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Synlett 2004(14): 2600-2602  
DOI: 10.1055/s-2004-834800
LETTER
© Georg Thieme Verlag Stuttgart · New York

New and Efficient Approach to Aryl Phosphoramidate Derivatives of AZT/d4T as Anti-HIV Prodrugs

Xueshu Lia, Hua Fu*a, Yuyang Jianga,b, Yufen Zhaoa, Jinyong Liua
a The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
b The Key Lab of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn;
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Publication History

Received 18 August 2004
Publication Date:
20 October 2004 (online)

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Abstract

Ester exchange of diaryl phosphite with AZT or d4T produced aryl AZT/d4T H-phosphonate, and the following reaction with amino acid esters in the presence of hexachloroethane and triethylamine yielded membrane-soluble anti-HIV prodrugs aryl phosphoramide derivatives of AZT and d4T in good yields.

Key words

aryl phosphoramidate - anti-HIV - AZT - d4T

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Analytical data of representative compound 9ae [2′,3′-dideoxy-2′,3′-didehydrothymidine 5′-(phenyl methoxy-phenylalaninyl phosphate)]: 13P NMR (121 MHz, CDCl3): δ = 3.30, 3.70 (a pair of diastereomers, ratio of peak area = 4:6) ppm. 1H NMR (300 MHz, CDCl3): δ = 1.78 (s, 3 H, 5-Me), 2.94-2.99 (m, 2 H, CH2Ph), 3.64 (s, 3 H, OMe), 3.84-4.19 (m, 4 H, Phe-CH, Phe-NH, 2H-5′), 4.89 (m, 1 H, H-4′), 5.82-5.88 (m, 1 H, H-3′), 6.20-6.29 (m, 1 H, H-2′), 7.12-7.27 (m, 12 H, 2 Ph, H-1′, H-6), 9.43 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.21 (C5), 40.30 (CH2Ph), 52.29 (OCH3), 55.45, 55.73 (Phe-CH), 66.20, 66.87 (C-5′), 84.36, 84.58 (C-4′), 89.42, 89.67 (C-1′), 111.20, 111.31 (C5), 119.91, 119.98 (OPh-ortho), 125.06 (OPh-para), 127.11, 127.21 (C-2′), 128.49, 129.34, 129.63 (CH2 Ph), 129.34, 129.63 (OPh-meta), 133.18-133.50 (C-3′), 135.46 (6-C), 150.18, 150.29 (OPh-ipso), 150.86 (C2), 163.84 (C4), 172.72 (Phe-CO). ESI-MS: m/z = 542 [M + H]+, 564 [M + Na]+.