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An Efficient Pd & Pt‐Catalyzed H/D Exchange Approach towards the Synthesis of Deuterium‐Labeled Antiviral Prodrugs, Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide
Author(s) -
Shen Hangzhou,
Liu Yingshuai,
Tian Xiaomeng,
Zhang Xiquan,
Zhang Yinsheng
Publication year - 2018
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201801990
Subject(s) - tenofovir alafenamide , tenofovir , chemistry , prodrug , catalysis , yield (engineering) , combinatorial chemistry , organic chemistry , human immunodeficiency virus (hiv) , virology , biochemistry , medicine , materials science , viral load , antiretroviral therapy , metallurgy
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.