Crystallization-based resolution of 1,4-benzodioxane-2-carboxylic acid enantiomers via diastereomeric 1-phenylethylamides

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.