2011 Volume 69 Issue 5 Pages 499-505
In order to overcome trial-and-error situation in the enantioseparation by the diastereomeric salt formation, we carried out systematic studies on the enantioseparation of racemic 1-arylethylamines with/without a substituent on the aryl group by using enantiopure arylglycolic acids. The studies revealed that there are three factors for the growth and stabilization of less-soluble diastereomeric salt crystals; 1)infinite hydrogen bonding interaction to form a 21-column, which enables a crystal to grow in one dimension, 2)effective van der Waals interaction between the columns to make the crystal growable in a three-dimensional manner, and 3)sufficient CH-π interaction in/between the columns, which also play an important role for three-dimensional crystal growth. On the basis of the observations, we propose molecular length rule and aromatic ring rule, which realize efficient van der Waals interaction and CH-π interaction, respectively.
Keeping in mind of these requirements for the molecular structure of a resolving agent, we industrialized an elegant process for the enantioseparation of racemic 1-phenylethylamine into the (R)-form, which is one of the most valuable chiral auxiliaries in the synthesis of drugs/drug intermediates in industrial scales, with (R)-mandelic acid upon optimizing conditions such as solvent, molar ratio, concentration, temperature, and additive, as well as the recycling process of (R)-mandelic acid and the racemizing process of (S)-1-phenylethylamine remained.
