Enantiopurification of Mandelic Acid by Crystallization-Induced Diastereomer Transformation: An Experimental and Computational Study
Tharit Lerdwiriyanupap, Ruel Cedeno, Phattananawee Nalaoh, Sareeya Bureekaew, Vinich Promarak, Adrian E. Flood
Abstract
Chiral purification is crucial in the pharmaceutical industry due to the dramatic differences in biological activity of the two enantiomers of most chiral drugs. In this work, we demonstrate a new enantiopurification route for an important drug precursor, mandelic acid, by forming a diastereomeric amide with enantiopure 1-phenylethylamine. We show that in the presence of a strong base, the resulting diastereomeric system not only undergoes a reversible epimerization reaction but also exhibits a surprising difference in crystallization behavior, i.e., at room temperature, one epimer forms a metastable gel phase, only converting to a more stable crystal over several days, while the other forms a stable crystalline phase. Exploiting these properties, a facile purification technique via crystallization-induced diastereomer transformation (CIDT) was achieved enabling good product yield (>70%) and excellent optical purity (>92%). Enantiopure mandelic acid (∼91% e.e. ) can then be recovered via acid hydrolysis. This work highlights that for compounds that are neither conveniently racemizable nor conglomerate-forming such as mandelic acid, CIDT is a powerful alternative to the deracemization technique, capable of yields greater than the 50% in contrast to traditional resolution techniques.