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Stage #1: 2-bromo-3-fluoroisonicotinic acid; <i>tert</i>-butyl alcohol With triethylamine In toluene at 110℃; for 0.5h; Inert atmosphere; Molecular sieve;
Stage #2: With diphenyl phosphoryl azide In toluene at 15 - 110℃; for 5h; Inert atmosphere; Molecular sieve;
[0521] A mixture of 2-bromo-3-fTuoroisonicotinic acid (90.0 g, 409 mmol, 1.00 equiv), 4 MS (50.0 g, 1.00 equiv) and TEA (124 g, 1.23 mol, 171 mL, 3.00 equiv) in toluene (50.0 mL) and t-BuOH (182 g, 2.45 mol, 235 mL, 6.00 equiv) was stirred at 1 10 °C for 0.5 hour under nitrogen. The mixture was cooled to 15 °C and DPP A (135 g, 491 mmol, 106 mL, 1.2 equiv) was added thereto. The mixture was stirred at 1 10 °C for 5 h prior to being diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate, 50:1 to 5:1) to afford tert- butyl (2-bromo-3-fluoiOpyridin-4-yl)carbamate (53.0 g, 39.4% yield) as a yellow solid. LCMS [ESI, M+l]: 291.
With diphenyl phosphoryl azide; triethylamine Reflux;
2-bromo-3-fluoroisonicotinic acid (5.33 g, 24.21 mmol) was dissolved in tert.-butyl alcohol (150 mL). Triethylamine (3.69 mL, 26.63 mmol) and diphenylphosphoryl azide (5.31 mL, 24.69 mmol) were added and the reaction mixture was refluxed overnight. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient yielding the desired product as a clear oil which solidified on standing, tert-butyl N-(2- bromo-3-fluoro-4-pyridyl)carbamate (6.71 g, 23.05 mmol) was dissolved in CH2C12 (20 mL), HC1 (6M in iPrOH, 75 mL, 450 mmol) was added and the reaction mixture was stirred for 2 days at room temperature. The volatiles were removed under reduced pressure and the residue was partitioned between water (100 mL) and CH2C12 (100 mL). The aqueous layer was basified and the organic layer was removed. The aqueous layer was extracted with CH2C12 (20 mL). The combined organic layers were dried over MgS04, filtered and evaporated to dryness yielding 2-bromo-3-fluoro-pyridin-4-amine (3.55 g) as a white powder.
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