An Efficient Pd & Pt‐Catalyzed H/D Exchange Approach towards the Synthesis of Deuterium‐Labeled Antiviral Prodrugs, Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide

To support clinical bioequivalence (BE) studies of tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF), both deuterium‐labeled TDF and TAF (or their free bases, TD & TA) are highly desired for use as an internal standard. We have developed a method to prepare racemic [D 8 ]9‐(2‐hydroxypropyl)adenine (racemic R/S‐HPA) using a 10%Pd/C & PtO 2 catalyzed H−D exchange reaction as the key step to introduce the label in a highly efficient and cost‐effective way. The labeled R/S‐HPA was converted to racemic [D 8 ]9‐[2‐phosphonomethoxypropyl]adenine ([D 8 ] R/S‐PMPA) in two steps. Using [D 8 ] R/S‐PMPA as a common intermediate, thus, we further synthesized [D 8 ] R/S‐tenofovir disoproxil fumarate and [D 8 ]tenofovir alafenamide in 2–3 steps with 60% and 20% overall yield, respectively.