Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib

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• 作者：Cheol K. Chung ; Paul G. Bulger ; Birgit Kosjek ; Kevin M. Belyk ; Nelo Rivera ; Mark E. Scott ; Guy R. Humphrey ; John Limanto ; Donald C. Bachert ; Khateeta M. Emerson
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：January 17, 2014
• 年：2014
• 卷：18
• 期：1
• 页码：215-227
• 全文大小：694K
• ISSN：1520-586X

文摘

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鈥揘 cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.