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Stage #1: at 110 - 120℃; Heating / reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water
To a flask charged with 8-bromoquinazoline-2,4-diol 2 (39.61 g, 164 mmol) was added PCI5 (68.4 g, 328 mmol) and POCI3, (250 mL). The mixture was refluxed at 110-1200C overnight with a drying tube attached. POCI3 was stripped off under vacuum. Toluene was added to azeotroped the remaining POCI3. The residue was taken into DCM (300 mL), washed with sat NaHCO3 (500 mL), filtered and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by chromatography to give the title compound as white solid (34.67 g, 76percent). 1HNMR (CDCI3, 400 MHz): δ 8.31 (dd, J = 1.2, 7.6 Hz, 1 H), 8.27 (dd, J = 1.2, 8.4 Hz, 1 H), 7.62 (dd, J = 7.6, 8.4 Hz, 1 H).
40%
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 110℃; for 18 h;
Compound 19-f (5.5 g, 22.9 mmol) was dissolved in phosphorus oxychloride (30 mL), N,N-dimethylaniline (5mL) was added and the reaction mixture was heated at 110°C for 18 hours. The reaction mixture was cooled to roomtemperature, the reaction mixture was concentrated under reduced pressure to remove phosphorus oxychloride. Theresidue was concentrated and dried. The residue was dissolved with dichloromethane (500 mL) and washed with water(500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane= 3: 1) to deliver a pale yellow solid 19-e (2.5 g, yield: 40percent). LC-MS (ESI): m/z = 277 [M+H]+.
2.5 g
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 110℃; for 18 h;
Compound 44-f (5.5 g, 22.9 mmol) was dissolved in phosphorus oxychloride (30 mL), N,N-dimethylaniline (5 mL) was added and the reaction solution was heated at 110° C. for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to remove phosphorus oxychloride. The residue was concentrated to dryness and the residue was dissolved in dichloromethane (500 mL) and washed with water (500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane=3:1) to give 44-e as a pale yellow solid (2.5 g, yield 40percent). LC-MS (ESI): m/z=277[M+H]+.
With trichlorophosphate In N,N-dimethyl-formamide at 130℃; for 12 h;
To a mixture of 8-bromoquinazoline-2,4(lH,3H)-dione (12.1 g, 50 mmol, 1 eq.) in POCl3(130 mL) was added DMF (0.5 mL). The mixture was stirred at 130 °C for 12 h, then cooled to r.t. and concentrated. The resulting residue was dissolved in EA (100 mL) and poured into ice-water with vigorous stirring. The organic phase was separated and washed with brine, dried over anhydrous Na2S04and concentrated. The resulting residue was purified via column chromatography (PE/EA==10: 1, v/v) to afford 8-bromo-2,4- dichloroquinazoline as a yellow solid (9.1 g, 60percent yield).
60%
With trichlorophosphate In N,N-dimethyl-formamide at 130℃; for 12 h;
[0287] To a mixture of 8-bromoquinazoline-2,4(1H,3H)-dione (12.1 g, 50 mmol, 1 eq.) in POC13 (130 mL) was added DMF (0.5 mL). The mixture was stirred at 130 °C for 12 h, then cooled to r.t. and concentrated. The resulting residue was dissolved in EA (100 mL) and poured into ice-water with vigorous stirring. The organic phase was separated and washed with brine, dried over anhydrous Na2 SO4 and concentrated. The resulting residue was purified via column chromatography (PE/EA==10:1, v/v) to afford 8-bromo-2,4- dichloroquinazoline as a yellow solid (9.1 g, 60percent yield).
With ammonia In methanol; dichloromethane at 20℃; for 16 h;
Compound 19-e (1.2 g, 4.35 mmol) was dissolved in dichloromethane (5 mL) and then ammonia (50 mL, 7 Min methanol), was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixturewas concentrated under reduced pressure and the residue was added to water (50 mL), a solid was precipitated andfiltered. The filter cake was washed with water (50 mL) and dried in vacuo to deliver a yellow solid 19-d (1.5 g, yield:100percent). This product was used directly for the next step without further purification
99%
With ammonia In dichloromethane at 20℃;
8-bromo-2,4-dichloroquinazoline (13.90 g, 50 mmol) was dissolved in DCM (60 mL) and ammonia was bubbled through the reaction solution with stirring overnight at room temperature. A suspension was formed, and the precipitate was collected by filtration to give crude title compound as a white solid (12.93 g, 99percent).
