[bromo(fluoro)methyl]benzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium turnings (500 mg) were placed in a dry 250 mL round bottom flask. Anhydrous ether (20 mL) was added under N2 at room temperature then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 40° C. for 2 hours. All magnesium was consumed resulting in a pale brownish-yellow solution. The 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH4Cl, and brine. The ethyl acetate solution was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The product was isolated as an orange residue. Purification using a silica gel column (20:80 ethyl acetate/pentanes) provided the title compound as a pale yellow powder (yield: 140 mg, 28%). 1H NMR (300 MHz, CDCl3) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m, 4H), 7.49 (d, J=9 Hz, 2H) 7.72 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5 H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23. All magnesium was consumed resulting in a pale brownish-yellow solution The mixture was heated for 3 hours was consumed ) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution The product was extracted with ethyl acetate (250 mL) and the organic layer was washed with saturated NH4Cl, and brine The ethyl acetate solution was dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The product was isolated as an orange residue Purification

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:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium turnings (500 mg) were placed in a dry 250 mL round bottom flask. Anhydrous ether (20 mL) was added under N2 at room temperature then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 40° C. for 2 hours. All magnesium was consumed resulting in a pale brownish-yellow solution. The 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH4Cl, and brine. The ethyl acetate solution was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The product was isolated as an orange residue. Purification using a silica gel column (20:80 ethyl acetate/pentanes) provided the title compound as a pale yellow powder (yield: 140 mg, 28%). 1H NMR (300 MHz, CDCl3) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m, 4H), 7.49 (d, J=9 Hz, 2H) 7.72 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23. All magnesium was consumed resulting in a pale brownish-yellow solution The mixture was heated for 3 hours was consumed ) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution The product was extracted with ethyl acetate (250 mL) and the organic layer was washed with saturated NH4Cl, and brine The ethyl acetate solution was dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The product was isolated as an orange residue Purification

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

実験手順: A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in acetonitrile (150 mL) was added to sodium iodide (360 mg, 2.4 mmol) and stirred under nitrogen during the addition of triethylamine (12 mL, 8.76 g, 86.6 mmol), followed by 3-fluorobenzyl bromide (5.9 mL, 9.09 g, 48.1 mmol). An immediate turbidity was observed on addition of the fluorobenzyl bromide, thickening to a white crystalline precipitate over one hour. The reaction mixture was stirred under nitrogen overnight at room temperature. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue. The copious white precipitate was collected by filtration, washed well with water and dried under vacuum at room temperature. (10.54 g, 89.2%). Calc. for C31H38FN3O 0.2 H2O: C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N, 8.49; F, 3.75%. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue The copious white precipitate was collected by filtration washed well with water dried under vacuum at room temperature

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

実験手順: A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in acetonitrile (150 mL) was added to sodium iodide (360 mg, 2.4 mmol) and stirred under nitrogen during the addition of triethylamine (12 mL, 8.76 g, 86.6 mmol), followed by 3-fluorobenzyl bromide (5.9 mL, 9.09 g, 48.1 mmol). An immediate turbidity was observed on addition of the fluorobenzyl bromide, thickening to a white crystalline precipitate over one hour. The reaction mixture was stirred under nitrogen overnight at room temperature. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue. The copious white precipitate was collected by filtration, washed well with water and dried under vacuum at room temperature. (10.54 g, 89.2%). Calc. for C31H38FN3O 0.2 H2O: C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N, 8.49; F, 3.75%. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue The copious white precipitate was collected by filtration washed well with water dried under vacuum at room temperature

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium turnings (500 mg) were placed in a dry 250 mL round bottom flask. Anhydrous ether (20 mL) was added under N2 at room temperature then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 40° C. for 2 hours. All magnesium was consumed resulting in a pale brownish-yellow solution. The 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH4Cl, and brine. The ethyl acetate solution was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The product was isolated as an orange residue. Purification using a silica gel column (20:80 ethyl acetate/pentanes) provided the title compound as a pale yellow powder (yield: 140 mg, 28%). 1H NMR (300 MHz, CDCl3) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m, 4H), 7.49 (d, J=9 Hz, 2H) 7.72 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5 H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23. All magnesium was consumed resulting in a pale brownish-yellow solution The mixture was heated for 3 hours was consumed ) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution The product was extracted with ethyl acetate (250 mL) and the organic layer was washed with saturated NH4Cl, and brine The ethyl acetate solution was dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The product was isolated as an orange residue Purification

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

実験手順: Following a procedure similar to that described in Preparation 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-chlorobutyryl chloride were used in place of the 2 fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a yellow oil in a yield of 79%.

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Magnesium turnings (500 mg) were placed in a dry 250 mL round bottom flask. Anhydrous ether (20 mL) was added under N2 at room temperature then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 40° C. for 2 hours. All magnesium was consumed resulting in a pale brownish-yellow solution. The 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH4Cl, and brine. The ethyl acetate solution was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The product was isolated as an orange residue. Purification using a silica gel column (20:80 ethyl acetate/pentanes) provided the title compound as a pale yellow powder (yield: 140 mg, 28%). 1H NMR (300 MHz, CDCl3) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m, 4H), 7.49 (d, J=9 Hz, 2H) 7.72 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23. All magnesium was consumed resulting in a pale brownish-yellow solution The mixture was heated for 3 hours was consumed ) The reaction was cooled to room temperature then quenched with a saturated NH4Cl solution The product was extracted with ethyl acetate (250 mL) and the organic layer was washed with saturated NH4Cl, and brine The ethyl acetate solution was dried over MgSO4 filtered The filtrate was concentrated under reduced pressure The product was isolated as an orange residue Purification

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

実験手順: A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in acetonitrile (150 mL) was added to sodium iodide (360 mg, 2.4 mmol) and stirred under nitrogen during the addition of triethylamine (12 mL, 8.76 g, 86.6 mmol), followed by 3-fluorobenzyl bromide (5.9 mL, 9.09 g, 48.1 mmol). An immediate turbidity was observed on addition of the fluorobenzyl bromide, thickening to a white crystalline precipitate over one hour. The reaction mixture was stirred under nitrogen overnight at room temperature. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue. The copious white precipitate was collected by filtration, washed well with water and dried under vacuum at room temperature. (10.54 g, 89.2%). Calc. for C31H38FN3O 0.2 H2O: C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N, 8.49; F, 3.75%. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) was added to the residue The copious white precipitate was collected by filtration washed well with water dried under vacuum at room temperature

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

実験手順: A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in acetonitrile (150 mL)) was added to sodium iodide (360 mg, 2.4 mmol) and stirred under nitrogen during the addition of triethylamine (12 mL, (8.76 g), 86.6 mmol), followed by 3-fluorobenzyl bromide (5.9 mL, (9.09 g), 48.1 mmol). An immediate turbidity was observed on addition of the fluorobenzyl bromide, thickening to a white crystalline precipitate over one hour. The reaction mixture was stirred under nitrogen overnight at room temperature. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) added to the residue. The copious white precipitate was filtered off, washed well with water and dried under vacuum at room temperature to give 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide (10.54 g, 89.2%). Calc. for C31H38FN3O 0.2 H2O: C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N, 8.49; F, 3.75%. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) added to the residue The copious white precipitate was filtered off washed well with water dried under vacuum at room temperature