 3-(1-(dimethylamino)ethyl)phenol and rivastigmine tartrate more efficiently and easily.
  • a process for the preparation of 3-(1-(dimethylamino)ethyl)phenol which comprises the steps of: [1-(3-benzyloxy-phenyl)- Ethyl]-dimethylamine (hydrazine)
  • the benzyl group is removed by hydrogenation.
  • [1-( 3-Benzyloxy-phenyl)-ethyl]-dimethylamine represented by the formula ⁇ can be used as an intermediate for the synthesis of rivastigmine tartrate:
  • [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine can be carried out by using 3-benzyloxyacetophenone with dimethylamine salt. Reductive amination is prepared.
  • the compound (oxime) can be produced by the following method: 3-benzyloxyacetophenone and dimethylamine hydrochloride in a lower alcohol, adding a base at a low temperature, and then adding a reducing agent And react at a reaction temperature above 20 ° C for at least 15 hours.
  • the term lower alcohol means a linear or branched alkanol containing from 1 to 6 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, pentanol and hexanol.
  • the lower alcohol is preferably one of C1 to C4 linear or branched alkanol or a mixture thereof, more preferably one of methanol, ethanol, isopropanol or their mixture.
  • the base used in the process may be an alkali metal C1-C4 alkoxide such as sodium methoxide, sodium ethoxide or sodium isopropoxide.
  • the reducing agent used in the process for preparing the compound ( ⁇ ) may be any reducing agent suitable for the reductive amination reaction known to those skilled in the art, such as an unsubstituted borane alkali metal salt or one to three selected from 1-3.
  • the reducing agent may be, for example, sodium borohydride or potassium borohydride.
  • the low temperature does not exceed 5 ° C, preferably between -5 ° C and 5 ° C.
  • the reaction temperature may be from 20 ° C to 80 ° C, more preferably from 25 ° C to 35 ° C.
  • the reaction time may be between 15 and 30 hours, preferably between 20 and 25 hours.
  • the 3-benzyloxyacetophenone (IV) used in the process for preparing the compound ( ⁇ ) is commercially available or can be obtained by a conventional condensation reaction of commercially available starting material 3-hydroxyacetophenone (III) with benzyl chloride. .
  • the compound ( ⁇ ) can be prepared according to the following procedure:
  • 3-hydroxyacetophenone (oxime) and benzyl chloride are reacted in an aprotic solvent under basic conditions at 30 ° C or higher for at least 20 hours to obtain 3-benzyloxyacetophenone (IV).
  • the aprotic solvent may be dichloroethane, toluene, diethyl ether, ethyl acetate, acetone, tetrahydrofuran or dimethylformamide, preferably toluene, dimethylformamide or dichloroethane.
  • the base may be an alkali metal carbonate, hydrogencarbonate, hydroxide, alkoxide, hydride or amino species such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, hydrogen Potassium oxide, sodium methoxide, sodium hydride or sodium amide, of which a carbonate such as sodium carbonate or potassium carbonate is preferred.
  • the obtained compound (IV) and dimethylamine hydrochloride are added to a base in a lower alcohol at a low temperature, and then a reducing agent is added thereto, and the mixture is reacted at 20 ° C or higher for at least 15 hours to obtain a compound (11).
  • the lower alcohol may be one of methanol, ethanol, isopropanol or a mixture thereof.
  • the base may be an alkali metal C1-4 alkoxide such as sodium methoxide, sodium ethoxide or sodium isopropoxide.
  • the low temperature is 5 ° C or less.
  • the reducing agent is any reducing agent known to those skilled in the art to be suitable for reductive amination, for example, unsubstituted or 1-3 borane metal substituted with cyano or C1-C4 alkanoyloxy Salts, including but not limited to sodium borohydride, potassium borohydride, cyanoborohydride Sodium, sodium triacetoxyborohydride, sodium malonyl borohydride, preferably sodium cyanoborohydride, sodium triacetoxyborohydride or sodium malonyl borohydride.
  • the reaction temperature is 20 ° C or higher, preferably 20 ° C to 80 ° C.