83.5%
With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5 h;
To a solution of ammonia hydroxide (25 mL, 330 mmol, 10 eq.) in THF (50 mL) cooled to 0 °C was added a solution of 8-bromo-2,4-dichloroquinazoline (9.1 g, 32.7 mmol, 1 eq.) in THF (50 mL). The mixture was stirred at 0 °C for 30 min, then diluted with EA (100 mL), washed with brine, dried over anhydrous Na2S04and concentrated. The resulting residue was purified via column chromatography (PE/EA=10: 1, v/v) to afford 8-bromo-2- chloroquinazolin-4-amine as a yellow solid (7.1 g, 83.5percent yield).
83.5%
With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5 h;
[0288] To a solution of ammonia hydroxide (25 mL, 330 mmol, 10 eq.) in THF (50 mL) cooled to 0 °C was added a solution of 8-bromo-2,4-dichloroquinazoline (9.1 g, 32.7 mmol, 1 eq.) in THF (50 mL). The mixture was stirred at 0 °C for 30 mm, then diluted with EA (100 mL), washed with brine, dried over anhydrous Na2504 and concentrated. The resulting residue was purified via column chromatography (PE/EA=10: 1, v/v) to afford 8-bromo-2- chloroquinazolin-4-amine as a yellow solid (7.1 g, 83.5percent yield).
To a flask charged with 8-bromoquinazoline-2,4-diol 2 (39.61 g, 164 mmol) was added PCI5 (68.4 g, 328 mmol) and POCI3, (250 mL). The mixture was refluxed at 110-1200C overnight with a drying tube attached. POCI3 was stripped off under vacuum. Toluene was added to azeotroped the remaining POCI3. The residue was taken into DCM (300 mL), washed with sat NaHCO3 (500 mL), filtered and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by chromatography to give the title compound as white solid (34.67 g, 76%). 1HNMR (CDCI3, 400 MHz): delta 8.31 (dd, J = 1.2, 7.6 Hz, 1 H), 8.27 (dd, J = 1.2, 8.4 Hz, 1 H), 7.62 (dd, J = 7.6, 8.4 Hz, 1 H).
40%
With trichlorophosphate; In N,N-dimethyl-aniline; at 110℃; for 18.0h;
Compound 19-f (5.5 g, 22.9 mmol) was dissolved in phosphorus oxychloride (30 mL), N,N-dimethylaniline (5mL) was added and the reaction mixture was heated at 110C for 18 hours. The reaction mixture was cooled to roomtemperature, the reaction mixture was concentrated under reduced pressure to remove phosphorus oxychloride. Theresidue was concentrated and dried. The residue was dissolved with dichloromethane (500 mL) and washed with water(500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane= 3: 1) to deliver a pale yellow solid 19-e (2.5 g, yield: 40%). LC-MS (ESI): m/z = 277 [M+H]+.
2.5 g
With trichlorophosphate; In N,N-dimethyl-aniline; at 110℃; for 18.0h;
Compound 44-f (5.5 g, 22.9 mmol) was dissolved in phosphorus oxychloride (30 mL), N,N-dimethylaniline (5 mL) was added and the reaction solution was heated at 110 C. for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to remove phosphorus oxychloride. The residue was concentrated to dryness and the residue was dissolved in dichloromethane (500 mL) and washed with water (500 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane=3:1) to give 44-e as a pale yellow solid (2.5 g, yield 40%). LC-MS (ESI): m/z=277[M+H]+.
With ammonia; In methanol; dichloromethane; at 20℃; for 16.0h;
Compound 19-e (1.2 g, 4.35 mmol) was dissolved in dichloromethane (5 mL) and then ammonia (50 mL, 7 Min methanol), was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixturewas concentrated under reduced pressure and the residue was added to water (50 mL), a solid was precipitated andfiltered. The filter cake was washed with water (50 mL) and dried in vacuo to deliver a yellow solid 19-d (1.5 g, yield:100%). This product was used directly for the next step without further purification
99%
With ammonia; In dichloromethane; at 20℃;
<strong>[331647-05-3]8-bromo-2,4-dichloroquinazoline</strong> (13.90 g, 50 mmol) was dissolved in DCM (60 mL) and ammonia was bubbled through the reaction solution with stirring overnight at room temperature. A suspension was formed, and the precipitate was collected by filtration to give crude title compound as a white solid (12.93 g, 99%).
