Industrial synthesis of the key precursor in the synthesis of the anti-influenza drug oseltamivir phosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate

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 Gi lead synthesis was not changed, However, significant improvements in each s tep led to a doubled overall yield, a 30% reduction in the number of unit o perations, and an excellent quality (greater than or equal to 99%) of the r esulting epoxide. A highly regioselective method for the dehydration of a q uinic acid to a shikimic acid derivative and for the reduction of a cyclic ketal was found, Alternatively, the title compound was synthesized in six c hemical steps and 63-65% yield from commercially available (-)-shikimic aci d, Compared to the optimized quinic acid route, the production time was red uced by about 50%, The quality of epoxide produced from either natural prod uct was equivalent, Therefore (-)-shikimic acid is the preferred raw materi al, The absolute configuration of the epoxide was determined by X-ray singl e crystal structure analysis and it was demonstrated that the epoxide was s tereoisomerically pure.