Synthesis of oseltamivir containing phosphonate congeners...

Details Synthesis of oseltamivir containing phosphonate congeners... Synthesis of oseltamivir containing phosphonate congeners...

A - Human Necessities

61

K

A61K 31/662 (2006.01) A61P 31/16 (2006.01)

Patent

CA 2697837

Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu®, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and > 20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5- cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio-- and stereoselective bromoamidation of a bromoarene cis- dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.

La présente invention décrit de nouveaux composés phosphonates qui présentent une activité inhibitrice de la neuraminidase contre les virus H1N1 et H5N1 sauvages et portant la mutation H274Y. La présente invention concerne également une voie de synthèse énantiosélective vers des inhibiteurs de la neuraminidase connus, l'oseltamivir et le médicament anti-grippal Tamiflu®, ainsi que de nouveaux composés phosphonates, par l'intermédiaire du D-xylose. Une autre synthèse efficace et souple du Tamiflu et du très puissant inhibiteur de la neuraminidase Tamiphosphor a également été obtenue en 11 étapes et a donné une augmentation de plus de 20% des rendements globaux du produit de fermentation facilement disponible (1S-cis)-3-bromo-3,5- cyclohexadiène-1,2-diol. Les produits intermédiaires de la réaction furent pour la plupart obtenus sous forme de cristaux sans procédure fastidieuse de purification. Les transformations clés comprennent une bromoamidation regiosélective et stéréosélective initiale d'un bromoarenecis- dihydrodiol, ainsi que la carbonylation et la phosphonylation finales catalysées par le palladium.

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