Crystal Structure of Chiral Drug Prenalterol and Its Precursor Prone to Spontaneous Resolution

Abstract

Due to the chiral uniformity of proteins and carbohydrates, the basic building blocks of living matter, the mirror symmetry characteristics of drugs are of exceptional importance for medicinal chemistry. In this work, we present a new synthesis of the mono-enantiomeric chiral drug prenalterol 1 based on the symmetry-breaking phenomenon, namely, the spontaneous resolution of 4-hydroxyphenyl glycerol ether 2. The single crystal X-ray diffraction method was used to investigate both rac- and (S)-1 as well as (R)-2. A feature of the main crystal-forming supramolecular motif (SMM) for diol 2 is the participation of three different molecules representing different types of hydroxyl groups in the formation of its repeating unit. The type of prenalterol SMM, as in the case of the related drugs propranolol 3 and pindolol 4, appears to be a chirality driven property, and is dictated by the enantiomeric composition of the crystals. In single-enantiomeric forms, infinite one-dimensional chains are realized, organized around helical axes, while in racemates, zero-dimensional cycles are realized, organized around inversion symmetry elements. The results obtained again demonstrate the influence of the chiral polarization of a substance not only on the general (selection of a space group), but also on particular characteristics of matter crystal organization, namely selection of a specific SMM.