Benzene, 1-bromo-4-(1,1-difluoroethyl)-

1-Bromo-4-(1, 1-difluoroethyl)benzene; Under argon, 3.0 g (15.07 mmol) of 1-(4-bromophenyl)ethanone were initially charged in 30 ml of dichloromethane, and 15.9 ml (120.57 mmol) of [ethyl(trifluoro-λExample 48A Example 68A1-Bromo-4-(1, 1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory)Deoxo-Fluor (registered trademark) (22.2 g) was added to 1-(4-bromophenyl)ethanone (20.0 g) and the mixturewas stirred at 85°C for 15 hours. Under icecooling, ice water and an aqueous solution of potassium carbonate wereadded to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound(13.0 g, yield 59percent) as a yellow oil.1H NMR (600 MHz, CDCl3) δ ppm 1.91 (t, J=18.2 Hz, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H).Step A: Preparation of l-bromo-4-(l, l-difluoroethyl)benzene. [00211] To a vial equipped with a magnetic stir bar were added a solution of l-(4- bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50percent solution of DeoxofluorUnder argon atmosphere, into a 500-ml reaction vessel made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulfur trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50°C for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid. [0134] The properties of Compound (4-1) were as follows. Under argon atmosphere, into a 500-ml reaction vessel 30 made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulthr trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50° C. for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid.The properties of Compound (4-1) were as follows. ‘H-NMR (400 MHz, CDC13, ö (ppm)); 1.90 (3H, t, J=18. 1 Hz), 7.54 (2H, d, J=2.3 Hz), 7.57 (2H, d, J=2.4 Hz)CI-MS; 222 (M+2)4045Example 63A1-Bromo-4-(1, 1-difluoroethyl)benzene; Under argon, 3.0 g (15.07 mmol) of 1-(4-bromophenyl)ethanone were initially charged in 30 ml of dichloromethane, and 15.9 ml (120.57 mmol) of [ethyl(trifluoro-λExample 48A Example 68A1-Bromo-4-(1, 1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory)Deoxo-Fluor (registered trademark) (22.2 g) was added to 1-(4-bromophenyl)ethanone (20.0 g) and the mixturewas stirred at 85°C for 15 hours. Under icecooling, ice water and an aqueous solution of potassium carbonate wereadded to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound(13.0 g, yield 59percent) as a yellow oil.1H NMR (600 MHz, CDCl3) δ ppm 1.91 (t, J=18.2 Hz, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H).Step A: Preparation of l-bromo-4-(l, l-difluoroethyl)benzene. [00211] To a vial equipped with a magnetic stir bar were added a solution of l-(4- bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50percent solution of DeoxofluorUnder argon atmosphere, into a 500-ml reaction vessel made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulfur trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50°C for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid. [0134] The properties of Compound (4-1) were as follows. Under argon atmosphere, into a 500-ml reaction vessel 30 made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulthr trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50° C. for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid.The properties of Compound (4-1) were as follows. ‘H-NMR (400 MHz, CDC13, ö (ppm)); 1.90 (3H, t, J=18. 1 Hz), 7.54 (2H, d, J=2.3 Hz), 7.57 (2H, d, J=2.4 Hz)CI-MS; 222 (M+2)4045After replacing the interior of the reaction vessel with nitrogen gas, 1-Bromo-4- (1, 1-difluoroethyl) benzene(13.00 g, 58.81 mmol)And tetrahydrofuran (130 mL) in this order, Was added to the reaction vessel.Next, the reaction vessel was cooled to -78 C., A 1.58 mol / L solution of n-butyllithium in tetrahydrofuran(45.0 mL, 71.1 mmol) was added dropwise, And the mixture was stirred at -78 C. for 1 hour.Subsequently, to the reaction mixture, triisopropyl borate(16.3 mL, 70.6 mmol) was added, The reaction temperature was changed from -78 C. to 0 C., and the mixture was stirred at 0 C. for 3 hours.To the reaction mixture was added 1 mol / L hydrochloric acid aqueous solution(71 mL, 71 mmol) was added dropwise, The reaction temperature was brought to 20 C. to 25 C. and stirred for 16 hours. Subsequently, the reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, Ethyl acetate was added to the reaction mixture, and liquid separation was performed to recover the organic layer.Anhydrous magnesium sulfate was added to the organic layer, dried, and after filtration, the organic layer was concentrated under reduced pressure.Subsequently, after adding water to the obtained solid and washing it, The solid was collected by filtration, To give the title compound as a white solid by dried under reduced pressure for 8 hours at 45 C.