WO2024077407A1 - Agent réducteur chiral et procédé de synthèse de nicotine chirale - Google Patents

Agent réducteur chiral et procédé de synthèse de nicotine chirale Download PDF

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Publication number
WO2024077407A1
WO2024077407A1 PCT/CN2022/123930 CN2022123930W WO2024077407A1 WO 2024077407 A1 WO2024077407 A1 WO 2024077407A1 CN 2022123930 W CN2022123930 W CN 2022123930W WO 2024077407 A1 WO2024077407 A1 WO 2024077407A1
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WO
WIPO (PCT)
Prior art keywords
chiral
compound
nicotine
reducing agent
synthesizing
Prior art date
Application number
PCT/CN2022/123930
Other languages
English (en)
Chinese (zh)
Inventor
谈平忠
谈平安
王利民
邓倩
陈琳
康少东
孙林杰
胡娜
Original Assignee
成都化润药业有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 成都化润药业有限公司 filed Critical 成都化润药业有限公司
Priority to CN202280041719.2A priority Critical patent/CN117480174A/zh
Priority to PCT/CN2022/123930 priority patent/WO2024077407A1/fr
Publication of WO2024077407A1 publication Critical patent/WO2024077407A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to the technical field of nicotine synthesis, and in particular to a chiral reducing agent and a method for synthesizing chiral nicotine.
  • Nicotine also known as nicotine, is a naturally occurring liquid alkaloid with strong physiological activity. Nicotine is usually found in natural tobacco and has important uses in agriculture, chemical industry, medicine and other fields. The levorotatory nicotine currently used in the market is mainly derived from plant extraction, and is therefore affected by many factors such as raw materials, climate, and cycle, while racemic nicotine can only be obtained through synthesis.
  • U.S. Patent US20160326134A1 reports a method for preparing optically active nicotine by chiral splitting. This method requires the use of tartaric acid ester as a splitting agent, and about 50% of the R-configuration nicotine will be discarded. The produced S-configuration nicotine is expensive.
  • Patent CN 110357853 B states a method for synthesizing (R, S) nicotine, using 3-bromopyridine and magnesium chips as raw materials to prepare the Grignard reagent of 3-bromopyridine; adding N-methylpyrrolidone to the system, carrying out condensation and hydrolysis reactions, adjusting the pH to alkaline, concentrating, and distilling to obtain an enamine intermediate; then carrying out a reduction reaction in the presence of a metal reduction catalyst such as Pd/C, Pt/C, and Raney nickel to obtain a racemic product R, S-nicotine, as shown below:
  • a metal reduction catalyst such as Pd/C, Pt/C, and Raney nickel
  • Chinese patent CN104341390A reports the use of cyclic imine As the starting material, in the presence of a chiral catalyst
  • the chiral nicotine precursor is obtained under the catalysis of high-pressure hydrogen, and then S-nicotine is obtained through reduction, debromination and methylation.
  • This method uses expensive chiral ligands and precious metal catalysts, as well as high-pressure hydrogenation equipment, which greatly increases the technical difficulty while also increasing the raw material and processing costs.
  • the present invention aims to provide a chiral reducing agent and a method for synthesizing chiral nicotine using the chiral reducing agent.
  • chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material.
  • the chiral reagent can be recycled, the price is low, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
  • the present invention provides a chiral reducing agent, wherein the chiral reducing agent is compound 1 , compound 2 , or a stereoisomer of compound 1 or compound 2 ;
  • the substituent group Ar is phenyl, 1-naphthyl or 2-naphthyl.
  • the present invention also provides an intermediate compound as an intermediate for synthesizing a chiral reducing agent, wherein the chiral intermediate is 1,1,4,4-
  • the present invention also provides a method for synthesizing chiral nicotine via a chiral reducing agent compound 1 or compound 2 , wherein the chiral reducing agent compound 1 or compound 2 is used to reduce dehydronicotine in the presence of a solvent, and then hydrolyzes and quenches to obtain chiral nicotine.
  • the present invention has the following advantages and beneficial effects:
  • the embodiments of the present invention provide a chiral reducing agent and a method for synthesizing chiral nicotine.
  • chiral nicotine can be prepared by reduction and hydrolysis reaction with dehydronicotine as a raw material.
  • the starting raw material is inexpensive, the reaction conditions are mild, and the yield and optical purity of nicotine synthesis are high.
  • references to "one embodiment,” “an embodiment,” “an example,” or “an example” mean that a particular feature, structure, or characteristic described in conjunction with the embodiment or example is included in at least one embodiment of the present invention. Therefore, the phrases “one embodiment,” “an embodiment,” “an example,” or “an example” appearing in various places throughout the specification do not necessarily all refer to the same embodiment or example. Furthermore, particular features, structures, or characteristics may be combined in one or more embodiments or examples in any suitable combination and/or subcombination. Furthermore, it will be understood by those of ordinary skill in the art that the term “and/or” as used herein includes any and all combinations of one or more of the associated listed items.
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • distillate is a colorless liquid, which is the chiral nicotine product; the reduction reaction yield is 86%, the HPLC purity is 98.1%, and the chiral HPLC analysis shows that the chiral purity is 97.3%.
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:
  • the embodiment of the present invention provides a method for synthesizing chiral nicotine via a chiral reducing agent, comprising the following steps:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un agent réducteur chiral et un procédé de synthèse de nicotine chirale. L'agent réducteur chiral est un composé 1 ou un composé 2, ou un stéréoisomère du composé 1 et du composé 2. Les formules développées du composé 1 et du composé 2 sont telles que représentées ci-dessous, le groupe substituant Ar étant phényle, 1-naphtyle ou 2-naphtyle. Dans la présente invention, l'agent réducteur chiral, c'est-à-dire le composé 1 ou le composé 2, est utilisé pour réduire la déhydronicotine en présence d'un solvant, et le produit résultant est hydrolysé pour obtenir de la nicotine chirale. Dans la présente invention, l'agent réducteur chiral est utilisé pour réduire la déhydronicotine au moyen d'agents réducteurs chiraux 1 et 2, puis soumise à une réaction d'hydrolyse, de façon à préparer de la nicotine chirale. La matière première de départ a un faible prix, les conditions de réaction sont modérées, et le rendement de synthèse et la pureté optique de la nicotine sont élevés.
PCT/CN2022/123930 2022-10-09 2022-10-09 Agent réducteur chiral et procédé de synthèse de nicotine chirale WO2024077407A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202280041719.2A CN117480174A (zh) 2022-10-09 2022-10-09 一种手性还原剂及合成手性尼古丁的方法
PCT/CN2022/123930 WO2024077407A1 (fr) 2022-10-09 2022-10-09 Agent réducteur chiral et procédé de synthèse de nicotine chirale

