WO2015139536A1 - Procédé de préparation d'eltrombopag - Google Patents

Procédé de préparation d'eltrombopag Download PDF

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Publication number
WO2015139536A1
WO2015139536A1 PCT/CN2015/072138 CN2015072138W WO2015139536A1 WO 2015139536 A1 WO2015139536 A1 WO 2015139536A1 CN 2015072138 W CN2015072138 W CN 2015072138W WO 2015139536 A1 WO2015139536 A1 WO 2015139536A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
eltrombopag
hydroxy
preparing
cyclization reaction
Prior art date
Application number
PCT/CN2015/072138
Other languages
English (en)
Chinese (zh)
Inventor
许学农
Original Assignee
苏州明锐医药科技有限公司
哲人药业南京有限公司
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 苏州明锐医药科技有限公司, 哲人药业南京有限公司 filed Critical 苏州明锐医药科技有限公司
Priority to KR1020167028052A priority Critical patent/KR101919097B1/ko
Publication of WO2015139536A1 publication Critical patent/WO2015139536A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of a therapeutic drug for thrombocytopenic purpura.
  • Eltrombopag is an oral thrombopoietin drug developed by GlaxoSmithKline in the UK and is a small molecule thrombopoietin receptor agonist that interacts with the thrombopoietin receptor in the human transmembrane region. Signal cascade amplification is generated to induce proliferation and differentiation of bone marrow megakaryocytes.
  • the drug was approved by the US Food and Drug Administration (FDA) in November 2008 for the treatment of glucocorticoids, immunoglobulin therapy, or chronic idiopathic thrombocytopenic purpura after splenectomy ( ITP) thrombocytopenia in patients.
  • FDA US Food and Drug Administration
  • ITP chronic idiopathic thrombocytopenic purpura after splenectomy
  • the trade name is Promacta.
  • Eltrombopa is the first oral non-peptide thrombopoietin receptor agonist approved for the treatment of adult chronic ITP patients, and its approval for the treatment of patients with ITP is an important milestone.
  • the drug is still undergoing clinical research to treat hepatitis C virus, chronic liver disease, and tumor-related thrombocytopenia.
  • the synthetic route of Eltrombopa is reported in the world patents WO2001/089457, WO2002/057300, WO2003/098992, WO2010/114943, WO2013/072921 and WO2013/04960, and the like. Line and preparation method. Although the reaction conditions or process parameters are different, the synthetic route is basically the same, that is, by 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (intermediate A) and 1-(3,4-xylene Eltrombopag (I) is obtained by condensation coupling reaction between 3-methyl-1H-pyrazole-5(4H)-one (Intermediate B).
  • the intermediate A is prepared by the reaction of nitrification, protection, reduction, Suzuki coupling and deprotection with 2-bromophenol and o-halobenzoic acid as starting materials.
  • the intermediate B is obtained by diazotizing and reducing to 3,4-dimethylaniline as a raw material, and then cyclizing with acetoacetate to obtain a pyrazolone derivative.
  • the object of the present invention is to overcome the defects of the prior art and provide an improved preparation method of Eltrombopa according to the synthesis concept of green chemistry, which is simple, economical and environmentally friendly, and is beneficial to the industrial production of the medicine, and can Promote this Economic and technological development of APIs.
  • the preparation method comprises the steps of: diazo coupling reaction with 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (II) and alkyl acetoacetate to obtain intermediate (Z)-2-[ 3'-(2'-Hydroxy-3-carboxylic acid biphenyl) fluorenylene]-3-oxobutanoic acid alkyl ester (III), intermediate (III) and 3,4-dimethylphenylhydrazine
  • the cyclization reaction is carried out to obtain Eltrombopag (I).
  • the feed ratio of the 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (II) and the alkyl acetoacetate of the diazo coupling reaction is from 1:1.0 to 2.0, preferably from 1:1.2 to 1.5.
  • the solvent of the diazo coupling reaction is a mixed solvent of an organic solvent and water, and the volume ratio of the organic solvent to water is 1:0.5-2.0, preferably 1:0.75-1.5;
  • the organic solvent is methanol, ethanol, propanol, and isopropyl Alcohol, tert-butanol, cyclohexanol, acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide, preferably methanol or ethanol.
  • the molar ratio of 3,4-dimethylphenylhydrazine is from 1:0.5 to 1.5, preferably from 1:1.0 to 1.2.
  • the temperature of the condensation cyclization reaction is from 50 to 150 ° C, preferably from 80 to 120 ° C.
  • the solvent for the condensation cyclization reaction is glacial acetic acid, dimethyl sulfoxide, toluene, xylene, dioxane, N,N-dimethylformamide or N,N-dimethylacetamide, preferably glacial acetic acid.
  • the preparation method of Eltrombopag according to the invention has the advantages of easy preparation, quick and convenient, economical and environmental protection, high product yield and high purity, and is suitable for large-scale production by the steps of diazo coupling and condensation cyclization. Industrial production.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'eltrombopag, la préparation de celui-ci comportant les étapes suivantes : l'utilisation d'acide 3'-amino-2'-hydroxybiphényl-3-carboxylique (II) et d'un acétoacétate d'ester d'alkyle dans une réaction de couplage pour obtenir un ester d'alkyle d'acide (Z)-2-[3'-(2'-hydroxy-3-acide carboxylique-biphényl)hydrazono]-3-oxo-butyrique (III), l'intermédiaire (III) étant soumis à une réaction de condensation cyclisation avec de la 3,4-diméthylphénylhydrazine pour obtenir l'Eltrombopag (I). Le procédé est simple et les matières de départ sont aisément disponibles ; l'invention est économique, respectueuse de l'environnement et est favorable à une production industrialisée, ce qui facilite le développement économique de l'Eltrombopag en tant que principe actif pharmaceutique.
PCT/CN2015/072138 2014-03-17 2015-02-03 Procédé de préparation d'eltrombopag WO2015139536A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020167028052A KR101919097B1 (ko) 2014-03-17 2015-02-03 엘트롬보패그의 제조방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2014100985094 2014-03-17
CN201410098509.4A CN103819406B (zh) 2014-03-17 2014-03-17 艾曲波帕的制备方法

