Reciprocal resolution of 1-(4-methylphenyl)ethylamine and 2-hydroxy-4-phenylbutyric acid, and habit modification of a less-soluble diastereomeric salt with a chiral additive

A reciprocal resolution was successfully carried out by a diastereomeric method between 1-(4-methylphenyl)ethylamine (1) and 2-hydroxy-4-phenylbutyric acid (2); enantiomerically pure 1 was obtained from water solvent involving hydrochloric acid (0.5 mol) by using enantiomerically pure 2 as a resolving agent, while enantiomerically pure 2 was obtained from water solvent involving sodium hydroxide (0.5 mol) by using enantiomerically pure 1. Upon the optical resolution of (RS)-1 with enantiomerically pure 2, the crystal morphology of the less-soluble salt (L-salt), (R)-1.(R)-2, was changed by addition of chiral secondary amines derived from enantiomerically pure amine 1. Effective additives for the habit modification were (R,R)- and (S,S)-bis[1-(4-methylphenyl)ethyl]amine (3). The habit modification experiments showed that molecular recognition by the cavity created on the surface of the diastereomeric salt was structure-specific but not stereospecific. The X-ray crystallography of the L-salt revealed that molecular recognition between resolving agent 2 and amine 1 or chiral additive 3 was due to the cavity structure constructed with the resolving agent.