摘要
开发了一种醛糖还原酶抑制剂(2S,4S)-6-氟-2,3-二氢-2',5'-二氧螺(4H-1-苯并吡喃-4,4'-咪唑基)-2-酰胺化合物的新合成方法,以价格优廉的马来酰亚胺和对氟苯酚为原料,经Oxo-Michael加成反应、水解反应、手性拆分试剂(S)-α苯乙胺拆分得到高光学纯度的(S)2-(4-氟苯氧基)-1,4丁二酸,后经环化反应、布克尔反应与酰胺化反应得目标产物,总收率24%。合成过程中所有的中间体及目标产物均经比旋光度、1HNMR测定并与参考文献值比较。本方法成本低、收率较高、反应条件温和、反应环境较为友好、合成后处理操作简便并且安全,适合大规模制备。
TDeveloped a new synthetic method of an aldose reductase inhibitor(2S,4S)-6-fluoro-2,3-dihydro-2',5'-dioxospiro (4H-1-benzopyran-4,4'-imidazolyl)-2-amide compound.The high optical purity(S)-2-(4-fluorophenoxy) -1,4 succinate was prepared from 4-fluoropehnol and N-phenylmaleimide,which are inexpcnsive and casily availabe starting material,via Oxo-Michael addition reaction hydrolysis reaction,the(S)-α-phenethylamine split chiral Reagents and the cyclization reaction.The objective product obtained by the Boekel reaction and amidation reaction,total yield 24%.All intermediates and target product of synthesis process were measured and compared with the reference value by the specific optical rotation,1H NMR.The method was suitable for large-scale preparation which was low cost,high yield,mild reaction conditions,environmental friendly and synthesis post-processing operation was simple and safe.
