The effect of SDE on the separation of diastereomeric salts: a case study for the resolution of mandelic acid derivatives with Pregabalin

A resolution method has been elaborated for mandelic acid and 2-chloromandelic acid applying the (R)-(−)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin) as the resolving agent. The formation of the corresponding diastereomers was kinetically controlled. This observation was rationalized by the behavior of enantiomeric mixtures of mandelic acid, 2-chloromandelic acid, and 3-(aminomethyl)-5-methylhexanoic acid. It was found that the eutectic composition of Pregabalin influenced the diastereomeric excess of the diastereomers formed under kinetic control.

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(−)-(R)-Mandelic acidC8H8O3ee = 80%[α]D25 = 121.6 (c 1, water)Source of chirality: resolutionAbsolute configuration: (R)

(−)-(R)-2-Chloromandelic acidC8H8ClO3ee = 92%[α]D25 = −111.3 (c 1, water)Source of chirality: resolutionAbsolute configuration: (R)