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Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2 , the synthetic precursor of the chiral drug xibenolol 1 , was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes ( S )- and ( R )- 3 , and then into the xibenolol enantiomers. Single crystals of (+)- and (−)- 1 ·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute ( R )- and ( S )-configurations were assigned to these compounds and to the other intermediate chiral substances.

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.

Racemic 3-(2-ethylphenoxy)propane-1,2-diol 2 has been effectively resolved into ( S )- and ( R )-enantiomers by a preferential crystallization procedure. Non-racemic diols 2 , obtained via a Mitsunobu reaction, have been converted into the non-racemic 1,2-epoxy-3-(2-ethylphenoxy)propanes ( S )- and ( R )- 5 and then into non-racemic 3-(2-ethylphenoxy)-1(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanols 1 . The characteristics of all four stereoisomers, ( S , S )- 1 (SR 59230), ( R , R )- 1 (SR 59483), ( R , S )- 1 and ( S , R )- 1 (SR 59231) and their hydrogen oxalates with a 1:1 composition have been presented. The crystalline oxalates ( S , S )- 1 ·C 2 H 2 O 4 (SR 59230A) and ( R , S )- 1 ·0.5C 2 H 2 O 4 were studied by single crystal X-ray diffraction.

The solubility of the chiral drug bevantolol hydrochloride 1 in water and the azeotropic mixture ethanol–water has been investigated. It was found that rac-1 meets the requirements of Meyerhoffer’s rule, so it was possible to reduce the ternary diagram, describing the solubility of 1, to a pseudo binary form, which facilitates the analysis of crystallization processes caused by temperature changes. On this basis, the effective and robust resolution procedure of racemic bevantolol hydrochloride by a preferential crystallization approach has been realized successfully.

The synthesis for a single enantiomer timolol maleate based on an initial Jacobsen hydrolytic kinetic resolution of racemic epichlorohydrin and on the stereochemistry of the subsequent chemical transformations has been proposed. The feature of this synthesis is that both products of the kinetic resolution, ( R )-epichlorohydrin ( R )- 4 and ( S )-3-chloropropane-1,2-diol ( S )- 5 , have been utilized in the synthesis of the target, ( S )-timolol. The mirror stereochemical results can be obtained with the use of ( R , R )-salen Co(III) catalyst instead of ( S , S )-salen Co(III).

Racemic 3-(2,6-dimethylphenoxy)propane-1,2-diol 8 undergoes spontaneous resolution upon crystallization. This fact is confirmed by the melting point inspection, vibration spectra and X-ray single crystal diffraction of racemic and scalemic crystalline samples of 8. Racemic 8 has been effectively resolved by a preferential crystallization procedure into (S)- and (R)-enantiomers with ee of approximately 90%. The enantiomeric purity of (S)- and (R)-8 could be increased to ee >99% through simple recrystallization. Nonracemic diols 8 were converted into nonracemic 1,2-epoxy-3-(2,6-dimethylphenoxy)propanes (S)- and (R)-7 with ee 98% via Mitsunobu reaction. The reaction proceeded without loss of enantiomeric purity, and the initial configuration of the stereogenic center was conserved. Enantiopure epoxides 7 were converted into nonracemic 1-(2,6-dimethylphenoxy)propan-2-ols 2, which are valuable intermediates in single-enantiomer mexiletine synthesis.

A series of enantiopure and racemic p -alkylphenyl glycerol ethers 1a – k were synthesized. A new, sensitive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was developed to obtain preliminary information on the crystallization types of these compounds. In order to detect the subtle differences in the organization of the chiral solid phase, a new easily implemented approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a single solution in equilibrium with a solid sample of arbitrary (0 n -Pr) and one borderline case (Alk = n -Bu) are disclosed. Higher members of the series of 1 (starting with an n -Bu derivative) are turned into liquid crystals upon melting; no significant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n -butyl, n -pentyl, n -hexyl, and n -heptyl substituted 1 were able to form supramolecular gels in hydrocarbon solvents; all racemic ethers 1 did not show such ability.

All ortho-substituted Cl, Br, I, and CN phenyl glycerol ethers crystallize as racemic conglomerates, whereas meta- and para-derivatives constitute racemic compounds in the solid state. Only meta-halogen-substituted phenyl glycerol ethers, alongside the thermodynamically preferential heterochiral racemic compound phase, reveal the simultaneous existence of a conglomerate phase; the last state is metastable and turns into a stable racemic compound just in the crystalline phase.

The β-adrenoblocker bunitrolol 1 as well as intermediate cyclic sulfate 6 and glycidyl ether 8 have been prepared in enantiopure form by starting from enantiopure o -cyanophenyl glycerol ether 2 by an entrainment resolution procedure. Thermal investigations reveal that 1 ·HCl forms a moderately stable racemic compound, whereas 2 , 6 and 8 are conglomerate forming substances potentially capable of entrainment resolution. Some chemical and chiroptical characteristics for bunitrolol and possible intermediates in its synthesis were corrected, and configurations were verified with the configuration of 1 ·HCl.

Five chiral arylglycerol ethers 2-R-C 6 H 4 -O-CH 2 CH(OH)CH 2 OH (R = OMe, OEt, OPr n , OPr i , OBu t ) have been prepared in racemic and enantiopure form. The melting points and enthalpies of fusion of every species were measured by differential scanning calorimetry. Binary phase diagrams were reconstructed for the whole family, the entropies of the mixing of the enantiomers in the liquid state, and Gibbs free energy of formation of the racemic compound, as well as Pettersson i -values were derived from the thermal data. The differences in the phase behavior of the investigated compounds were associated with the conformations of the alkoxy fragments.

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

Racemic expectorant guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol 2 undergoes spontaneous resolution upon crystallization. This fact is confirmed by thermal analysis (single eutectic V-shape binary melting phase diagram, adequate entropy and free energy characteristics). Racemic 2 could be effectively resolved into (S)- and (R)-2 by a preferential crystallization procedure. Single enantiomer drugs levomoprolol and levotensin were obtained by starting from enantiomeric 2 through the sulfite route.

Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1 , by thermal analysis (single eutectic V-shape binary melting phase diagram), and X-ray analysis (space group P 2 1 2 1 2 1 , Z = 4). Racemic 1 could be resolved into ( S )-(+)- and ( R )-(−)- 1 by a preferential crystallization procedure.