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WO2022111564A1 - Procédé de racémisation et d'utilisation d'un dérivé de pyridine - Google Patents

Procédé de racémisation et d'utilisation d'un dérivé de pyridine Download PDF

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Publication number
WO2022111564A1
WO2022111564A1 PCT/CN2021/133027 CN2021133027W WO2022111564A1 WO 2022111564 A1 WO2022111564 A1 WO 2022111564A1 CN 2021133027 W CN2021133027 W CN 2021133027W WO 2022111564 A1 WO2022111564 A1 WO 2022111564A1
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Prior art keywords
crown
racemization
reaction
pyridine derivative
pyridine
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English (en)
Chinese (zh)
Inventor
郑生伟
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Hainan Chemicalface Enterprise Management Partnership LP
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Hainan Chemicalface Enterprise Management Partnership LP
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Definitions

  • the invention belongs to the field of medicine, in particular to a racemization method and application of a pyridine derivative.
  • Pyridine derivatives are important chiral compounds that play an important role in medicine, food and other fields.
  • the 3-substituted pyridine derivatives are racemized, so determining a racemization method of the 3-substituted pyridine derivatives is of great significance for obtaining chiral compounds of the 3-substituted pyridine derivatives.
  • the object of the present invention is to provide a racemization method and application of a pyridine derivative, the method can realize the racemization of the 3-substituted pyridine derivative under mild conditions, and the racemization speed is fast, the side reaction is few, and the yield is high , low cost, high practical value, suitable for large-scale industrial production applications.
  • the present invention provides a racemization method of a pyridine derivative, comprising the following steps:
  • the pyridine derivative shown in the following formula I is subjected to a racemization reaction under the action of a base and a phase transfer catalyst, and the pyridine derivative racemate is obtained by post-processing;
  • n is selected from -3, -2, -1, 0, 1, 2 or 3;
  • R represents hydrogen or a C 1 -C 7 carbon-containing group
  • alkali is selected from at least one in potassium hydroxide, sodium hydroxide, alkali metal alkoxide;
  • the phase transfer catalyst is selected from 18-crown-6, 18-crown-6 derivatives, 15-crown-5 or 15-crown-5 derivatives;
  • the reaction temperature is 20°C-200°C.
  • the present invention provides a racemization method for pyridine derivatives.
  • the 3-substituted pyridine derivatives represented by formula I can achieve racemization by the combined action of a base and a phase transfer catalyst.
  • the reaction can be performed at 20°C to 200°C.
  • the addition of 18-crown-6, 18-crown-6 derivatives, 15-crown-5 or 15-crown-5 derivatives can significantly reduce the temperature of the racemization reaction, so that the racemization reaction can be It is carried out at a lower temperature, effectively reducing the production cost, and at the same time, the reaction has few side reactions and high yield, so the racemization method provided by the present invention has high practical value and is suitable for large-scale industrial production applications.
  • the present invention provides the application of the pyridine derivative racemate prepared by the pyridine derivative racemization method described in the first aspect in the preparation of medicine.
  • the present embodiment provides a racemization method of a pyridine derivative, comprising the following steps:
  • the pyridine derivative shown in the following formula I is subjected to a racemization reaction under the action of a base and a phase transfer catalyst, and the pyridine derivative racemate is obtained by post-processing;
  • n is selected from -3, -2, -1, 0, 1, 2 or 3;
  • R represents hydrogen or a C 1 -C 7 carbon-containing group
  • alkali is selected from at least one in potassium hydroxide, sodium hydroxide, alkali metal alkoxide;
  • the phase transfer catalyst is selected from 18-crown-6, 18-crown-6 derivatives, 15-crown-5 or 15-crown-5 derivatives;
  • the reaction temperature is 20°C-200°C.
  • This embodiment provides a racemization method for pyridine derivatives.
