Fadraciclib的合成方法改进

DOI: 10.16597/j.cnki.issn.1002-154x.2024.06.002

作者： 王栋，王霞，范为正

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（CDK）小分子抑制剂Fadraciclib（1,CYC065）的合成路线进行了优化。以4,6-二甲基-2-氧代-1,2-二氢吡啶-3-腈（2）为原料，通过卤化、脱卤素、氰基还原及氨基甲酸叔丁酯的酸解得到关键中间体（4,6-二甲基吡啶-3-基）甲胺（6）的三氟乙酸盐。终产物的合成利用微波反应减少了能耗，提高了反应效率。改进后路线总收率为9.0%（以2计）。该方法使用的原材料简单易得，后处理操作简便，产物纯化多采用打浆重结晶，便于放大生产，同时也可为Fadraciclib及其衍生物的合成提供参考。

关键词： 急性髓系白血病，细胞周期蛋白激酶抑制剂，Fadraciclib，合成

Authors: WANG Dong, WANG Xia, FAN Weizheng

Affiliation: College of Life Science and Health Engineering, Jiangnan University, Wuxi 214122, China

Abstract: In this study, the synthetic route of Fadraciclib (1, CYC065), a small molecule inhibitor of cyclin kinase, was optimized. Using 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2) as raw material, 2-chloro-3-cyano-4,6-dimethylpyridine (3) was obtained by reflux reaction with phosphorus oxychloride. Compound 3 was reduced by zinc powder to obtain 3-cyano-4,6-dimethylpyridine (4), which was then reduced by Raney Ni/H2, and the amino group was protected by di-tert-butyl dicarbonate. The key intermediate (4,6-dimethylpyridin-3-yl)methylamine (6, in the form of trifluoroacetate) was obtained after deprotection. Compound N-[(4,6-dimethylpyridin-3-yl)methyl]-2-fluoro-9-isopropyl-9H-purine-6-amine (9) was obtained by nucleophilic substitution of 6 with 6-chloro-2-fluoro-9H-purine (7) and isopropanol bromide. The target compound 1 was obtained by microwave reaction of 9 with (2R,3S)-3-aminopent-2-ol (10). The total yield of this route was 9.0% (based on 2) with cheap and easily available raw materials 2, and the cost was also reduced by microwave reactor, which provided a reference for the industrial synthesis of 1 and its structural analogues.

Keywords: acute myeloid leukemia, cyclin kinase inhibitor, Fadraciclib, synthesis