Abstract

TiContinuous Flow Synthesis of Alpha-Haloketones – Essential Building Blocks of Antiretroviral Agents

Oliver Kappe, Professor, Karl Franzens University of Graz

In the last two decades a series of highly potent, orally bioavailable viral protease inhibitors have gained approval for HIV treatment. HIV protease inhibitors are commonly used together with reverse transcriptase inhibitors for highly active antiretroviral therapy (HAART). Viral protease inhibitors, such as Atazanvir and Saquinavir are listed by the World Health Organization as essential medicines for a basic health care system. The protease inhibitors are peptidomimetics, resembling substrates in which the scissile bond is replaced by a nonhydrolyzable hydroxyethylene or hydroxyethylamine structure. In fact, most of the approved HIV protease inhibitors contain a chiral aminoalcohol structure in the central core. In this presentation the three step continuous flow synthesis of the chiral aminoalcohol motif required for the preparation of Atazanavir will be described. This requires the continuous generation of anhydrous diazomethane from the respective amino acid. Diazomethane is a volatile, highly irritating, poisonous and carcinogenic compound and furthermore is exceedingly heat-, light- and shock sensitive and tends to decompose explosively. A safe continuous strategy that relies on membrane separation technology for the preparation of anhydrous diazomethane will be described in this presentation.