单核细胞趋化蛋白1抑制剂宾达利的合成及表征

Synthesis and characterization of bindarit, an inhibitor of monocyte chemoattractant protein 1

摘要:

为了解决目前宾达利(BIN)合成工艺难放大生产的问题，报道了一种高效制备BIN的新方法。以吲唑-3-羧酸为起始原料，经酯化反应得到吲唑-3-羧酸甲酯(Ⅰ)，该中间体与苄溴反应得到1-苄基吲唑-3-羧酸甲酯(Ⅱ)，随后酯基进一步被硼氢化钠还原得到1-苄基吲唑-3-甲醇(Ⅲ)。最后中间体Ⅲ与氯仿、丙酮在碱性条件下反应得到目标产物BIN，通过核磁氢谱、碳谱、质谱和元素分析对BIN结构进行了表征。该反应的最佳条件为：n(Ⅲ)∶n(NaOH)∶n(CHCl3) = 1∶10∶4，反应温度为55 ℃，反应时间为3 h，BIN产率65%。该方案步骤简单，原料廉价易得，总收率可达38.4%，易于工业化生产。

Abstract:

In order to solve the problem that bindarit (BIN) is difficult to industrially produce, a new and efficient method for the synthesis of BIN was reported. Firstly, methyl 1H-indazole-3-carboxylate (Ⅰ) was prepared by using 1H-indazole-3-carboxylic acid as the starting material. Then, the intermediate Ⅰ reacted with benzyl bromide to obtain methyl 1-benzyl-1H-indazole-3-carboxylate (Ⅱ), and the ester group was further converted to (1-benzyl-1H-indazol-3-yl)methanol (Ⅲ) by reaction with sodium borohydride. Finally, the target product BIN was obtained by the reaction of the intermediate Ⅲ with chloroform and acetone in the presence of sodium hydroxide. The optimum conditions for the synthesis of BIN were obtained as follows: n(Ⅲ)∶n(NaOH)∶n(CHCl3) = 1∶10∶4, reaction temperature is 55 ℃, reaction time is 3 hours. The structure of the BIN was confirmed by 1H NMR, 13C NMR, HR-MS and elemental analysis. This method is characterized by high yield, simple and convenient operation, cheap and easily available raw materials and easy industrialized production.