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Carbon‐13 synthesis and NMR spectroscopic geometric isomer evaluation to support the filing of teriflunomide
Author(s) -
Kurz Michael,
Gretzke Dirk,
Hörlein Rolf,
Turpault Sandrine,
Atzrodt Jens,
Derdau Volker
Publication year - 2021
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3876
Subject(s) - chemistry , heteronuclear molecule , nuclear magnetic resonance spectroscopy , carbon 13 nmr , fluorine 19 nmr , carbon 13 nmr satellite , isotopomers , teriflunomide , proton nmr , nuclear overhauser effect , sulfoxide , analytical chemistry (journal) , stereochemistry , organic chemistry , molecule , psychiatry , multiple sclerosis , fingolimod , psychology
The two isotopomers of teriflunomide were synthesized starting from isotopically stable‐labeled stocks of [ 13 C]potassium cyanide and [1‐ 13 C]ethyl bromoacetate. The two 13 C‐labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z‐isomers (ratio of 8:92) was determined by initial 13 C‐carbon NMR experiments. To get insights into the E/Z ratio of teriflunomide under in vivo conditions, advanced heteronuclear NMR (heteronuclear Overhauser effect spectroscopy [HOESY]) in D 2 O and mixtures of D 2 O/plasma were performed. Whereas NMR experiments in mixtures of water and plasma failed owing to extreme line broadening, NMR spectra in water at pH 7.4 showed only the Z‐isomer.