Sodium hydride → 6-[2-(2-Chloro-4-methoxy-phenyl)-acetyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one

Participants

Reaction Conditions

Reaction Steps

To a solution of 7-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (Example 136, step 2, 1.98 g) in N,N-dimethylformamide (66 ml) was added 1,1′-carbonyldiimidazole (1.43 g). The mixture was stirred at 50° C. for 90 min. The mixture was cooled to −10° C. and (2-chloro-5-methoxy-phenyl)-acetic acid methyl ester (1.8 g) was added. Sodium hydride (60% dispersion in mineral oil, 1.12 g) was added portionwise over 30 min. The mixture was slowly warmed to room temperature and stirred for 4 h. The mixture was poured into ice water (135 ml) and saturated aqueous ammonium chloride solution (42 ml) and was extracted with ethyl acetate (5×). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was dissolved in dimethylsulfoxide (18 ml). NaCl (0.54 g) and water (0.23 ml) were added and the mixture was heated to 140° C. for 40 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give a light brown solid. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>95:5) to give the title compound as a light yellow solid (318 mg). MS (m/e)=364.1 [M+H+].

Provenance & Evidence