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Synfacts 2019; 15(10): 1091
DOI: 10.1055/s-0039-1690625
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of AZD6738

Contributor(s):
Philip Kocienski
Goundry WR. F. * Dai K, Gonzalez M, Legg D, O’Kearney-McMullan A, Morrison J, Stark A, Siedlecki P, Tomlin P, Yang J. AstraZeneca, Macclesfield, UK; Changzhou SynTheAll Pharmaceutical Co., Ltd., Changzhou and Asymchem Laboratories Co. Ltd., Tianjin, P. R. of China
Development and Scale-up of a Route to ATR Inhibitor AZD6738.

Org. Process Res. Dev. 2019;
23: 1333-1342
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Further Information

Publication History

Publication Date:
17 September 2019 (online)

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Key words

AZD6738 - asymmetric sulfoxidation - sulfoximines - biocatalysis - rhodium catalysis

Significance

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.


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Comment

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.


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