(8.71 g, yield 84%, 1 equivalent of compound (18)The yield was calculated as equivalent to 3 equivalents of the compound (17)).Nitrogen, Titration in the following -60 1.6M n-butyllithium in hexane (0.4 mL)in1-Bromo-4- (1, 1-difluoroethyl) benzene(0.17 g)Of tetrahydrofuran (0.61 g)The solution was stirred for an additional 1 hour and titrated for 4 minutes5-cyclopropyl-6-methoxymethylpyridinecarbonitrile(0.10 g)In tetrahydrofuran (0.30 g).After stirring for 2 hours and 2 minutes, the temperature was further raised to room temperature.After adding 5% aqueous hydrochloric acid solution (0.93 g) and stirring, Water and ethyl acetate were added, The mixture was separated into a mixture of an organic layer and an aqueous layer.Ethyl acetate (4 mL) was added to the resulting aqueous layer, Mixed and separated into an organic layer and an aqueous layer.Mixing the organic layers of both, The mixture was separated by adding 5% aqueous sodium hydrogencarbonate solution, and the organic layer and the aqueous layer were mixed.Ethyl acetate (2 mL) was added to the resulting aqueous layer, Mixed and separated into an organic layer and an aqueous layer.The organic layers were mixed, and the organic layer and the aqueous layer were mixed by adding water. Ethyl acetate (2 mL) was added to the obtained aqueous layer, mixed, and separated into an organic layer and an aqueous layer. The organic layers were mixed, dried by addition of sodium sulfate, and after the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 49/1, v / v)To obtain the title compound (0.14 g, yield 75.1%) as a pale yellow oily substance.Nitrogen, Below -70 C, A 1.6 M solution of n-butyllithium in hexane (13.9 mL) was titrated over 24 minutes1-Bromo-4- (1, 1-difluoroethyl) benzene(5.54 g)In tetrahydrofuran (5.41 g)Washed with tetrahydrofuran (2.71 g).After stirring at -70 C for 1 hour, In -70 below the cost of 15 minutes titration5-cyclopropylmethylpyridine nitrile(Picolinonitrile)(2.77 g)In tetrahydrofuran (4.20 g)And washed with tetrahydrofuran (2.74 g).After stirring for 4 hours and 19 minutes, And then raised to room temperature.After adding concentrated hydrochloric acid (4.48 g) and water (5.43 g) and stirring for 8 minutes, And the mixture was separated into an organic layer and an aqueous layer.Ethyl acetate (11.08 g) was added to the resulting aqueous layer, After stirring for 10 minutes, And the mixture was separated into an organic layer and an aqueous layer.The resulting organic layer was mixed, An aqueous solution of potassium bicarbonate (1.35 g) and water (8.43 g) was added and stirred for 6 minutes, and the mixture was separated into an organic layer and an aqueous layer. An aqueous solution of sodium chloride (0.55 g) and water (8.43 g) was added to the resultant organic layer, and the mixture was stirred for 5 minutes and then separated into an organic layer and an aqueous layer. The resulting organic layer was subjected to distillation under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19/1, v / v) to give an oily substance (5.87 g).The resulting oily substance was added with hexane (10.19 g) and ethyl acetate (1.03 g), the temperature was increased to 50C, and the mixture was cooled. Ethyl acetate (0.51 g) was added at 36C. Followed by ice-cooling and stirring for 4 minutes to obtain a suspension. The resulting solid was filtered, washed with a mixed solution of cooled ethyl acetate (0.75 g) and hexane (4.95 g), and dried under reduced pressure at 40 C to give the title compound as a white solid (3.98 G, yield 72.1%).

Molecular Weight:221.04
XLogP3:3.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:219.96992
Monoisotopic Mass:219.96992
Heavy Atom Count:11
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes