| 阿维莫泮合成中Aza-Michael加成反应的优化 |
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| 引用本文： | 陈忠,;鲁毅,;黄杨威,;林燕琴,;王娟,;魏宗有,;赵学清.阿维莫泮合成中Aza-Michael加成反应的优化[J].广东药学,2014(12):844-847. |
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| 作者姓名： | 陈忠 ;鲁毅 ;黄杨威 ;林燕琴 ;王娟 ;魏宗有 ;赵学清 |
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| 作者单位： | [1]福建省微生物研究所,福建福州350007; [2]福建省新药(微生物)筛选重点实验室,福建福州350007; [3]福建省中医药大学药学院,福建福州350122 |
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| 基金项目： | 福建省科技计划重点项目（编号：2012Y0075） |
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| 摘 要： | 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。
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| 关 键 词： | 阿维莫泮 硝酸铈铵 Aza-Michael加成 手性诱导合成 |
Optimization of Aza-Michael Addition Reaction in Synthesis of Alvimopan |
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| Institution: | CHEN Zhong, LU Yi, HUANG Yangwei, LIN Yanqin, WANG Juan, WEI Zongyou, ZHAO Xueiqng (1. Fujian Institute of Microbiology, Fuzhou, Fujian 350007, China;2. Fujian key laboratory of novel drugs(Mierobialogy), Fuzhou, Fujian, 350007, China; 3. Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, China) |
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| Abstract: | 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. |
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| Keywords: | alvimopan ceric ammonium nitrate aza-michael addition chiral induction synthesis |
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