Grant: Idea to Innovation

The proposed project is concerned with providing a short synthesis of oseltamivir phosphate (Tamiflu) with potential for producing this important antiviral agent on a commercial scale. Tamiflu is one of the few compounds effective against H5N1 influenza virus, and many world governments have stockpiled it as insurance in the event of a major breakout of avian or other forms of influenza. The amounts required for Canada and the U.S. have been estimated at 25 tons of the raw drug. Current commercial syntheses, and several academic efforts, produce Tamiflu in sequences ranging from 8 to 21 steps. Almost all syntheses originate from either natural products or other chiral pool reagents. The first objective of the project to optimize an eight-step first-generation synthesis, recently accomplished in our laboratory, to a scale of 100 grams of Tamiflu. Provision of detailed experimental procedures will make it possible for a large-scale process group to take the scale to kilogram level and beyond. The synthesis begins with the enzymatic oxidation of a commodity chemical, bromobenzene. This first-generation effort constitutes proof of principle. A second objective is optimization of a second-generation synthesis, which also takes advantage of enzymatic oxidation of a commodity chemical, to yield 100 grams of the product. Each of these two syntheses has the potential of producing the substance in fewer than six operations. The best route will be chosen for commercialization, possibly as part of Phase II of the Idea to Innovation program. Any intermediate produced during the synthesis resembling oseltamivir in structure or functionality will be screened for antiviral activity, and any active compound will be subjected to lead optimization. Structure-activity relationships will be investigated in collaboration with an industrial partner during Phase II. Once optimized, these first- and second-generation efforts hold great potential as means of large-scale supply of this important medicinal agent. It is estimated that the project will be completed in 12 months with the effort of two postdoctoral fellows.