| 61.8% |
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; |
125.1
1) Synthesis of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone To a stirring solution of diisopropylamine (56.4 g, 0.55 mol) in THF (500 mL) at - 40°C, n-butyl lithium (200 mL, 2.66 M hexane solution) was added dropwise. The mixture was stirred at -40°C for 1 hour and then cooled to -78°C. Then, a solution of 4-fluorobromobenzene (87.5 g, 0.50 mol) in THF (100 mL) was slowly added dropwise thereto such that the inner temperature of the reaction solution did not exceed -70°C. After the reaction solution was stirred at -78°C for 1 hour, a solution of ethyl trifluoroacetate (65.4 mL, 0.55 mol) in THF (100 mL) was added thereto at the same temperature. After the temperature of the reaction solution was raised to 0°C over 1 hour under stirring, a saturated aqueous ammonium chloride solution was added thereto, and the solution was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ hexane = 1/4), and the resulting yellow oily substance was purified again by distillation under reduced pressure (1 mmHg, 53°C), whereby the objective compound (83.8 g, 61.8%) was obtained as a yellow oily substance. 1H-NMR (400 MHz, CDCl3) δ: 7.15 (1H, dd, J = 10.2, 8.8 Hz), 7.78 (1H, ddd, J = 8.8, 4.4, 2.4 Hz), 7.99 (1H, dd, J = 6.3, 2.4 Hz) |
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Stage #1: 1-Bromo-4-fluorobenzene With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -68℃; for 0.1h; Inert atmosphere; Cooling with acetone-dry ice;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran; hexane Inert atmosphere; |
8.a 1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone
A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at -68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 min. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 min, and was then cooled back down to -68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added rapidly dropwise over 5 min. The reaction was then stirred in the cold bath for another 6 min, and the pale yellow reaction was then treated rapidly dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over 8 min (internal temp rose to -47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hrs). The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil |
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Stage #1: 1-Bromo-4-fluorobenzene With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - -40℃; for 1h;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran; hexane at 0℃; |
2.1
Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to -40 °C, Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at -40 °C for 1 h, then cooled to -78 °C, A solution of l-bromo-4-fluoiO- benzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at -78 °C for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0 °C over an hour. The reaction was quenched with NH4C1 (aq, sat), and extracted with EtOAc, washed with brine, and dried over a2S0 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided 1 -(5-biOmo-2-fluorophenyl)-2;2,2-trifluoroethanone |
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Stage #1: 1-Bromo-4-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran; hexane at -68℃; for 0.183333h; Inert atmosphere;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran; hexane at -47℃; Inert atmosphere; |
2.a 1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone
A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at -68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to -68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added rapidly dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated rapidly dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over -8 minutes (internal temp rose to -47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2*50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. |
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Stage #1: 1-Bromo-4-fluorobenzene With n-butyllithium; diisopropylamine In tetrahydrofuran at -80 - -40℃; for 1.16667h; Inert atmosphere;
Stage #2: ethyl trifluoroacetate, at -80℃; for 2.25h; |
57.A Step A: 1 -(5 -bromo-2-fluorophenyl)-2 ,2 ,2 -trifluoroethanone
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diisopropylamine (280 g, 2.77 mol, 1.10 equiv) in tetrahydrofuran (4400 mL). This was followed by the addition of butyllithium (1106 mL, 1.10 equiv) dropwise with stirring at -40°C in 15 mm. The mixture was stirred for 40 mm at-50°C. To this was added 1-bromo-4-fluorobenzene (440 g, 2.51 mol, 1.00 equiv) at |
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With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane |
1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone
Intermediate 7: Step a 1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at -68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to -68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 minutes (internal temp rose to -47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2*50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. |
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Stage #1: 1-Bromo-4-fluorobenzene With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 0.5h;
Stage #2: ethyl trifluoroacetate, In tetrahydrofuran at -70 - 0℃; for 2.5h; |
42.1 Step 1 : Preparation of l-(5-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone:
To a solution of LDA (2 M, 21.43 mL, 1.50 eq ) in THF (5 mL) was added 1 -bromo-4-fluoro- benzene (5 g, 28.57 mmol, 3.14 mL, 1 eq) in THF (5 mL) at -70 °C. The mixture was stirred at -70 °C for 0.5 hr and then ethyl 2,2,2-trifluoroacetate (8.12 g, 57.14 mmol, 7.88 mL, 2 eq) in THF (5 mL) was added drop-wise. The mixture was stirred at -70 °C for 0.5 hr and warmed to 0 °C and stirred for 2 hours. The mixture was quenched by addition of saturated aqueous NH C1 (50 mL) at 0 °C, extracted with EtOAc (40 mL*2). The combined organic layers were washed with H20 (50 mL), brine (50 mL), dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petr oleum ether gradient 100 mL/min) to afford the product l-(5- bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3 g, 6.03 mmol, 21.10% yield, 54.45% purity) as yellow oil which has no mass response on LCMS. |
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