Stefan Abrecht1,2, Peter J. Harrington3, Hans Iding4, Martin Karpf1,2, René Trussardi4, Beat Wirz, Ulrich Zutter1,2
1La Roche Ltd Pharmaceuticals Division, Non-Clinical Development a Synthesis & Process Research
2Switzerland
3Roche Colorado Corporation Boulder Technology Center 2075 North 55th Street Boulder, Colorado 80301, USA
4Biotechnology Grenzacherstrasse 124 CH-4070 Basel
Tóm tắt
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.
