4-Chloro-5-(trifluoromethyl)quinazoline

436-73-7

16499-63-1

The general procedure for the synthesis of 4-chloro-5-(trifluoromethyl)quinazolin-4(3H)-one from 5-(trifluoromethyl)quinazolin-4(3H)-one was as follows: triethylamine (29.3 ml, 210 mmol) was slowly added to a mixture of phosphoryl chloride (331 g, 2.16 mol) containing intermediate 14-b (8.00 g, 37.4 mmol) at 0 °C. The reaction mixture was heated to reflux for 2 hours. After completion of the reaction, the solvent was removed by vacuum evaporation. The residue was dissolved in ethyl acetate (200 ml) and the solution was quenched by slowly pouring it into ice (200 g). After separation of the organic layer, it was washed sequentially with water (1 x 100 ml), 10% aqueous sodium bicarbonate solution (2 x 100 ml), water (1 x 100 ml) and brine (1 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography with the eluent of petroleum ether/ethyl acetate (ratio tapered from 1/0 to 1/1) to afford the target product Intermediate 14 (7.97 g, 91.38% yield). The product was characterized by 1H NMR (400 MHz, CDCl3) with chemical shifts δppm of 7.89-8.06 (m, 1H), 8.22 (d, J=7.50 Hz, 1H), 8.31 (d, J=8.38 Hz, 1H), 9.11 (s, 1H).