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目的改进脂蛋白酶A2抑制剂darapladib的合成方法。方法以对甲酰基苯硼酸(2)为原料,经醛胺缩合、氢化还原和Suzuki偶联一锅法合成N,N-二乙基-N’-(4’-三氟甲基-4-联苯基甲基)-1,2-乙二胺(4);以己二酸二甲酯(5)为原料,经Dieckmann缩合环化、杂环化和硫醚化制得[2-(4-氟苄硫基)-4-氧代-4,5,6,7-四氢-1H-环戊并嘧啶-1-基]乙酸(8);中间体8与4经酰胺化缩合制得darapladib。结果与结论 Darapladib及关键中间体的结构经1H-NMR谱确证,合成darapladib的4步反应总收率达49.8%(以己二酸二甲酯计)。本合成路线具有原料易得、工艺简单、收率高等优点,适合于规模化制备。
Objective To improve the synthesis of lipoprotein A2 inhibitor darapladib. Methods The p-formylbenzeneboronic acid (2) was used as a starting material to synthesize N, N-diethyl-N ’- (4’-trifluoromethyl- Biphenyl methyl) -1,2-ethylenediamine (4); dimethyl adipate (5) as raw material, Dieckmann condensation cyclization, heterocyclic and thioether [2- Fluorobenzylthio) -4-oxo-4,5,6,7-tetrahydro-1H-cyclopentapyrimidin-1-yl] acetic acid (8); Intermediate 8 and 4 were subjected to amidation condensation Got darapladib. RESULTS AND CONCLUSIONS The structures of Darapladib and key intermediates were confirmed by 1H-NMR spectroscopy. The total yield of 4-step synthesis of darapladib was 49.8% (as dimethyl adipate). The synthetic route has the advantages of readily available raw materials, simple process and high yield, and is suitable for large-scale preparation.