药物Osimertinib(奥希替尼)合成检索总结报告.pdf

药物Osimertinib（奥希替尼）合成检索总结报告

一、Osimertinib（奥希替尼）简介
Osimertinib（奥希替尼）用于治疗转移性表皮生长因子受体
(EGFR)T790M突变阳性以及其他EGFR．阻断剂治疗后疾病恶化的
非小细胞肺癌(NSCLC)患者。Osimertinib（奥希替尼）不良反应有：
腹泻，皮疹，皮肤干燥和指甲毒性。
Osimertinib（奥希替尼）分子结构式如下:

英文名称：Osimertinib
中文名称：奥希替尼
本文主要对Osimertinib（奥希替尼）的合成路线、关键中间体的
合成方法及实验操作方法进行了文献检索并作出了总结。
二、Osimertinib（奥希替尼）合成路线一

三、Osimertinib（奥希替尼）合成路线二

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四、Osimertinib（奥希替尼）合成路线一检索总结报告
(一)Osimertinib（奥希替尼）中间体3的合成（路线一）

合成方法实验步骤参考文献
Theindole1(236.0g,2.02mol),Tetrahydrofuran(1200mL)
wasaddedtothereactionflask.Coolto0oC,nitrogen
protection,Methylmagnesiumbromide(672mL,3mol/L
2-methyltetrahydrofuransolution)wasaddeddropwisetothe
system.Afterthedropwiseadditionwascompleted,the
mixturewasstirredfor1hour.Add2,4-dichloropyrimidine2
(120.0g,0.81mol),Stirfor1hour.Heatedtoaninternal
temperatureof70°Catthistemperature.Stirthereactionfor
5h,stopheating,Cooltoroomtemperature.Ethylacetate
(600mL)wasaddedtothereactionflask.Asaturated
aqueoussolutionofammoniumchloride(1200mL)wasCN109761960;
操作方法added.Thelayerswerestirredandtheorganicphasewas(2019);(A)
一retained.TheaqueousphasewasextractedwithethylChinese
acetate,theorganicphaseswerecombined,andanhydrous
sulfuricacidwasadded.Sodium,stirredatroom
temperature,filtered,andthefiltratewasconcentratedand
evaporated.Ayellowsolidwasobtained.Ethylacetate(1200
mL)wasaddedthereto,andthemixturewasheatedtoasolid

2
solution,andthenn-hexane(1200mL)wasaddeddropwise.
Aftertheadditionwascompleted,itwascooledtoroom
temperature.Filtrationanddryinggave3-(2-chloropyrimidin
-4-yl)-1H-indole3(123.0g)asapaleyellowsolid,yield:
66.5%.
Partiallyaddedtoasolutionofcompound2(21g,0.14mol)

indichloromethane(500mL)underN2.AlCl3(22.5g,0.17
mol)wasaddedover10minutes.Aftertheresulting
suspensionwasstirredatroomtemperaturefor10minutes,
thereactionsystemwassubstantiallyclear.Compound1
(16.5g,0.14mol)wasaddedportionwisetotheabove
reactionmixtureatroomtemperature,andwasaddedoverCN105153122;
操作方法10minutes.Theresultingbrownsuspensionwasstirred(2018);(B)
二overnightat