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2022/123930 WO2024077407A1 (fr) 2022-10-09 2022-10-09 Agent réducteur chiral et procédé de synthèse de nicotine chirale

Publications (1)

Publication Number Publication Date
WO2024077407A1 true WO2024077407A1 (fr) 2024-04-18

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PCT/CN2022/123930 WO2024077407A1 (fr) 2022-10-09 2022-10-09 Agent réducteur chiral et procédé de synthèse de nicotine chirale

Country Status (2)

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CN (1) CN117480174A (fr)
WO (1) WO2024077407A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104341390A (zh) * 2014-11-04 2015-02-11 南开大学 一种植物源农药烟碱和毒藜碱的不对称合成方法
KR20180060319A (ko) * 2016-11-28 2018-06-07 가천대학교 산학협력단 [10B]Pinacolborane을 이용한 [10B]-L-4-boronophenylalanine (LBPA)의 새로운 합성법
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104341390A (zh) * 2014-11-04 2015-02-11 南开大学 一种植物源农药烟碱和毒藜碱的不对称合成方法
KR20180060319A (ko) * 2016-11-28 2018-06-07 가천대학교 산학협력단 [10B]Pinacolborane을 이용한 [10B]-L-4-boronophenylalanine (LBPA)의 새로운 합성법
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

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CRIEGEE, RUDOLF : "Über den Verlauf der Ozonspaltung (III. Mitteilung) = Ozonization cleavage. III.", JUSTUS LIEBIGS ANNALEN DER CHEMIE, VERLAG CHEMIE GMBH., DE, vol. 583, no. 1, 8 October 1953 (1953-10-08), DE , pages 1 - 36, XP009554463, ISSN: 0075-4617, DOI: 10.1002/jlac.19535830102 *
JÖRG PIETRUSZKA: "Enantiomerically pure cyclopropylboronic esters: auxiliary- versus substrate-control", ROYAL CHEMICAL SOCIETY. JOURNAL. PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, GB, no. 24, 1 January 2000 (2000-01-01), GB , pages 4293 - 4300, XP093159469, ISSN: 1470-4358, DOI: 10.1039/b006970l *
MASAKO NAKAGAWA ET AL.: "Asymmetric reductions of imines and ketiones by chiral oxaborolidines", TETRAHEDRON, vol. 49, no. 9, 31 December 1993 (1993-12-31), pages 1739 - 1748, XP026608057, DOI: 10.1016/S0040-4020(01)80531-7 *
TOMOHIKO KAWATE: "Asymmetric Reduction of Imines with Chiral Dia~koxyboranes", TETRAHEDRON: ASYMMETRY, vol. 3, no. 2, 1 January 1992 (1992-01-01), pages 227 - 230, XP093159468 *

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