A convenient synthesis of ¹³C₄‐Leflunomide and its primary metabolite ¹³C₄‐A77 1726

Abstract

SummaryA convenient synthesis of leflunomide and its primary pharmacologically active metabolite A77 1726, each labeled with four 13 C atoms has been achieved. Starting from 13 C 4 -ethyl acetoacetate, each step of the synthesis proceeds in 60-82% yield. Analysis of the mass spectra of the labeled and unlabeled materials demonstrates that the compounds prepared herein will be suitable as analytical standards for bioavailability studies.

On the interactions of leflunomide and teriflunomide within receptor cavity — NMR studies and energy calculations

“…Particular attention was given to the amide bond and isoxazole ring in the first solvation sphere. The obtained results were correlated with the experimental data of Faragher et al [ 21 ]. Furthermore, we estimated the interaction energy of teriflunomide 2 with tyrosine and, through a water molecule, with arginine, both in the enzymatic binding site.…”

“…To show the results more clearly, only four rotamers of the lowest energy were considered, optimized at the B3LYP/6-31G(d,p) (conformers I – IV , Tables S1 , supplementary material) and B3LYP/6-311+G(d,p) (conformers V – VIII , Table S2, respectively, supplementary material) level of theory (CPCM solvation model and water as solvent). The calculated values (Table S1 and S2) show a strong correlation with the NMR experimental data for compound 1 [ 21 ]. Only the amide proton has a high relative error of the chemical shift, equal to 29 % at the B3LYP/6-31G(d,p)/CPCM level of theory and to 28 % at the B3LYP/6-311+G(d,p)/CPCM level of theory.…”

NIS-mediated oxidative cyclization of N-(2-trifluoromethyl-3-alkynyl) hydroxylamines: a facile access to 4-trifluoromethyl-5-acylisoxazoles

“…The corresponding carboxylic acid 7 was then prepared in 80% yield by the hydrolysis under acidic conditions. 16 Subsequent condensation of acid 7 with 4-trifluoromethyl aniline with the use of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) as a coupling reagent produced the final product 8. 17…”

Understanding Chemistry and Unique NMR Characters of Novel Amide and Ester Leflunomide Analogues

“…The chemical shift of C5 CH3 and C3 H in 1 H-NMR and C4 C=O in 13 C-NMR having nearly the e chemical shift value meaning a similar special arrangement like 5-Methylisoxazole-4-carboxylic d [19]. Due to planar delocalization, 13 C-NMR chemical shifts for the amidic CON indicates (amidic carbon near 188 Hz) due to electronic interactions and steric effects over these atoms.…”