马来酸阿法替尼的合成与放大  

Synthesis and Amplification of Afatinib Dimaleate

作　　者：霍素红[1] 刘军凯[1] 孙双月[1] Huo Suhong;Liu Junkai;Sun Shuangyue(Engineering college,Yanching Institute of Technology,Langfang 065201,China)

机构地区：[1]燕京理工学院工学院,河北廊坊065201

出　　处：《广东化工》2020年第6期29-30,5,共3页Guangdong Chemical Industry

基　　金：河北省教育厅项目(Z2017068)。

摘　　要：通过对抗肿瘤药物马来酸阿法替尼合成工艺的研究,开发适合工业化生产的合成工艺,并放大至单批次近2kg级规模。以6-硝基-4-[(3-氯-4-氟苯基)氨基]-7-氯喹唑啉(3)为原料,与S-羟基四氢呋喃(4)经反应后利用锌粉-醋酸体系还原,得到的固体在CDI存在下与2-(二乙氧基磷酰基)乙酸(7)反应后与N,N-二甲氨基乙醛(9)经Horner-Wadsworth-Emmons反应得到的阿法替尼碱(2)与马来酸在THF中常温搅拌成盐而合成马来酸阿法替尼(1),纯度>99%,总收率61.3%(以3计)。By studying the synthesis process of afatinib dimaleate, a antitumor drug, the synthetic process suitable for industrial production was developed and magnified to about 2 kg grade per batch. 6-nitro-4-[(3-chloro-4-fluorophenyl) amino]-7-chloroquinazoline(3) as raw material, was reacted with S-hydroxytetrahydrofuran(4), then reduced using zinc powder-acetic acid system. The acquired solid reacted with 2-(diethoxyphosphoryl) acetic acid(7) in the presence of CDI, and then reacted with N, N-dimethylaminoethanal(9) via Horner-Wadsworth-Emmons reaction. The obtained afatinib(2) stirred at room temperature with maleic acid in THF solution to synthesize afatinib dimaleate(1). The purity of the product>99 % and total recovery is 61.3 %(based on 3).

关 键 词：阿法替尼碱 马来酸阿法替尼 合成 放大 

分 类 号：TQ[化学工程]