芬太尼合成方法的优化改进

A developed method for synthesis of fentanyl

目的优化芬太尼的合成方法。方法以β-苯乙胺为起始原料,经过aza-Michael加成、Dieckmann酯缩合、还原胺化以及酰化4步反应合成芬太尼。其中aza-Michael加成反应以硼酸为催化剂、水为溶剂;Dieck-mann酯缩合反应以氢化钠为碱、甲苯为溶剂;还原胺化反应中,胺化以对甲苯磺酸为催化剂、异丙醚为溶剂,还原以硼氢化钠为还原剂、甲醇为溶剂。结果与结论aza-Michael加成反应收率为92%,Dieckmann酯缩合反应收率为85%,还原胺化收率为66%,合成芬太尼的总收率为45%。该合成方法路线简短、原料易得、操作简单、收率较高。

Fentanyl is a potent analgesic agent characterized by high potency,rapid onset and short duration of action and is extensively used in clinics.The methods for synthesis of fentanyl reported in literatures employed N-substituted piperidin-4-one as starting material.The developed synthesis we reported involved an efficient construction of N-（2-phenylethyl） piperidin-4-one,which was carried out from β-phenylethylamine and methyl acrylate by performing aza-Michael addition and Dieckmann condensation followed by decarboxylation.N-（2-phenylethyl） piperidin-4-one was then converted to fentanyl via reductive amination and propionylation.Reactions of aza-Michael addition,Dieckmann condensation and reductive amination were studied in detail.Boric acid was used as catalyst and water as solvent to perform aza-Michael addition reaction.Hydride sodium was used as base and THF as solvent to perform Dieckmann condensation.In the procedure of reductive amination,diisopropyl ether was employed as solvent to remove the produced water by azeotropic distillation so as to promote the amination;Schiff base was then reduced by NaBH4.The yield was 92%,85% and 66% respectively.The overall yield was 45%.The purity（GC）=99%.The developed method has many advantages over other methods such as simple starting materials,mild reaction conditions,ease operations and high yield.