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) T790M 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.