  • the compound [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine ( ⁇ ) can be used as an intermediate in the synthesis of rivastigmine tartrate, especially for the synthesis of 3-(1-(dimethyl) Base amino) ethyl) phenol (V). Accordingly, the present invention also includes a process for the preparation of 3-(1-(dimethylamino)ethyl)phenol (V), which comprises: [1-(3-benzyloxy-phenyl)-ethyl] - Dimethylamine (hydrazine) The benzyl group is removed by hydrogenation.
  • [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine is hydrogenated in the presence of a metal catalyst using a lower alcohol as a solvent. Debenzylation gives the compound (V).
  • the lower alcohol may be a linear or branched alkanol containing from 1 to 6, preferably from 1 to 4 carbon atoms, for example, methanol, ethanol, isopropanol, n-butyl One of the alcohols or a mixture thereof.
  • the metal catalyst is selected from the group consisting of palladium on carbon (Pd/C) or Raney nickel (Ran e y Ni).
  • the catalytic hydrogenation reaction can be carried out under normal pressure.
  • the invention also relates to a process for the preparation of rivastigmine tartrate comprising the steps of: reductive amination of 3-benzyloxyacetophenone with dimethylamine salt to give [1-(3-benzyloxy-phenyl)- Ethyl]-dimethylamine (II); the compound ( ⁇ ) is subjected to hydrogenation to remove the benzyl group to give 3-(1-(dimethylamino)ethyl)phenol (V); N-methyl-N-ethylcarbamoyl chloride is subjected to a condensation reaction to give phenyl(N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylcarbamate ( The ectsin of rivastigmine, which is resolved by D-(+)-p-methyldibenzoyltartaric acid, is reacted with L-(+)-tartaric acid to give rivastigmine tartrate (1)
  • the compound ( ⁇ ) and the compound (V) can be produced in the same manner as described above.
  • the compound (V) is subjected to a condensation reaction with N-methyl-N-ethylcarbamoyl chloride under a strong base such as sodium hydride and/or sodium amide at room temperature to obtain a (s)-N-ethyl group.
  • the strong base used in the condensation reaction of 3-(1-(dimethylamino)ethyl)phenol with N-methyl-N-ethylcarbamoyl chloride may be any suitable one known to those skilled in the art.
  • sodium hydride sodium amide.
  • the carbendine racemate is resolved by D-(+)-p-methyldibenzoyltartaric acid to give (S)-N-ethyl-3-[(1-dimethylamino)ethyl]- Phenyl N-methylcarbamate (S-type rivastigmine base), which is salted with L-(+)-tartaric acid, gives rivastigmine tartrate.
  • the second method can be found in the literature: Stepankova Hana et al., WO2004037771, 2003-10-23; Albert Enz, US005602176, 1995-06-06.
  • the method of the invention solves the problem that the intermediate 3-(1-(dimethylamino)ethyl)phenol in the preparation technology of the rivastigmine tartrate is not easy to be separated and purified, and the production efficiency is not high.
  • each unit in the method of the invention is normal pressure and normal temperature reaction, and the operation is simple and safe.
  • the raw materials, reagents and catalysts used in the method of the invention are all commercially available conventional reagents, and the cost is low, and the raw materials are easily available.
  • the inter-body is easy to separate and purify, the process is simple and convenient, and large-scale industrial production.
  • the synthesis method of the invention has good economy, high reaction selectivity, less reaction by-products and improved production efficiency.
  • All the raw materials and reagents of the present invention are commercially available.
  • Main raw materials and reagents 3-hydroxyacetophenone, Xu Ruisai Technology Industrial Co., Ltd.; N methyl-N-ethylcarbamoyl chloride, Shanghai Canhe Chemical Co., Ltd.; sodium cyanoborohydride, Yingkou Sanxin Chemical Co., Ltd. Company; sodium triethoxyborohydride, Shanghai Haiqu Chemical Co., Ltd.; D-(+)-p-methyldibenzoyltartaric acid, Zhejiang Dongyang Lingxing Biochemical Co., Ltd.; L (10) Tartaric acid, Changmao Biochemistry Engineering Co., Ltd.
  • the solid salt was dissolved in 6 ml of dichloromethane, and 5 ml of a 1 mol/L sodium hydroxide solution was added thereto. After fully extracting, the organic layer was separated, washed with water (3 ml> ⁇ 2), dried over anhydrous magnesium sulfate and evaporated. Solvent, a colorless liquid (S) - rivastigmine base ( ⁇ , 0.68g), this colorless liquid and L- ( + ) - tartaric acid (0.45g, 3mmol) were dissolved in 20ml of ethanol, added In 100 ml of ethyl acetate, precipitation was precipitated.
