Practical resolution of 1-phenyl-2-(4-methylphenyl)ethylamine using a single resolving agent controlled by the dielectric constant of the solvent

A practical resolution of 1-phenyl-2-(4-methylphenyl)ethylamine 1 for obtaining (R)- and (S)-enantiomers by a dielectrically controlled resolution (DCR) method using a single resolving agent, (S)-mandelic acid 2, has been studied. The configuration of the excess enantiomer I in the less-soluble diastereomeric salt was found to vary depending on the solvent controlled by adjusting the solvent dielectric constant e and the water content of the alcohol solvent. It was found that the presence of water molecules and the solvent molecular structures was key to controlling the configurational change phenomenon in the chiral discrimination between molecules 1 and 2. Moreover, the reaction environment controlled by the solvent dielectric constant plays a very distinct role in utilizing water molecules for crystallizing the less-soluble diastereomeric salt during the resolution. Based on the results, a practical resolution process for (R)-1 and (S)-1 production has been developed involving a simple solvent switch method; the (S)-1(.)(S)-2(.)H(2)O salt (33% yield, 96% de, E 64%) was obtained by the crystallization from 74% (w/w) aqueous ethanol in the first resolution, while the (R)-1(.)(S)-2 salt (23% yield, 98% de, E 46%) was crystallized from 100% ethanol of the condensate of the mother liquor after the first resolution. (C) 2004 Elsevier Ltd. All rights reserved.