Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib
Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib
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DOI：
10.1021/op400233z
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发表时间：
2014-01-01
影响因子：
3.4
通讯作者：
Emerson, Khateeta M.
中科院分区：
文献类型：
--
作者：
Chung, Cheol K.;Bulger, Paul G.;Emerson, Khateeta M.
描述了口服活性聚（ADP-核糖）聚合酶抑制剂Niraparib的合成工艺开发。两个新的不对称路线的报告，这收敛于一个高产率，区域选择性，铜催化的N-芳基化的吲唑衍生物作为后期的片段耦合步骤。新型转氨酶介导的动态动力学拆分外消旋醛替代品提供了对映选择性合成的3-芳基-哌啶偶联伴侣。C-N交叉偶联产物转化为最终API通过脱保护和盐复分解以分离所需结晶盐形式来实现。
Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N-arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C-N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.