A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald–Hartwig Amination and Bruylants Reactions

Abstract

A practical, chromatography-free synthesis for a chemokine receptor antagonist NIBR-1282 (1) is described. Highlights of this scalable synthesis include (1) Buchwald–Hartwig amination reaction using (t-Bu)3P as the ligand and 5–12 mol % of water as an additive affording 6 with yield increase of more than 2-fold; (2) a variant of the Bruylants reaction for the synthesis of α-methyl amine 10 via aminotriazole 15a, instead of classical amino nitrile 8; and (3) development of a crystallization-induced, atropisomer transformation leading to predominantly one atropisomer 1. The new approach was employed for the manufacturing of kilogram quantities of the target active pharmaceutical ingredient.