The general procedure for the synthesis of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine from 7-fluoro-6-nitro-4-hydroxyquinazoline and 3-chloro-4-fluoroaniline is as follows:
Method 1 (one-pot reaction):
1. 7-fluoro-6-nitro-4-hydroxyquinazoline (5 g, 23.9 mmol) was added to a 100 mL single neck flask.
2. Phosphoryl chloride (44.6 mL, 478 mmol) was added and heated to reflux at 150 °C for 5 hours.
3. Upon completion of the reaction, phosphorous trichloride was removed by evaporation.
4. The residue was diluted with anhydrous dichloromethane and evaporated again, and the process was repeated 3 times.
5. After dilution with acetonitrile (100 mL), 3-chloro-4-fluoroaniline (2.3 g, 15.8 mmol) was added. 6.
6. Heat to reflux overnight and a yellow solid precipitated during the reaction.
7. The yellow solid was filtered and dried to afford the target product N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine (4.8 g, 56% yield).
Product characterization data:
1H-NMR (d-DMSO, 400 MHz, δppm): 10.61 (br, 1H), 9.68 (d, J=10.8 Hz, 1H), 8.81 (s, 1H), 8.10-8.13 (d, J=7.6 Hz, 1H), 8.05-8.07 (d, J=8 Hz, 1H), 7.81-7.85 (m. 1H), 7.50-7.54 (d, J=8Hz, 1H).
