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Synthesis 2003(13): 1989-1994
DOI: 10.1055/s-2003-41039
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© Georg Thieme Verlag Stuttgart · New York

Synthesis of Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs

Changxue Lina, Hua Fu*a, Guangzhong Tub, Yufen Zhao*a
a The Key Laboratory of Bioorganic Phosphorus Chemistry, Ministry of Education, Department of Chemistry, School of Life Sciences and Engineering, Tsinghua University, Beijing 100084, P. R. China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn ;
b Beijing Institute of Microchemistry, Beijing 100091, P. R. China
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Publication History

Received 6 May 2003
Publication Date:
28 August 2003 (online)

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Abstract

Sequential transesterification of diphenyl phosphite with 5′-O-(4,4′-dimethoxytrityl)thymidine (1) and hydrogen sulfide gave O-[5′-O-(4,4′-dimethoxytrityl)thymidine-3′-yl] H-thiophosphonate (2), and subsequent condensation of 2 with AZT or d4T in the presence of diphenyl chlorophosphoate provided the dinucleotide H-thiophosphonates 3 or 3′. The Antherton-Todd reaction of 3 or 3′ with l-amino acid methyl ester in a solution of CCl4-Et3N-H2O-MeCN gave the dinuleotide thiophosphoramidates 4 or 4′, and removal of the dimethoxytrityl protecting group in formic acid yielded the target products AZT/d4T thiophosphoramidates 5 and 5′.

Key words

nucleotides - phosphorus - antiviral agents - esterification - drugs