An efficient and scalable process to produce morpholine-d8

ABSTRACTIncorporation of isotopes has long been used as a research tool to label carbons and elucidate biochemical pathways. More recently, H→D exchange has led to analogs of therapeutic agents with improved metabolic stability and properties. Such compounds also have the potential for an improved drug/drug interaction profile and may even avoid the formation of toxic metabolites. Hence, a clear need for an efficient access to deuterated intermediates on large scale has emerged. In the context of an ongoing drug discovery program, we required large quantities of morpholine-d8. We herein report the successful optimization of a one-pot process allowing a near complete exchange of all methylene hydrogens in morpholine to deuterium atoms using D2O as the sole source of deuterium and Raney Nickel as catalyst. This facile and safe protocol will be used to scale up the synthesis of morpholine-d8 in due course.