沃塞洛托的合成工艺研究

Study on the synthetic process of voxelotor

目的改进沃塞洛托的合成工艺。方法以2,6-二羟基苯甲酸(2)为起始原料,与丙酮反应得到5-羟基-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮,其与3-溴丙烯反应得到5-(烯丙氧基)-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮,经DIBAL-H还原得到2-(烯丙氧基)-6-羟基苯甲醛,再经羟烷基化反应得到2-(烯丙氧基)-6-{[2-(1-异丙基-1H-吡唑-5-基)吡啶-3-基]甲氧基}苯甲醛,最后脱除烯丙基保护基得到沃塞洛托。结果与结论目标化合物及其中间体的结构经^(1)H-NMR和ESI-MS谱确证,总收率为64.3%(以化合物2计),纯度为98.3%(HPLC法)。本工艺操作简便,原料价廉易得,适合工业化生产。

The synthetic process of voxelotor was reported.The 2,6-dihydroxy-benzoic acid(2)was used as the starting material,which reacted with acetone to give 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one.The latter was reacted with 3-bromoprop-1-ene to produce 5-(allyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one.Then it was reduced by DIBAL-H to afford 2-(allyloxy)-6-hydroxy-benzaldehyde,which was followed by a hydroxyl alkylation reaction to afford 2-(allyloxy)-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.Finally,the target compound was obtained by removing the allyl protecting group with a total yield of 64.3%(based on compound 2)and a purity of 98.3%(HPLC).The synthetic process has many advantages,such as simple operation,low cost,easy availability of raw materials.