  • the 3-substituted pyridine derivatives represented by formula I can be racemized by the combined action of a base and a phase transfer catalyst, and the reaction can be carried out at 20°C- 200 °C, the addition of 18-crown-6, 18-crown-6 derivatives, 15-crown-5 or 15-crown-5 derivatives can significantly reduce the temperature of the racemization reaction, making the racemization
  • the reaction can be carried out at a lower temperature, effectively reducing the production cost, and at the same time, the reaction has few side reactions and high yield, so the racemization method provided in this embodiment has high practical value and is suitable for large-scale industrial production. application.
  • the reaction temperature can be set to 20°C, 40°C, 50°C, 100°C, 120°C, 150°C or 200°C, etc. Under the above reaction temperature, all the pyridine derivatives represented by formula I can be reversely racemized reaction, and the yield of the target product is higher and the purity is higher.
  • the reaction temperature is 60°C-90°C, for example, the reaction temperature can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or 90°C, and under the above reaction temperature, the reaction temperature can be relatively low
  • the temperature completes the reaction, the reaction rate is lower and the temperature is faster, and the cost is higher and lower.
  • the reaction temperature is controlled to be 60 °C-90 °C, the reaction can be completed in a shorter time, the cost is reduced, and the obtained target product yield is higher.
  • the C 1 -C 7 carbon-containing group is selected from methyl, ethyl, propyl, isopropyl, vinyl, allyl, benzyl or phenyl.
  • the alkali metal alkoxide is selected from sodium alkoxide with 1-8 carbon atoms or potassium alkoxide with 1-8 carbon atoms.
  • the alkali metal alkoxide is selected from potassium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium neopentoxide, potassium cyclohexanate, Sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, neopentyl alcohol or sodium cyclohexanoxide. All of the above-mentioned alkali metal alkoxides can make the racemization reaction proceed smoothly.
  • the phase transfer catalyst when the base is a sodium alkoxide with 1-8 carbon atoms or sodium hydroxide, the phase transfer catalyst is 15-crown-5 or a 15-crown-5 derivative; when the base is When it is a potassium alkoxide salt of 1-8 carbon atoms or potassium hydroxide, the phase transfer catalyst is 18-crown-6 and 18-crown-6 derivatives.
  • 1-8 carbon atoms sodium alkoxide and 15-crown-5 are used in combination, 1-8 carbon atoms alkoxide sodium salt and 15-crown-5 derivatives are used in combination, sodium hydroxide and 15- Crown-5 as a combination, sodium hydroxide and 15-crown-5 derivatives as a combination, 1-8 carbon alkoxide potassium salts and 18-crown-6 as a combination, 1-8 carbons Atomic alkoxide potassium salt and 18-crown-6 derivatives are used in combination, potassium hydroxide and 18-crown-6 are used in combination, and potassium hydroxide and 18-crown-6 derivatives can be used in combination.
  • the lowering of the temperature of the racemization reaction enables the racemization reaction to be carried out under mild experimental conditions, effectively reducing the production cost.
  • the 18-crown-6 derivative is selected from benzo-18-crown-6 or dibenzo-18-crown-6; the 15-crown-5 derivative is benzo-15-crown ether-5.
  • the post-processing to obtain the pyridine derivative racemate includes: after a preset reaction time, the reaction solution is cooled, filtered, and distilled under reduced pressure to obtain the pyridine derivative racemate.
  • the post-processing to obtain the pyridine derivative racemate includes: after a preset reaction time, the reaction solution is cooled, poured into saturated brine, extracted with an organic solvent, evaporated to dryness of the organic solvent, and then distilled under reduced pressure, A pyridine derivative racemate is obtained, wherein the organic solvent can be at least one of ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran.
  • the pyridine derivative shown in the following formula I is subjected to a racemization reaction under the action of a base and a phase transfer catalyst, including: adding the pyridine derivative shown in the following formula I, a base and a phase transfer catalyst into a reaction solvent to carry out Racemization reaction;
  • the reaction solvent is selected from dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, polyethylene glycol, benzene series solvent, substituted benzene series solvent, 3-10 carbon atoms Ketone solvents, ether solvents of 4-10 carbon atoms, ester solvents of 3-10 carbon atoms or amide solvents of 1-10 carbon atoms.
