Chemoenzymatic Synthesis of tert-Butyl ((3R, 6R)-6-methyl-piperidin-3-yl)carbamate: A Key Intermediate in Orexin Receptor Antagonist and IRAK4 Inhibitor

Abstract

tert-Butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate is a pivotal pharmaceutical intermediate and active pharmacophore in drug synthesis, encompassing applications in orexin receptor antagonist and IRAK4 inhibitor. To date, a simple and efficient synthetic route remains a challenging issue for chemists in constructing chiral centers. In this study, we present a practical process for the preparation of tert-butyl ((3R,6R)-6-methylpiperidin-3-yl)carbamate, the key chiral intermediate via a chemoenzymatic strategy from commercially available ethyl N-Boc-D-pyroglutamate, which undergoes transamination-spontaneous cyclization process by transaminase (ATA) biocatalyst. Our study outlines a shortened-step streamlined procedure circumventing a significant amount of toxic chemicals and hazardous reaction conditions, and features cost-effective and high optical purity with >99.9% enantiomeric excess. The process features great prospect of industrialization application.