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CC BY 4.0 · Pharmaceutical Fronts 2023; 05(01): e38-e45
DOI: 10.1055/s-0043-1763512
Original Article

Chiral Analysis of the Key Intermediates of Tenofovir Alafenamide Fumarate

Man Li
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Ting Zhou
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Qing-Wen Zhang
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations
Funding This work was supported in part by the Science and Technology Commission of Shanghai Municipality (STCSM) (Grant No. 20S11900800), which is gratefully acknowledged.
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Abstract

(R)-Tenofovir phenyl ester ((R)-1) and (R)-tenofovir diphenyl ester ((R)-2) are key intermediates for the practical synthesis of tenofovir alafenamide fumarate, which is a mainstay antiretroviral for the treatment of chronic hepatitis B and HIV-1 infections. This article deals with the chiral analysis of (R)-1 and (R)-2 against their respective optical impurity (S)-tenofovir phenyl ester ((S)-1) and (S)-tenofovir diphenyl ester ((S)-2) using a polysaccharide-coated chiral stationary phase (CSP) by normal-phase high-performance liquid chromatography (HPLC). To this end, a chiral synthetic strategy for (S)-2 was efficiently executed capitalizing on a classical Mitsunobu reaction to stereospecifically invert the configuration of chiral carbon in readily accessible (R)-HPA ((R)-4) to deliver (S)-HPA ((S)-4), from which (S)--tenofovir ((S)-3) was in turn prepared and further transformed into (S)-2. With reference substance (S)-2 in hand, a chiral analytical method for (R)-2 using Chiralpak AD-H as CSP by normal-phase HPLC has been developed and validated. The validation results indicated that this chiral analytical method has been achieved with satisfactory separation effect, high sensitivity, and good precision and accuracy, and thus can be deployed for the determination of optical impurities in samples of (R)-1 (via derivation to (R)-2) and (R)-2.

Keywords

tenofovir alafenamide fumarate - optical impurity - Mitsunobu reaction - reference substances - chiral stationary phase

Supplementary Material



Publication History

Received: 22 December 2022

Accepted: 20 January 2023

Article published online:
16 March 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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