Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker

Abstract

Preparation of 2,4,5-trisubstituted thiazole derivatives via a new solid-phase synthetic route has been conducted in this study. The synthetic route begins with the synthesis of a core skeleton 2,4-diamino(thiazol-5-yl)-substituted phenylmethanone resin obtained through a cyclization reaction with a carbamimidothioate linker. The core skeleton was substituted with diverse building blocks such as amines, alkyl halides, and acid chlorides. The products were cleaved from the solid support via a TFA/CH2Cl2 cleavage cocktail. Overall, the strategy permits the incorporation of three points of diversity into the thiazole ring system with good overall yields (Lee, T.; et al. J. Comb. Chem. 2009, 11 (2), 288-293). Finally, the library of 2,4,5-trisubstituted thiazole derivatives showed oral bioavailability through calculation of the physicochemical properties.