Affiliation:
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
Abstract
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.
Funder
Science and Technology Commission of Shanghai Municipality
Subject
General Earth and Planetary Sciences,General Environmental Science
Cited by
1 articles.
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