[Synthesis]
General procedure for the synthesis of 4-chloro-2,6-dimethylquinazolines from 2,6-dimethylquinazolin-4(1H)-ones:
1. Synthesis of 4-chloro-6-methyl-2-methylquinazoline: 2,6-dimethylquinazolin-4(1H)-one (5 g, 32 mmol) was dissolved in acetic anhydride (25 mL) and heated at reflux for 12 hours. After completion of the reaction, the mixture was concentrated to give a solid. The solid was dissolved in a mixture of ethanol (50 mL) and ammonia (50 mL) and stirred at 80 °C for 5 hours. The progress of the reaction was monitored by TLC (Spreader: EtOAc/PE = 1:1) and after confirming the consumption of raw materials and the appearance of new spots, the reaction mixture was cooled to room temperature, filtered and the filter cake was collected to afford 4-chloro-6-methyl-2-methyl quinazoline (3.5 g, yield: 60.9%).
2. Synthesis of 4-chloro-2,6-dimethylquinazoline: 4-chloro-6-methyl-2-methylquinazoline (7 g, 40 mmol) was dissolved in toluene (70 mL), N,N-diisopropylethylamine (DIPEA, 10.3 g, 80 mmol) and phosphorus oxychloride (POCl3, 10.4 g, 64 mmol) were added. The mixture was stirred at 80 °C for 4 hours. The progress of the reaction was monitored by TLC (unfolding agent: PE/EtOAc = 3:1) and after confirming the consumption of raw materials and the appearance of new spots, the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (eluent: PE/EtOAc = 20:1) to afford the target compound 4-chloro-2,6-dimethylquinazoline (5 g, yield: 64.7%) as a white solid.
1H NMR (CDCl3, 400 MHz): δ = 7.94 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.72 (m, J = 10.8 Hz, 1H), 2.81 (s, 3H), 2.55 (s, 3H). |