József Schindler

Separation of non-racemic mixtures of enantiomers: an essential part of optical resolution

Non-racemic enantiomeric mixtures form homochiral and heterochiral aggregates in melt or suspension, during adsorption or recrystallization, and these diastereomeric associations determine the distribution of the enantiomers between the solid and other (liquid or vapour) phases. That distribution depends on the stability order of the homo- and heterochiral aggregates (conglomerate or racemate formation). Therefore, there is a correlation between the binary melting point phase diagrams and the experimental ee(I)vs. ee(0) curves (ee(I) refers to the crystallized enantiomeric mixtures, ee(0) is the composition of the starting ones). Accordingly, distribution of the enantiomeric mixtures between two phases is characteristic and usually significant enrichment can be achieved. There are two exceptions: no enrichment could be observed under thermodynamically controlled conditions when the starting enantiomer composition corresponded to the eutectic composition, or when the method used was unsuitable for separation. In several cases, when kinetic control governed the crystallization, the character of the ee(0)-ee(I) curve did not correlate with the melting point binary phase diagram.

Resolution of α-phenylethylamine by its acidic derivatives

Abstract α-Phenylethylamine was resolved by its own derivatives formed with a homologous series of dicarboxylic acids. The structure of the oxalamic acid diastereoisomeric salts was investigated by the single-crystal X-ray diffraction method.

Resolution of the flumequine intermediate 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline

Abstract Racemic 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (FTHQ) was resolved by the N -phthaloyl derivative of the ( R )-enantiomer. The enantiomeric mixture was very effectively enriched by recrystallisation from either the melt (working best for mixtures of relatively high starting enantiomeric purities) or from solution of its hydrochloride salt (giving good results when applied for mixtures of moderate to medium enantiomeric purities).

Optical resolution of 1-(1-naphthyl)ethylamine by its dicarboxylic acid derivatives: Structural features of the oxalic acid derivative diastereomeric salt pair

Optical resolution methods were established for racemic 1-(1-naphthyl) ethylamine. The resolving agents were synthesized by N-derivatizing (R)-1-(1-naphthyl) ethylamine with dicarboxylic acids. Oxalic, malonic, and succinic acid derivatives were found to be suitable resolving agents. These resolutions are parallel to a series of optical resolutions of 1-phenylethylamine which had been previously performed by our research group using similar derivative resolving agents (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518.) The comparison of the results of the enantiomer separations is performed. The diastereomeric salts formed with (R)-N-[1-(1-naphthyl)ethyl]oxalamic acid were investigated by single crystal X-ray diffraction. The crystal structures were compared with the previously published structures of the diastereomers of the phenyl-substituted analogue, namely (R)- and (S)-1-phenylethylammonium (R)-N-(1-phenylethyl)oxalamates (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518).

8.6 Physical Separations: Behavior of Structurally Similar Molecules in the Resolution Processes

The resolution of racemic compounds with structurally similar resolving agents is examined. Summarizing experimental results, it can be established that the SDE (self-disproportionation of enantiomers) characteristic for the mixture of enantiomers of the racemic compound determines the results of the separations of the enantiomeric mixtures and the diastereomers. In addition, SDE influences the behavior of diastereomers obtained.

Chiral P-Heterocycles: Efficient Method for the Resolution of 3-Methyl-3-phospholene 1-Oxides

The enantiomers of 1-aryl-, 1-alkyl- and 1-alkoxy-3-methyl-3-phospholene 1-oxides were separated in good yields and in high enantiomeric excesses (up to > 99% ee) by resolution via formation of diastereomeric complexes with (–)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane (TADDOL) or (–)-(2R,3R)-α,α,α′,α′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol.