Lazertinib(拉泽替尼)合成检索总结报告.docVIP

PAGE PAGE 1 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 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 实验步骤 参考文献 操作方法一 A mixture of 4-fluoro-2-methoxy-5-nitroaniline 1 (60.0 g, 0.322 mol) and dichloromethane (500.0 mL) was cooled to 0-5°C. A solution of dibutyl dicarbonate (91.5 g, 0.419 mol) in dichloromethane (120.0 mL), 4-dimethylaminopyridine (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%) WO2019/22487; (2019); (A1) English 操作方法二 A solution of 4-fluoro-2-methoxy-5-nitroaniline 1 (8.0g, 43.0 mmol) in DCM (dichloromethane) (100 mL) was cooled to 0-5oC in an ice/water bath. Boc2O (9.4g, 43.0 mmol) in DCM (30 mL) was added to the mixture slowly. The progress of the reaction was monitored by TLC. After 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) (12.0 g, 42.1 mmol, 98%) as a yellow solid. m.p. 88-90°C. Journal of Chemical Research; vol. 39; nb. 6; (2015); p. 318-320; Bioorganic and Medicinal Chemistry; vol. 26; nb. 8; (2018); p. 1810-1822. 操作方法三 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 the filter cake was washed with an acetonitrile solvent to obtain a pure intermediate 2. To the obtained filtrate, BOC anhydride (8 g) was added to continue t