Separation of the racemic mixtures by crystallization. Part 1, Optymlization of resolution conditions

Methods for obtaining optically active compounds in enantiopure form are commonly classified into three categories: utilization of chiral pool starting materials (stereoselective multistep synthesis), creation of chirality from achiral precursors (asymmetric synthesis) and separation of racemates into their enantiomer constituents (crystallization, chromatography on chiral phases, kinetic resolution). The most important method for the separation of enantiomers is the crystallization. The crystallization can be carried out in the variants: direct crystallization of enantiomer mixtures (homo- and heterochiral aggregates – Scheme 2, 3) and separation of diastereoisomer mixtures (classical resolution) (Scheme 1) [1–5]. The most widely used method for the separation of enantiomers rests on the crystallization of diastereoisomers formed from a racemate and an enantiopure reagent – resolving agent (resolution via salt-formation and complex-formation). The pair of diastereoisomers exhibit different physicochemical properties (e.g., solubility, melting point, boiling point, adsorbtion, phase distribution). For this reason, the crystalline material can be separated from the residue by filtration (Scheme 22) [4, 27], distillation (Scheme 23, 24) [28, 29], sublimation (Scheme 25) [4, 30], or extraction (Scheme 26) [2, 31]. The composition of crystalline diastereoisomers is influenced by resolving agent (structure (Scheme 4) [4] and amount of resolving agent (Scheme 5) [4]), structure of racemates (Scheme 10) [2, 15], the character and amount of supplementary additives (Scheme 6–9) [4, 12–15], nature of the solvent (crystallization with solvent) – Scheme 11–18 [2, 4, 16–23] and time of crystaillzation (Scheme 19–21) [4, 14, 25, 26]