Synthesis of 5‐Fluorocytosine Using 2‐Cyano‐2‐fluoroethenolate as a Key Intermediate

There is an urgent demand for 5‐fluorocytosine (5‐FC) due to its activity against HIV‐induced fungal infections as well as its use as a key intermediate in the synthesis of the clinically highly important anti‐HIV drug emtricitabine (FTC). We report a simple, low‐cost five steps synthesis of 5‐FC starting from chloroacetamide. Overall yields up to 46 % were achieved and the route is devoid of any chromatographic purifications. The previously unknown key intermediate ( Z )‐2‐cyano‐2‐fluoroethenolate is obtained through a Claisen‐type condensation from fluoroacetonitrile. As the direct cyclization with urea only gave poor yields, 5‐fluoro‐2‐methoxypyrimidin‐4‐amine, 5‐fluoro‐2‐(methylsulfanyl)pyrimidin‐4‐amine and 5‐fluoropyrimidine‐2,4‐diamine served as synthetic intermediates.