定义Definition
汉奇吡啶合成是醛、两分子 β-酮酸酯（如乙酰乙酸乙酯）和氨（或乙酸铵）的多组分缩合，先生成 1,4-二氢吡啶，再经氧化得到吡啶衍生物。
The Hantzsch synthesis is a multicomponent condensation of an aldehyde, two equivalents of a β-keto ester (such as ethyl acetoacetate) and ammonia (or ammonium acetate) giving a 1,4-dihydropyridine, which is oxidised to the pyridine.
机理Mechanism
一分子 β-酮酸酯与醛发生克诺文纳格尔缩合生成 α,β-不饱和羰基化合物；另一分子与氨生成烯胺。烯胺对不饱和体系迈克尔加成，再分子内缩合、脱水闭环成 1,4-二氢吡啶。
One keto ester undergoes Knoevenagel condensation with the aldehyde; the other forms an enamine with ammonia. Michael addition of the enamine, intramolecular condensation and dehydration close the 1,4-dihydropyridine ring.
由来Origin
德国化学家阿图尔·汉奇于 1881 年报道，是最早的多组分反应之一。
Reported by the German chemist Arthur Hantzsch in 1881 — one of the earliest multicomponent reactions.
药物与生物学意义Medicinal and biological relevance
1,4-二氢吡啶本身是重要药物骨架：硝苯地平、氨氯地平等钙通道阻滞剂用于治疗高血压和心绞痛。二氢吡啶也模拟了 NADH 的还原作用（汉奇酯常用作有机还原剂）。
1,4-Dihydropyridines are a major drug scaffold: calcium-channel blockers such as nifedipine and amlodipine treat hypertension and angina. They also mimic NADH, and ‘Hantzsch ester’ is a common organic hydride donor.
反应Reactions
乙醇回流；氧化可用 HNO₃、MnO₂、DDQ 等
Refluxing ethanol; oxidation with HNO₃, MnO₂, DDQ, etc.
醛与 β-酮酸酯克诺文纳格尔缩合。
Knoevenagel condensation of aldehyde and keto ester.
另一分子 β-酮酸酯与氨生成烯胺。
The second keto ester forms an enamine with ammonia.
迈克尔加成后环化脱水得 1,4-二氢吡啶。
Michael addition, cyclisation and dehydration give the dihydropyridine.
氧化芳构化得吡啶。
Oxidation aromatises to the pyridine.
钙通道阻滞剂的合成。
Synthesis of the calcium-channel blocker nifedipine.
年表Timeline
- 1881
汉奇报道该合成
Hantzsch reports the synthesis
- 1975
硝苯地平作为降压药上市
Nifedipine is launched as an antihypertensive