doi:10.16597/j.cnki.issn.1002-154x.2023.05.002
波齐替尼合成工艺研究
袁昕 焦小雨 唐春雷∗
(江南大学 生命科学与健康工程学院,江苏 无锡 214122)
Study on the Synthesis Process of Poziotinib
Yuan Xin Jiao Xiaoyu Tang Chunlei ∗
(School of Life Science and Health Engineering, Jiangnan University, Jiangsu Wuxi 214112)
摘要:
本研究改进了表皮生长因子受体(EGFR)酪氨酸激酶抑制剂波齐替尼(Poziotinib,1)的合成工艺。 以价廉易得的 3,4-二氢-7-甲氧基-4-氧代喹唑啉-6-醇乙酸酯(5)为起始原料,经氯化、取代、酯水解反应得到中间体 4-(3, 4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-醇(14);化合物 14 与 4-(甲苯-4-磺酰氧)哌啶-1-羧酸叔丁酯(11)经酯化、脱保护得中间体 N-(3,4-二氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺(10); 化合物 10 再与丙 烯酰氯经酰化反应得到目标产物 EGFR 酪氨酸激酶抑制剂 Poziotinib(1)。 终产物 HPLC 纯度为 99. 46%(面积归一化法),以 3,4-二氢-7-甲氧基-4-氧代喹唑啉-6-醇乙酸酯(5)计,总收率为 43. 2%。 目标终产物及关键中间体的结构 经 HRMS 和1H NMR 确证。 该方法与原研专利相比,缩短了合成路线,总收率较高,后处理简单,适合工业化生产,本研究可为 Poziotinib(1)的生成及其衍生物的合成提供理论参考。
关键词：波齐替尼 表皮生长因子受体酪氨酸激酶抑制剂 工艺改进；
Abstract：
The synthesis method of Poziotinib ( 1 ), a human epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor, was improved in this study. The intermediate 4-(3,4-dichloro-2-fluorophenylamino) - 7 - methoxyquinazoline - 6 - alcohol ( 14 ) was prepared by chlorination, substitution and ester hydrolysis from the cheap and readily available 3, 4 - dihydro - 7- methoxy - 4 - oxoquinoline - 6 - alcohol acetate ( 5 ) as the starting material. The intermediate 4 - ( 3, 4 - dichloro - 2 - fluorophenyl) - 7 - methoxy - 6 - ( piperidine-4 - oxy) quinazoline - 4 - amine ( 10 ) was prepared by esterification and deprotection of 14 with 4 - ( toluene - 4 - sulfonyloxy) piperidine-1-carboxylate tert-butyl ester (11). Poziotinib(1), a tyrosine kinase inhibitor of EGFR, was obtained by acylation with acryloyl chloride. The HPLC purity of the final product was 99. 46% ( area normalization method), and the total yield was 43. 2%. The structures of the final products and key intermediates were confirmed by HRMS and 1H NMR. Compared with the original research patent, this method has shorter synthesis route, higher overall yield, simple post-treatment, and is suitable for mass preparation. This paper can provide a theoretical reference for the synthesis of Poziotinib (1) and its derivatives.
Keywords：Poziotinib; epidermal growth factor receptor tyrosine kinase inhibitor; process improvement;