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Stage #1: Heating / reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1 h;
To a 250 mL flask charged with methyl 2,4-dihydroxyquinazoline-7-carboxylate was added POCI3(76 mL), PCI5 (12.1 g, 58.1 mmol), and the suspension heated at reflux overnight under nitrogen. In morning a dark orange solution has formed. The POCI3 was removed and the residue azeotroped with toluene to yield an orange solid that was taken into DCM (50 mL) and added slowly to stirred satd NaHCO3 (300 mL). The bi-phasic solution was then diluted with DCM (100 mL) and water (30 mL) and stirred for 1 hour at room temp. DCM (500 mL) was added and the mix transferred to a sep-funnel. The DCM layer was removed along with a large amount of ppt. The aq. was extracted with DCM ( 3 x 100 mL) and the combined organics dried over MgSO4, filtered and stripped to a orange solid that was purified by Biotage 65 flash chromatography eluting with DCM - 3percent MeOH/DCM over 3.5 L to reveal the title compound as a white solid, 4.4 g, 59percent.1H NMR (400 MHz, DMSO-D6) δ ppm 8.47 (1 H, d, J=1.01 Hz) 8.43 (1 H, d, J=8.84 Hz) 8.29 (1 H, dd, J=8.72, 1.64 Hz) 3.96 (3 H, s); MS (API+) for C10H6N2CI2O2 m/z 257.0 (M+H)+.
Step 1: 2,4-Dioxo-l,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl esterTo a 250 mL round bottom flask, 2-amino dimethyl terephthalate (3 g, 0.0143 mol) and urea (4.3 g, 0.0717 mol) were added. The reaction mixture was stirred at 200°C for 3 h. The reaction mixture was allowed to reach 100 °C and water was added. The aqueous reaction mixture was stirred at 100°C for 5-10 min then allowed to reach room temperature. The solid was filtered, washed with chloroform dried and azeotroped with toluene to afford the title compound [2.5 g, 80percent]. This material was taken to the next step without any further purification. 1H NMR; (400 MHz, DMSO-d6): δ 11.25 (brs, 2H), 7.98 (d, 1H, J= 8.2 Hz), 7.78 (s, 1H), 7.65 (d, J= 8.2, 1.2 Hz, 1H), 3.98 (s, 3H): LC-MS (ESI): Calculated mass: 220.0; Observed mass: 221.0 [M+H]+ (RT: 0.19 min)
To a 250 mL flask charged with methyl 2,4-dihydroxyquinazoline-7-carboxylate was added POCI3(76 mL), PCI5 (12.1 g, 58.1 mmol), and the suspension heated at reflux overnight under nitrogen. In morning a dark orange solution has formed. The POCI3 was removed and the residue azeotroped with toluene to yield an orange solid that was taken into DCM (50 mL) and added slowly to stirred satd NaHCO3 (300 mL). The bi-phasic solution was then diluted with DCM (100 mL) and water (30 mL) and stirred for 1 hour at room temp. DCM (500 mL) was added and the mix transferred to a sep-funnel. The DCM layer was removed along with a large amount of ppt. The aq. was extracted with DCM ( 3 x 100 mL) and the combined organics dried over MgSO4, filtered and stripped to a orange solid that was purified by Biotage 65 flash chromatography eluting with DCM - 3% MeOH/DCM over 3.5 L to reveal the title compound as a white solid, 4.4 g, 59%.1H NMR (400 MHz, DMSO-D6) delta ppm 8.47 (1 H, d, J=1.01 Hz) 8.43 (1 H, d, J=8.84 Hz) 8.29 (1 H, dd, J=8.72, 1.64 Hz) 3.96 (3 H, s); MS (API+) for C10H6N2CI2O2 m/z 257.0 (M+H)+.
With N,N-dimethyl-aniline; trichlorophosphate; at 100.0℃; for 0.25h;
[00315] 2-CHLORO-4-DIMETHYLAMINOQUINAZOLINE-7-CARBOXYLIC acid methyl ester. A stirring suspension of 2, 4-DIOXO-1, 2,3, 4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (12.2 g, 55.4 mmol), N, N DIMETHYLANILINE (14.0 mL, 110. 8 mmol), and POC13 (25 mL), under N2, was heated at 100 C for 15 minutes. The solution was evaporated to dryness under reduced pressure and the residual oil was poured into ice-water (800 mL). The mixture was made strongly basic by the addition of 50% aqueous NaOH solution at 0 C. The mixture was partitioned between CH2CL2 and H20 and the organic portion was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 70% hexanes/30% EtOAc to obtain the intermediate chloride as a white solid (5.1 g, 19. 8 mmol). The obtained intermediate was dissolved in CH2C12 (100 ML). THE solution was cooled to 0 C followed by the addition OF ET3N (5.5 ML, 39.6 mmol) and dimethylamine hydrochloride (1.6 g, 19. 8 mmol). The mixture was then stirred at 0 C for 30 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired amine as a white solid (3.3 g, 12.4 mmol, 11% yield). LC/MS (10-99%) M/Z 268.0 retention time 2. 85 min.
With N,N-dimethyl-aniline; trichlorophosphate; at 120.0℃; for 2.0h;
To a 250 mL round bottom flask, 7-methylcarboxylate-lH-quinazoline-2,4-dione (1.4 g 0.00636 mol) was added. To the same flask POCl3 (20 mL) and N,N- dimethylaniline (0.62 g, 0.00509 mol) were added. The reaction mixture was maintained at 120C for 5 h. The volatiles were evaporated and azeotroped with toluene to provide the crude residue. The crude residue was titurated with DCM and filtered through a Celite pad. The filtrate was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to provide 7-methylcarboxylate-2,4-dichloro-quinazoline
Step 1: 2,4-Dioxo-l,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl esterTo a 250 mL round bottom flask, 2-amino dimethyl terephthalate (3 g, 0.0143 mol) and urea (4.3 g, 0.0717 mol) were added. The reaction mixture was stirred at 200C for 3 h. The reaction mixture was allowed to reach 100 C and water was added. The aqueous reaction mixture was stirred at 100C for 5-10 min then allowed to reach room temperature. The solid was filtered, washed with chloroform dried and azeotroped with toluene to afford the title compound [2.5 g, 80%]. This material was taken to the next step without any further purification. 1H NMR; (400 MHz, DMSO-d6): delta 11.25 (brs, 2H), 7.98 (d, 1H, J= 8.2 Hz), 7.78 (s, 1H), 7.65 (d, J= 8.2, 1.2 Hz, 1H), 3.98 (s, 3H): LC-MS (ESI): Calculated mass: 220.0; Observed mass: 221.0 [M+H]+ (RT: 0.19 min)
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