Quinazoline, 2-chloro-7-methoxy-4-methyl- synthesis

Yield:58487-56-2 95.9%

Reaction Conditions:

with N-ethyl-N,N-diisopropylamine;trichlorophosphate in toluene at 80; for 6 h;

Steps:

Synthesis of 2-chloro-7-methoxy-4-methyl-quinazoline

Synthesis of 2-chloro-7-methoxy-4-methyl-quinazoline BCI3 (40.65 mL, 0.046mol, 1 M solution in toluene) was added dropwise toa solution of compound 6 (5.0 g, 0.046 mol)in dry toluene (50 mL) at -5°C over a periodof 1 hour. MeCN (2.26 g 0.055 mol) was then added dropwise at 0-5°C over a period of 10min, the mixture was stirred at 0°C for 40 min, solid AICI3 (6.73 g, 0.051 mol)was added at 0-5°C. The mixture was stirred for 2 hours at 25 °C and heated toreflux for 20 hours. The mixture was cooled to 0°C and quenched by adding /^'-PrOH (30 mL) and H₂O (50 mL) at 0-5°C. The mixture was stirred for 2 hours and reflux for3h and cooled to r.t. The mixture was basified to pH = 3 with 25% aq. NaOH, andextracted with CH₂CI₂ (50 mL x 3), the organic layers were concentratedin vacuum, the residue was washed by MTBE to give compound 6a (2.1 g, yield: 31.3%). m/z = 165 [M +H]⁺ .To a solution of the compound 6a (3.0g, 18.2 mmol) in 30 mL of THF was added DMAP (2.18 g, 21 .8mmol) and CI3CCOCI(3.31 g, 18.2 mmol) at 0°C, then the mixture was stirred at room temperaturefor 6 hours. The resulting mixture was diluted with ice water (50 mL),extracted with EtOAc (20 mL ^χ 3), the organiclayers were concentrated in vacuum, the residue was purified by chromatographyon silica gel (PE / EtOAc = 20: 1 ) to give compound 6b (3.01 g, yield: 53.6%).To a solution of the compound 6b (1.0 g, 3.2 mmol) in 15 mL of DMSO was added CH₃COONH₄ (1 .242 g, 16.1 mmol), themixture was stirred at room temperature for 20 hours. The resulting mixture wasdiluted with cold H₂O, the formedprecipitate was collected by filtration and dried under vacuum to affordcompound 7-methoxy-4-methyl-1 H-quinazolin-2-one (0.25 g, yield: 41 .1 %),which was used for next step without further purification, m/z = 191 [M + H]⁺ .To a solution of the compound7-methoxy-4-methyl-1 H-quinazolin-2-one (300 mg, 1 .56 mmol) in 10 mL of toluene was added POCI3 (405.8 mg, 2.65mmol) and DIPEA (402.5 mg, 3.12 mmol), then the mixture was stirred at 80°C for6 hours. The resulting mixture was poured into 10mL of K2CO3, extracted with CH2CI2 (5 mL x 3), the organic layers wereconcentrated in vacuum to give 2- chloro-7-methoxy-4-methyl-quinazoline (291mg, yield: 95.9%).

References:

WO2013/50527,2013,A1 Location in patent:Page/Page column 48; 49; 50