奥莫替尼合成路线图解
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摘要
综述了奥莫替尼(■)的合成工艺,并针对其不同的合成路线进行了分析和研究,提出适合工业化生产的路线。以2-硫代-2,3-二氢噻吩并嘧啶-4-酮(■)为起始原料,经过甲基化、磺酰基化及亲核取代等一系列反应得到关键中间体2-((4-(4-甲基哌嗪-1-基)苯基)氨基)噻吩并[3,2-d]嘧啶-4(3H)-酮(■),最后中间体■经过氯代及亲核取代反应制得目标化合物■。该合成路线易于操作,收率较高,成本偏低,适合工业化生产。
This paper reviewed the existing synthesis methods of Olmutinib( ■), and through research and analysis on different synthetic processes, a aroute suitable for industrial production was proposed. 2-Thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4(1 H)-one(■) was used as a starting material;through a series of reactions including methylation, sulfonylation and nucleophilic substitution key intermediates 2-((4-(4-methylpiperazin-1-yl)phenyl)amino)thieno [3,2-d]pyrimidin-4(3 H)-one(■) was obtained. This compound ■ was then subjected to chlorination and nucleophilic substitution to give the target compound ■. This route is simple and easy to operate, has low cost and high yield, and is suitable for industrial production.
This paper reviewed the existing synthesis methods of Olmutinib( ■), and through research and analysis on different synthetic processes, a aroute suitable for industrial production was proposed. 2-Thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4(1 H)-one(■) was used as a starting material;through a series of reactions including methylation, sulfonylation and nucleophilic substitution key intermediates 2-((4-(4-methylpiperazin-1-yl)phenyl)amino)thieno [3,2-d]pyrimidin-4(3 H)-one(■) was obtained. This compound ■ was then subjected to chlorination and nucleophilic substitution to give the target compound ■. This route is simple and easy to operate, has low cost and high yield, and is suitable for industrial production.
引文
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[12]Cai X,Zhai H,Lai C,et al.Phosphoinositide 3-kinase inhibitors with a zinc binding moiety:US:2017362251A1[P].2017-12-21.
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[15]Phuangsawai O,Beswick P,Ratanabunyong S,et al.Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diaminopyrimidine-based kinase inhibitors[J].European Journal of Medicinal Chemistry,2016,124:896-905.
[16]Mutorwa M,Salisu S,Blatch G L,et al.3-Substituted anilines as scaffolds for the construction of glutamine synthetase and DXP-reductoisomeraseinhibitors[J].Synthetic Communications誖,2009,39(15):2 723-2 736.
[17]Jang W,Moon Y H,Ha T H,et al.Novel process for preparing thienopyrimidine compound and intermediates used therein:WO,2017074147 A1[P].2017-05-04.
[2]Kim D W,Lee D H,Kang J H,et al.Clinical activity and safety of HM61713,an EGFR-mutant selective inhibitor,in advanced nonsmall cell lung cancer(NSCLC)patients(pts)with EGFR mutations who had received EGFR tyrosine kinase inhibitors(TKIs)[J].Journal of Clinical Oncology,2014,32(15-suppl):8 011.
[3]Song H N,Jung K S,Yoo K H,et al.Acquired C797S mutation upon treatment with a T790M-specific third-generation EGFRinhibitor(HM61713)in non-small cell lung cancer[J].Journal of Thoracic Oncology,2016,11(4):45-47.
[4]Park K,Lee J S,Lee K H,et al.Updated safety and efficacy results from phase I/II study of HM61713 in patients(pts)with EGFRmutation positive non-small cell lung cancer(NSCLC)who failed previous EGFR-tyrosine kinase inhibitor(TKI)[J].Journal of Clinical Oncology,2015,33(15-suppl):8 084.
[5]Lee K O,Cha M Y,Kim M,et al.Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor[J].Cancer Research,2014,74(19-suppl):100.
[6]张敬.噻吩并[3,2-d]嘧啶氨基酸酯衍生物的合成及抗肿瘤活性研究[D].郑州:郑州大学,2017.
[7]Zhu W,Chen C,Sun C,et al.Design,synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as m TOR/PI3Kαinhibitors[J].European Journal of Medicinal Chemistry,2015,93:64-73.
[8]Deng J,Peng L,Zhang G,et al.The highly potent and selective dipeptidyl peptidase IV inhibitors bearing a thienopyrimidine scaffold effectively treat type 2 diabetes[J].European Journal of Medicinal Chemistry,2011,46(1):71-76.
[9]白种旭,郑载赫,金镐硕,等.用于制备噻吩并嘧啶化合物的新型方法及其中使用的中间体:中国,107108649A[P].2017-08-29.
[10]SéverineD,Tambutet G,Masurier N,et al.Synthesis of thieno[3,2-e][1,4]diazepin-2-ones:application of an uncatalysed pictetspengler reaction[J].European Journal of Organic Chemistry,2015,2:7 146-7 153.
[11]Huddleston P R,Barker J M,Adamczewska Y Z,et al.Synthesis and chemistry of some thieno(3,2-d)-1,2,3-triazin-4(3H)-ones[J].Chem In form,1993,24(25):548-575.
[12]Cai X,Zhai H,Lai C,et al.Phosphoinositide 3-kinase inhibitors with a zinc binding moiety:US:2017362251A1[P].2017-12-21.
[13]Brown J W,Gangloff A R,Kiryanov A A.Poly(ADP-ribose)polymerase(PARP)inhibitors:US,8980902B2[P].2015-03-17.
[14]Wurster S,Engstrom M,Savola J M,et al.Derivatives of quinoline as alpha-2 antagonists:US,20010046991A1[P].2001-02-28.
[15]Phuangsawai O,Beswick P,Ratanabunyong S,et al.Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diaminopyrimidine-based kinase inhibitors[J].European Journal of Medicinal Chemistry,2016,124:896-905.
[16]Mutorwa M,Salisu S,Blatch G L,et al.3-Substituted anilines as scaffolds for the construction of glutamine synthetase and DXP-reductoisomeraseinhibitors[J].Synthetic Communications誖,2009,39(15):2 723-2 736.
[17]Jang W,Moon Y H,Ha T H,et al.Novel process for preparing thienopyrimidine compound and intermediates used therein:WO,2017074147 A1[P].2017-05-04.