摘要
目的对JAK1/2抑制剂momelotinib的合成工艺进行优化。方法以4-甲基苯硼酸为起始原料,依次经氧化、苯硼酸酯化、Suzuki偶联和成酰胺缩合得到中间体N-(氰甲基)4-(2-氯嘧啶4-基)苯甲酰胺(6);以4-氟硝基苯为另一起始原料,经亲核取代和还原反应制得中间体4-(4-吗琳基)苯胺(9);中间体6与中间体9经C-N偶联制得目标化合物momelotinib。结果与结论目标化合物的结构经MSJH-NMR和13C-NMR确证。总收率为38.8%(以4-甲基苯硼酸计),产品纯度达99.90%(HPLC法)。本路线的原料廉价易得,涉及的中间体均易制备并纯度较高,所用试剂均为常用试剂,反应条件温和,后处理简单,可为工业化生产提供参考。
An optimal process to prepare momelotinib has been developed basing on the synthetic methods of momelotinib reported in literatures and a large number of experiments.With p-tolylboronic acid as starting material,the key intermediate N-(cyanomethyl)4-(2-chloropyrimidin4-yl)benzamide(6)was synthesized by oxidation,esterification,Suzuki cross-coupling and condensation.Another key intermediate 4-morpholinoaniline(9)was prepared by substitution and reduction.Momelotinib was prepared via coupled reaction of intermediate 6 with 9.The total yield of momelotinib was 38.8%calculated from p-tolylboronic acid with the purity of 99.90%.The structures of the target compound and some intermediates were identified by 1H-NMR,l3C-NMR and MS.
作者
杜世美
李颖修
陈延峰
罗勇
徐莉英
赵燕芳
DU Shi-mei;LI Ying-xiu;CHEN Yan-fcng;LUO Yong;XU Li-ying;ZHAO Yan-fang(Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2019年第2期131-134,共4页
Chinese Journal of Medicinal Chemistry
