Synthesis of Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs

Changxue Lin; Hua Fu; Guangzhong Tu; Yufen Zhao

doi:10.1055/s-2003-41039

PAPER

Synthesis of Dinucleotide Thiophosphoramidates as Anti-HIV New Prodrugs

Changxue Lin^a, Hua Fu*^a, Guangzhong Tu^b, 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

Abstract

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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

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