title: Isoxazole mediated synthesis of 4-(1H)pyridones: improved preparation of antimalarial candidate GSK932121.
abstract: 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-(1H)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.
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, C/Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain. Jorge.m.fernandez-molina@gsk.com.
authors.forename: Jorge
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, C/Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain. Jorge.m.fernandez-molina@gsk.com.
authors.forename: Jesús
authors.initials: J
authors.lastname: Chicharro
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, C/Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain. Jorge.m.fernandez-molina@gsk.com.
authors.forename: José M
authors.initials: JM
authors.lastname: Bueno
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, C/Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain. Jorge.m.fernandez-molina@gsk.com.
authors.forename: Milagros
authors.initials: M
authors.lastname: Lorenzo