Revisiting Tautomerism and Rotamerism of 1,2-Dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine (Drug Xymedon) in Aqueous and Lipophilic Media

Abstract

Combined Raman and quantum chemical studies of the rotamerism and tautomerism of 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine in solids and solutions revealed that its structural flexibility at ambient conditions is limited to conformational transformations within two groups of conformers. OH and C=O moieties of 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine are spatially separated in conformers of the first group, two of which are found experimentally in single crystals and in solid powder. The conformers of the second group, spectroscopically detected in solid powder of 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine and in its solutions in dichloromethane, are stabilized by intramolecular hydrogen bonds between OH and C=O moieties. Water tends to stabilize multiple conformers of the first group, which results in their strong domination in aqueous solutions of 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine. The conformers can be distinguished by positions of their bands in the Raman spectra. Representatives of the second group produce Raman bands at ~1090–1110 cm^–1, while the bands at ~1290 and ~1070 cm^–1 indicate a presence of the first three most abundant in aqueous 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine conformers from the first group. One of these three conformers is found also in single crystals of 1,2-dyhidro-N-(2-hydroxyethyl)-4,6-dimethyl-2-oxopyrimidine and in dichloromethane solution, where it produces the Raman band at ~1340 cm^–1. The results of quantum chemical free energies calculations are in agreement with the experimental observations.