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To a IN solution of borane in tetrahydrofuran (30 ml) was added 2-chloro-4-trifluoromethylbenzoic acid (2.50 g) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into IN hydrochloric acid, and the mixture was extracted with, ethyl acetate . The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated 0 brine, dried (MgSO4) , and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:24 - 1:4, v/v) to give 2-chloro-4- trifluoromethylbenzyl alcohol (2.23 g, yield: 96percent) as a colorless oil. 5 1H-NMR (300 MHz, CDCl3) δ:4.85 (2 H, d, J = 9.0 Hz), 7.52 - EPO <DP n="167"/>7 . 80 ( 3 H, m) .
96%
With borane In tetrahydrofuran
Reference Example 129 To a 1N solution (30 ml) of borane in tetrahydrofuran was added 2-chloro-4-(trifluoromethyl)benzoic acid (2.50 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:24 to 1:4, v/v) to give 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.23 g, yield 96percent) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ:4.85 (2 H, d, J = 9.0 Hz), 7.52 - 7.80 (3 H, m).
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 30℃; for 2h;
To a solution of <strong>[56456-51-0]2-chloro-4-trifluoromethylbenzyl alcohol</strong> (2.23 g) and triphenylphosphine (4.17 g) in tetrahydrofuran (25 ml) was added carbon tetrabromide (5.27 g) , and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, hexane and diethyl ether was added to the residue, and the insoluble material was filtered off. The mother liquor was concentrated, and the obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (0:1 - 1:4, v/'v) to give 2-chloro-4- trifluoromethylbenzylbromide (2.90 g, yield: 99%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) 5:4.59 (2 H, s) , 7.46 - 7.60 (2 H, m) , 7.65 (1 H, s)
To a IN solution of borane in tetrahydrofuran (30 ml) was added 2-chloro-4-trifluoromethylbenzoic acid (2.50 g) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into IN hydrochloric acid, and the mixture was extracted with, ethyl acetate . The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated 0 brine, dried (MgSO4) , and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:24 - 1:4, v/v) to give 2-chloro-4- trifluoromethylbenzyl alcohol (2.23 g, yield: 96%) as a colorless oil. 5 1H-NMR (300 MHz, CDCl3) delta:4.85 (2 H, d, J = 9.0 Hz), 7.52 - EPO <DP n="167"/>7 . 80 ( 3 H, m) .
96%
With borane; In tetrahydrofuran;
Reference Example 129 To a 1N solution (30 ml) of borane in tetrahydrofuran was added 2-chloro-4-(trifluoromethyl)benzoic acid (2.50 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:24 to 1:4, v/v) to give 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.23 g, yield 96%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) delta:4.85 (2 H, d, J = 9.0 Hz), 7.52 - 7.80 (3 H, m).
PRODUCTION EXAMPLE 11 Production of 2-Chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene Methanesulfonyl chloride (1.1 ml) was added dropwise to a solution of <strong>[56456-51-0]2-chloro-4-(trifluoromethyl)benzyl alcohol</strong> (2.64 g) and anhydrous triethylamine (2.3 ml) in anhydrous dichloromethane (30 ml) in a nitrogen stream under ice-cooling and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was successively washed with water, aqueous sodium hydrogencarbonate, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene as white crystals (3.62 g). [Physicochemical Property of the Compound] 1H-NMR (CDCl3): 3.08(3H, s), 5.37(2H, s), 7.58(1H, d, J=8 Hz), 7.65(1H, d, J=8 Hz), 7.70(1H, s).
With pyridine; thionyl chloride; In tetrahydrofuran; diethyl ether; at 0 - 30℃; for 15h;
To a solution of <strong>[56456-51-0]2-chloro-4-trifluoromethylbenzyl alcohol</strong> (38.8 g) and pyridine (3.0 ml) in diethyl ether (320 ml)- tetrahydrofuran (80 ml) was added thionyl chloride (32.8 g) , and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated, water was poured' into the residue and the mixture was extracted with ethyl acetate. The o ethyl acetate layer was washed with IN hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:25 - 1:12, v/v) to give 2-chloro- 4-trifluoromethylbenzyl chloride (38.9 g, yield: 92%) as a colorless oil.1H-NMR (300 MHz, CDCl3) delta:4.72 (2 H,, s) , 7.51 - 7.57 (1 H, m) , 7.60 - 7.70 (2 H, m) .
With triphenylphosphine; In tetrahydrofuran; diethyl ether; hexane;
Reference Example 130 To a solution of <strong>[56456-51-0]2-chloro-4-(trifluoromethyl)benzyl alcohol</strong> (2.23 g) and triphenylphosphine (4.17 g) in tetrahydrofuran (25 ml) was added carbon tetrabromide (5.27 g), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, hexane and diethyl ether were added to the residue, and the insoluble substance was removed by filtration. The filtrate was concentrated, and the obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (0:1 to 1:4, v/v) to give 2-chloro-4-(trifluoromethyl)benzyl bromide (2.90 g, yield 99%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) delta:4.59 (2 H, s), 7.46 - 7.60 (2 H, m), 7.65 (1 H, s).
Step 1. 1- (2-Chloro-4- (trifluoromethyl) phenyl) ethan-1-ol:DMSO (7.73 ml, 109 mmol) was added to a -78 solution of oxalyl chloride (4.77 ml, 54.5 mmol) in dichloromethane (100 ml) . The mixture was stirred for 10 minutes before the addition of (2-chloro-4- (trifluoromethyl) -phenyl) methanol (7.65 g, 36.3 mmol) as a solution in dichloromethane (100 ml) . This mixture was stirred for 30 minutes at-78 and then treated with triethylamine (25.3 ml, 182 mmol) . The resulting mixture was stirred for 20 minutes at-78 and then warmed to RT and stirred for 1 h. The reaction was then quenched with saturated NaHCO3solution and the aqueous layer was extracted with dichloromethane. The organic extracts were combined and washed with 1N HCl, water, and then dried over Na2SO4. This mixture was filtered and concentrated. The crude aldehyde was then dissolved in THF (85 ml) and the solution was cooled to 0 before the addition of methylmagnesium bromide (15.74 ml, 47.2 mmol) . After 5 minutes the reaction was quenched with saturated NH4Cl solution and the product was extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel chromatography (0-30 ethyl acetate in hexanes) to furnish the title compound.1H NMR (500 MHz, CDCl3) delta: 7.78 (d, J 8 Hz, 1H) , 7.62 (s, 1H) , 7.58 (d, J 8 Hz, 1H) , 5.34 (q, J 6 Hz, 1H) , 2.15 (broad, 1H) , 1.53 (d, J 6 Hz, 3H) .
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