Development of a Safe and Scalable Method to Prepare 3-Bromo-N-alkyl-1,6-naphthyridones via Enamine Cyclization

A safe and efficient method to make N-alkyl-1,6-naphthyridones from primary amines is described. Due to issues with existing methodology involving strong exotherms and harsh reagents (triazine/alkyl halides), to prepare N-alkyl-1,6-naphthyridones, a method was developed that avoids these hazardous reagents and conditions. The developed route involved the preparation of a key enamine intermediate as a stable and isolatable solid, which could then undergo cyclization with primary amines to afford a variety of N-alkyl-1,6-naphthyridones that are of high interest in the preparation of pharmaceutically relevant molecules.