General procedure for the synthesis of methyl 2,4-dichloroquinazoline-7-carboxylate from methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate: 2,4-dihydroxyquinazoline-7-carboxylic acid methyl 2,4-dihydroxyquinazoline-7-carboxylate was added (raw material) to a 250 mL flask, followed by phosphorus trichloride (POCl3, 76 mL) and phosphorus pentachloride (PCl5, 12.1 g, 58.1 mmol). The suspension was heated to reflux overnight under nitrogen protection. Upon completion of the reaction, formation of a dark orange solution was observed. Excess POCl3 was removed by distillation under reduced pressure and the residue was azeotroped with toluene to further remove residual POCl3 to give an orange solid. The solid was dissolved in dichloromethane (DCM, 50 mL) and slowly added to a stirred solution of saturated sodium bicarbonate (NaHCO3, 300 mL). The resulting biphasic solution was diluted with DCM (100 mL) and water (30 mL) and stirred for 1 hour at room temperature. Subsequently, DCM (500 mL) was added and the mixture was transferred to a partition funnel. The DCM layer was separated and the aqueous layer was extracted with DCM (3 x 100 mL). The organic phases were combined, dried with anhydrous magnesium sulfate (MgSO4), filtered and concentrated to give an orange solid. Purification by Biotage 65 fast chromatography using DCM-3% methanol/DCM as eluent in an elution volume of 3.5 L resulted in methyl 2,4-dichloroquinazoline-7-carboxylate as a white solid with a yield of 4.4 g in 59% yield. The product was confirmed by 1H NMR (400 MHz, DMSO-d6) and mass spectrometry (API+): 1H NMR δ 8.47 (1H, d, J = 1.01 Hz), 8.43 (1H, d, J = 8.84 Hz), 8.29 (1H, dd, J = 8.72, 1.64 Hz), 3.96 (3H, s); MS (API+) m/z 257.0 (M + H)+.
