左西孟旦中间体6-(4-氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮的合成新方法

A novel synthesis of levosimendan intermediate 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone

目的:设计经济、安全、实用的制备6-(4-氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮的路线。方法:以乙酰苯胺和2-氯丙酰氯为起始原料,经傅克酰化,缩合,水解脱羧及环合得到目标产物。结果:酰化、缩合、水解脱羧和环合收率分别为85%,90%,88%和96%,总收率64.6%。各步产物结构经HPLC和核磁共振氢谱确证,终产物纯度99%以上。结论:新合成路线以2-氯丙酰氯与乙酰苯胺的傅克酰化一步反应代替文献中的两步反应,具有原料价廉易得、操作简便、安全性好等优点,适合工业化生产。

Objective：To develop an economical,safe and practical method to produce levosimendan intermediate 6-（4-aminophenyl）-5-methyl-4,5-dihydro-3（2H）-pyridazinone.Methods：Acetanilide was acylated with 2-chloropropionyl chloride,condensed with diethyl malonate,hydrolysed and decarboxylated,and cyclized to obtain the targeted compound.Results：Yields of acylation,condensation,hydrolysis and decarboxylation,and cyclization were 85%,90%,88% and 96%,respectively.The overall yield was 64.6% and all compounds were characterized by HPLC and 1H-NMR spectroscopy.Conclusion：The new method includes two-step literature processes of Friedel-Crafts acylation of acetanilide with propionyl chloride,and bromination replaced by direct Friedel-Crafts acylation of acetanilide with 2-chloropropionyl chloride.The novel process combines the advantages of lower materials cost,simpler process,and safer operation,and can be scaled up readily.