Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin

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• 作者：Gösta Rimmler ; Andre Alker ; Marcello Bosco ; Ralph Diodone ; Dan Fishlock ; Stefan Hildbrand ; Bernd Kuhn ; Christian Moessner ; Carsten Peters ; Pankaj D. Rege ; Markus Schantz
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：December 16, 2016
• 年：2016
• 卷：20
• 期：12
• 页码：2057-2066
• 全文大小：466K
• ISSN：1520-586X

文摘

A concise catalytic asymmetric synthesis of idasanutlin (1) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction. Further development of the [3 + 2] cycloaddition reaction resulted in an improvement in diastereoselectivity and enantioselectivity by changing the catalyst system to Cu(I)/BINAP. While producing equivalent high quality API, the copper(I) catalyzed process not only increased the overall yield but also demonstrated benefit with respect to cycle times, waste streams, and processability. The optimized copper(I) catalyzed process has been used to prepare more than 1500 kg of idasanutlin (1).