Enantioselective synthesis of a key intermediate in a new process for Orlistat using asymmetric hydrogenation and a Grignard reagent promoted lactone cyclization

摘要

A new enantioselective synthesis of Orlistat suitable for largescale preparation is described. Therein, the first isolated key intermediate (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran2- one ( 12) is prepared via ( a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to ( S)-3-hydroxytetradecanoate ( 9); (b) the acylation of 9 with 2-bromooctanoyl halide ( bromide/chloride) to ( R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoic acid methyl ester (11) and finally (c) the tert-butyl magnesium chloride promoted cyclization of 11 to the single enantiomer 12. The single enantiomer intermediate 12, previously published as a mixture of enantiomers 2, has been carried on through several steps to Orlistat ( 1) without any process changes.