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

• Mark A. Graham*^a
• Gary Noonan*^a
• Janette H. Cherryman^a
• Miguel Gonzalez^b
• Lucinda V. Jackson^a
• Kevin Leslie^a
• Zhi-qing Liu^b
• David McKinney^a
• Rachel H. Munday^a
• Chris D. Parsons^c
• David T. E. Whittaker^c
• En-xuan Zhang^b
• Jun-wang Zhang^b

• ^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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