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CN105358529A - 一种合成阿哌沙班重要中间体的新方法 - Google Patents

一种合成阿哌沙班重要中间体的新方法 Download PDF

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Publication number
CN105358529A
CN105358529A CN201480027912.6A CN201480027912A CN105358529A CN 105358529 A CN105358529 A CN 105358529A CN 201480027912 A CN201480027912 A CN 201480027912A CN 105358529 A CN105358529 A CN 105358529A
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CN
China
Prior art keywords
apixaban
formula
novel method
key intermediate
synthesizing
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.)
Granted
Application number
CN201480027912.6A
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English (en)
Other versions
CN105358529B (zh
CN105358529A8 (zh
Inventor
汪博宇
姚金烽
黄鲁宁
张席妮
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.)
Shanghai Kesheng Pharmaceutical Research And Development Co ltd
Zhejiang Huahai Pharmaceutical Co Ltd
Original Assignee
Shanghai Kesheng Pharmaceutical Research And Development Co ltd
Zhejiang Huahai 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 Shanghai Kesheng Pharmaceutical Research And Development Co ltd, Zhejiang Huahai Pharmaceutical Co Ltd filed Critical Shanghai Kesheng Pharmaceutical Research And Development Co ltd
Priority to CN201480027912.6A priority Critical patent/CN105358529B/zh
Publication of CN105358529A publication Critical patent/CN105358529A/zh
Publication of CN105358529A8 publication Critical patent/CN105358529A8/zh
Application granted granted Critical
Publication of CN105358529B publication Critical patent/CN105358529B/zh
Active legal-status Critical Current
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明涉及一种合成阿哌沙班中间体的方法，该方法将式I所示化合物与5-氯戊酰氯在无机碱存在的条件下，在惰性溶剂中反应得到式II所示化合物，反应式为(A)。其中，R选自硝基及基团(B)。该方法反应条件温和、操作简单、便于纯化、生产成本低廉，对环境友好，适合工业化生产。

Description

PCT国内申请，说明书已公开。

Claims (1)

  1. PCT国内申请，权利要求书已公开。
CN201480027912.6A 2013-08-02 2014-07-29 一种合成阿哌沙班重要中间体的新方法 Active CN105358529B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201480027912.6A CN105358529B (zh) 2013-08-02 2014-07-29 一种合成阿哌沙班重要中间体的新方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201310335663.4A CN104341336B (zh) 2013-08-02 2013-08-02 一种合成阿哌沙班重要中间体的新方法
CN2013103356634 2013-08-02
CN201480027912.6A CN105358529B (zh) 2013-08-02 2014-07-29 一种合成阿哌沙班重要中间体的新方法
PCT/CN2014/083228 WO2015018289A1 (zh) 2013-08-02 2014-07-29 一种合成阿哌沙班重要中间体的新方法

Publications (3)

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CN105358529A true CN105358529A (zh) 2016-02-24
CN105358529A8 CN105358529A8 (zh) 2017-05-17
CN105358529B CN105358529B (zh) 2018-09-25

Family

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CN201310335663.4A Active CN104341336B (zh) 2013-08-02 2013-08-02 一种合成阿哌沙班重要中间体的新方法
CN201480027912.6A Active CN105358529B (zh) 2013-08-02 2014-07-29 一种合成阿哌沙班重要中间体的新方法

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Country Status (5)

Country Link
US (1) US9656958B2 (zh)
EP (1) EP3029028B1 (zh)
CN (2) CN104341336B (zh)
ES (1) ES2687244T3 (zh)
WO (1) WO2015018289A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2881373T3 (es) 2014-09-05 2021-11-29 Unichem Lab Ltd Un procedimiento mejorado para la preparación de apixabán e intermedios del mismo
EP3064497A1 (en) 2015-07-20 2016-09-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Dimer impurities of apixaban and method to remove them
WO2018158620A1 (en) * 2017-02-28 2018-09-07 Sun Pharmaceutical Industries Limited Preparation of active pharmaceutical ingredients and intermediates thereof
CN108558741B (zh) * 2017-12-27 2020-10-30 浙江天宇药业股份有限公司 一种阿哌沙班的中间体的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030983A2 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceuticals, Inc. Pyrazole carboxamide inhibitors of factor xa
CN101967145A (zh) * 2010-09-09 2011-02-09 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
CN103159670A (zh) * 2011-12-16 2013-06-19 中国科学院兰州化学物理研究所 阿哌沙班中间体1-(4-硝基苯基)-2-哌啶酮的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1098656C (zh) * 1997-06-25 2003-01-15 董定彪 无烟香烟的生产方法
SK4732002A3 (en) * 1999-10-13 2002-12-03 Pfizer Prod Inc Biaryl ether derivatives useful as monoamine reuptake inhibitors
CN101065379B (zh) * 2004-09-28 2011-05-11 布里斯托尔-迈尔斯斯奎布公司 制备4,5-二氢-吡唑并[3,4-c]吡啶-2-酮的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030983A2 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceuticals, Inc. Pyrazole carboxamide inhibitors of factor xa
CN101967145A (zh) * 2010-09-09 2011-02-09 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
CN103159670A (zh) * 2011-12-16 2013-06-19 中国科学院兰州化学物理研究所 阿哌沙班中间体1-(4-硝基苯基)-2-哌啶酮的合成方法

Also Published As

Publication number Publication date
CN105358529B (zh) 2018-09-25
CN104341336A (zh) 2015-02-11
WO2015018289A1 (zh) 2015-02-12
CN104341336B (zh) 2018-10-16
EP3029028A1 (en) 2016-06-08
US9656958B2 (en) 2017-05-23
EP3029028A4 (en) 2016-12-28
US20160280646A1 (en) 2016-09-29
ES2687244T3 (es) 2018-10-24
EP3029028B1 (en) 2018-07-11
CN105358529A8 (zh) 2017-05-17

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CI01 Publication of corrected invention patent application

Correction item: National priority

Correct: 201310335663.4 2013.08.02 CN

False: 201310335663.4 2013.08.05 CN

Number: 08

Volume: 32

CI01 Publication of corrected invention patent application
CI02 Correction of invention patent application

Correction item: National priority

Correct: 201310335663.4 2013.08.02 CN

False: 201310335663.4 2013.08.05 CN

Number: 08

Page: The title page

Volume: 32

CI02 Correction of invention patent application
GR01 Patent grant
GR01 Patent grant