小分子c-Met激酶抑制剂Foretinib的合成

Synthesis of The Small Molecule c-Met Kinase Inhibitor Foretinib

Foretinib是处于临床研究阶段的小分子c-Met激酶抑制剂,而现有的合成路线普遍存在总收率较低的问题。本文以4'-羟基-3'-甲氧基苯乙酮(2)作为起始原料,经醚化、硝化、亲核取代、缩合、还原环合、氯代、醚化、还原和酰化反应制得目标化合物Foretinib(1),总收率为26.06%,纯度为99.40%。Foretinib及反应中间体的结构经1H NMR和MS(ESI)确征。上述合成路线反应条件温和,操作简便且收率高,适合工业化生产。

Foretinib(1)is a small molecule c-Met kinase inhibitor in clinical trials.The reported synthetic routes generally have low yield.In this paper,4'-hydroxy-3'-methoxyacetophenone(2)was used as starting material to prepare the target compound Foretinib via etherification,nitrification,nucleophilic substitution,condensation,reduction cyclization,chlorine substitution,etherification,reduction and acylation reaction.The total yield was 26.06%and the purity was 99.40%.The chemical structures of Foretinib and its intermediates were confirmed by 1H NMR and MS(ESI).The above synthetic route exhibited advantages of mild reaction conditions,simple experimental operation and high total yield.It is suitable for industrial production.