Resolution of 1-phenyl-2-( p-tolyl)ethylamine via diastereomeric salt formation

( S)-1-Phenyl-2-( p-tolyl)ethylamine ( S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of ( S)-isopropylidene glycerol ( R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of ( S)-1] was achieved by a simple precipitation of ( S)-1·( R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble ( R)-1·( R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the ( S)-1·( R)-2/( R)-1·( R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of ( S)-1·( R)-2.