Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor

Abstract

The conformation and tautomeric structure of (Z)-4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide, C27H22F3N3O5, in the solid state has been resolved by single-crystal X-ray crystallography. The electron distribution in the molecule was evaluated by refinements with invarioms, aspherical scattering factors by the method of Dittrich et al. [Acta Cryst. (2005), A61, 314-320] that are based on the Hansen-Coppens multipole model [Hansen & Coppens (1978). Acta Cryst. A34, 909-921]. The β-diketo portion of the molecule exists in the enol form. The enol -OH hydrogen forms a strong asymmetric hydrogen bond with the carbonyl O atom on the β-C atom of the chain. Weak intramolecular hydrogen bonds exist between the weakly acidic α-CH hydrogen of the keto-enol group and the pyridinone carbonyl O atom, and also between the hydrazine N-H group and the carbonyl group in the β-position from the hydrazine N-H group. The electrostatic properties of the molecule were derived from the molecular charge density. The molecule is in a lengthened conformation and the rings of the two benzyl groups are nearly orthogonal. Results from a high-field (1)H and (13)C NMR correlation spectroscopy study confirm that the same tautomer exists in solution as in the solid state.

Probing Ionic Crystals by the Invariom Approach: An Electron Density Study of Guanidinium Chloride and Carbonate

“…[4] By using database entries [5] of multipolar parameters computed at ah igh level of theory [6] within the Hansen-Coppensf ormalism [7] for each atom in ag iven covalente nvironment,i tp erforms as fast as IAM [6,8] and provides results that are as informative as those from conventional multipole refinement of high-resolution X-ray diffraction data. [8] Although the invariom approximation is based on pseudo-atomsd erived from isolated molecules andt hus does not take crystal environment into account,i tr eproduces features of covalent bonds with the accuracyo fafull multipole refinement [8][9][10] and gives ar ather adequate description of intermolecular interactions in crystals formed by hydrogen bonds [3,[10][11][12][13] and an even better one for those formed by weak van derW aalsc ontacts. [14] It also has an advantage of providing experimental electron densities (as they are still based on X-ray diffraction data) for systemst hat are not accessible otherwise;t hose of al arger size, [4,15] having poor reflectivep ower, [4,6,12,16] suffering from disorder [15] or twinning, [17] and so on.…”

Probing Weak Intermolecular Interactions by Using the Invariom Approach: A Comparative Study ofs‐Tetrazine

“…Although by the definition of invarioms,2 the resulting electron density does not contain the information on crystal packing effects, attempts have been made to use them for examining intermolecular interactions in organic crystals, but in all cases H‐bonds were mostly commented on 4. 12, 15, 19, 20 Their influence on molecular and crystal properties was quantified by the analysis of Hirshfeld surfaces,15, 19, 21 mapping of electrostatic potential (thus revealing important implications for drug research),4, 8, 9, 12, 15, 20, 21 or by topological features within Bader’s “Atoms in Molecules” theory (AIM) 4. 19 The results were encouraging, but still conventional multipole refinement against high‐resolution X‐ray diffraction data is recommended for studying crystal packing effects that are a priori not included in the invariom density 9.…”

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor

“…This is supported by NMR correlation spectroscopy and a single-crystal X-ray structure determination. 21 …”