1-溴-2-(三氟甲氧基)苯

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 2-bromo(trifluoromethyloxy)benzene (0.26 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 80° C. for 2 hours. After cooling, the solution was is concentrated under reduced pressure and taken up in acetone and filtered through a small plug of silica. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.145 g). Prepared After cooling the solution was is concentrated under reduced pressure filtered through a small plug of silica The filtrate was concentrated under reduced pressure dissolved in dichloromethane filtered purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 ml of ether is added dropwise to a mixture of 2.8 g of magnesium in 20 ml of ether, the reflux being maintained once it has started. At the end of the addition, the mixture is refluxed for one hour. A mixture of 7.5 g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at a temperature below 40° C., followed by refluxing for one hour. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with EtOAc, the organic phase is washed with water and with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 6.5 g of the expected product are obtained after crystallization from a DCM/iso ether mixture (20/80; v/v); m.p.=214° C. the reflux being maintained once it At the end of the addition the mixture is refluxed for one hour is then added, at a temperature below 40° C. by refluxing for one hour extracted with EtOAc the organic phase is washed with water and with 1N NaOH solution dried over Na2SO4 the solvent is evaporated off under vacuum

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79(br. s, 2H); MS m/z: 361 [MH]+. The flask was fitted with a rubber septum purged with nitrogen then charged with anhydrous THF (20 ml) to warm to room temperature over 5 hours the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride Ethyl acetate (50 ml) was added the layers were separated The aqueous fraction was extracted three times with ethyl acetate the combined organic fractions were washed with brine dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79(br. s, 2H); MS m/z: 361 [MH]+. The flask was fitted with a rubber septum purged with nitrogen then charged with anhydrous THF (20 ml) to warm to room temperature over 5 hours the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride Ethyl acetate (50 ml) was added the layers were separated The aqueous fraction was extracted three times with ethyl acetate the combined organic fractions were washed with brine dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79(br. s, 2H); MS m/z: 361 [MH]+. The flask was fitted with a rubber septum purged with nitrogen then charged with anhydrous THF (20 ml) to warm to room temperature over 5 hours the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride Ethyl acetate (50 ml) was added the layers were separated The aqueous fraction was extracted three times with ethyl acetate the combined organic fractions were washed with brine dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound. were added dropwise the reaction to completion

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-bromo-2-(trifluoromethoxy)benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ml) at −78° C. and stirred for 45 minutes. Triisopropyl borate (2.58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NaOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCl, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65%) as a white solid. the solution was slowly brought to room temperature over 16 hours The reaction mixture was quenched with water extracted with ethyl acetate stirred for 1 hour at room temperature extracted into ethyl acetate The organic layer was washed with water, brine solution dried over sodium sulfate It was filtered concentrated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78 ° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH]+. The flask was fitted with a rubber septum purged with nitrogen then charged with anhydrous THF (20 ml) to warm to room temperature over 5 hours the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride Ethyl acetate (50 ml) was added the layers were separated The aqueous fraction was extracted three times with ethyl acetate the combined organic fractions were washed with brine dried (Na2SO4) filtered concentrated Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid: 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH+]. The flask was fitted with a rubber septum purged with nitrogen then charged with anhydrous THF (20 ml) to warm to room temperature over 5 hours the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride Ethyl acetate (50 ml) was added the layers were separated The aqueous fraction was extracted three times with ethyl acetate the combined organic fractions were washed with brine dried (Na2SO4 filtered concentrated Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (commercially available) (1-bromo-2-trifluoromethoxy-benzene) in DME (first degased with argon) under argon was added 3 mol % Pd(PPh3)4, pyridyl-4-boronic acid and 2N Na2CO3, the resulting reaction mixture was vigorously stirred under reflux. After 5 h at reflux, reaction as monitored by TLC showed completion. Two phases were separated, evaporation of most of the DME, redissolution of the residue in EtOAc and washing with aq. NaOH followed by evaporation gave a yellow oil. Flash Chromatography on SiO2 gel with a mixture of CH2Cl2/MeOH gave the title compound in 51% yield. the resulting reaction mixture under reflux After 5 h at reflux reaction Two phases were separated evaporation of most of the DME, redissolution of the residue in EtOAc washing with aq. NaOH followed by evaporation gave a yellow oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (commercially available) (1-bromo-2-trifluoromethoxy-benzene) in DME (first degased with argon) under argon was added 3 mol % Pd(PPh3)4, pyridyl-4-boronic acid and 2N Na2CO3, the resulting reaction mixture was vigorously stirred under reflux. After 5 h at reflux, reaction as monitored by TLC showed completion. Two phases were separated, evaporation of most of the DME, redissolution of the residue in EtOAc and washing with aq. NaOH followed by evaporation gave a yellow oil. Flash Chromatography on SiO2 gel with a mixture of CH2Cl2/MeOH gave the title compound in 51% yield. the resulting reaction mixture under reflux After 5 h at reflux reaction Two phases were separated evaporation of most of the DME, redissolution of the residue in EtOAc washing with aq. NaOH followed by evaporation gave a yellow oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound. were added dropwise the reaction to completion