Catalytic Deuterium Incorporation within Metabolically Stable β-Amino C–H Bonds of Drug Molecules

Abstract

An efficient deuteration process of β-amino C─H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C 6 F 5 ) 3 and Brønsted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d 6 to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation.

Electrocatalytic Deuteration of Halides with D2O as the Deuterium Source over a Copper Nanowire Arrays Cathode

“…Impressively, one‐pot halogenation–deuterodehalogenation of original C−H bonds to C−D bonds was feasibly realized with good yields and deuterium contents, allowing us to produce deuterated aromatics bypassing the tedious purification of halide precursors (Table , 2 t – 2 w ). The deuterium incorporation could alter the drug's metabolism and pharmacokinetic properties . Our method can be applied to the deuteration of top‐selling pharmaceuticals via the halogenation–deuterodehalogenation of original drug molecules (Table , 4 a – 4 d ).…”

Electrocatalytic Deuteration of Halides with D2O as the Deuterium Source over a Copper Nanowire Arrays Cathode

“…Deuterium labeling plays a crucial role in synthetic chemistry, materials science, and pharmaceutical industry due to the kinetic isotope effect . Since the first deuterated drug, Austedo, has been approved, the research interest has been boosted rapidly to the synthesis of deuterated pharmaceuticals (Figure a) . However, precise deuteration with controllable numbers and locations still remains a great challenge.…”

Semiconductor photocatalysis to engineering deuterated N-alkyl pharmaceuticals enabled by synergistic activation of water and alkanols

“…2a). Recently, catalytic hydrogen isotope exchange (HIE) of αor βamines [31][32][33][34][35][36][37] has been emerged as a promising way to incorporate multi-deuterium or tritium atoms into N-alkyl amine-based drugs ( Supplementary Fig. 2b).…”