Synthesis and Anti‐HIV‐1 Activity of New Fluoro‐HEPT Analogues: An Investigation on Fluoro versus Hydroxy Substituents

Coupling of 6‐benzyl‐5‐hydroxymethyluracil (1) with formaldehyde acetals followed by fluorination using (diethylamino)sulfur trifluoride (DAST) afforded 1‐alkenyloxymethyl and 1‐propargyloxymethyl 5‐fluoromethyl‐6‐benzyluracils 3a–c. 6‐(3,5‐Dimethylbenzyl)‐5‐ethyl‐1‐[(2‐fluoroethoxy)methyl]pyrimidine‐2,4(1H,3H)‐dione (6) was synthesized by fluorination of the corresponding hydroxy derivative 5. Sonogoshira reaction was performed on 6‐(3,5‐dimethylbenzyl)‐5‐ethyl‐1‐(4‐iodobenzyl)uracil (7) with propargyl alcohol to afford 8 which was fluorinated to give the fluoro propargyl derivative 9. Compound 7 was synthesized by N1‐alkylation of the corresponding uracil. Significant activity was found against HIV‐1 except for compounds with 5‐hydroxymethyl and 5‐fluoromethyl substituents.

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