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 D 2 O, deuterated fragment of ribociclib was synthesized for use as a mass spectroscopy internal standard. Furthermore, systematic studies on D 0 (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 D 0 residue.