2,4-DICHLORO-6-FLUOROQUINAZOLINE

Phosphorus pentachloride (12.5 g, 60.0 mmol) and phosphorus oxychloride (46.00 mL, 502.50 mmol) were sequentially added to a 250 mL of a single jar, and6-fluoroquinazolin-2, 4- (1H, 3H) -dione(3.60 g, 20.00 mmol) was slowly added under stirring. The reaction mixture was gradually warmed to reflux and reacted. After the reaction of 9 h, the reaction mixture was cooled, the solvent was removed in vacuo, and the residue was slowly poured into a mixture of ice and water (400 mL) . After being stirred for 0.5 h, the resulting mixture was extracted with dichloromethane (250 mL x 3) . The combined organic layers were concentrated. The residue was purified by silica gel column chromatography eluted with (petroleum ether/ethyl acetate (v/v) 30/1) to give the title compound (as a white solid, 3.74 g, 86) . MS (ESI, pos. ion) m/z: 216.9 [M+H]Step 2) Synthesis of 2, 4-dichloro-6-fluoroquinazoline To phosphorus oxychloride (46.0 mL, 502.5 mmol) was added phosphorous pentachloride (12.5 g, 60.0 mmol) , then 6-fluoroquinazoline-2, 4 (1H, 3H) -dione (3.6 g, 20.0 mmol) was added slowly with stirring. The reaction mixture was heated to reflux and stirred for 9 hours, and then cooled and the solvent was removed in vacuo. To an ice water mixture (400 mL) was added the residue, the mixture was stirred for 0.5 hour and extracted with DCM (250 mL ' 3) . The combined DCM layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (PE/EtOAc (v/v) =30/1) to give the title compound as a white solid (3.735 g, 86.0 percent) .MS (ESI, pos. ion) m/z: 216.9 [M+H] +; and1H NMR (CDCl3, 400 MHz) ' (ppm) : 8.03 (dd, J = 9.2 Hz, 4.9 Hz, 1H) , 7.86 (dd, J = 8.1 Hz, 2.7 Hz, 1H) , 7.79-7.73 (m, 1H) .Phosphorus pentachloride (12.5g, 60.0mmol), phosphorous oxychloride (46.0mL, 502.5mmol) were added to a 250mL one-neck flask, was slowly added with stirring 6-fluoro-quinazoline -2, 4 (1H, 3H) - dione (3.6g, 20.0mmol), the reaction was gradually warmed to reflux, the reaction is stopped after 9 hours, cooled, solvent was distilled off under reduced pressure, the residue was slowly poured into 400mL ice-water mixture. after stirring for 0.5 hours, extracted with dichloromethane (250mL × 3), combined dichloromethane layer was separated and purified directly by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 30/1) to give the title compound (white solid, 3.735g , 86.0percent).General procedure: A mixture of quinazoline-2, 4(1H, 3H)-dione 4a (0.48 g, 2.96 mmol) in POCl3 (3.31 mL, 35.52 mmol) was stirred at room temperature for 30 min. AfterN, N-diethylaniline (0.167 mL, 0.86 mmol) was added drop-wise, the reaction mixture was heated to reflux for 14 h. After cooling to rt, remained POCl3 was removed under reduced pressure. Thereaction residue was extracted three times with CH2Cl2 (30 mL), dried over MgSO4, concentrated under reduced pressure, and purifiedby column chromatography (EtOAc/n-Hex = 1:9) on silica gelto get the title product 5a in 87percent yield (513 mg).A mixture of 6-fluoro-quinazoline -2, 4 (1H, 3H) - dione (1.50g, 8.33mmol) was added to phosphorus oxychloride (20 mL) was then added phosphorous pentachloride (5.21g, 21.98mmol) . The reaction temperature was raised to 100 deg.] C for 10 hours. The reaction was stopped, cooled to room temperature, ice water (50 mL) quenched the pH adjusted to 9 with solid sodium bicarbonate and sodium hydroxide; with dichloromethane (20mLx3) extracted, and the combined organic phases. The organic phase was washed with saturated brine (20mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1) to give the title compound as as a white solid (708mg, 39.1percent).

Molecular Weight:217.02
XLogP3:3.6
Hydrogen Bond Acceptor Count:3
Exact Mass:215.9657317
Monoisotopic Mass:215.9657317
Topological Polar Surface Area:25.8
Heavy Atom Count:13
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes