BERNARD KAPTEIN, BEN DE LANGE*
*Corresponding author
InnoSyn BV, Geleen, The Netherlands

Abstract

In recent years a renaissance in chiral crystallization technologies has enabled the complete deracemization of chiral compounds. Attrition-enhanced deracemization (Viedma ripening) and temperature cycling induced deracemization (TCID) technologies have been developed by which the solid phase of racemic mixtures can be transformed into the desired pure enantiomer in a sustainable manner. No additional chiral auxiliaries are needed and by recycling of the racemizing mother liquor complete conversion can be achieved. In this paper the requirements for these new technologies will be discussed and an overview of the applications will be presented, with emphasis on pharmaceutically interesting compounds.

INTRODUCTION
Chiral separation of racemates by crystallization remains one of the preferred technologies for the preparation of enantiopure pharmaceutical intermediates. This Pasteurian resolution of racemates – either by diastereomeric salt crystallization or by preferential crystallization – for more than 150 years has been the state-of-the-art for separating enantiomers by crystallization (1).
Intrinsically, resolution via diastereomeric salt formation can only be applied if acidic or basic functional groups are present in the racemate and 1-2 equivalents of a chiral resolving agent are required based on the preferred enantiomer. In addition, the yield of a resolution is intrinsically limited to maximum 50%, unless the unwanted enantiomer can be racemized. Elegant combinations of resolution with in situ racemization, so-called crystallization induced diastereomeric transformation (CIDT), have been described and reviewed (2, 3).

On the other hand, direct resolution of enantiomers by crystallization is limited to conglomerates – racemates in which both enantiomers crystallize separately. This only hold for 5-10% of al ...