Crystal Structures of a New Oral Iron Chelator, 1,2-Dimethyl-3-hydroxy-4- pyridone, and its Solvates with Acetic Acid and Formic Acid

Abstract

The crystal structures of a new oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone (DMHP), and of its 1:1 solvates with formic acid (DMHP,F) and acetic acid (DMHP,A) were determined by single-crystal X-ray diffraction. The data were collected at temperatures of 23 ± 1°C for DMHP, -64 ± 1°C for DMHP,F, and -120 ± 1°C for DMHP,A. The iron chelator DMHP is orthorhombic [Pbca, a = 7.290(5) Å, b = 13.046(4) Å, c = 13.748(6) Å, Z = 8]. The DMHP molecules form centric dimers, each in a 10-membered ring in which the OH group of one molecule is hydrogen-bonded to the CO oxygen of the other [O-H–O; 0.91(4) Å, 153(3), 1.85(4) Å], in each DMHP molecule, the OH group and CO oxygen are insignificantly intramolecularly hydrogen-bonded [C-H-O; 0.91(4) Å, 107(3)°, 2.33(4) Å]. DMHP,F is monoclinic [C2/c, a = 21.825(9) Å, b = 3.811(5) Å, c = 20.491(6) Å, β = 92.80(3)°, Z = 8]. The fundamental intermolecular and insignificant intramolecular hydrogen-bonded dimer structure of DMHP is maintained but is distorted and is supplemented by hydrogen bonds between the CO oxygen of each DMHP molecule and the OH group of one formic acid molecule [O-H-O; 0.99(5) Å, 176(3)°, 1.53(4) A]. However, the two DMHP and the two formic acid molecules are twisted out of plane like the blades of a four-bladed propeller. DMHP,A is triclinic [P°, a = 8.458(2) Å, b = 5.471(2) Å, c = 6.986(3) Å, α = 104.33(2)°, β = 92.57(2)°, β = 88.78(2)°, Z = 2]. The unit cell contains two DMHP and two acetic acid molecules alternating in an approximately planar 14-membered ring involving four intermolecular hydrogen bonds. The OH group of the DMHP molecule is hydrogen-bonded, both intrarnolecularly and weakly, to the CO oxygen of the same DMHP [O-H-O; 0.94(4) Å, 116(3)°, 2.12(4) Å] and intermolecularly to the OH oxygen of acetic acid [O-H-O, 0.94(4) Å, 139(3)°, 2.00(4 Å)]. The OH hydrogen of the latter is hydrogen-bonded to the CO oxygen in the second DMHP molecule [O-H-O, 1.06(4) Å, 1.68(3)°, 1.44(4) Å]. The qualitative differences in structure of the two solvates may be ascribed to the smaller molecular size and much stronger proton-donating capacity (acidity) of formic acid than that of acetic acid. The CO group in formic acid or acetic acid is not involved in hydrogen bonding.