CDK4/6抑制剂abemaciclib合成工艺的优化

对采用异丙胺和6-溴-3-吡啶甲醛为原料合成肿瘤抑制剂abemaciclib的工艺路线进行了优化，结果表明:在合成中间体6-（2-氯-5-氟嘧啶-4-基）-4-氟-1-异丙基-2-甲基-1H-苯并［d］咪唑的过程中，苯环亲核取代反应采用t-BuONa为碱，产率为83.0%；Suzuki偶联反应中硼酸酯化和脱硼酸酯，催化剂均可采用PdCl2（PPh3）2。在合成中间体5-（（4-乙基哌嗪-1-基）甲基）吡啶-2-胺的过程中，还原胺化反应时加入催化量的乙酸，反应可完全进行；氨基取代吡啶环上溴原子的反应中以乙二醇为溶剂，N，N′-二甲基乙二胺（DMEDA）为配体，收率达90.0%。两中间体发生Buchwald-Hart wig偶联反应时，以K2CO3为碱，收率达92.4%。优化后总收率为44.6%，较原工艺提高19.6%，且反应条件温和，适合工业化生产。

Synthetic Process Optimization of CDK4/6 Inhibitor Abemaciclib

The synthetic process of tumor inhibitor abemaciclib using isopropylamine and 6-bromo-3-pyridine formaldehyde as starting materials was optimized. The results showed that during the process of synthesizing the intermediate 6-（2-chloro-5-fluoropyrimidin-1-isopropyl-2-methyl-1H-benzo［d］ imidazole， the yield in nucleophilic substitution reaction on benzene ring was 83.0% using t-BuONa as the base and PdCl2（PPh3）2 as the catalyst in boric acid and de-boric acid esterifications. During the process of synthesizing other intermediate 5-（（4-ethylpiperazin-1-yl）methyl）pyridin-2-amine， reductive amination reaction occurred completely by adding a catalytic amount of acetic acid. The yield of the substitution reaction of bromo atom in pyridine by amino group was 90.0% using ethylene glycol as solvent and N，N′-dimethylethane-1，2-diamine （DMEDA）? as ligand. The yield of the Buchwald-Hart wig coupling reaction of two intermediates was 92.4% employing K2CO3 as the base. The total yield was 44.6% after optimization， which was 19.6% more than that of the original process. The reaction conditions are mild and suitable for industrial production.