反应详情

At −10° C., 90% fuming nitric acid (25 mL) was added to concentrate sulfuric acid (50 mL) slowly to keep the temperature below 0° C. At −20° C., 1-fluoro-4-trifluoromethoxy-benzene (5 g, 27.7 mmol) was added portionwise to keep the temperature of the reaction mixture below 0° C. After addition, the reaction mixture was kept at 0° C. for 30 min, poured into ice-water, extracted with EtOAc. The extracts were concentrated to give a mixture (6.05 g) of 4-fluoro-2-nitro-1-trifluoromethoxy-benzene and 1-fluoro-2-nitro-4-trifluoromethoxy-benzene in a 3:1 ratio. The crude nitration product (6.05 g) was dissolved in ethanol (40 mL) and shacked with 10% Pd/C (310 mg) and concentrate HCl (2.8 mL) under H2 (50 psi) for 3.5 h. Filtration and concentration gave a mixture (8.0 g) of 5-fluoro-2-trifluoromethoxy-phenylamine and its isomer 2-fluoro-5-trifluoromethoxy-phenylamine in 3:1 ratio. Without purification, the phenylamines (7 g, 35.8 mmol) were suspended in dichloromethane (100 mL), treated with trifluoroacetic anhydride (71 mmol) and triethylamine (20 mL) for 16 h. The reaction mixture was washed with saturated NaHCO3 and brine. The organic phase was further purified by silica gel chromatography (hexane/EtOAc 9:1) to give a mixture (5.29 g) of 2,2,2-trifluoro-N-(5-fluoro-2-trifluoromethoxy-phenyl)-acetamide and its isomer in 1:4 ratio, which was nitrated in a same procedure as the first step. The nitrate (3 g) was heated under reflux with morpholine (10 mL) in 1,2-dichloroethane (30 mL) for 3 h. Evaporation to remove excess morpholine. The residue was diluted with dichloromethane, washed with HCl (0.5N, 100 mL). The organic phase was purified by FC (hexane/EtOAc 7:3 to 1:1) to give the title compound 5-morpholin-4-yl-4-nitro-2-trifluoromethoxy-phenylamine (2.48 g). LC-MS: m/e=306.1 (M−H), 308.2 (M+H). 1H-NMR (500 MHz, CDCl3): 8.04 (s, 1H), 6.35 (s, 1H), 4.54 (br. s, 1H), 3.90 (t, 4H), 3.07 (t, 4H).

1. concentrationto concentrate sulfuric acid (50 mL) slowly
2. customthe temperature below 0° C
3. customthe temperature of the reaction mixture below 0° C
4. additionAfter addition
5. extractionextracted with EtOAc
6. concentrationThe extracts were concentrated