反应详情

温度

85 °C

To a stirred solution of tert-butyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation 24, 4.60 g, 18.8 mmol) in carbon tetrachloride (60 mL) was added NBS (3.70 g, 20.7 mmol) and dibenzoyl peroxide (228 mg, 0.94 mmol). The resulting mixture was stirred under nitrogen at 85° C. for 18 hours. Additional NBS (7.60 g, 41.4 mmol) was added and the mixture stirred for 4 hours. Further NBS (1.00 g, 5.6 mmol) and dibenzoyl peroxide (200 mg, 0.85 mmol) were then added and the reaction mixture was left to stir under nitrogen at 85° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), aqueous sodium thiosulfate solution (50 mL), dried over MgSO4, and concentrated under vacuum to give the crude product as a yellow oil. The crude product was purified by column chromatography on silica (eluent 95:5 heptane/EtOAc) yielding a 2:1 mixture of the title compound (tert-butyl 5-chloro-4-(bromomethyl)-2-fluorobenzoate) and tert-butyl 5-chloro-4-(dibromomethyl)-2-fluorobenzoate (3.96 g). To a stirred solution of the mixture of tert-butyl 5-chloro-4-(bromomethyl)-2-fluorobenzoate and tert-butyl 5-chloro-4-(dibromomethyl)-2-fluorobenzoate in EtOAc (25 mL) were added N,N-diisopropylethylamine (2.60 mL, 14.8 mmol) and diethyl phosphate (1.30 ml, 9.80 mmol) dropwise. The reaction mixture was stirred under nitrogen at room temperature for 18 hours. The reaction mixture was washed with aqueous solution of 1M HCl (30 mL) and brine (30 mL), dried over MgSO4 and concentrated under vacuum to give the crude product as an orange oil. This was purified by column chromatography on silica (eluent 9:1 heptane/EtOAc) yielding the title compound as an orange oil (2.9 g, 48%).

1. stirringthe mixture stirred for 4 hours
2. waitthe reaction mixture was left
3. stirringto stir under nitrogen at 85° C. for 18 hours
4. temperatureThe reaction mixture was then cooled to room temperature
5. washThe organic layer was washed with water (50 mL), aqueous sodium thiosulfate solution (50 mL)
6. dry with materialdried over MgSO4
7. concentrationconcentrated under vacuum
8. customto give the crude product as a yellow oil
9. customThe crude product was purified by column chromatography on silica (eluent 95:5 heptane/EtOAc)
10. customyielding