Multinuclear NMR Measurements and DFT Calculations for Capecitabine Tautomeric Form Assignment in a Solution

Abstract

The molecular structure of capecitabine (a widely applied prodrug of 5-fluorouracil) was studied by multinuclear NMR measurements and DFT quantum mechanical calculations. One or two tautomeric forms in a solution were detected depending on the solvent used. In the organic solvents, a mixture of two forms of capecitabine was observed: carbamate and imine tautomers. In the aqueous solution, only the carbamate form was found. The methylation of capecitabine yields mainly two products in different proportions: N3-methylcapecitabine and N7-methylcapecitabine. The protonation of capecitabine in organic solvents with perchloric acid occurs at the N3 nitrogen atom. DFT calculations strongly support the results coming from the analysis of the NMR spectra.

The Synergy between Nuclear Magnetic Resonance and Density Functional Theory Calculations

“…Cmoch et al [ 29 ] investigated the structure of capecitane (see Figure 10 ) in various solvents and used DFT calculations to produce chemical shifts which could be observed not unambiguously.…”

“…In cases in which other intramolecular effects, such as hydrogen bonding to nitrogen, is present, DFT calculations of the structure are invaluable (see Figure 9). Cmoch et al [29] investigated the structure of capecitane (see Figure 10) in various solvents and used DFT calculations to produce chemical shifts which could be observed not unambiguously.…”

Synthesis of Thiol Derivatives of Biological Active Compounds for Nanotechnology Application

“…In an effort to obtain a thiol derivative of capecitabine ( 3 ), we utilized its known derivative 29 ( Scheme 5 ) [ 19 ]. To our satisfaction, the acylation of 29 yielded 30 in 73% yield smoothly.…”

“…According to the literature, compounds 1 – 9 and their respective derivatives show anticancer [ 11 , 12 , 13 ], antibacterial [ 14 ], antifungal [ 15 ], and anti-inflammatory [ 13 , 15 , 16 ] activities. Some of them are widely used in therapy as the registered drugs: flumethasone [ 17 ], fluticasone propionate [ 18 ], and capecitabine [ 19 , 20 ].…”

Impact of solvent interactions on1H and13C chemical shifts investigated using DFT and a reference dataset recorded in CDCl3and CCl4

“…via hydrogen bonds), which are not trivial to account for in DFT calculations. [15][16][17] Also vibrational contributions to the chemical shift are usually neglected.…”