Magnesium Ethoxide Promoted Conversion of Nitriles to Amidines and Its Application in 5,6-Dihydroimidazobenzoxazepine Synthesis

Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6-dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method

Development of an Efficient Manufacturing Process for Reversible Bruton’s Tyrosine Kinase Inhibitor GDC-0853

Efforts toward the process development of reversible Bruton’s tyrosine kinase (BTK) inhibitor GDC-0853 (<b>1</b>) are described. A practical synthesis of GDC-0853 was accomplished via a key highly regioselective Pd-catalyzed C–N coupling of tricyclic lactam <b>5</b> with 2,4-dichloronicotinaldehyde (<b>6</b>) to afford the C–N coupling product <b>3</b>, a Suzuki–Miyaura cross-coupling of intermediate <b>3</b> with boronic ester <b>4</b> derived from a Pd-catalyzed borylation of tetracyclic bromide <b>7</b>, to generate penultimate aldehyde intermediate <b>2</b> and subsequent aldehyde reduction and recrystallization. Process development of starting materials <b>5</b>, <b>6</b>, and <b>7</b> is also discussed