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WO2019028669A1 - Procédé sans solvant permettant de préparer du lévétiracétam - Google Patents

Procédé sans solvant permettant de préparer du lévétiracétam Download PDF

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Publication number
WO2019028669A1
WO2019028669A1 PCT/CN2017/096408 CN2017096408W WO2019028669A1 WO 2019028669 A1 WO2019028669 A1 WO 2019028669A1 CN 2017096408 W CN2017096408 W CN 2017096408W WO 2019028669 A1 WO2019028669 A1 WO 2019028669A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
reaction
oxo
dimethylbutyl
levetiracetam
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2017/096408
Other languages
English (en)
Chinese (zh)
Inventor
潘洪杰
张文灵
王鹏
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.)
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
Original Assignee
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
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 Zhejiang Huahai Pharmaceutical Co Ltd, Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd filed Critical Zhejiang Huahai Pharmaceutical Co Ltd
Priority to CN201780092609.8A priority Critical patent/CN110799494B/zh
Priority to PCT/CN2017/096408 priority patent/WO2019028669A1/fr
Publication of WO2019028669A1 publication Critical patent/WO2019028669A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing levetiracetam without solvent.
  • Levetiracetam is a high-efficiency, broad-spectrum antiepileptic drug developed by UCB of Belgium. It is mainly used for the treatment of localized and secondary generalized epilepsy.
  • the chemical name is (S)- ⁇ -B. Keto-2-oxo-1-pyrrolidine acetamide.
  • the method of the present invention is less polluting to the environment.
  • the object of the present invention is achieved by the following technical solutions.
  • R in the formula (I) is a C 1 -C 6 alkyl group, wherein the C 1 -C 6 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2 -methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3 - dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-eth
  • the molar ratio of liquid ammonia to the raw material (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetate (I) is 1:1 to 100. : 1.
  • the molar ratio of liquid ammonia to the starting material (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetate (I) is from 5:1 to 30:1, preferably from 5:1 to 20 : 1.
  • the temperature of the aminolysis reaction is -80 to 50 °C.
  • liquid ammonia is in a liquid state, and the liquid ammonia concentration in the reaction system is large, but when the temperature is low, the reaction rate is slow; under high temperature conditions, liquid ammonia exhibits a gaseous state, and the liquid ammonia concentration in the reaction system is low.
  • the temperature of the aminolysis reaction is -30 to 20 °C.
  • the reaction system pressure of the aminolysis reaction is 0.2 to 5.0 MPa.
  • the reaction system pressure is from 0.5 to 3.0 MPa, and the reaction time is from 24-96 hours.
  • the method of the present invention further includes the following post-treatment: after the end of the aminolysis reaction, the liquid ammonia is recovered to obtain a crude levetiracetam. It was recrystallized by adding an organic solvent to obtain levetiracetam.
  • the organic solvent used for recrystallization is selected from a mixture of one or more of C 1 -C 4 alcohols, ketones, esters, and ethers.
  • the above C 1 -C 4 alcohols are selected from the group consisting of methanol, ethanol, isopropanol or butanol; the ketones are selected from the group consisting of acetone, methyl ethyl ketone or methyl isobutyl ketone; the above esters are ethyl acetate; the above ethers It is methyl tert-butyl ether.
  • the organic solvent used for recrystallization is selected from one or a mixture of acetone, ethyl acetate or methyl isobutyl ketone.
  • the recrystallization temperature is -20 to 20 ° C, and the recrystallization temperature is preferably -5 to 5 °C.
  • the present invention has the following advantages:
  • the preparation method of levetiracetam of the invention avoids the use of a large amount of organic solvent, reduces the three wastes (waste water, waste gas and waste residue), reduces the cost, and has simple operation and high yield, and the obtained levetiracetam is obtained.
  • the HPLC purity and optical purity are high, and the HPLC purity and optical purity are both above 99.5%, which fully meets the requirements of industrial production.
  • Acetone 200 g was added to dissolve the solid, and the mixture was heated to reflux. Slowly cool to 0 ° C, heat crystallization for 2 to 4 hours, filter, and dry to obtain levetiracetam. The yield was 32.7 g, the yield was 96.0%, the HPLC purity was 99.8%, and the isomer: 0.07%.

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation de lévétiracétam, caractérisé par la réalisation d'une ammonolyse avec de l'ammoniac liquide à l'aide d'acétate de (S)-α-éthyl-2-oxo-1-pyrrolidine en tant que matière première dans une condition exempte de solvant pour obtenir du lévétiracétam. Le procédé selon l'invention présente les avantages de faibles déchets, d'un rendement et d'une pureté élevés, et répond aux exigences d'une production industrielle.
PCT/CN2017/096408 2017-08-08 2017-08-08 Procédé sans solvant permettant de préparer du lévétiracétam Ceased WO2019028669A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780092609.8A CN110799494B (zh) 2017-08-08 2017-08-08 一种无溶剂制备左乙拉西坦的方法
PCT/CN2017/096408 WO2019028669A1 (fr) 2017-08-08 2017-08-08 Procédé sans solvant permettant de préparer du lévétiracétam

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/096408 WO2019028669A1 (fr) 2017-08-08 2017-08-08 Procédé sans solvant permettant de préparer du lévétiracétam

Publications (1)

Publication Number Publication Date
WO2019028669A1 true WO2019028669A1 (fr) 2019-02-14

Family

ID=65273316

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/096408 Ceased WO2019028669A1 (fr) 2017-08-08 2017-08-08 Procédé sans solvant permettant de préparer du lévétiracétam

Country Status (2)

Country Link
CN (1) CN110799494B (fr)
WO (1) WO2019028669A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11384050B1 (en) 2021-02-03 2022-07-12 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006095362A1 (fr) * 2005-03-10 2006-09-14 Rubamin Limited Procede de preparation du levetiracetam
EP1419144B1 (fr) * 2001-08-10 2008-10-08 UCB Pharma S.A. Composes d'oxopyrrolidine, preparation de ces composes et utilisation de ceux-ci dans la fabrication de levetiracetam et d'analogues
CN101511786A (zh) * 2006-07-25 2009-08-19 Zach系统股份公司 制备左乙拉西坦的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1419144B1 (fr) * 2001-08-10 2008-10-08 UCB Pharma S.A. Composes d'oxopyrrolidine, preparation de ces composes et utilisation de ceux-ci dans la fabrication de levetiracetam et d'analogues
WO2006095362A1 (fr) * 2005-03-10 2006-09-14 Rubamin Limited Procede de preparation du levetiracetam
CN101511786A (zh) * 2006-07-25 2009-08-19 Zach系统股份公司 制备左乙拉西坦的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU, YUEJIN ET AL.: "Synthesis of Levetiracetam and Its Derivatives", CHINESE JOURNAL OF NEW DRUGS, vol. 16, no. 11, 31 December 2007 (2007-12-31), pages 860 - 864, XP055577025 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11384050B1 (en) 2021-02-03 2022-07-12 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof

Also Published As

Publication number Publication date
CN110799494A (zh) 2020-02-14
CN110799494B (zh) 2023-06-06

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