Publications (1)

Publication Number Publication Date
WO2015139536A1 true WO2015139536A1 (fr) 2015-09-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/072138 WO2015139536A1 (fr) 2014-03-17 2015-02-03 Procédé de préparation d'eltrombopag

Country Status (3)

Country Link
KR (1) KR101919097B1 (fr)
CN (1) CN103819406B (fr)
WO (1) WO2015139536A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336706B2 (en) 2014-09-05 2019-07-02 Hetero Research Foundation Crystalline form of Eltrombopag free acid

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146330B (zh) * 2015-04-21 2018-04-06 江苏威凯尔医药科技有限公司 一种制备艾曲波帕中间体的方法
CN108101845B (zh) * 2016-11-25 2020-05-15 苏州科伦药物研究有限公司 一种艾曲泊帕的制备方法
CN107021928B (zh) * 2017-04-01 2022-11-18 常州制药厂有限公司 艾曲波帕新的中间体及其制备方法和应用
CN112321454B (zh) * 2020-11-25 2023-03-17 长沙创新药物工业技术研究院有限公司 一种艾曲泊帕中间体及其制备方法以及用该中间体制备艾曲泊帕的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101343250A (zh) * 2000-05-25 2009-01-14 史密丝克莱恩比彻姆公司 血小板生成素模拟物
CN102448942A (zh) * 2009-04-01 2012-05-09 普利瓦赫尔瓦茨卡有限公司 艾曲波帕和艾曲波帕盐的多晶型物及其制备方法
WO2013072921A2 (fr) * 2011-09-13 2013-05-23 Glenmark Generics Limited Procédé de préparation de composés substitués de l'acide 3'-hydrazino-biphényl-3-carboxylique
EP2799425A1 (fr) * 2013-04-29 2014-11-05 Esteve Química, S.A. Procédé de préparation d'un agoniste du récepteur de la thrombopoïétine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101544631B (zh) * 2008-03-26 2012-05-23 中国科学院上海药物研究所 吡唑类5-脂氧酶小分子抑制剂及其制备方法、药物组合物和应用
WO2013049605A1 (fr) * 2011-09-28 2013-04-04 Assia Chemical Industries Ltd. Procédés de préparation d'un intermédiaire dans la synthèse de l'eltrombopag
US8470077B2 (en) * 2011-11-17 2013-06-25 Alstom Technology Ltd Low pressure stripping in a gas purification process and systems thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101343250A (zh) * 2000-05-25 2009-01-14 史密丝克莱恩比彻姆公司 血小板生成素模拟物
CN102448942A (zh) * 2009-04-01 2012-05-09 普利瓦赫尔瓦茨卡有限公司 艾曲波帕和艾曲波帕盐的多晶型物及其制备方法
WO2013072921A2 (fr) * 2011-09-13 2013-05-23 Glenmark Generics Limited Procédé de préparation de composés substitués de l'acide 3'-hydrazino-biphényl-3-carboxylique
EP2799425A1 (fr) * 2013-04-29 2014-11-05 Esteve Química, S.A. Procédé de préparation d'un agoniste du récepteur de la thrombopoïétine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336706B2 (en) 2014-09-05 2019-07-02 Hetero Research Foundation Crystalline form of Eltrombopag free acid

Also Published As

Publication number Publication date
CN103819406A (zh) 2014-05-28
KR101919097B1 (ko) 2018-11-15
CN103819406B (zh) 2015-04-08
KR20170005404A (ko) 2017-01-13

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