1-(1-溴乙基)-4-氟苯

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A solution of 0.15 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one in 5 cm3 of dimethylformamide is poured into a mixture containing 31 mg of sodium hydride (60% in oil) and 10 cm3 of dimethylformamide at a temperature close to 20° C. under an inert atmosphere. Then a solution of 0.2 g of 1-(1-bromoethyl)-4-fluorobenzene in 5 cm3 of dimethylformamide is poured into the reaction mixture. The latter is stirred for 20 h at a temperature close to 20° C. Water and ethyl acetate are added to the reaction mixture. After decanting, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 325 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 20% ethyl acetate/80% cyclohexane). After concentrating the fractions under reduced pressure, 146 mg of 5-bromo-2-[1-(4-fluorophenyl)ethyl]-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a thick pale yellow oil. close to 20° C. under an inert atmosphere close to 20° C After decanting the organic phase is washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate filtered then concentrated a rotary evaporator under reduced pressure (5 kPa)

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

实验步骤: 0.5 g of 1-(4-fluorophenyl)ethanol is dissolved in 20 cm3 of dichloromethane, under an inert atmosphere, at a temperature close to 20° C. 1.24 cm3 of pure bromo(trimethyl)silane are introduced in two lots to the reaction mixture. The latter is stirred at a temperature close to 20° C. for 48 h, then it is washed with a saturated aqueous solution of sodium chloride, dried over a phase separation cartridge and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 700 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 10% ethyl acetate/90% cyclohexane). After concentrating the fractions under reduced pressure, 439 mg of 1-(1-bromoethyl)-4-fluorobenzene are obtained in the form of a colorless thick oil. close to 20° C close to 20° C. for 48 h it is washed with a saturated aqueous solution of sodium chloride dried over a phase separation cartridge concentrated a rotary evaporator under reduced pressure (5 kPa)

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H−Boc)+. Cool to ambient temperature extract the aqueous phase twice with EtOAc Dry the combined organic extracts over anhydrous Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1)

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H−Boc)+. Cool to ambient temperature extract the aqueous phase twice with EtOAc Dry the combined organic extracts over anhydrous Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1)

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

实验步骤: The alkylation of 7-bromo-1-hydroxy-3,5-diazaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-fluoro-benzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(4-fluorobenzyl)-7-3-phenylprop-1-ynyl-2H-3,5-diazaisoquinolin-1-one Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1

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

实验步骤: The alkylation of 7-bromo-1-hydroxy-3,5-diazaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-fluoro-benzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(4-fluorobenzyl)-7-3-phenylprop-1-ynyl-2H-3,5-diazaisoquinolin-1-one Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1

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

实验步骤: A solution of 0.15 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one in 5 cm3 of dimethylformamide is poured into a mixture containing 31 mg of sodium hydride (60% in oil) and 10 cm3 of dimethylformamide at a temperature close to 20° C. under an inert atmosphere. Then a solution of 0.2 g of 1-(1-bromoethyl)-4-fluorobenzene in 5 cm3 of dimethylformamide is poured into the reaction mixture. The latter is stirred for 20 h at a temperature close to 20° C. Water and ethyl acetate are added to the reaction mixture. After decanting, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 325 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 20% ethyl acetate/80% cyclohexane). After concentrating the fractions under reduced pressure, 146 mg of 5-bromo-2-[1-(4-fluorophenyl)ethyl]-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a thick pale yellow oil. close to 20° C. under an inert atmosphere close to 20° C After decanting the organic phase is washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate filtered then concentrated a rotary evaporator under reduced pressure (5 kPa)

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

实验步骤: 0.5 g of 1-(4-fluorophenyl)ethanol is dissolved in 20 cm3 of dichloromethane, under an inert atmosphere, at a temperature close to 20° C. 1.24 cm3 of pure bromo(trimethyl)silane are introduced in two lots to the reaction mixture. The latter is stirred at a temperature close to 20° C. for 48 h, then it is washed with a saturated aqueous solution of sodium chloride, dried over a phase separation cartridge and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 700 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 10% ethyl acetate/90% cyclohexane). After concentrating the fractions under reduced pressure, 439 mg of 1-(1-bromoethyl)-4-fluorobenzene are obtained in the form of a colorless thick oil. close to 20° C close to 20° C. for 48 h it is washed with a saturated aqueous solution of sodium chloride dried over a phase separation cartridge concentrated a rotary evaporator under reduced pressure (5 kPa)

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

实验步骤: To a suspension of 200 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 211 mg of potassium carbonate in 2 ml of N,N-dimethylformamide, 155 mg of 1-(1-bromoethyl)-4-fluorobenzene was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 171 mg of the desired product as a pale yellow resinous substance. was added After completion of the reaction extracted with ethyl acetate (3 ml×2) washed with water (3 ml×1) dried over saturated aqueous sodium chloride anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a suspension of 200 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 211 mg of potassium carbonate in 2 ml of N,N-dimethylformamide, 155 mg of 1-(1-bromoethyl)-4-fluorobenzene was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 171 mg of the desired product as a pale yellow resinous substance. was added After completion of the reaction extracted with ethyl acetate (3 ml×2) washed with water (3 ml×1) dried over saturated aqueous sodium chloride anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography