CDK4/6抑制剂abemaciclib合成工艺的优化

Synthetic Process Optimization of CDK4/6 Inhibitor Abemaciclib

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-Bu ONa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Pd Cl2(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。

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-l-isopropyl-2-methyl-lH-benzo [d] imidazole, the yield in nucleophilic substitution reaction on benzene ring was 83.0% using t-BuONa as the base and PdC12 （PPh3）2 as the catalyst in boric acid and de-boric acid esterifications. During the process of synthesizing other intermediate 5-（（4-ethylpiperazin-l-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.