Synthesis Of Oseltamivir And Carbamate-type Prodrugs

Oseltamivir phosphate(1), an influenza neuraminidase inhibitor, was developed by Gilead Sciences Inc. and then licensed to F. Hoffmann-La Roche Ltd. for co-development and marketing worldwide. It was first launched as Tamiflu(?) in Switzerland in October 1999 for the treatment of influenza caused by the influenza virus A and B.Some influenza neuraminidase inhibitors were reviewed in this thesis. Starting from (-)-shikimic acid, oseltamivir phosphate was prepared via 12 steps in a total yield of 36.6% and its structure was confirmed by 1H-NMR and MS. The key steps of the process were investigated and optimized.Oseltamivir phosphate is the only effective oral drug for highly pathogenic avian influenza. The carbamate functional groups were introduced to the free amino group of oseltamivir, by optimizing the size and type of ester substituent to adjust lipid/water partition coefficient and improve pharmacokinetic properties, which is expected to further increase its bioavailability and reduce the irritation of gastrointestinal tract.Eleven novel carbamate-type prodrugs of oseltamivir were synthesized and metabolism research is in progress.