  • Acid chloride (12.4g, 0.1mol), temperature control below 25 °C, continue to stir at room temperature after the drop is completed 6 small Then, slowly add 100ml of water to the water layer, and then remove the water layer. The toluene layer is washed three times with water (40ml/time), and the aqueous layer is separated and the solvent is distilled off to obtain the carbomerine racemate (20.2g, The rate is 95.8%).
  • the solid salt was dissolved in 6 ml of dichloromethane, and 5 ml of a 1 mol/L sodium hydroxide solution was added thereto. After fully extracting, the organic layer was separated, washed with water (3 ml > ⁇ 2), dried over anhydrous magnesium sulfate and evaporated. The solvent was obtained as a colorless liquid (S) - rivastigmine base (W, 0.67 g, ). This colorless liquid and L-(+)-tartaric acid (0.45 g, 3.0 mmol) were dissolved in 20 ml of ethanol. . After stirring until clarification, it was added to 100 ml of ethyl acetate to precipitate.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des procédés de préparation du tartrate de rivastigmine et de son intermédiaire ainsi que l'intermédiaire lui-même. Plus spécifiquement, l'invention concerne le composé intermédiaire [1-(3-benzyloxy-phényl)-éthyl]-diméthylamine, son procédé de préparation et des procédés de préparation du 3-(1-(diméthylamino) éthyl) phénol et du tartrate de rivastigmine à l'aide du composé intermédiaire.
PCT/CN2010/070848 2009-03-03 2010-03-03 Procédés de préparation de rivastigmine et de son intermédiaire WO2010099745A1 (fr)

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CN200910025634.1 2009-03-03
CN2009100256341A CN101823970B (zh) 2009-03-03 2009-03-03 卡巴拉汀及其中间体的合成方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664702A (zh) * 2013-12-18 2014-03-26 成都医路康医学技术服务有限公司 一种卡巴拉汀的生产工艺
CN113461554A (zh) * 2020-03-30 2021-10-01 北京泰德制药股份有限公司 一种卡巴拉汀中间体的纯化方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285904B (zh) * 2011-07-11 2013-06-05 中国科学院成都生物研究所 一种卡巴拉汀的制备方法
CN102898333A (zh) * 2012-10-22 2013-01-30 哈药集团三精制药股份有限公司 一种重酒石酸卡巴拉汀的制备方法
CN111362814B (zh) * 2020-04-22 2022-09-13 暨明医药科技（苏州）有限公司 一种卡巴拉汀手性中间体的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5602176A (en) * 1987-03-04 1997-02-11 Sandoz Ltd. Phenyl carbamate
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate
CN1962624A (zh) * 2006-11-10 2007-05-16 暨南大学 一种卡巴拉汀的合成方法
CN101270058A (zh) * 2007-03-21 2008-09-24 北京德众万全药物技术开发有限公司 一种3-(1-二甲氨基乙基)苯酚的制备方法
CN101343237A (zh) * 2007-07-10 2009-01-14 上海三维制药有限公司 利伐斯的明中间体3-羟基-α-N,N-二甲基苯乙胺的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5602176A (en) * 1987-03-04 1997-02-11 Sandoz Ltd. Phenyl carbamate
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate
CN1962624A (zh) * 2006-11-10 2007-05-16 暨南大学 一种卡巴拉汀的合成方法
CN101270058A (zh) * 2007-03-21 2008-09-24 北京德众万全药物技术开发有限公司 一种3-(1-二甲氨基乙基)苯酚的制备方法
CN101343237A (zh) * 2007-07-10 2009-01-14 上海三维制药有限公司 利伐斯的明中间体3-羟基-α-N,N-二甲基苯乙胺的制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664702A (zh) * 2013-12-18 2014-03-26 成都医路康医学技术服务有限公司 一种卡巴拉汀的生产工艺
CN113461554A (zh) * 2020-03-30 2021-10-01 北京泰德制药股份有限公司 一种卡巴拉汀中间体的纯化方法

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