  • the racemization reaction is carried out in the reaction solvent. It should be noted that the racemization reaction can also be carried out without the reaction solvent.
  • the reaction solvent when the reaction solvent is polyethylene glycol, it means that the reaction solvent can be polyethylene glycol series solvents, such as polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, etc.; when the reaction solvent is polyethylene glycol When it is a benzene-based solvent, the reaction solvent can be toluene, xylene, etc.; when the reaction solvent is a ketone-based solvent with 3-10 carbon atoms, the reaction solvent can be acetone, methyl butanone, methyl isobutyl ketone, N - methyl pyrrolidone, etc.; when the reaction solvent is an ether solvent, the reaction solvent can be propyl ether, butyl ether, amyl ether, hexyl ether, methyl tert-butyl ether, ethyl isopropyl ether, etc.; when the reaction solvent is When the ester solvent is used, the reaction solvent can be methyl acetate, ethyl
  • Step S10 prepare a base and a phase transfer catalyst, wherein the base and the phase transfer catalyst are selected from sodium alkoxides of 1-8 carbon atoms and 15-crown-5, sodium alkoxides of 1-8 carbon atoms and benzo-15 - Crown ether-5, potassium alkoxide salts of 1-8 carbon atoms and 18-crown ether-6, potassium alkoxide salts of 1-8 carbon atoms and benzo 18-crown ether-6, 1-8 carbon atoms alkoxide potassium salt and dibenzo-18-crown-6.
  • the base and the phase transfer catalyst are selected from sodium alkoxides of 1-8 carbon atoms and 15-crown-5, sodium alkoxides of 1-8 carbon atoms and benzo-15 - Crown ether-5, potassium alkoxide salts of 1-8 carbon atoms and 18-crown ether-6, potassium alkoxide salts of 1-8 carbon atoms and benzo 18-crown ether-6, 1-8 carbon
  • step S20 the pyridine derivative is mixed with the base and the phase transfer catalyst to generate a reverse racemization reaction, and the reaction temperature is controlled to be 60°C-90°C.
  • step S30 after a preset reaction time, the reaction solution is cooled, poured into saturated brine, extracted with ethyl acetate solvent, evaporated to dryness and then distilled under reduced pressure to obtain a pyridine derivative racemate.
  • the present invention provides the application of the pyridine derivative racemate prepared by the pyridine derivative racemization method described in the first aspect in the preparation of medicine.
  • reaction solution was cooled to room temperature, poured into 20 mL of saturated brine, extracted three times with 30 mL of ethyl acetate, evaporated to dryness with a water pump, and distilled under reduced pressure with an oil pump to obtain 9.2 g of 3-(1-methyl) -2-pyrrolidinyl)pyridine racemate, yield 92.0%.
  • the purity of the 3-(1-methyl-2-pyrrolidinyl)pyridine racemate was determined to be 99% by gas chromatography.
  • reaction solution was cooled to room temperature, poured into 30 mL of saturated brine, extracted 3 times with 150 mL of ethyl acetate, evaporated to dryness with a water pump, and distilled under reduced pressure with an oil pump to obtain 8.7 g of 3-(1-methyl) -2-pyrrolidinyl) pyridine racemate, yield 87%.
  • the purity of the 3-(1-methyl-2-pyrrolidinyl)pyridine racemate was determined to be 99% by gas chromatography.
  • reaction solution was cooled to room temperature, poured into 30 mL of saturated brine, extracted three times with 150 mL of ethyl acetate, evaporated to dryness by water pump, and separated by silica gel column chromatography to obtain 8.2 g of 3-(1-ethyl acetate).
  • the yield of 3-(1-ethyl-2-pyrrolidinyl)pyridine racemate was 82%, and the purity of 3-(1-ethyl-2-pyrrolidinyl)pyridine racemate was 99% as measured by gas chromatography.
