迪纳西利的合成方法改进

Improved Synthesis of Dinaciclib

作者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,1经偶联、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。

In this paper,the synthesis method of Dinaciclib,a small molecule inhibitor of cyclin kinase(CDKs),was improved.An important intermediate 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine(4)was synthesized from 3-amino-4-bromopyrazole(1)and 3-aminomethylpyridine(5)by coupling,cyclization and chlorination.An other important intermediate 4-aminomethylpyridine-N-oxide dihydrochloride(8)was obtained by substitution and oxidation of 3-aminomethylpyridine(5).(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,and the purity was 98%.The total yield was 75%based on 4.Compared to the original research route,the improved process route reduced costs,increased yields,and shortened route time,making it suitable for large-scale industrial production.