Identification of unexpected unlabeled N,N-dimethylamide formation in the synthesis of deuterated fragment of ribociclib by a HATU-mediated coupling reaction

: Starting from N,N-dimethylamine and D2 O, deuterated fragment of ribociclib was synthesized for use as a mass spectroscopy internal standard. Furthermore, systematic studies on D0 (unlabeled material) formation during the amidation reaction were performed, leading to the identification of a coupling reagent, HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), as main cause. Finally, an alternative route was designed using EDCI/HOBT as coupling reagents to produce the desired deuterated compound without D0 residue.