尼拉帕尼关键中间体的合成工艺改进

Improvement of synthetic process for key niraparib intermediate

本研究报道了一条尼拉帕尼关键中间体(S)-叔丁基3-(4-氨基苯基)哌啶-1-羧酸(1)的新合成路线。以3-溴吡啶作为原料,经过熊田偶联、催化氢化、拆分、硝化、还原、Boc保护制得1。采用镍催化的熊田偶联替代原来钯催化的Suzuki偶联,不仅大幅降低了成本,同时还提高了收率;用Pd/C催化氢化替代PtO2催化,Pd/C催化剂可实现多次套用活性不下降,显著降低了成本;将氨基放在拆分之后引入,可以将拆分收率提升一倍,同时提高了产品的ee值。总收率17.5%,产品纯度98.95%,手性纯度99.92%。

A novel route for the synthesis of key intermediate(S)-tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate(1)was established.Using 3-bromopyridine as raw material,1 was prepared by Kumada coupling,catalytic hydrogenation,separation,nitrification,reduction and Boc protection.The Kumada coupling catalyzed by nickel was used instead of palladiumcatalyzed Suzuki coupling,which can not only greatly reduce the cost,but also improve the yield.Using Pd/C catalytic hydrogenation instead of PtO2 catalyst,the Pd/C catalyst can achieve repeated application without activity decrease,and the cost can be significantly reduced.Adding the amino group after the resolution can double the yield and increase the ee value of the product with total yield 17.5%,product purity 98.95% and chiral purity 99.92%.