- Tricyclic nucleotide analogue as well as synthesis method and application thereof
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The invention belongs to the field of chemical synthesis, and particularly relates to tricyclic nucleotide analogues shown as formulas (I), (II), (III) and (IV) as well as a synthesis method and application thereof. The structural formulas of the tricyclic nucleotide analogues are shown in formulas (I), (II), (III) and (IV), wherein the compounds in the formulas (I), (II), (III) and (IV) are compounds containing a ternary aza fused ring skeleton. According to the synthesis, AcOH which is relatively friendly to the environment is used as a solvent, Ac2O is used as an additive, 1, 1, 3, 3-tetramethoxypropane is connected with imino groups on guanosine or 2 '-deoxyguanosine and cyclization is carried out, so that a series of tricyclic nucleotide analogues with novel structures are constructed. The experiment process is simple and convenient to operate, the yield is high, the chemical selectivity is good, a series of tricyclic nucleotide analogues with novel structures can be efficiently constructed, and a new method and thought are provided for synthesis of the compounds.
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- Synthesis of diastereomerically pure nucleotide phosphoramidates
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Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5′-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.
- Ross, Bruce S.,Ganapati Reddy,Zhang, Hai-Ren,Rachakonda, Suguna,Sofia, Michael J.
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experimental part
p. 8311 - 8319
(2012/01/03)
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