Mobocertinib的合成工艺研究

Study on the synthetic process of mobocertinib

目的改进第四代表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors)mobocertinib(1)的合成工艺。方法以4-氟-2-甲氧基-5-硝基苯胺(2)为起始原料,经氨基保护、取代、还原、缩合和氨基脱保护得到重要中间体N-(5-氨基-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(7);以2,4-二羟基-5-嘧啶羧酸(8)为起始原料,经氯代、酯化、傅克反应合成中间体2-氯-4-(1-甲基-1H-吲哚-3-基)嘧啶-5-羧酸异丙酯(11);中间体7与11经取代反应得到目标化合物1。结果与结论以4-氟-2-甲氧基-5-硝基苯胺计,1的总收率为47.1%,HPLC纯度为98.7%(HPLC面积归一化法);目标化合物及关键中间体的结构经MS、1H-NMR谱确证。该方法所使用的起始原料4-氟-2-甲氧基-5-硝基苯胺和2,4-二羟基-5嘧啶羧酸均价廉易得,总收率较高,反应条件相对温和,后处理操作简便,适合大量制备,可为mobocertinib的生产及其衍生物的合成提供理论参考。

Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs)plays a vital role in the regulation of cell proliferation, differentiation and survival.Overexpression of EGFR had been observed in many human tumors such as lung, breast, head and neck cancers.EGFR had been emerged as one of the most effective and attractive therapeutic targets for anti-cancer therapy.Mobocertinib, an EGFR TKIs inhibitor, was developed by Takeda pharmaceutical.The original synthetic route to mobocertinib was improved in this study by using 2,4-dihydroxypyrimidine-5-carboxylic acid as a raw material with the overall yield of 47.1%.The structure of mobocertinib was confirmed by 1H-NMR and ESI-MS.Compared with the literature route, this process optimized the experimental steps, used low-cost materials made the operation easier and provided a theoretical reference for the synthesis of mobocertinib and its derivatives.