Traceless solid-phase synthesis of 2,4,6-trisubstituted thiazolo[4,5-d]pyrimidine-5,7-dione derivatives

An expedient, traceless, solid-phase synthesis of 2,4,6-trisubstituted thiazolo[4,5-d]pyrimidine-5,7-dione derivatives has been developed. The solid-phase synthetic route utilizes urea formation by a microwave irradiation promoted reaction of a thiazole amino ester resin with an isocyanate. The resulting urea resin is converted to a thiazolopyrimidinedione resin, containing two diversity elements at N-4 and N-6, by using a one-pot cyclization/N-alkylation process. After oxidation to form a sulfone, nucleophilic C-2 substitution with amines, the third diversity element, gives the target 2,4,6-trisubstituted thiazolo[4,5-d]pyrimide-5,7-dione derivatives. This highly efficient solid-phase synthetic sequence enables the incorporation of three points of diversity into the preparation of the thiazolo[4,5-d]pyrimidine-5,7-dione ring system.