  • reaction solution was poured into 30 mL of saturated brine, extracted three times with 150 mL of ethyl acetate, and the ethyl acetate was evaporated to dryness by water pump, and then separated by silica gel column chromatography to obtain 7.9 g of 3-(1-ethyl-2-pyrrolidine) base) pyridine racemate, yield 79%.
  • the purity of the 3-(1-ethyl-2-pyrrolidinyl)pyridine racemate was determined to be 99% by gas chromatography.
  • reaction solution was cooled to room temperature, poured into 50 mL of saturated brine, extracted three times with 200 mL of ethyl acetate, evaporated to dryness by water pump, and separated by silica gel column chromatography to obtain 8.1 g of 3-(1-benzyl) base-2-pyrrolidinyl)pyridine racemate, yield 81%.
  • the purity of the 3-(1-benzyl-2-pyrrolidinyl)pyridine racemate was determined to be 99% by gas chromatography.
  • reaction solution was cooled to room temperature, poured into 30 mL of saturated brine, extracted 3 times with 150 mL of ethyl acetate, evaporated to dryness with a water pump, and distilled under reduced pressure with an oil pump to obtain 8.3 g of 3-(1-methyl) -2-pyrrolidinyl) pyridine racemate, yield 83%.
  • the purity of the 3-(1-methyl-2-pyrrolidinyl)pyridine racemate was determined to be 99% by gas chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un procédé de racémisation et d'utilisation d'un dérivé de pyridine. Le procédé comprend les étapes suivantes consistant à : soumettre un dérivé de pyridine tel que représenté dans la formule I suivante à une réaction de racémisation sous l'action d'une base et d'un catalyseur de transfert de phase, et le soumettre à un post-traitement pour obtenir un racémate de dérivé de pyridine, la formule I étant telle que représentée de la manière suivante, n étant choisi parmi -3, -2, -1, 0, 1, 2 ou 3, et R représente de l'hydrogène ou un groupe contenant du carbone en C1-C7 ; la base est choisie parmi au moins l'un parmi l'hydroxyde de potassium, l'hydroxyde de sodium et l'alcoxyde de métal alcalin ; le catalyseur de transfert de phase est choisi parmi les dérivés de 18-éther couronne-6, des dérivés de 18-éther couronne-6, 15-éther couronne-5 et des dérivés de 15-éther couronne-5 ; et la température de réaction est de 20 °C à 200 °C. Le procédé de racémisation d'un dérivé de pyridine selon la présente invention a des conditions modérées, une vitesse de racémisation élevée, peu de réactions secondaires, un rendement élevé, un faible coût et une valeur pratique élevée, et est approprié pour une production et une utilisation industrielles à grande échelle.
PCT/CN2021/133027 2020-11-27 2021-11-25 Procédé de racémisation et d'utilisation d'un dérivé de pyridine Ceased WO2022111564A1 (fr)

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CN112174763B (zh) * 2020-11-27 2021-04-27 北京邦克凯姆医药科技有限公司 一种吡啶衍生物的消旋方法及应用
CN113416180A (zh) * 2021-08-09 2021-09-21 东莞市鸿馥生物科技有限公司 一种(s)-1-甲基-2-(3-吡啶基)吡咯烷的拆分方法
CN117000305A (zh) * 2023-08-04 2023-11-07 国家烟草质量监督检验中心 季铵碱在制备右旋烟碱中的应用

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JPS5869878A (ja) * 1981-10-23 1983-04-26 Japan Tobacco Inc ｄｌ−ニコチンの製造法
WO2002058635A2 (fr) * 2001-01-26 2002-08-01 The Scripps Research Institute Immunogenes a la nicotine, anticorps et leurs applications
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SI23573A (sl) * 2010-12-22 2012-06-29 EN-FIST center odliÄŤnosti Postopek za pripravo racemnega nikotina
CN110357853A (zh) * 2019-08-05 2019-10-22 济南悟通生物科技有限公司 (r,s-)尼古丁的合成方法
CN112174763A (zh) * 2020-11-27 2021-01-05 北京邦克凯姆医药科技有限公司 一种吡啶衍生物的消旋方法及应用

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