一种Voxelotor衍生物的合成

Synthesis of A Voxelotor Derivative

以沃塞洛托(Voxelotor,2)为原料,通过亲核加成、氧化等2步反应,得到Voxelotor衍生物2-羟基-6-((2-(1-异丙基-1H-吡唑-5-基)吡啶-3-基)甲氧基)苯基丙-2-烯-1-酮(1),通过1HNMR和ESI-MS对中间体4及目标化合物1的结构进行了表征,并对中间体4及目标化合物1的合成条件进行了优化。结果表明,最佳亲核加成反应条件为:物料比n(乙烯基溴化镁)∶n(2)为2.0∶1、反应时间为2 h,在此条件下,中间体4收率为62%;最佳氧化反应条件为:反应溶剂为二氯甲烷、氧化剂2-碘酰基苯甲酸(IBX)用量n(IBX)∶n(4)为1.2∶1、反应时间为22 h,在此条件下,目标化合物1收率为54%。

Using Voxelotor(2)as a starting material,we obtained Voxelotor derivative 2-hydroxy-6-((2-(1-isopropyl-1 H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenylpropyl-2-ene-1-one(1)through a two-step reaction of nucleophilic addition and oxidation.Moreover,we characterized the structures of intermediate 4 and target compound 1 by 1 HNMR and ESI-MS,and optimized the synthesis conditions of intermediate 4 and target compound 1.The results show that the yield of intermediate 4 can reach 62%under the optimal nucleophilic addition reaction conditions as follows:the material ratio of n(vinylmagnesium bromide)∶n(2)is 2.0∶1,and the reaction time is 2 h.In addition,the yield of target compound 1 can reach 54%under the optimal oxidation reaction conditions as follows:dichloromethane is adopted as the reaction solvent,the dosage of oxidant 2-iodoacyl benzoic acid(IBX)n(IBX)∶n(4)is 1.2∶1,and the reaction time is 22 h.