一种HCV抑制剂中间体9-羟基-6-氧-4-甲基菲啶的全合成
Total synthesis of 9-hydroxy-6-oxo-4-methylphenanthridine for a HCV-inhibiting intermediate
云南民族大学学报:自然科学版,2016,25(6):499-502

杨碧娟 YBJ

摘要


石蒜碱具有明显的抗丙肝病毒感染HCV(hepatitis C virus,HCV)活性,在对石蒜碱衍生物进行抗HCV活性研究时发现其中菲啶类化合物普遍具有比较良好的抗HCV活性,由于此类化合物活性优良,毒性较低,因此有必要对其进行深入的结构修饰与构效关系研究.对菲啶类衍生物重要合成中间体 9-羟基-6-氧-4-甲基菲啶进行了全合成,该方法以2-溴-5-甲氧基苯甲酸为原料,包括酰胺化、偶联反应、以及脱甲基等3步,其中钯催化芳基-芳基,N-芳基一步偶联为该合成方法关键步骤,该方法步骤简便,原料简单易得,收率较高(总收率54%)可以为后续研究提供稳定的化合物来源. The previous studies reveal that galanthidine has obvious anti- HCV activities. The phenanthridine compounds as the derivative of galanthidine have good anti- HCV activities and low toxicity, which deserves further studies. This research focuses on a three-step synthesis of 9-hydroxy-6-oxo-4-methylphenanthridine, as the key intermediate of a series of potent HCV inhibitors. This synthesis features a consecutive aryl-aryl and N-aryl coupling, leading to 9-methyl-6-oxo-4-methylphenanthridine, whose structure is determined by the spectroscopic analysis and X-ray crystallography, in a one-pot aryl-aryl and N-aryl coupling sequence with the presence of palladium catalyst and the usage of TFP (Tri(2-furyl)phosphine) as the ligand. For higher yields, the conditions of the key reaction are studied and optimized with an overall yield of 54%.

参考



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