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With potassium carbonate; In acetone; at 40℃; for 6h;
4-Fluoro-3-nitrophenol (3.14 g) was dissolved in acetone (40 ml) . To the solution were added methyl iodide (5.68 g) and potassium carbonate (5.53 g) , and the mixture was stirred at 40°C for 6 hours. Then, methylene chloride (50 ml) was added thereto, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) . The organic layer was washed with 1 N sodium hydroxide aqueous solution, water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give l-fluoro-4- methoxy-2 -nitrobenzene (3.47 g) as a brown oil.
With sodium hydrogencarbonate; In acetonitrile; at 70℃; for 13h;
A CH3CN (50 mL) solution of <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (4.71 g, 30 mmol), NaHCO3 (2.65 g, 31.5 mmol) and piperidine (3.02 mL, 30.6 mmol) was stirred at 70° C. for 13 days until less than 2percent starting material was left unreacted. Volatiles were removed in vacuo and the product was purified by silica gel column chromatography. Compound 3-nitro-4-(piperidin-1-yl)phenol was obtained as a reddish-brown color oil: 6.6 g (>99percent yield); 1H NMR (300 MHz, Chloroform-d) delta 7.23 (d, J=3.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 3.0 Hz, 1H), 5.14 (br s, 1H), 2.92-2.88 (m, 4H), 1.73-1.64 (m, 4H), 1.58-1.52 (m, 2H); LRMS (M+H) m/z 223.41.
With peracetic acid; sulfuric acid; nitric acid; acetic acid; In water;
Example 23 Preparation of 4-fluoro-3-nitrophenol (23) To 15 mL of concentrated sulfuric acid at 0° C. is added 6.9 g (0.05 mmol) of 4-fluoroacetophenone. To the resulting solution is rapidly added a mixture of 4 mL nitric acid and 6 mL concentrated sulfuric acid. The reaction mixture is stirred at 0-5° C. for 3 hours. The reaction mixture is then poured into ice water, and the resulting mixture is extracted with chloroform. The combined organic fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified using column chromatography on silica gel, eluding with 20percent ethyl acetate/hexanes, yielding 6.0 g of 4-fluoro-3-nitroacetophenone (60percent yield). Concentrated sulfuric acid (200 mL) and acetic acid (120) mL are mixed at 0° C. To this solution is added 15 g (0.082 mol) of 4-fluoro-3-nitroacetophenone with stirring. To the cold reaction mixture is added 36 mL of 36percent peracetic acid. The reaction mixture is then stirred at room temperature for 4 hours. Water (500 mL) is added to the mixture, and the crude product is extracted into diethyl ether. The combined ether fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified using column chromatography on silica gel, eluding with 3percent methanol/chloroform, giving 3.2 g of Compound 23 (20percent yield). mp: 86-87° C. 1 H-NMR (CDCl3) 7.56 (dd, 1H); 7.29 (t, 1H), 7.12 (m, 1H); 5.36 (s, 1H). 19 F-NMR (d6 -DMSO) 147.60 (s). Anal. calc. for C6 H4 FNO3: C, 45.87; H, 2.57; N, 8.92. Found: C, 45.80; H. 2.51; N, 8.69.
With iron; ammonium chloride; In ethanol; water; at 80℃; for 4h;
3-Amino-4-fluorophenol 4-Fluoro-3-nitrophenol (300 mg, 1.91 mmol) was initially charged in water (12.5 ml) and ethanol (12.5 ml). Ammonium chloride (552 mg, 10.31 mmol) and iron filings (640 mg, 11.46 mmol) were added and the mixture was stirred at 80° C. for 4 h. The reaction mixture was then cooled to RT and filtered through kieselguhr, and the filtrate was extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. 126 mg (39percent of theory) of the title compound were obtained. LC/MS (Method 6, ESIpos): Rt=0.99 min, m/z=128 [M+H]+.
2.18 g (100%)
With H2;palladium on charcoal; In ethyl acetate;
Example 24 Preparation of 3-amino-4-fluorophenol (24) A mixture of <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (2.70 g, 17.2 mmol) and palladium on charcoal (10percent, 0.31 g) in 60 mL ethyl acetate is hydrogenated under 50 psi of H2 using a Parr hydrogenation reactor. After shaking for 1 hour, the reaction mixture is filtered using a diatomaceous earth pad to remove catalyst. The filtrate is concentrated in vacuo, and the residue is sublimed to yield 2.18 g (100percent) of Compound 24 as a white solid. MP: 142-144° C. 1 H-NMR (d6 -DMSO) 8.82 (s, 1H); 6.70 (dd, 1H); 6.17 (dd, 1H); 5.85 (m, 1H); 4.92 (s, 2H). 19 F-NMR (d6 -DMSO) 142.78 (t, 13.0 Hz). Anal. calc. for C6 H6 FNO: C, 56.69; H, 4.76; N, 11.02. Found: C, 57.28; H, 4.86; N, 10.65.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 2h;
Reference Example 21; 2-Fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]aniline; To a solution of <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (this compound was synthesized according to the procedure described in the International publication WO97/39064) (0.2 g), 1-(2-fluoro-6-methoxyphenyl)ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (40percent toluene solution, 0.84 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane - n-hexane/ethyl acetate = 8/1) to give 2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]-1-nitrobenzene (0.15 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 3/1) to give the title compound (0.11 g).
To a DMF (10 mL) solution of <strong>[2105-96-6]4-fluoro-3-nitro-phenol</strong> (628 mg), sodium hydride (purity: 55percent or higher, 209 mg) was added in small portions at room temperature. After 30 minutes, ethyl iodide (0.38 mL) was added thereto at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (685 mg, 93percent) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta (ppm) = 7.52 (1H, dd, J = 5.9 and 3.1 Hz), 7.23-7.13 (2H, m), 4.07 (2H, q, J = 7.0 Hz), 1.45 (3H, t, J = 7.0 Hz).
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