Diastereomeric 2-aminomethyl-1,4-benzodioxane mandelates: phase diagrams and resolution

Abstract

The diastereomeric salts of (R)- and (S)-2-aminomethyl-1,4-benzodioxane with unichiral mandelic acid form a simple eutectic, whose binary phase melting point diagram shows the unique eutectic at 0.35M ratio of the less soluble diastereomer. Such an eutectic composition, near to 0.5, is consistent with the modest efficiency previously reported for their separation via crystallization from ethanol/ethyl acetate. However, the ternary solubility phase diagram, obtained from solubility measurements in methanol, shifts the eutectic to a lower molar ratio (0.10) of the less soluble diastereomer, thus indicating an optimal resolvability of the diastereomeric mandelates. This was confirmed by the highly efficient resolution of racemic 2-aminomethyl-1,4-benzodioxane with (R)-mandelic acid via a single crystallization from methanol. The ready availability of both the racemic substrate and the resolving acid makes this simple and efficient resolution procedure very attractive to obtain the enantiomers of 2-aminomethyl-1,4-benzodioxane, which are important synthetic intermediates.