2-溴-4-氟-6-甲基苯胺

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.51 mmol) in hydrochloric acid (8 M, 22 mL, 176 mmol) at 0° C. was added a solution of sodium nitrite (1.78 g, 25.7 mmol) in water (ca. 5.5 mL) dropwise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (2.76 mL, 24.5 mmol) in ethanol (57 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (14 mL) and transferred to a solution of potassium tert-butoxide (22 g, 196 mmol) in dimethylsulfoxide (140 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Prep HPLC gave 1.66 g (31.5%) as a pale solid. LC/MS (HPLC method 3): tR=2.337 min, 215.01(MH)+. The resulting mixture was poured onto ice the resulting mixture was extracted into diethyl ether (2×) The ethereal was washed with water brine, dried over magnesium sulfate concentrated The resulting residue was dissolved in dimethylsulfoxide (14 mL) (ca. 10° C.) The bath was removed stirring continued for 30 min The reaction mixture was poured onto ice/concentrated hydrochloric acid The resulting mixture was extracted with dichloromethane (2×) washed with water (3×) brine, dried over magnesium sulfate concentrated Prep HPLC gave 1.66 g (31.5%) as a pale solid

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N-bromosuccinimide (18.7 g, 0.105 mol) in 70 mL of N,N-dimethylformamide was added dropwise to a solution of 4-fluoro-2-methylaniline in 70 mL of N,N-dimethylformamide at 20° C. The reaction mixture was stirred overnight. The dark solution was poured into a mixture of water (1000 mL), brine (50 mL) and ethyl acetate (300 mL). The mixture was transferred into a separatory funnel, shacked and separated. The aqueous phase was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (5×100 mL), brine (2×100 mL), dried with sodium sulfate, filtered and concentrated. The 1H NMR spectrum of the crude material showed at least 95% purity. The product was further purified on silica gel pad (eluent system ethyl acetate/n-hexane: 1/8). The pure fractions were combined and evaporated to give 14.9 g of product. The impure fractions were combined, concentrated, redissolved in diethyl ether (30 mL) and extracted with 5% hydrochloric acid (5×10 mL). The acidic phase was basified with aq. potassium hydroxide and extracted with diethyl ether to provide 0.8 g of the title compound. Total yield was 15.7 g (77%). The mixture was transferred into a separatory funnel separated The aqueous phase was extracted with ethyl acetate (4×150 mL) The combined organic layers were washed with water (5×100 mL), brine (2×100 mL) dried with sodium sulfate filtered concentrated The product was further purified on silica gel pad (eluent system ethyl acetate/n-hexane: 1/8) evaporated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.51 mmol) in hydrochloric acid (8 M, 22 mL, 176 mmol) at 0° C. was added a solution of sodium nitrite (1.78 g, 25.7 mmol) in water (ca. 5.5 mL) dropwise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (2.76 mL, 24.5 mmol) in ethanol (57 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (14 mL) and transferred to a solution of potassium tert-butoxide (22 g, 196 mmol) in dimethylsulfoxide (140 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Prep HPLC gave 1.66 g (31.5%) as a pale solid. LC/MS (HPLC method 3): tR=2.337 min, 215.01(MH)+. The resulting mixture was poured onto ice the resulting mixture was extracted into diethyl ether (2×) The ethereal was washed with water brine, dried over magnesium sulfate concentrated The resulting residue was dissolved in dimethylsulfoxide (14 mL) (ca. 10° C.) The bath was removed stirring continued for 30 min The reaction mixture was poured onto ice/concentrated hydrochloric acid The resulting mixture was extracted with dichloromethane (2×) washed with water (3×) brine, dried over magnesium sulfate concentrated Prep HPLC gave 1.66 g (31.5%) as a pale solid