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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic Chemistry
Volume 37, 2007 - Issue 14
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Original Articles

Synthesis of 1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils as Potent Nonnucleoside HIV‐1 RT Inhibitors

, , , , &
Pages 2421-2431 | Received 14 Dec 2006, Published online: 11 Jul 2007
 

Abstract

1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyl uracils (1) and (2) are analogs of MKC‐442, which is a very potent inhibitor of HIV‐1 reverse transcriptase. The target compound 1 was synthesized by the first approach, from the corresponding 1,3‐dibenzyl‐5‐(dimethylamino)‐6‐phenethylpyrimidine‐2,4(1H,3H)‐dione (7), which was synthesized in four steps from 6‐methyluracil (3) by nitration, benzylation, reduction, and methylation of the amino group. Compound 7 was then debenzylated to give the complete deprotected compound 8 with very low yield. To improve the yield, another pathway was developed for introducing the ethoxymethyl group at N‐1 of the uracil ring first. The result of adjusting reaction sequences increased the overall yield dramatically. All synthesized compounds were tested for their inhibition of HIV‐1 reverse transcriptase, and moderate activity was found for target compound 1.

Acknowledgments

We thank the National Science Foundation of China and the 985 Program of the Ministry of Education of China for financial support.

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