Starting from (−)-quinic acid, the title compound was synthesized in seven chemical steps and an overall yield of 35−38%. The route of the improved Gilead synthesis was not changed. However, significant improvements in each step led to a doubled overall yield, a 30% reduction in the number of unit operations, and an excellent quality (≥99%) of the resulting epoxide. A highly regioselective method for the dehydration of a quinic acid to a shikimic acid derivative and for the reduction of a cyclic ketal was found. Alternatively, the title compound was synthesized in six chemical steps and 63−65% yield from commercially available (−)-shikimic acid. Compared to the optimized quinic acid route, the production time was reduced by about 50%. The quality of epoxide produced from either natural product was equivalent. Therefore (−)-shikimic acid is the preferred raw material. The absolute configuration of the epoxide was determined by X-ray single crystal structure analysis and it was demonstrated that the epoxide was stereoisomerically pure.

The clinical development of the first orally available neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu™) proceeded very fast. In order to support this program an unprecedented team effort in chemical process research, development, piloting, production and analytics took place, which allowed the successful launch of Tamiflu™ in 1999, only two and a half years after it was licensed from Gilead Sciences. This article describes selected aspects of the commercially used synthesis route and a brief summary of alternative syntheses devised by Roche chemists.

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FEDERSPIEL, M. C.; ESTERMANN, H.; FISCHER, R.; KARPF, M.; MAIR, H.-J.; OBERHAUSER, T.; RIMMLER, G.; TRUSSARDI, R.; ZUTTER, U.; Chimia 61 (2007) 3, 93-99; Pharma Div., F. Hoffmann-La Roche AG, CH-4070 Basel, Switz.; Eng.) -Lindner 38-255