2-(2,4-difluorophenyl)acetonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup. the solution was heated at 60° C. for 24 hours It was then quenched with water at 0° C. concentrated The residue was extracted with ethyl acetate (25 mL) washed three times with water (15 mL) The organic layer was dried over sodium sulfate filtered concentrated Purification by column chromatography (hexane:ethyl acetate 4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup. the solution was heated at 60° C. for 24 hours It was then quenched with water at 0° C. concentrated The residue was extracted with ethyl acetate (25 mL) washed three times with water (15 mL) The organic layer was dried over sodium sulfate filtered concentrated Purification by column chromatography (hexane:ethyl acetate 4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.7 g (69 mmol) of potassium tert-butoxide was dissolved in 200 ml of THF, and 10 g (65 mmol) of 2,4-difluorophenyl acetonitrile was dropwise added thereto under cooling with ice. Ten minutes later, 13.5 g (69 mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one was dropwise added thereto, followed by stirring at room temperature for 4 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water, acidified to pH 1 with 1N hydrochloric acid and then extracted with ethyl acetate. After washing with water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. And then, the ethyl acetate was distilled off under reduced pressure. To the obtained residue, 150 ml of concentrated hydrochloric acid was added, followed by stirring for 4 hours under heating and refluxing. This reaction solution was poured into ice water and extracted with ethyl acecate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 13.8 g (yield: 76%) of the desired product. Melting point: 98-100° C. under cooling with ice THF was distilled off under reduced pressure Then, the obtained residue was poured into water extracted with ethyl acetate After washing with water an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate And then, the ethyl acetate was distilled off under reduced pressure To the obtained residue, 150 ml of concentrated hydrochloric acid was added by stirring for 4 hours under heating refluxing This reaction solution was poured into ice water extracted with ethyl acecate by washing with water The organic layer was dried over anhydrous magnesium sulfate ethyl acetate was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 2-(2,4-difluorophenyl)acetonitrile (Aldrich), HCl gas and ethanol were processed using the method described for Example 3A to obtain the titled compound except that the reaction time was 72 hours. MS (ESI+) m/z 200 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (1.000 g, 6.7046 mmol) and 2,4-difluoro phenyl acetonitrile (1.27 g, 8.0455 mmol) in absolute ethanol (20 ml), an ice-cooled solution of sodium methoxide (0.543 g, 10.0569 mmol) in absolute ethanol (10 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜2 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as brown solid (1.10 g, 48% yield). M.p. 152-156.5° C. LC-ESI-HRMS of [M+H]+ shows 303.1046 Da. Calc. 303.105742 Da, dev. −3.8 ppm. is added drop-wise The resulting reaction mixture is evaporated the residue is dissolved in methylene chloride washed with water, brine dried over MgSO4 filtered evaporated to afford ˜2 g of crude material as brownish solid This material is purified by crystallization from methylene chloride and petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.7 g (69 mmol) of potassium tert-butoxide was dissolved in 200 ml of THF, and 10 g (65 mmol) of 2,4-difluorophenyl acetonitrile was dropwise added thereto under cooling with ice. Ten minutes later, 13.5 g (69 immol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one was dropwise added thereto, followed by stirring at room temperature for 4 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water, acidified to pH 1 with 1N hydrochloric acid and then extracted with ethyl acetate. After washing with water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. And then, the ethyl acetate was distilled off under reduced pressure. To the obtained residue, 150 ml of concentrated hydrochloric acid was added, followed by stirring for 4 hours under heating and refluxing. This reaction solution was poured into ice water and extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 13.8 g (yield: 76%) of the desired product. Melting point: 98-100° C. 1H-NMR (400 MHz, CDCl3) δ value: 6.78(1H,d), 6.95(2H,m), 7.52(1H,d), 7.56(1H,q)ppm. under cooling with ice THF was distilled off under reduced pressure Then, the obtained residue was poured into water extracted with ethyl acetate After washing with water an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate And then, the ethyl acetate was distilled off under reduced pressure To the obtained residue, 150 ml of concentrated hydrochloric acid was added by stirring for 4 hours under heating refluxing This reaction solution was poured into ice water extracted with ethyl acetate by washing with water The organic layer was dried over anhydrous magnesium sulfate ethyl acetate was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup. the solution was heated at 60° C. for 24 hours It was then quenched with water at 0° C. concentrated The residue was extracted with ethyl acetate (25 mL) washed three times with water (15 mL) The organic layer was dried over sodium sulfate filtered concentrated Purification by column chromatography (hexane:ethyl acetate 4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.7 g (69 mmol) of potassium tert-butoxide was dissolved in 200 ml of THF, and 10 g (65 mmol) of 2,4-difluorophenyl acetonitrile was dropwise added thereto under cooling with ice. Ten minutes later, 13.5 g (69 mmol) of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one was dropwise added thereto, followed by stirring at room temperature for 4 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water, acidified to pH 1 with 1N hydrochloric acid and then extracted with ethyl acetate. After washing with water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. And then, the ethyl acetate was distilled off under reduced pressure. To the obtained residue, 150 ml of concentrated hydrochloric acid was added, followed by stirring for 4 hours under heating and refluxing. This reaction solution was poured into ice water and extracted with ethyl acecate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 13.8 g (yield: 76%) of the desired product. Melting point: 98-100° C. under cooling with ice THF was distilled off under reduced pressure Then, the obtained residue was poured into water extracted with ethyl acetate After washing with water an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate And then, the ethyl acetate was distilled off under reduced pressure To the obtained residue, 150 ml of concentrated hydrochloric acid was added by stirring for 4 hours under heating refluxing This reaction solution was poured into ice water extracted with ethyl acecate by washing with water The organic layer was dried over anhydrous magnesium sulfate ethyl acetate was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography