Synthesis of 5‐trifluoromethyl‐5,8‐dideazafolic acid and 5‐trifluoromethyl‐5,8‐dideazaisofolic acid

The target folate analogue 5‐trifluoromethyl‐5,8‐dideazafolic acid has been elaborated in a seven‐step reaction sequence beginning with 2‐fluoro‐6‐trifluoromethylbenzonitrile. The bridge‐reversed isomer 5‐trifluoromethyl‐5,8‐dideazaisofolic acid was prepared in six steps using the common intermediate 2,6‐diamino‐3,4‐dihydro‐4‐oxo‐5‐trifluoromethylquinazoline. The key intermediate 2‐amino‐3,4‐dihydro‐4‐oxo‐5‐trifluoromethyl‐quinazoline was prepared using two distinct synthetic routes and the resulting products were found to be identical.