Solid-phase synthesis of 2,4,6-triaminopyrimidines

Substituted pyrimidines are an important class of kinase inhibitors. We therefore developed a synthetic route suitable for the solid-phase synthesis of 2,4,6-triaminopyrimidines through displacement reactions on deactivated pyrimidines. Functionalising the pyrimidines was achieved using a range of primary and secondary amines and aniline and was realised on polystyrene resin with temperatures up to 140 degrees C. Two different amination reactions were performed following the anchoring of 4,6-dichloro-2-thiomethyl-pyrimidine (4) onto Rink-amide derivatised resin. The regio- and chemoselectivity for the displacement was studied for different leaving groups. The most consistent results were obtained when chlorine was used in 6-position and a methylsulfonyl group in the 2-position. A small library of substituted pyrimidines was prepared to ascertain the extent of the developed chemistry.