Efficient Fast Screening Methodology for Optical Resolution Agents:  Solvent Effects Are Used To Affect the Efficiency of the Resolution Process

Abstract

An efficient and fast screening methodology for optical resolution agents through the classical crystallization of the corresponding diastereomeric salts is described. In this contribution, we demonstrate that the determination of the eutectic composition by chiral analysis of the corresponding mother liquor (ML) obtained under appropriate experimental conditions provides us with a very fast screening methodology. We also demonstrate that solvent can have a profound effect not only on the efficiency of the resolution process by modifying the eutectic composition but also on the ease of crystallization.

Enantioenrichment by Crystallization

“…Racemic resolution by crystallization began in 1848 when Pasteur observed crystals of sodium ammonium tartrate that were mirror images with respect to one another. Until now, separation of enantiomers by crystallization can be classified into two main categories: (1) use of a foreign chiral element to form diastereomers followed by fractional crystallization – or formation of a diastereoselective host–guest inclusion complex, and (2) direct crystallization of one enantiomer from a racemic mixture, which includes the well-known “preferential crystallization” of pure enantiomers from conglomerate mixtures, ,– an unusual enantiomeric resolution referred to as “preferential enrichment”, – and application of crystallization inhibitors to chiral separation in racemic compound-forming systems. – Again, these processes do not always guarantee a product with an ee meeting regulatory requirement, and in those cases further chiral purification will be required.…”

Rational approach to the selection of conditions for diastereomeric resolution of chiral amines by diacid resolving agents

“…For given resolution conditions, resolution yield (Y) and enantiomeric excess (ee) can be calculated from the eutectic composition, avoiding the need for obtaining the complete ternary phase system, and so determination of eutectic points can also be used for the selection of the resolution system. [8][9][10][11] During selection of the resolving agent, it is important to note that the main advantage of the diastereomeric resolution is the relatively low costs of the process, which are mainly associated with the resolving agent costs. Looking at the commonly available resolving agents, tartaric acid and its derivatives are the most popular choice for resolving chiral bases, accounting, for 1368 resolutions of chiral bases reported by Kozma.…”

Resolution of sertraline with (R)‐mandelic acid: Chiral discrimination mechanism study

“…For the past several decades, numerous efforts have been made to understand the chiral discrimination mechanism and thus to develop a quick and rational way to screen optimal resolving agent for a target racemate. Some researchers3–5 proposed a methodology to choose resolving agents based on thermal analysis of the diastereomeric salts. If the pair of diastereomeric salts formed with a certain resolving agent exhibited large difference in melting point and heat of fusion, the resolving agent would be a good candidate.…”