| 67% |
With Cs2CO3 In tetrahydrofuran at 25℃; for 8h; |
10.1
Step 1. 4-fluoro-1 -nitro-2-[(2,2,2-trifluoroethyl)oxy]benzeneA mixture of 2, 4-difluoro-1 -nitrobenzene (10 g, 62.9 mmol) and 2,2,2- trifluoroethanol (6.29 g, 62.9 mmol) in THF (100 mL) at 25 °C was treated with Cs2C03 (20.5 g, 62.9 mmol) and stirred for 8 hours before being diluted with the addition of water and extracted with EtOAc. The organic extract was dried (Na2S04), concentrated, and subjected to flash chromatography (3% EtOAc-petroleum ether) to give 4-fluoro-1-nitro-2- [(2,2,2-trifluoroethyl)oxy]benzene (10 g, 67%) as a yellow solid. MS (m/z) 240.0 (M+H+)- |
| 67% |
With Cs2CO3 In tetrahydrofuran at 25℃; for 8h; |
1
PREPARATION 13 5-amino-2-fluoro-/V-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamidStep 1. 4-fluoro-1 -nitro-2-[(2,2,2-trifluoroethyl)oxy]benzeneA mixture of 2, 4-difluoro-1 -nitrobenzene (10 g, 62.9 mmol) and 2,2,2- trifluoroethanol (6.29 g, 62.9 mmol) in THF (100 mL) at 25 °C was treated with Cs2C03 (20.5 g, 62.9 mmol) and stirred for 8 h before being diluted with the addition of water and extracted with EtOAc. The organic extract was dried (Na2S04), concentrated, and subjected to flash chromatography (3% EtOAc-petroleum ether) to give 4-fluoro-1-nitro-2- [(2,2,2-trifluoroethyl)oxy]benzene (10 g, 67%) as a yellow solid. MS (m/z) 240.0 (M+H)+. |
| 50% |
With sodium hydride In toluene; mineral oil at 0 - 45℃; for 15h; |
Intermediate 4: 4-Fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene
Intermediate 4: 4-Fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene To a 100 mL round-bottomed flask were added 2,4-difluoro-1-nitrobenzene (1.6 g, 10 mmol), 2,2,2-trifluoroethanol (1.4 g, 14 mmol), and toluene (20 mL) and the mixture cooled to 0° C. The reaction was treated with NaH (60% in mineral oil, 0.48 g, 12 mmol) in four portions over 5 min and was stirred at 45° C. for 15 h. The mixture was cooled to rt, diluted with water (30 mL), and extracted with EtOAc (3*20 mL). The combined organic phases were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (1.2 g, 50%) as a red oil, which was used in the next reaction without any further purification. 1H NMR (300 MHz, CDCl3): δ 8.00 (dd, J=9.3 Hz, 6.0 Hz, 1H), 6.92-6.86 (m, 1H), 6.82 (dd, J=9.3 Hz, 2.4 Hz, 1H), 4.48 (q, J=7.8 Hz, 2H). |
|
With sodium hydroxide In toluene at 30 - 50℃; for 16h; |
2420.1 4-Fluoro-l-nitfo-2-(2,2,2-tfifluoro-ethoxy)-benzene
To a solution of 2,4-difIuoronitrobenzene (300,0 g, 1.89 mol) and 2,2,2- trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90,5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40°C. After the temperature had dropped to 30°C, the reaction mixture was heated to 45-50°C using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 N H2SO4 (200- 300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 'H NMR (300 MHz, CDCI3TMS): 5 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J= 7,7 Hz, 2H).13C NMR (75 MHz, CDC13/TMS): δ 165.0 (d, JCF= 259.6 Hz), 152.3 (d, 13.1 Hz), 128.2 (d,3JCR;;;11.9 Hz), 122.4 (d, VCF;;;273.4 Hz), 1 10.1 (d,2JCF;;;22.5 Hz), 105.9 (q, CF 242.6 Hz), 104.3 (d,2JCF26.1 Hz), 67.6 |
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