热休克蛋白90抑制剂SNX-2112的合成与优化

Synthesis and optimization of heat shock protein 90 inhibitor SNX-2112

目的对热休克蛋白90(HSP90)抑制剂SNX-2112合成方法的探索及优化。方法以2-氟-4-溴苄腈作为起始原料,通过N-烃化、环化、脱保护、乌尔曼偶联、水解等反应得到目标产物。中间体及目标化合物的结构经MS和1H NMR确认。同时,采用微波法对关键中间体D的合成方法进行了优化。结果与结论微波法使中间体D合成方法操作简便可控,虽产率略低于文献报道值,但大大缩短反应时间,提高起始物料反应的原子经济性,更适合产业化。

Objective To explore and optimize the synthesis of heat shock protein 90（HSP90）inhibitor SNX-2112. Methods Starting from 2-fluoro-4-bromobenzonitrile,the target product was obtained by the reaction of N-alkylation,cyclization,deprotection,Ullmann coupling and hydrolysis. The structures of intermediates and target compound were confirmed by MS and1 H NMR.Meanwhile,synthesis of the key intermediate D was optimized through microwave system. Results and Conclusion Although the yield of intermediate D is slightly lower than the literature value,the use of microwave synthesis could greatly reduce the reaction time and improve the atomic economy of the starting material reaction,which might be easier to control and be more suitable for industrialization.