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

• Main Authors: Ming-Shu Wang, Yi Gong, Zhi-Cheng Yu, Yan-Guang Tian, Lin-Sheng Zhuo, Wei Huang, Neng-Fang She
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Molecules
• Subjects: 1,6-naphthyridine; Grignard reagent; kinase inhibitor; antitumor drug candidate
• Online Access: https://www.mdpi.com/1420-3049/25/23/5667

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives <b>13</b> via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (<b>15</b>) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives <b>13</b> 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.