DOI: 10.16597/j.cnki.issn.1002-154x.2024.04.005
迪纳西利的合成方法改进
作者： 李梓铭，张艳
单位： 江南大学生命科学与健康工程学院，无锡 214122
摘要： 本研究对细胞周期蛋白激酶(CDKs)小分子抑制剂迪纳西利(dinaciclib)的合成方法进行了改进。以价格较低的3-氨基-4-溴吡唑(1)和3-氨甲基吡啶(5)为起始原料，通过偶联、成环、氯代反应得到重要中间体5,7-二氯-3-乙基吡唑[1,5-a]并嘧啶(4)；5经取代、氧化反应得到重要中间体4-氨基甲基吡啶-N-氧化物二盐酸盐(8)。化合物4与化合物8经取代反应得到(5-氯-3-乙基-吡唑并[1,5-a]嘧啶-7-基)-(1-氧-吡啶-3-亚甲基)-胺(9)；化合物9与(S)-(-)-2-哌啶乙醇经取代反应得到目标产物迪纳西利。目标产物经HPLC检测，纯度为98%，以化合物4计，总收率为75%，并通过NMR对其结构进行确证。相较于原研路线，改进后的工艺路线成本降低、收率提高、路线耗时缩短，适合工业化大量生产。
关键词： 迪纳西利，细胞周期蛋白激酶抑制剂，工艺改进
Improved Synthesis of Dinaciclib
Authors: LI Ziming, ZHANG Yan*
Affiliation: School of Life Science and Health Engineering, Jiangnan University, Wuxi 214122, China
Abstract: This study improved the synthesis method of Dinaciclib, a small molecule inhibitor of cyclin-dependent kinases (CDKs). Starting with the low-cost 3-amino-4-bromopyrazole (1) and 3-aminomethylpyridine (5), the important intermediate 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (4) was obtained through coupling, cyclization, and chlorination reactions; 5 was transformed into another important intermediate 4-aminomethylpyridine-N-oxide dihydrochloride (8) through substitution and oxidation reactions. The compound (5-chloro-3-ethyl-pyrazolo[1,5-a]pyrimidin-7-yl)-(1-oxo-pyridine-3-methylene)-amine (9) was obtained by substitution reaction of compound 4 with compound 8. The target product Dinaciclib was obtained by substitution reaction of compound 9 with (S)-(-)-2-piperidineethanol. The target product was detected by HPLC, with a purity of 98% and an overall yield of 75% based on compound 4, and its structure was confirmed by NMR. Compared to the original research route, the improved process route reduced costs, increased yields, and shortened the route time, making it suitable for large-scale industrial production.
Keywords: Dinaciclib, cyclin kinase inhibitor, process improvement