Abstract
A new and improved synthetic route to tucatinib is described that involves three key
intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over
five steps and 99% purity. Next, N
4 -(4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield
over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole
trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two
steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity
(HPLC). Purification methods used to isolate the product and the intermediates involved
in the route are also reported.
Key Words tucatinib - irbinitinib - new route - synthetic process
