1-(2-Amino-6-fluorophenyl)ethanone synthesis

Yield:869937-08-6 36.8%

Reaction Conditions:

in tetrahydrofuran at -10 - 70; for 5 h;

Steps:

Synthesis of 2-chloro-5-fluoro-4-methyl-quinazoline

Synthesis of 2-chloro-5-fluoro-4-methyl-quinazoline To a solution of compound 4 (5.0 g,37 mmol) in 20 mL of THF was added dropwise MeMgBr (85.76 mL, 3.0 M in ether)at -10°C, then the mixture was stirred at70°C for 5 hours. The resulting mixture was quenched with 30 mL of 10 % HCI, heated to reflux for a hour, made alkaline by addition of NaHCO3 andextracted with EtOAc (30 mL χ 3), the organic layers were concentrated invacuum, the residue was purified by chromatography on silica gel (PE / EtOAc =100: 1 ) to afford compound 4a (2.09 g, yield: 36.8%).To a solution of the compound 4a (2.0g, 13.3 mmol) in 35 mL of THF was added DMAP (1 .596 g, 16.6 mmol) and CI₃CCOCI (2.42 g, 13.3 mmol) at 0°C, then themixture was stirred at room temperature for 7 hours. The resulting mixture wasdiluted with ice water (50 mL), extracted with EtOAc (15 mL χ 3), the organiclayers were concentrated in vacuum, the residue was purified by chromatographyon silica gel (PE / EtOAc = 60: 1 ) to afford compound 4b (3.0 g, yield:75.76%). m/z = 297 [M + H]⁺ .To a solution of the compound 4b (1.4 g, 4.7 mmol) in 10 mL of DMSO was addedCH3COONH4 (1 .3 g, 23 mmol), the mixture was stirred at room temperature for 24hours. The resulting mixture was diluted with cold water, the formedprecipitate was collected by filtration and dried under vacuum to affordcompound 5-fluoro-4-methyl-1 H-quinazolin-2-one (0.8 g, yield: 95.6%), whichwas used for next step without further purification, m/z = 179 [M + H]+ .A mixture of 5-fluoro-4-methyl-1 H-quinazolin-2-one(300 mg, 1 .68 mmol) in 3 mL of POCI3 was stirred at 80°C for 12hours. Theresulting mixture was poured into 20 mL of aq. K2CO3 solution, extracted withEtOAc (5 mL ^χ 3), the organic layers wereconcentrated in vacuum, the residue was purified by chromatography on silicagel (PE / EtOAc = 50: 1 ) to give 2-chloro-5-fluoro-4-methyl-quinazoline (140mg, yield: 42.5%) as white solid. m/z = 197 [M + H]⁺ .

References:

WO2013/50527,2013,A1 Location in patent:Page/Page column 46; 47