CN103992273B - 一种选择性非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法 - Google Patents

一种选择性非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法 Download PDF

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CN103992273B
CN103992273B CN201410157851.7A CN201410157851A CN103992273B CN 103992273 B CN103992273 B CN 103992273B CN 201410157851 A CN201410157851 A CN 201410157851A CN 103992273 B CN103992273 B CN 103992273B
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steroidal anti
inflammatory drug
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CN103992273A (zh
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王小龙
张大成
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Nanjing University of Chinese Medicine
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Nanjing University of Chinese Medicine
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    • 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
    • C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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

Abstract

本发明涉及一种非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法，该发明以化合物一和化合物二为原料，在硫酸铜和抗坏血酸共同催化下，分子间通过[3+2]偶极环加成反应合成塞来昔布分子的吡唑坏，从而合成了塞来昔布(见图1)。该方法操作简单，条件温和，收率较高，是一种有效合成塞来昔布的新方法。

Description

一种选择性非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法
技术领域
本发明涉及医药化工领域，具体涉及一种选择性非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法。
背景技术
Celebrex(塞来昔布)是1999年通过美国国家食品与药品监督管理局(FDA)的批准正式上市，标志着全球首款选择性非甾体抗炎镇痛药诞生。塞来昔布为新一代选择性COX-2抑制剂，只抑制COX-2，不影响COX-1功能，因此具有保护胃肠道作用的COX-1合成产物生成不会被抑制，成功解决了传统非甾体抗炎镇痛药胃肠损伤方面的百年难题，被喻为“里程碑式的突破”。
目前关于塞来昔布的合成方法主要有US5521207的合成方法(方程式如图1所示)和WO2003024400(方程式如图2所示)等。
附图说明
图1是US5521207中塞来昔布合成方法方程式。
图2是WO2003024400中塞来昔布合成方法方程式。
图3是本发明中设计的一种塞来昔布合成方法方程式。
具体操作实施
室温下将化合物一(1.0mmol)和化合物二(1.0mmol)溶于乙腈(3mL)中后加入水(1.0mL)，接下来加入10％硫酸铜溶液(0.02mL，0.1mmol)，20％抗坏血酸溶液(0.02mL，0.2mmol)，和醋酸钠(382mg，4.0mmol)。混合溶液加热于45℃反应1小时。将反应液减压旋干后加入甲醇(1mL)和氨水(5mL)，用乙酸乙酯萃取，干燥，旋干过柱分离得产物(方程式如图3所示)。

Claims (4)

1.一种选择性非甾体抗炎镇痛药Celebrex(塞来西布)的合成方法，反应方程式如下：
其合成方法是：以化合物一和化合物二为原料，首先溶解于相应的溶剂中，再加入适宜量的硫酸铜、抗坏血酸和醋酸钠水溶液，将混合溶液加热反应数小时，后处理得到目标产物，
2.根据权利要求1所述的合成方法，其中化合物一和化合物二的摩尔比为1.0∶0.8，或1.0∶0.9，或1.0∶1.0，或1.0∶1.1，或1.0∶1.2。
3.根据权利要求1所述的合成方法，其中所维持温度为0-100摄氏度。
4.根据权利要求1所述的合成方法，其中反应时间为0.5或1或1.5或2或3小时。
CN201410157851.7A 2014-04-18 2014-04-18 一种选择性非甾体抗炎镇痛药Celebrex(塞来昔布)的合成方法 Active CN103992273B (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521207A (en) * 1993-11-30 1996-05-28 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamide for the treatment of inflammation
WO2003024400A2 (en) * 2001-09-18 2003-03-27 Onconova Therapeutics, Inc. Process for the preparation of 1,5-diarylpyrazoles
EP2246332A1 (en) * 2009-04-22 2010-11-03 The Ohio State University Research Foundation Pyrazole derivatives as anti-francisella agents
CN102558056A (zh) * 2012-01-06 2012-07-11 湖南方盛制药股份有限公司 塞来昔布及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521207A (en) * 1993-11-30 1996-05-28 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamide for the treatment of inflammation
WO2003024400A2 (en) * 2001-09-18 2003-03-27 Onconova Therapeutics, Inc. Process for the preparation of 1,5-diarylpyrazoles
EP2246332A1 (en) * 2009-04-22 2010-11-03 The Ohio State University Research Foundation Pyrazole derivatives as anti-francisella agents
CN102558056A (zh) * 2012-01-06 2012-07-11 湖南方盛制药股份有限公司 塞来昔布及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"A new efficient synthesis of pyrazoles from hydrazonoyl halides and β -oxophosphonates";Sun Aixue等;《Tetrahedron Letters》;20131219;第55卷;第889-892页 *
"Copper(I)-Catalyzed Synthesis of Pyrazoles from Phenylhydrazones and Dialkyl Ethylenedicarboxylates in the Presence of Bases";Ma Chaowei等;《Synlett》;20110505(第9期);第1321-1323页 *
"Synthesis of celecoxib via 1,3-dipolar cycloaddition";Lynette M. Oh等;《Tetrahedron Letters》;20060925;第47卷;第7943-7946页 *
"The Cycloaddition of Nitrilimines with 1,2-Dibenzoylethylenes";Tatsuo Oida等;《Bull. Chem. Soc. Jpn.》;19811231;第54卷;第1429-1433页 *

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