Martin Karpf

The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu®): A challenge for synthesis & process research

The evolution of the synthesis of oseltamivir phosphate (Tamiflu®), used for the oral treatment and prevention of influenza virus infections (viral flu) is described. Oseltamivir phosphate is the ethyl ester prodrug of the corresponding acid, a potent and selective inhibitor of influenza neuraminidase. The discovery chemistry route and scalable routes used for kilo laboratory production as well as the technical access to oseltamivir phosphate from (-)-shikimic acid proceeding via a synthetically well-developed epoxide building block followed by azide transformations are reviewed. Synthesis and process research investigations towards azide-free conversions of the key epoxide building block to oseltamivir phosphate are discussed. The search for new routes to oseltamivir phosphate independent of shikimic acid including Diels-Alder approaches and transformations of aromatic rings employing a desymmetrization concept are presented in view of large-scale production requirements.

Ammonolysis with supercritical NH3

Abstract Ammonolysis of a mesylate with anhydrous supercritical ammonia leads to the corresponding amine in high yield (96%) and represents an interesting alternative to the normally practiced azide substitution/hydrogenation sequence to introduce an amino function. A quasi-reaction mechanism is proposed, together with the kinetics which are needed for the reactor analysis and design.