PF-4989216的合成工艺优化

Research on the synthesis of PF-4989216

以价廉易得的丙二腈为起始原料,经二硫化碳/碘甲烷取代、巯基乙酸乙酯环合、桑德迈尔反应制得中间体(5),5再经钨酸钠/双氧水体系氧化进而得到中间体(6),6经吗啉取代后再与2-氟-4-氰基苯硼酸进行Suzuki偶联得到中间体(8),8与甲酰胺/甲醇钠反应进一步制得酰胺9,9与DMF-DMA发生缩合后再与水合肼环合制得PF-4989216,总收率19.6%(以2计),纯度99.73%。该路线反应条件温和、操作简单,具有较好的工业化前景。

Starting from inexpensive and readily available malononitrile,intermediate 5 was synthesized via 3 steps through carbon disulfide/iodomethane substitution,cyclization with ethyl mercaptoacetate and Sandmeyer reaction,5 was then oxidized to sulfone 6 under the condition of sodium tungstate dihydrate and hydrogen peroxide,further substituted with morpholine and Suzuki coupling with(4-cyano-2-fluorophenyl)boronic acid provided 8,which was then converted to the amide 9 with formamide/sodium methoxide,subsequent condensation with DMF-DMA and cyclization with hydrazine hydrate obtained PF-4989216.The total yield was 19.6%and the purity was 99.73%.With the advantages of easy availability of raw materials,easy to handle,this route was suitable for the industrial production.