Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b]pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity

A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an S_NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6-chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The S_NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100–110 °C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.