Abstract
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.
Highlights
Naphthyridine scaffolds represent attractive building blocks widely used in pharmaceuticals [1,2], agrochemicals [3], and fluorescent probes [4,5,6]
The synthesis of 1,6-naphthyridine, especially for 1,6-naphthyridin-4-one derivatives, has attracted continuous interest in the pharmaceutical industry for its wide-ranging pharmacological activity [26,27], and it has been used as a multi-kinase inhibitor (I) [28], an anti-HCMV inhibitor (II) [29], an antidiabetic agent (III) [30], and antibacterial [31] and antiviral agents (IV) [1] (Figure 1)
After completing the enrichment of compound 13a, a kilogram- scale protocol for the creation of our 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidate VI was applied through acid-catalyzed nucleophilic substitution of 5-Cl atoms with high yields (90%) and simple operation
Summary
Naphthyridine scaffolds represent attractive building blocks widely used in pharmaceuticals [1,2], agrochemicals [3], and fluorescent probes [4,5,6]. The synthesis of 1,6-naphthyridine, especially for 1,6-naphthyridin-4-one derivatives, has attracted continuous interest in the pharmaceutical industry for its wide-ranging pharmacological activity [26,27], and it has been used as a multi-kinase inhibitor (I) [28], an anti-HCMV inhibitor (II) [29], an antidiabetic agent (III) [30], and antibacterial [31] and antiviral agents (IV) [1] (Figure 1). 3-phenyl-1,6-naphthyridin-4-one was developed as a potent privileged skeleton for the discovery of a MET kinase inhibitor [20,21,22,23] from the key building block of
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