Chiral Analysis of the Key Intermediates of Tenofovir Alafenamide Fumarate

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

Publikationsverlauf

Eingereicht: 22. Dezember 2022

Angenommen: 20. Januar 2023

Artikel online veröffentlicht:
16. März 2023

• References

• 1 Chapman H, Kernan M, Rohloff J, Sparacino M, Terhorst T. Purification of PMPA amidate prodrugs by SMB chromatography and x-ray crystallography of the diastereomerically pure GS-7340. Nucleosides Nucleotides Nucleic Acids 2001; 20 (4–7): 1085-1090
• 2 Caplan MR, Daar ES, Corado KC. Next generation fixed dose combination pharmacotherapies for treating HIV. Expert Opin Pharmacother 2018; 19 (06) 589-596
• 3 Lim YS, Seto WK, Kurosaki M. et al. Review article: switching patients with chronic hepatitis B to tenofovir alafenamide-a review of current data. Aliment Pharmacol Ther 2022; 55 (08) 921-943
• 4 Orlandini S, Hancu G, Szabó ZI. et al. New trends in the quality control of enantiomeric drugs: quality by design-compliant development of chiral capillary electrophoresis methods. Molecules 2022; 27 (20) 7058
• 5 Colby DA, Martins AA, Roberts BJ, Scott RW, White NS. Methods for preparing anti-viral nucleotide analogs. U.S. Patent 8664386 B2. March, 2014
• 6 Flick AC, Ding HX, Leverett CA, Fink SJ, O'Donnell CJ. Synthetic approaches to new drugs approved during 2016. J Med Chem 2018; 61 (16) 7004-7031
• 7 Wang Y, Lin S, Zhang T. Preparation method of key intermediate TAF (tenofovir alafenamide fumarate) [in Chinese]. CN Patent 108822149 B. August, 2020
• 8 Wei Y, Qiu G, Lu Y, Zhu G. Method for preparing nucleoside analogue and intermediate thereof [in Chinese]. PCT Application. WO Patent 2015161781 A1. October, 2015
• 9 Ripin DHB, Teager DS, Fortunak J. et al. Process improvements for the manufacture of tenofovir disoproxil fumarate at commercial scale. Org Process Res Dev 2010; 14 (05) 1194-1201
• 10 Dietz J-P, Ferenc D, Jamison TF, Gupton BF, Di Opatz T. Di-tert-butyl phosphonate route to the antiviral drug tenofovir. Org Process Res Dev 2021; 25 (04) 789-798
• 11 Larrow JF, Schaus SE, Jacobsen EN. Kinetic resolution of terminal epoxides via highly regioselective and enantioselective ring opening with TMSN₃. An efficient, catalytic route to 1,2-amino alcohols. J Am Chem Soc 1996; 118 (31) 7420-7421
• 12 Zhang Q, Ma BW, Wang QQ. et al. The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation. Org Lett 2014; 16 (07) 2014-2017
• 13 Yan M, Liao Z, Liu Y, Luo Q. Preparation method of tenofovir alafenamide fumarate enantiomer from (S)-9-[2-(phenoxyphosphorylmethoxy)propyl]adenine [in Chinese]. CN Patent 112679544A. April, 2021
• 14 Ma Z, Wang X, Wang P, Liu G, Wei NT. The separation of tenofovir alafenamide fumarate and its enantiomers by chiral stationary phase high performance liquid chromatography (HPLC) was Studied [in Chinese]. Shandong Huagong 2021; 50 (24) 58-61
• 15 Chen G, Cai Z, Wu F. Tenofovir alafenamide fumarate impurity preparing method. CN Patent 105330700A. February, 2016
• 16 Mitsunobu O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1981; 1981 (01) 1-28
• 17 Munawar S, Zahoor AF, Ali S. et al. Mitsunobu reaction: a powerful tool for the synthesis of natural products: a review. Molecules 2022; 27 (20) 6953
• 18 Holy A, Masojidkova M. Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. I. The stepwise approach. Collect Czech Chem Commun 1995; 60 (07) 1196-1212
• 19 Holy A, Dvorakova H, Masojidkova M. Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. II. The synthon approach. Collect Czech Chem Commun 1995; 60 (08) 1390-1409
• 20 Krait S, Schneidmadel FR, Scriba GKE. Quality by design-assisted development of a capillary electrophoresis method for the enantiomeric purity determination of tenofovir. Electrophoresis 2022; 43 (9-10): 964-969
• 21 Ikai T, Okamoto Y. Structure control of polysaccharide derivatives for efficient separation of enantiomers by chromatography. Chem Rev 2009; 109 (11) 6077-6101
• 22 Liu X, Ren J, Zhang Q, Li W. Synthesis of tenofovir alafenamide fumarate [in Chinese]. Zhongguo Yiyao Gongye Zazhi 2019; 50 (08) 863-867