Synthesis of AZD6738
Development and Scale-up of a Route to ATR Inhibitor AZD6738.
Org. Process Res. Dev. 2019;
17 September 2019 (online)
Workers at AstraZeneca recently reported a mol-scale synthesis of ATR inhibitor AZD6738 based on the use of chiral HPLC to access the chiral sulfoxide intermediate G (J. Med. Chem. 2018, 61, 9889). A plant scale synthesis of AZD6738 is now reported that features a biocatalytic asymmetric sulfoxidation reaction (F → G) and a cyclopropanation (J → L) in continuous stirred tank reactors.
The sulfoxidation reaction uses a Baeyer–Villiger monooxygenase in tandem with nicotinamide adenine dinucleotide phosphate (NADPH), which is oxidized to NADP+. NADPH is then regenerated through reduction of NADP+ by a ketoreductase (KRED) enzyme, which in turn oxidizes the co-solvent isopropanol to acetone. Efficient gas–liquid mass transfer of oxygen is key to obtaining a high yield.