合成路线1

A new industrial synthesis of (3R,4S,5S)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, a key intermediate in the synthesis of the oseltamivir phosphate has been developed: The esterification of (-)-shikimic acid (I) with SOCl2 and ethanol gives the expected ethyl ester (II), which is treated with 2,2-dimethoxypropane and p-toluenesulfonic acid in ethyl acetate to yield the acetonide (III). Mesylation of (III) with mesyl chloride and triethylamine in ethyl acetate affords mesylate (IV), which is trans-ketalized with 3-pentanone and trifluoromethanesulfonic acid giving the pentylidene ketal (V). Reductive opening of the ketal ring of (V) with triethylsilane and TiCl4 in dichloromethane gives the hydroxyether (VI), which is converted into the target epoxide by a treatment with NaHCO3 in ethanol/water. Another route to pentylidene ketal (V) has also been developed: The direct ketalization of ester (II) with 3-pentanone and trifluoromethanesulfonic acid gives the pentylidene ketal (VIII), which is then mesylated with mesyl chloride and triethylamine as before yielding the alredy described mesylate (V). From the above two routes, the route through the mesylate (IV) is preferred even though it is one step longer. Compound (IV) is a highly crystalline compound which can be purified efficiently. In contrast, intermediates (VIII) and (V) are oils and cannot be purified easily and often, the resulting epoxide (VII) obtained through pentylidene ketal (VIII) do not meet the quality requirements and may be reprocessed.