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.