Isoxazole mediated synthesis of 4-(1)pyridones: improved preparation of antimalarial candidate GSK932121

A new synthesis of the antimalarial clinical candidate GSK932121 is described. This approach has two key reactions, the selective acylation of an unprotected 3-hydroxymethyl-5-methyl isoxazole and the reductive N-O bond cleavage of the previously functionalized isoxazole derivative, to give the 4-(1 H )pyridone ring present in the final structure. The complete synthesis consists of 5 steps ( versus 10 steps in previously published reports) and has enabled the preparation of the material in kilogram scale to support clinical studies. A new synthesis of the antimalarial clinical candidate GSK932121 is described.