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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Bibliographic Details
Published inOrganic process research & development Vol. 23; no. 3; pp. 382 - 388
Main Authors Tao, Yong, Keene, Nandell F, Wiglesworth, Kristin E, Sitter, Barbara, McWilliams, J. Christopher
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 15.03.2019
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
amidation
SEM deprotection
Negishi coupling
EGFR T790 M inhibitor
regioselective SNAr reaction
Buchwald−Hartwig coupling
Buchwald-Hartwig coupling
IMIDAZOLES
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Summary: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