Grignard Reagent Utilization Enables a Practical and Scalable Construction of 3-Substituted 5-Chloro-1,6-naphthyridin-4-one Derivatives.

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition–acidolysis–cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.