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Thionyl chloride (0.29 mL, 4.08 mmol) was added to a slurry of 6-fluoronicotinic acid (13, 0.48 g, 3.40 mmol) and N,N-dimethylformamide (0.1 mL, catalytic amount) in benzene (40 mL) at room temperature under nitrogen, after which the mixture was heated at reflux for 3 h. The solvent was removed under reduced pressure to provide an amber oil that was dissolved in 1,4-dioxane (25 mL) under nitrogen. The solution was treated with sodium borohydride (0.26 g, 6.80 mmol) and the mixture was stirred at room temperature for 24 h. The suspension was diluted with sat. NaHCO3 solution (200 mL) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvents were removed under reduced pressure to provide the title compound as a colorless oil: 1H NMR (300 MHz) 8.20 (s, 1H), 7.87-7.81 (dt, J=8.0, 2.3 Hz, 1H), 6.97-6.93 (dd, J=8.4, 2.8 Hz, 1H), 4.73 (s, 2H), 2.04 (bs, 1H) ppm.
With methanol; sodium tetrahydroborate; for 1h;Cooling with ice;
Production Example 4-1; (6-Fluoropyridin-3 -yl)methanol; Sodium borohydride (2.4 g) was gradually added to a methanol solution (100 mL) of commercially available 6-fluoronicotinaldehyde (7.8 g) under ice-cooled conditions. The mixture was stirred at the same temperature for 1 hour, and water was added after removing the methanol under reduced pressure. After extracting the reaction mixture with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to give the title compound (4.9 g) as a colorless solid.
With methanol; sodium tetrahydroborate; for 1h;Cooling with ice;
Production Example 4-1(6-Fluoropyridin-3-yl)methanolSodium borohydride (2.4 g) was gradually added to a methanol solution (100 mL) of commercially available 6-fluoronicotinaldehyde (7.8 g) under ice-cooled conditions. The mixture was stirred at the same temperature for 1 hour, and water was added after removing the methanol under reduced pressure. After extracting the reaction mixture with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (4.9 g) as a colorless solid.
Production Example 4-2; (5-Bromo-6-fluoropyridin-3-yl)methanol; A THF solution (200 mL) of the compound (4.9 g) obtained in Production Example 4- 1 and NjNjN^-tetramethylethylenediamine (14.4 mL) was cooled to -78C, and a hexane solution (25 mL) of 1.63 M n-butyllithium, and a heptane solution (36.2 mL) of 1.58 M /-butyllithium were successively added dropwise. The reaction mixture was stirred at -780C for 1 hour, gradually raised to -35C to -300C, and further stirred at the same temperature for 2 hours. After cooling to -78C, 1,2- dibromotetrafluoroethane (13 mL) was gradually added dropwise. The reaction mixture was stirred at -780C for 5 minutes, gradually raised to room temperature, and further stirred at room temperature for 30 minutes. After treatment with a saturated ammonium chloride solution and extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give the title compound (1.8 g) as a yellow solid.
Production Example 4-2(5-Bromo-6-fluoropyridin-3-yl)methanolA THF solution (200 mL) of the compound (4.9 g) obtained in Production Example 4-1 and N,N,N',N'-tetramethylethylenediamine (14.4 mL) was cooled to -78 C., and a hexane solution (25 mL) of 1.63 M n-butyllithium, and a heptane solution (36.2 mL) of 1.58 M t-butyllithium were successively added dropwise. The reaction mixture was stirred at -78 C. for 1 hour, gradually raised to -35 C. to -30 C., and further stirred at the same temperature for 2 hours. After cooling to -78 C., 1,2-dibromotetrafluoroethane (13 mL) was gradually added dropwise. The reaction mixture was stirred at -78 C. for 5 minutes, gradually raised to room temperature, and further stirred at room temperature for 30 minutes. After treatment with a saturated ammonium chloride solution and extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (1.8 g) as a yellow solid.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.0833333h;
Example 30A (6-Fluoropyridin-3-yl)methyl methanesulphonate At 0 C., 3.4 ml (43.4 mmol) of methanesulphonyl chloride were added slowly to a solution of 4.60 g (36.2 mmol) of <strong>[39891-05-9](6-fluoropyridin-3-yl)methanol</strong> and 6.6 ml (47.0 mmol) of triethylamine in 100 ml of THF. The cooling bath was removed and the mixture was stirred at RT for 5 min. Water, saturated aqueous sodium bicarbonate solution and ethyl acetate were then added to the mixture. After phase separation, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 7.44 g (93% of theory, purity 93%) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.29 (d, 1H), 7.91 (td, 1H), 7.01 (dd, 1H), 5.25 (s, 2H), 3.04 (s, 3H). LC/MS (Method 5, ESIpos): Rt=0.53 min, m/z=206 [M+H]+.
With triethylamine; In dichloromethane; at 0℃;
Example 14A 2-fluoro-5-(methylsulfonylmethyl)pyridine <strong>[39891-05-9](6-Fluoropyridin-3-yl)methanol</strong> (215 mg, 1.69 mmol) in CH2Cl2 (10 mL) containing triethylamine (354 muL, 2.54 mmol) was treated with methanesulfonyl chloride (291 mg, 2.54 mmol) dropwise at 0 C., stirred at 0 C. for 30 min, diluted with water, and extracted with CH2Cl2 (2*10 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated to afford a crude oil.
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