RESUMEN
LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.
Asunto(s)
Aminobutiratos , Antagonistas de Receptores de Angiotensina , Biocatálisis , Compuestos de Bifenilo , Combinación de Medicamentos , Humanos , Tetrazoles , ValsartánRESUMEN
A convergent synthesis of bafilomycin A(1), a potent inhibitor of V-type ATPases, is presented. The synthesis relies on the zinc triflate mediated diastereoselective addition of a complex enyne to a sensitive aldehyde as the key fragment coupling. A ruthenium-catalyzed trans-reduction of the resulting propargylic enyne efficiently installs the required C10-C13 trans,trans-diene subunit, implementing an alternative strategy to traditional palladium-catalyzed cross-coupling strategies. A highly selective oxidation of a secondary hydroxyl group in a triol sets the stage for the completion of the synthesis.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Macrólidos/síntesis química , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , Catálisis , Inhibidores Enzimáticos/metabolismo , Macrólidos/química , Modelos Moleculares , Oxidación-Reducción , EstereoisomerismoRESUMEN
The asymmetric gold(I)-catalyzed ring expansion of 1-allenylcyclopropanols is described. The method provides synthetically valuable cyclobutanones with a vinyl-substituted quaternary stereogenic center in high enantioselectivities and yields. The method shows a broad substrate scope, tolerating protected alcohols and amines, alkenes, unsaturated esters, and acetals. The reaction is easily adjustable to large-scale synthesis, leading to product formation without significant loss of selectivity or yield with only 0.5 mol% catalyst loading.
RESUMEN
[chemical reaction: see text]. We report the reduction of 2,3-dihydroisoxazoles to beta-amino ketones and beta-amino alcohols. The latter are obtained in high diastereoselectivity with preference for the syn isomer.
