【摘要】 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,与三氯氧磷回流反应得到2-氯-3-氰基-4,6-二甲基吡啶(3),3经过锌粉还原脱卤素得3-氰基-4,6-二甲基吡啶(4),随后用二碳酸二叔丁酯保护氨基,通过雷尼镍/氢气还原,脱保护后得到关键中间体(4,6-二甲基吡啶-3-基)甲胺(6)的三氟乙酸盐。6的三氟乙酸盐与6-氯-2-氟-9H-嘌呤(7)、异丙醇溴经亲核取代,得N-[(4,6-二甲基吡啶-3-基)甲基]-2-氟-9-异丙基-9H-嘌呤-6-胺(9),9与(2R,3S)-3-氨基戊-2-醇(10)通过微波反应得到目标化合物1。该路线总收率为9.0%(以2计),原料2经济易得,利用微波合成降低成本,可为1及其结构类似物的合成提供一定的参考。更多还原

【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.更多还原