83.5%
With ammonium hydroxide; In tetrahydrofuran; at 0℃; for 0.5h;
To a solution of ammonia hydroxide (25 mL, 330 mmol, 10 eq.) in THF (50 mL) cooled to 0 C was added a solution of <strong>[331647-05-3]8-bromo-2,4-dichloroquinazoline</strong> (9.1 g, 32.7 mmol, 1 eq.) in THF (50 mL). The mixture was stirred at 0 C for 30 min, then diluted with EA (100 mL), washed with brine, dried over anhydrous Na2S04and concentrated. The resulting residue was purified via column chromatography (PE/EA=10: 1, v/v) to afford 8-bromo-2- chloroquinazolin-4-amine as a yellow solid (7.1 g, 83.5% yield).
83.5%
With ammonium hydroxide; In tetrahydrofuran; at 0℃; for 0.5h;
[0288] To a solution of ammonia hydroxide (25 mL, 330 mmol, 10 eq.) in THF (50 mL) cooled to 0 C was added a solution of <strong>[331647-05-3]8-bromo-2,4-dichloroquinazoline</strong> (9.1 g, 32.7 mmol, 1 eq.) in THF (50 mL). The mixture was stirred at 0 C for 30 mm, then diluted with EA (100 mL), washed with brine, dried over anhydrous Na2504 and concentrated. The resulting residue was purified via column chromatography (PE/EA=10: 1, v/v) to afford 8-bromo-2- chloroquinazolin-4-amine as a yellow solid (7.1 g, 83.5% yield).
With ammonia; In methanol; dichloromethane; at 20℃; for 16.0h;
Compound 44-e (1.2 g, 4.35 mmol) was dissolved in dichloromethane (5 mL), then 7M ammonia in methanol (50 mL) was added and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was added with water (50 mL) and solid was precipitated out. The solid was filtered out and the filter cake was washed with water (50 mL) and dried in vacuo to give 44-d as a yellow solid (1.5 g, yield 100%), which was used for the next step without further purification.
8-bromo-2-chloro-N-methylquinazolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 20℃; for 0.25h;
Step 1: Synthesis of 8-bromo-2-chloro-7V-methylquinazolin-4-amine (compound 30a) Compound 30a [0321] 8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) was dissolved in 6 mL of 20% solution of methylamine in ethanol and the reaction was stirred at room temperature for 15 minutes. Volatiles were removed under reduced pressure and the solid residue was suspended in water. The solid product was filtered off and washed with water (3x5 mL) and pentane (3x5 mL) to give the title compound 30a. NMR (400 MHz, DMSO-</6) delta 8.96 (d, .7=4.7 Hz, 1H), 8.19 (dd, J= 8.3 Hz,J= 1.2 Hz, 1H), 8.11 (dd,J = 7.7 Hz, J= 1.2 Hz, 1 H), 7.42 (t, J = 7.9 Hz, 1H), 3.00 (d, J= 4.3 Hz, 3H). HRMS: (ESI+) calculated for C9H8N3BrCl [M+H] 271.9585, found 271.9585. LCMS (m/z) 272.0 [M+H], Tr 3.80 min (LCMS method 1).
With water; sodium hydroxide; In tetrahydrofuran; at 20℃; for 0.5h;
Step 1: Synthesis of 8-bromo-2-chloroquinazolin-4(3H)-one (Compound 34a) Compound 34a [0330] Aqueous sodium hydroxide (30 mL, 0.2 M, 6 mmol) was added into a solution of <strong>[331647-05-3]8-bromo-2,4-dichloroquinazoline</strong> (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 0.5 hour. Then the reaction mixture was acidified with glacial acetic acid to pH = 5 and concentrated down under reduced pressure. Water was added and the solid product was filtered off and washed with water (3 x 20 ml) to afford the title compound 34a. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i ) 5 13.51 (s, 1 H), 8.15 (d, J= 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1H), 7.42 - 7.51 (m, 1 H). HRMS: (ESI+) calculated for C8H4ON2BrClNa [M+Na] 280.9088, found 280.9089. LCMS (m/z) 259.0 [M+H], Tr 3.58 min (LCMS method 1 ).
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