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8-bromo-4-chloro-6-methylquinazoline. A mixture of neat 2-amino-3-bromo-5-methylbenzoic acid (2 g, 8.69 mmol) and formamidine acetate (1.005 g, 9.65 mmol) was heated with a heat gun and shaking in a 100 ml round bottom flask under a N2 balloon until the material was melted together (4 minutes). To the crude 8-bromo-6-methylquinazolin-4(3H)-one (1.68 g) was added POCl3 (13 mL, 139 mmol) and the mixture was heated at reflux overnight. Excess POCl3 was removed by rotovap and ice was added to the residue. The pH of the mixture was neutralized to pH 7 using NaOH and saturated aqueous Na2CO3. The aqueous layer was then extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography (SiO2) eluting with 0-20% EtOAc in hexanes gave the product (1.24 g, 4.82 mmol, 55%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 9.09 (1H, s), 8.12 (1H, d, J=1.76 Hz), 8.01 (1H, d, J=1.01 Hz), 2.59 (3H, s). Mass 258.97 [M+H]+.
8-bromo-4-chloro-6-methylquinazoline. A mixture of neat 2-amino-3-bromo-5-methylbenzoic acid (2 g, 8.69 mmol) and formamidine acetate (1.005 g, 9.65 mmol) was heated with a heat gun and shaking in a 100 ml round bottom flask under a N2 balloon until the material was melted together (4 minutes). To the crude <strong>[215115-09-6]8-bromo-6-methylquinazolin-4(3H)-one</strong> (1.68 g) was added POCl3 (13 mL, 139 mmol) and the mixture was heated at reflux overnight. Excess POCl3 was removed by rotovap and ice was added to the residue. The pH of the mixture was neutralized to pH 7 using NaOH and saturated aqueous Na2CO3. The aqueous layer was then extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography (SiO2) eluding with 0-20% EtOAc in hexanes gave the product (1.24 g, 4.82 mmol, 55%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 9.09 (1H, s), 8.12 (1H, d, J=1.76 Hz), 8.01 (1H, d, J=1.01 Hz), 2.59 (3H, s). Mass 258.97 [M+H]+.
Step A: A suspension of <strong>[13091-43-5]2-amino-3-bromo-5-methylbenzoic acid</strong> (3.50 g, 15.0 mmol) and formamidine acetate (4.88 g, 46.8 mmol) in anhydrous ethanol (20.0 mL) was heated at 80 C for 48 hours. After cooling to room temperature, the solid was filtered and dried under high vacuum to afford 8-bromo-6-methylquinazolin-4-ol (3.48 g, 99%). 1H NMR (500 MHz, DMSO- J6) delta 12.42 (s, IH), 8.12 (s, IH), 8.00 (s, IH), 7.93 (s, IH), 2.40 (s, 3H). LC/MS: m/z 239.0 [M+l].
With triethylamine; In ethanol; at 60.0℃; for 12.0h;
General procedure: To a stirred solution of the corresponding quinazoline-4-ones 18a-h (1.0 mmol) in EtOH (10 mL) were added 15 (0.5 eq) and triethylamine(0.5 eq). The mixture was heated at 60 oC for 12 h, and then concentrated in vacuum to dryness. The residue was purified by preparative TLC (CH2Cl2/acetone: 8/2) to afford the alcohols 16a-iand 16a?-i? in 35-74%. A ratio of 6/4 was determined for 16a?-i?/16a-i.
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