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With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 60.0℃; for 3.0h; |
Synthesis of 2-chloro-5-methoxy-4-methyl-quinazoline 8d To a solution of the compound 8 (3.0g, 0.015 mol) in 50 ml_ of anhydrous CH2CI2 was added SOCI2 (6.6 ml, 0.09 mol) and DMF (0.2 ml_), then themixture was stirred at 60C for 3 hours. The resulting mixture was concentratedin vacuum to give compound 8a (2.0 g, yield: 62.5%) as ayellow solid, which was used for next step without further purification.To a solution of Mg (0.45 g, 0.022mol) in 5 ml_ of anhydrous THF was added EtOH (0.8 ml_) and CCI4 (0.2 ml_) at 50C. After being stirred for 30min, a solution of 1A (2.7 g, 0.012 mol) andEtOH (1 ml_) in 10 ml_ of anhydrous THF wasadded, the mixture was stirred at 60C for 2 hours. To this solution was addeddropwise a solution of compound 8a (2.0 g,0.01 mol) in 10 mL of THF, the mixture wasstirred at 60C for 1 hour. The reaction mixture was cooled and quenched with 10 ml of aqueous H2SO4 (10%), the organic layers were concentrate in vacuum to give an yellow oil. Tothis oil was added a mixture of CH3COOH (15mL), H2SO4 (2 mL) and H2O (10 mL), the mixture was stirred atreflux for 16 hours. The resulting mixture was extracted with EtOAc (50 mL x3), the organic layers were concentrated to afford crude compound 8b (0.5 g,yield: 27.8%). m/z = 196 [M + H]+ .To a solution of compound 8b (0.5 g,0.01 mol) in 20 mL of MeOH was added 0.05 g of 10%Pd/C under N2, then the suspension wasstirred under H2 at room temperature for 5hours. The resulting mixture was filtered through apad of celite, the filtrate was concentrated in vacuum to give compound 8C (0.4g, yield: 95.3%). m/z = 166 [M + H]+ .To a solution of the compound 8c(0.85 g, 5.15 mmol) in 20 mL of THF was added DMAP (0.69 g, 5.67 mmol) andCI3CCOCI (0.63 mL, 5.67 mmol) at 0C, then the mixture was stirred at roomtemperature for 2 hours. The resulting mixture was diluted with ice water (50mL), extracted with EtOAc (50 mL x 3), the organic layers were concentrated invacuum to give compound 8d (1 .2 g, yield: 76%), which was used for next stepwithout further purification.To a solution of the compound 8d (0.7g, 2.3 mmol) in 10 mL of DMSO was added CH3COONH4 (1 .75 g, 22.7 mmol), the mixture was stirred at room temperature for20 hours. The resulting mixture was diluted with H2O (200 mL), extracted with EtOAc (30 mL chi 3), the organic layers were concentrated in vacuum to give5-methoxy-4-methyl-1 H-quinazolin-2-one (0.3 g, yield: 69.7%), which was usedfor next step without further purification, m/z = 191 [M + H]+ .To a solutionof the compound 5-methoxy-4-methyl-1 H-quinazolin-2-one (200 mg, 1 .05 mmol) in15 mL of toluene was added POCI3 (0.2 mL, 2.1 mmol) and DIPEA (0.38 mL, 2.1mmol), then the mixture was stirred at 90C for 4 hours. The resulting mixturewas concentrated in vacuum, the residue was dissolved with Et2O(50 mL), the organic layer was collected and dried to give2-chloro-5-methoxy-4-methyl-quinazoline (120 mg, yield: 49.2%). m/z = 209 [M +H]+ |
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