Synthesis Of Oseltamivir Phosphate (Tamiflu) And Its Derevatives Starting From (-)-Shikimc Acid

Oseltamivir phosphate (Tamiflu) is a potent inhibitor of neuraminidase and has been used worldwide as an orally administrated drug for prevention and treatment of both types A and B influenza. Considering the structure similarity of oseltamivir phosphate and the naturally abundant (-)-shikimic acid, six new routes for the synthesis of oseltamivir phosphate starting from readily available and inexpensive shikimic acid are designed and studied in this thesis. All the new synthetic routes featured with the highly chemo-and rigioselective functional substitutions based on high reactivities of allylic positions.(1) In the first synthetic route, oseltamivir phosphate was obtained through13steps in40%total yield starting from the readily available naturally abudant (-)-shikimic acid. This synthetic route are characterized by minimal protecting group manipulation, highly regioselective and stereo selective azide substitution and aziridine opening with3-pentanol. Moreover, the synthesis has merits such as use of inexpensive reagents in all steps, ease of manipulation of every step, mildness of the reaction conditions and high yields for each step.(2) In the second synthetic route, oseltamivir phosphate was obtained through8steps in47%total yield starting from the readily available naturally abudant (-)-shikimic acid. Apart from the advantages of the first route, the second route involved a protecting-free strategy, which minimize length of the whole synthesis to8steps with a total yield of47%. The short route, less and inexpensive reagents and low cost made this route a good example for atom-economy.(3) In the third synthetic route, oseltamivir phosphate was obtained through9steps in39%total yield starting from the readily available naturally abudant (-)-shikimic acid. The highly regioselective azide-attacked ring-opening of the cyclic sulfite and the intramolecular Mitsunobu reaction are the two key characteristic steps. By using the large water-solubility of the aziridine intermediate compound, we overcame the obstacle for the separation of the aziridine intermediate from the byproduct triphenylphosphine oxide, which was formed in the Staudinger reaction.(4) In the fourth synthetic route, oseltamivir phosphate was obtained through11steps in55%total yield starting from the readily available naturally abudant (-)-shikimic acid. The highly regioselective azide-attacked ring-opening of the cyclic sulfite and the epoxy-assisted Staudinger reaction are the two key characteristic steps. Also, many functional groups can be planted on the5-position via this route to produce different C-5derivatives of oseltamivir phosphate.(5) In the fifth synthetic route, oseltamivir phosphate was obtained through5steps in65%total yield from Roche’s key epoxide intermediate Ⅲ-66, which could also be prepared via6steps in65%overall yield starting from the readily available naturally abudant (-)-shikimic acid. This azide-free synthetic route are featured with the characteristic steps such as BF3-OEt2-catalyzed highly regioselective MeCN-attacked epoxide-opening and the diallylamine-attacked aziridine-opening. Moreover, this synthetic route allows the easy preparation of various C-5derivatives of oseltamivir phosphate.(6) In the sixth synthetic route, oseltamivir phosphate was obtained through11steps in48%total yield starting from the readily available naturally abundant (-)-shikimic acid. The characteristic steps of this route are highly regioselective chlorination at C-3position of shikimate and the regioselective epoxy ring opening with allylamine to introduce nitrogen-containing functional groups. This synthetic route provides an azide-free and high-yielding approach to oseltamivir phosphate and its C-5variously substituted derivatives.