Development of a Scalable Synthesis of a Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor: Efficient Construction of a 6-Etherified [1,2,4]Triazolo[1,5-a]pyridine-2-amine Core

A practical and scalable synthesis of the vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitor 1 has been developed. The key features of the process development include facile preparation of the key raw material 3-amino-4-fluorophenol, chemoselective nucleophilic aromatic substitution of 5-chloro-2-nitropyridine with phenol, a safe one-pot synthesis of a substituted urea using an isothiocyanate generated in situ from inexpensive materials, and improvement of the yield of acylation in the end game. The optimized six-step synthesis afforded 1·H2O in 54% overall yield, twice as much as the yield of the original synthesis, without chromatographic purification. In addition, a robust recrystallization procedure to afford the desired crystal form of 1 was also developed.