N-methyl-N-trimethylsilyltrifluoroacetamidepromoted synthesis and mass spectrometric characterization of deuterated ephedrines

Synthesis and mass spectrometric characterization of drugs or metabolites labeled by stable isotopes have been of great interest in the fields of clinical, forensic and doping control analysis. Deuterated ephedrine and p-hydroxypseudoephedrine were prepared from corresponding amines by a novel procedure utilizing N-methyl-N-trimethylsilyltrifluoroacetamide and deuterated iodomethane. The mechanism of methylation was studied by mass spectrometry using phenylethylamine as a model compound and a rearrangement based on an intermediate six-membered ring structure with a trimethylsilyl-enol- ether is proposed giving rise to a leaving group of trimethyliodosilane and the desired monomethylated product. Deuterated analogs to frequently quantitated ephedrines were readily synthesized with purities > 90% and mass spectra recorded under different ionization and dissociation conditions presented distinct fragmentation processes, including eliminations of water and methylamine as well as the generation of a benzyl cation.