Stage #1: at -5 - -4℃; for 1 h; Stage #2: at 15 - 30℃; for 72 h;
Thionyl chloride (2.68g, 0.023 mol) was added dropwise to methanol (12 mL) at -5° C via a syringe keeping the temperature at or below -4° C. The resulting mixture was stirred at or below -5° C for 1 hr., then 4-amino- 3-(trifluoromethoxy)benzoic acid (0.5g, 0.003 mol) [Alfa Aesar] was added in one portion. The reaction mixture was stirred at ambient temperature for 3 days after which the mixture was concentrated in vacuo. Water (10 mL) was added to the residue and sodium bicarbonate (0.46g, 5.4 mmol) was added in one portion and the mixture was stirred at ambient temperature for 30 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 1.02g (96.2percent) of methyl 4-amino-3-(trifiuoromethoxy)berrzoate as a red oil that slowly sodified to a brown solid on cooling. MS: m/z 236.1 (MH+). 1H NMR (500 MHz, DMSO-d6): δ 3.771 (s, 3H), 6.329 (s, 2H), 6.834 (d, 1H), 7.6181 (s, 1H), 7.655 (dd, 1H).
95%
With hydrogenchloride In 1,4-dioxane at 20℃; for 72 h;
A. Methyl 4-amino-3-(trifluoromethoxy)benzoate A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (8.88 g 40.2 mmol), MeOH (142 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 142 mL, 568 mmol) was stirred at room temperature for 72 h. After removal of the organic solvent the pH of the residue was adjusted to pH 8 and the aqueous layer was extracted with ethyl acetate (50 mL*3). The combined organic layers were dried and concentrated under vacuum to afford the title compound (9.3 g, 39.6 mmol, 95percent yield). MS (ESI) m/z 236.1 [M+1]+.
To a solution of 4-bromo-2-(trifluoromethoxy)aniline (10 g, 50.21 mmol) in methanol (150 mL) in a pressure tank reactor was added TEA (11.84 g, 117.01 mmol), Pd(dppf)Ci2 CH2Q2 (2.4 g, 2.94 mmol). Then the reactor was charged with CO (g) (20 atm). The resulting reaction was stirred for 1.5 days at 100°C. Then it was diluted with water (200 mL), extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried in an oven under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :50) to afford methyl 4- amino-3-(trifluoromethoxy)benzoate as yellow solid (5 g, 54percent).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; at 100℃; under 15201.0 Torr; for 36h;
To a solution of <strong>[175278-09-8]4-bromo-2-(trifluoromethoxy)aniline</strong> (10 g, 50.21 mmol) in methanol (150 mL) in a pressure tank reactor was added TEA (11.84 g, 117.01 mmol), Pd(dppf)Ci2 CH2Q2 (2.4 g, 2.94 mmol). Then the reactor was charged with CO (g) (20 atm). The resulting reaction was stirred for 1.5 days at 100C. Then it was diluted with water (200 mL), extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried in an oven under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :50) to afford methyl 4- amino-3-(trifluoromethoxy)benzoate as yellow solid (5 g, 54%).
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