doi:10.16597/j.cnki.issn.1002-154x.2023.04.002
BTK抑制剂 LOXO-305 的合成工艺研究
项良华 王霞 袁昕 姜虹羽 王杰 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 BTK Inhibitor LOXO-305
Xiang Lianghua Wang Xia Yuan Xin Jiang Hongyu Wang Jie Tang Chunlei ∗
(School of Life Science and Health Engineering, Jiangnan University, Jiangsu Wuxi 214122)
摘要:
本研究改进了布鲁顿酪氨酸激酶(BTK)抑制剂 LOXO-305 的合成工艺。 以 5-氟-2-甲氧基苯甲酸为起始原料,经两步缩合得到中间体 N-((4-(2,2-二氰基-1-羟基乙烯基)苯基)甲基) -5-氟-2-甲氧基苯甲酰胺,随后经甲基化、关环反应、水解反应得到目标化合物 LOXO-305。 以 5-氟-2-甲氧基苯甲酸计,LOXO-305 合成总收率为 35.9%,终产物 HPLC 纯度为 99.5%(HPLC 面积归一化法),目标终产物及关键中间体的结构经 MS、1H NMR 确证。 该方法与原研专利路线相比,反应条件相对温和,反应时间短,后处理操作简便,适合放大生产,可为 LOXO-305 的生产及其衍生物的合成提供参考。
关键词：LOXO-305 BTK 抑制剂 可逆抑制剂 工艺改进；
Abstract：
This study improved the synthesis process of Bruton's tyrosine kinase ( BTK) inhibitor LOXO - 305. With 5-fluoro - 2 -methoxybenzoic acid as the starting material, the intermediate N- (( 4 - ( 2,2 - dicyano - 1-hydroxyvinyl) phenyl) methyl) - 5 -fluoro - 2 -methoxybenzamide was obtained through two steps condensation. Then the target compound LOXO - 305 was obtained through methylation, ring closing reaction and hydrolysis reaction. Based on 5-fluoro-2-methoxybenzoic acid, the overall synthesis yield of LOXO-305 was 35. 9%, and the HPLC purity of the end product was 99. 5% (HPLC area normalization method). The structures of the target end products and key intermediates were confirmed by MS and 1H NMR. Compared with the original patented route, this method has relatively mild reaction conditions, short reaction time, simple post-treatment operation, and is suitable for scale-up production, which can provide a reference for the production of LOXO-305 and the synthesis of its derivatives.
Keywords：LOXO-305 BTK; inhibitors; reversible inhibitor; process optimization;