2-chloro-6-methoxy-4-methylquinazoline synthesis

6-methoxy-4-methyl-1,2-dihydroquinazolin-2-one

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952434-87-6
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Yield:952434-87-6 51.6%

Reaction Conditions:

with N-ethyl-N,N-diisopropylamine;trichlorophosphate in toluene at 90; for 4 h;

Steps:

Synthesis of 2-chloro-6-methoxy-4-methyl-quinazoline

Synthesis of 2-chloro-6-methoxy-4-methyl-quinazoline To a solution of compound 7 (10 g, 0.081 mol) in 20 mL of 1 ,2-dichloroethanewas added dropwise BCI₃ (200 mL, 1 .0 Min toluene) at 0°C. After being stirred at 0°C for 30 min, 50 mL of CH₃CN was added, then the mixture was stirred at80°C for 12 hours. The resulting mixture was concentrated in vacuum, theresidue was dissolved in 100 mL of HCI (2M) at 0°C and the mixture was stirredat 80°C for 30 min, the reaction mixture was neutralized with aqueous Na2CO3till pH = 7, and extracted with CH2CI2, the organic layers were concentrated invacuum, the residue was purified by chromatography on silica gel (PE / EtOAc =30: 1 ) to afford compound 7a (0.9 g, yield: 6.7%). m/z = 166 [M + H]⁺ .To a solution of the compound 7a (0.9g, 5.45 mmol) in 20 mL of THF was added DMAP (0.73 g, 6.0 mmol) and CI3CCOCI(0.66 mL, 6.0 mmol) at 0°C, then the mixture was stirred at room temperaturefor 2 hours. The resulting mixture was diluted with ice water (50 mL),extracted with EtOAc (50 mL ^χ 3), the organiclayers were concentrated in vacuum to give compound 7b (1 .6 g, yield: 94.6%),which was used for next step without further purification. To a solution of the compound 7b (1 .7 g, 5.5 mmol)in 20 mL of DMSO was added CH₃COONH (1 .7 g, 22 mmol),the mixture was stirred at room temperature for 20 hours. The resulting mixturewas diluted with H₂O (200 ml_),extracted with EtOAc (50 ml_ χ 3), the organic layers were concentrated invacuum to give 6-methoxy-4-methyl-1 H-quinazolin-2-one (0.6 g, yield: 60%),which was used for next step without further purification, m/z = 191 [M + H]⁺ .To a solutionof the compound 6-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 90°C 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-6-methoxy-4-methyl-quinazoline (120 mg, yield: 51 .6%). m/z = 209 [M +H]⁺

References:

WO2013/50527,2013,A1 Location in patent:Page/Page column 50; 51