Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction

    • Mark A. Graham*a
    • Gary Noonan*a
    • Janette H. Cherrymana
    • Miguel Gonzalezb
    • Lucinda V. Jacksona
    • Kevin Lesliea
    • Zhi-qing Liub
    • David McKinneya
    • Rachel H. Mundaya
    • Chris D. Parsonsc
    • David T. E. Whittakerc
    • En-xuan Zhangb
    • Jun-wang Zhangb
    • aChemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 2NA, U.K.
    • bAsymchem Laboratories (Tianjin) Co. Ltd., TEDA, Tianjin 300457, P. R. China
    • cEarly Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield SK10 2NA, U.K.

    New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern–Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proof-of-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

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