An efficient and scalable process to produce morpholine-d₈

ABSTRACT

Incorporation 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.

GRAPHICAL ABSTRACT

KEYWORDS:

• Isotope
• deuterium
• Raney nickel

Acknowledgments

The authors would like to thank Helen Slobodian, Norman Chu, and Xiangdong Jiao for supporting the final purification and characterization of morpholine-d₈ hydrochloride salt. This study was sponsored and managed by AstraZeneca.