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With lithium aluminium tetrahydride In tetrahydrofuran at -50℃; for 3 h;
A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to -50°C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of methyl 4-trifluoromethylnicotinate dissolved in 30 ml of THF. The mixture was stirred at -50°C for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3percent) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]:
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -50℃; for 3 h; Stage #2: With ethyl acetate In tetrahydrofuran
REFERENCE EXAMPLE 46 Production of (4-trifluoromethylpyridin-3-yl)-methanol; A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to -50° C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of methyl 4-trifluoromethylnicotinate dissolved in 30 ml of THF. The mixture was stirred at -50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3percent) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]: 9.00 (1H,s), 8.73 (1H,d), 7.51 (1H,d), 4.95 (2H,s)
Reference：
[1] Patent: EP1364946, 2003, A1, . Location in patent: Page/Page column 200-201
[2] Patent: US2005/256004, 2005, A1, . Location in patent: Page/Page column 35
[3] Patent: US5756497, 1998, A,
With lithium aluminium tetrahydride; In tetrahydrofuran; at -50.0℃; for 3.0h;
A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to -50C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of <strong>[175204-82-7]methyl 4-trifluoromethylnicotinate</strong> dissolved in 30 ml of THF. The mixture was stirred at -50C for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3%) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance. 1H-NMR [CDCl3/TMS, delta (ppm)]: 9.00 (1H,s), 8.73 (1H,d), 7.51 (1H,d), 4.95 (2H,s)
35.3%
REFERENCE EXAMPLE 46 Production of (4-trifluoromethylpyridin-3-yl)-methanol; A solution of 0.37 g (9.7 mmoles) of lithium aluminum hydride dissolved in 100 ml of THF was cooled to -50 C. Thereto was gradually added dropwise a solution of 2.0 g (9.8 mmoles) of <strong>[175204-82-7]methyl 4-trifluoromethylnicotinate</strong> dissolved in 30 ml of THF. The mixture was stirred at -50 C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 35.3%) of (4-trifluoromethylpyridin-3-yl)-methanol as a yellow oily substance. 1H-NMR [CDCl3/TMS, delta (ppm)]: 9.00 (1H,s), 8.73 (1H,d), 7.51 (1H,d), 4.95 (2H,s)
With lithium aluminium tetrahydride; In tetrahydrofuran;
Step 1. To a stirred suspension of LAH (0.64 g, 17.0 mmol) in THF (30 mL) at -78 C. was added dropwise <strong>[175204-82-7]methyl 4-trifluoromethylnicotinate</strong> (1.74 g, 8.48 mmol) in THF (20 mL). The mixture was stirred for 1 h then carefully quenched with aqueous NaHCO3 (80 mL) and extracted with CH2 Cl2 (3*100 mL). The combined organic extracts were dried (Na2 SO4) and concentrated in vacuo to give 3-hydroxymethyl-4-trifluoromethylpyridine as an oil (TLC: Rf = 0.35 (1:1 hexane:EtOAc)).
With phosphorus tribromide In diethyl ether at -30 - 20℃; for 12h;
47 Production of 3-bromomethyl-4-trifluoromethylpyridine
A solution of 0.6 g (3.4 mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to -30°C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]: 8.88 (1H,s), 8.73 (1H,d), 7.54 (1H,d), 4.63 (2H,s)
75.3%
With phosphorus tribromide In diethyl ether at -30 - 20℃; for 12h;
47
REFERENCE EXAMPLE 47 Production of 3-bromomethyl-4-trifluoromethylpyridine; A solution of 0.6 g (3.4 mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to -30° C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]: 8.88 (1H,s), 8.73 (1H,d), 7.54 (1H,d), 4.63 (2H,s)
With phosphorus tribromide In dichloromethane at 0 - 20℃; for 2h;
135
To a solution of [4-(trifluoromethyl)pyridin-3-yl)methanol (980 mg, 5.5 mmol) in anhydrous dichloromethane (35 mL) was added dropwise a solution of tribromophosphane (530 μL, 5.5 mmol) in anhydrous dichloromethane (5 mL) at 0°C. The mixture was stirred for 2 hours at room temperature. The mixture was evaporated, and crude 3-(bromomethyl)-4-(trifluoromethyl)pyridine was used in the next step without further purification
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1.5h;
To a solution of sodium borohydride (324 mg, 8.6 mmol) in methanol (20 mL) was added a solution of <strong>[1083197-78-7]4-(trifluoromethyl)pyridine-3-carbaldehyde</strong> (1.0 g, 5.7 mmol) in methanol (10 mL) at O0C. The mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, [4-(trifluoromethyl)pyridin-3- yl)methanol was obtained as an oil (980 mg, 97% yield) and used in the next step without further purification.
Stage #1: 3-bromo-4-(trifluoromethyl)pyridine; N,N-dimethyl-formamide With n-butyllithium In toluene at -78℃; for 0.666667h; Inert atmosphere;
Stage #2: With methanol; sodium tetrahydroborate In toluene at -78 - 25℃; for 1h; Inert atmosphere;
52.1 Step 1:
Step 1: Preparation of (4-(trifluoromethyl)pyridin-3-yl)methanol To a solution of 3-bromo-4-(trifluoromethyl)pyridine (2.26 g, 10.0 mmol) in toluene (50 mL) at -78° C. was added n-butyllithium (4.8 mL, 12 mmol) under nitrogen. The mixture was stirred at -78° C. for 30 min before N,N-dimethylformamide (1.1 g, 15 mmol) was added. The reaction mixture was stirred at -78° C. for 10 min then sodium borohydride (0.756 g, 20 mmol) and methanol (5 mL) was added sequentially at -78° C. and the reaction was warmed to 25° C. and stirred for 1 h. After completion, aqueous ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate (80 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=2/1 to 1/1) to give (4-(trifluoromethyl)pyridin-3-yl)methanol (1.23 g, 6.95 mmol, 69%) as a colorless oil. LCMS (ESI) m/z: 178.1 [M+H]+.
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