Fentanyl and Its Analogue N-(1-Phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl]propanamide: 1H- and 13C-NMR Spectroscopy, X-Ray Crystallography, and Theoretical Calculations

Abstract

The oxalate salts and free bases of fentanyl and N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide, a new lead compound for long-acting analgesia, have been characterized by (1)H- and (13)C-NMR spectroscopy. The crystal structure of the hydrochloride of N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide monohydrate has been determined. Two centrosymmetrically related cations, joined through C(phenyl)-H em leader pi contacts, encapsulate a large void that contains pairs of anions and bridged water molecules into a zero-dimensional (0D) supramolecular motif. The cations are linked to this framework via N(+)H em leader Cl(-) contacts. GIAO/B3LYP calculations have been carried out to compare the experimental (13)C chemical shifts with the absolute shieldings thus calculated. The protonation of both molecules takes place on the piperidine ring (axial protonation), as has been verified both in the solid state (X-ray) and in solution (NMR).

Effects of Cogrinding with β-Cyclodextrin on the Solid State Fentanyl

“…The chemical structure and NMR spectrum of fentanyl base and β‐CD are shown in Figures 6 and 7a, respectively. The solid state 13 C NMR spectrum of β‐CD and fentanyl base was assigned on the basis of 13 C NMR spectral literature data of the compound in the solid form29–31 and in solution,32 respectively. Furthermore, the experimental solid state 13 C NMR spectrum of fentanyl base was compared to the corresponding theoretical DFT values, used for the assignments.…”

“…Furthermore, the experimental solid state 13 C NMR spectrum of fentanyl base was compared to the corresponding theoretical DFT values, used for the assignments. The theoretical and experimental chemical shifts of fentanyl base, together with the literature values,32 are shown in Table 1. The experimental chemical shifts are similar to those reported by Jimeno et al32 and with the DFT calculations.…”

“…The theoretical and experimental chemical shifts of fentanyl base, together with the literature values,32 are shown in Table 1. The experimental chemical shifts are similar to those reported by Jimeno et al32 and with the DFT calculations.…”

Interaction of fentanyl with various cyclodextrins in aqueous solutions

“…1 H‐NMR is a well‐known analytical method that provides direct information regarding the complex structure via comparisons of the proton chemical shifts observed for the host–guest mixture with those observed for individual species. In this study, the NMR spectra of β‐CD, G1‐β‐CD, fentanyl base and fentanyl citrate were assigned on the basis of 1 H‐, 13 C‐ and two‐dimensional NMR measurements; the theoretical calculations; and the NMR spectral literature data of the compounds [17,20,32–35]. Figure presents the 1 H‐NMR spectra of the mixture of fentanyl citrate and G1‐β‐CD (a), the mixture of fentanyl citrate and β‐CD (b), and fentanyl citrate (c) at 0.7–3.2 (I) and 7.0–7.5 ppm (II).…”

“…In this study, the NMR spectra of β-CD, G1-β-CD, fentanyl base and fentanyl citrate were assigned on the basis of 1 H-, 13 Cand two-dimensional NMR measurements; the theoretical calculations; and the NMR spectral literature data of the compounds. [17,20,[32][33][34][35] Figure 4 presents the 1 H-NMR spectra of the mixture of fentanyl citrate and G1-β-CD (a), the mixture of fentanyl citrate and β-CD (b), and fentanyl citrate (c) at 0.7-3.2 (I) and 7.0-7.5 ppm (II). Compared to fentanyl citrate, several changes were observed in the 1 H-NMR spectra of the mixtures with CDs ( Figure 4).…”