Crystallization-based resolution of 1, 4-benzodioxane-2-carboxylic acid enantiomers via diastereomeric 1-phenylethylamides. Issue 18 (4th May 2016) - Fumagalli, Laura
Graphical abstract: Highlights: rac -1, 4-Benzodioxane-2-carboxylic acid is amidified with ( R )-1-phenylethylamine. The two diastereomeric amides are resolved by precipitation of the S, R stereoisomer. The R, R diastereoisomer is isolated from the mother liquors by chromatography. Hydrolysis of the two amides yields 1, 4-benzodioxane-2-carboxylic acid enantiomers. The resolving agent ( R )-1-phenylethylamine is quantitatively recovered. Abstract: Unlike the diastereomeric 1-phenylethylammonium salts, the diastereomeric N -1-phenylethylamides of ( S )- and ( R )-1, 4-benzodioxane-2-carboxylic acid show significant differences in fusibility and solubility so as to be efficiently resolved by precipitation of the less soluble diastereomer (>98% de), while chromatographic purification of the unprecipitated fraction affords the more soluble one (>99% de). Overall, 95% of the former and 80% of the latter are recovered. The hydrolysis of the two resolved amides provides the two acid enantiomers and the resolving amine in quantitative yield and with unchanged stereoisomeric purity.