Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization

Abstract

A new enantioselective synthesis of Orlistat suitable for large-scale preparation is described. Therein, the first isolated key intermediate ( R )-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2 H -pyran-2-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.