Lazertinib(拉泽替尼)合成检索总结报告.docxVIP

Lazertinib（拉泽替尼）合成检索总结报告 一、Lazertinib（拉泽替尼）简介 2019 年 10 月，Janssen 与 Yuhan开启非小细胞肺癌药物 Lazertinib 二期临床研究。2020 年 3 月 11 日获 FDA 突破性疗法认定。 Lazertinib（拉泽替尼）分子结构式如下: 英文名称：Lazertinib 中文名称：拉泽替尼 本文主要对 Lazertinib（拉泽替尼）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、Lazertinib（拉泽替尼）合成路线一 三、Lazertinib（拉泽替尼）合成路线二 1 四、Lazertinib（拉泽替尼）合成路线一检索总结报告 (一) Lazertinib（拉泽替尼）中间体 2 的合成（路线一） 合成方法 WO2019/22487; (2019); (A1) English (3.9 g, 0.032 mol), and triethylamine (65.2 g, 0.645 mol) were added to the mixture. The reaction mixture was stilted at 20-30°C for 4 hours and then concentrated under reduced pressure to obtain 92.3 g of the titled compound 2. (Yield: 100.0%) A solution of 4-fluoro-2-methoxy-5-nitroaniline 1 (8.0g, 43.0 Journal of Chemical Research; vol. 39; nb. 6; (2015); p. 318-320; o 2 completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The crude productwas purified by flash silica chromatography, with gradient 10-40% EtOAc in hexane to yield intermediate (2) Bioorganic and Medicinal Chemistry; vol. 26; nb. 8; (2018); 2 (12.0 g, 42.1 mmol, 98%) as a yellow solid. m.p. 88-90°C. After dissolving 1 (10 g, 1.0 eq) in acetonitrile (30 mL), Boc anhydride (14 g, 1.2 eq) was added dropwise at 25°C, then raised to 60°C, reaction time 10 h, some solvent was distilled off, cooled, and filtered. The filter cake was obtained, and 操作方法 the filter cake was washed with an acetonitrile solvent to p. 1810-1822. CN2019/1102831 62; (2019); (A) CN2019/1103578 63; (2019); (A); CN2019/1104078 52; (2019); (A); CN2019/1103960 95; (2019); (A). progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure, isolated and purified by column chromatography [PE:EA=80:20] to give the title compound 2 (12.56 g, 73%). (二) Lazertinib（拉泽替尼）中间体 4 的合成（路线一） 合成方法 实验步骤 Appropriate alkyl amine 3 (27.0 mmol) was added to a solutionof intermediate 2 (6.3 g, 22.0 mmol) and DIPEA (N,N-Diisopropylethylamine) (3.82 mL, 22