阿维莫泮合成中Aza-Michael加成反应的优化

Optimization of Aza-Michael Addition Reaction in Synthesis of Alvimopan

目的改进阿维莫泮关键中间体的合成工艺。方法在阿维莫泮的手性诱导合成—(3R,4R)-4-(3-羟苯基)-3,4-二甲基哌啶与α,β-不饱和酯(或酰胺)的Aza-Michael加成反应中,添加硝酸铈铵(CAN)可以提高反应的立体选择性和收率,缩短反应时间。结果当底物为α,β-不饱和酰胺时,加入硝酸铈铵,-20℃下反应6 h,两个非对映异构体产物的比例为15.5∶1,收率达到88%。结论该路线简捷,昂贵的哌啶原料消耗少,具有较好的应用价值。

Objective To improve the synthesis process of a key intermediate for Alvimopan. Methods After ceric ammonium nitrate（ CAN） was used as an additive in the asymmetric Aza-Michael addition of（ 3R,4R）-4-（ 3-hydroxyphenyl）-3,4-dimethylpiperidine to α,β-unsaturated ester（ or amide）,both the diastereomeric ratio（ d. r） and yield were increased sharply,and reaction time was drastically shorted. Results For α,β-unsaturated ester amide as a substrate in the presence of CAN,the reaction at-20 ℃ was completed at a d. r of 15. 5 ∶1 in 88% yield within 6 h. Conclusion This brief synthetic technology with less consumption for the expensive piperidine may be more valuable for industry.