Early Process Development of an Irreversible Epidermal Growth Factor Receptor (EGFR) T790 M Inhibitor

The original synthesis of the irreversible epidermal growth factor receptor (EGFR) T790 M inhibitor 1 was enabled by successful application of ammonium hydroxide to cleanly cleave the N-hydroxymethyl group and by development of high yielding conditions for the subsequent amidation reaction. Furtherm...

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Veröffentlicht in:Organic process research & development 2019-03, Vol.23 (3), p.382-388
Hauptverfasser: Tao, Yong, Keene, Nandell F, Wiglesworth, Kristin E, Sitter, Barbara, McWilliams, J. Christopher
Format: Artikel
Sprache:eng
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Zusammenfassung:The original synthesis of the irreversible epidermal growth factor receptor (EGFR) T790 M inhibitor 1 was enabled by successful application of ammonium hydroxide to cleanly cleave the N-hydroxymethyl group and by development of high yielding conditions for the subsequent amidation reaction. Furthermore, a protection-free and regioselective new synthetic route was developed that shortened the synthesis from the original 8 steps to 6 steps and improved the overall yield from 5% to 34% on scale. Crystallizations of 1 and intermediates were correspondingly developed to control the quality en route.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.8b00437