2-溴-5-氟溴苄

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (12, 5.36 g, 20.0 mmol) in dry DMF (20 mL) was added NaI (1.20 g, 8.00 mmol) and KSCN (3.88 g, 40.0 mmol). The mixture was heated under N2 at 80° C. for 12 h. After cooling to RT, the mixture was diluted with water (100 mL), and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13). After cooling to RT extracted with EtOAc (50 mL×2) The combined extracts were washed with brine dried over MgSO4 concentrated to give crude product This was purified by column chromatography on silica gel eluted with petroleum ether

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

实验步骤: To a solution of (2-bromo-5-fluorophenyl)methanol (11, 4.10 g, 20.0 mmol) in dry DME (40 mL) at 0° C. was added a solution of PBr3 (3.25 g, 12.0 mmol) in dry DME (40 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at for another 3 h. The mixture was diluted with water (100 mL), and extracted with 1:1 petroleum-ether-EtOAc (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-fluorobenzene (12). extracted with 1:1 petroleum-ether-EtOAc (100 mL×2) The combined extracts were washed with saturated NaHCO3 and brine dried over MgSO4 concentrated

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

实验步骤: Hunig's base (1.3 eq) and 3-aminopropan-1-ol (1.3 eq) were added to a solution of 2-bromo-5-fluoro-benzyl bromide (1 eq) in acetonitrile (0.6 M) and the resulting mixture stirred at RT under nitrogen for 12 h. Concentrated in vacuo to give 3-(((2-bromo-5-fluorophenyl)methyl)amino)propan-1-ol as a clear oil. EI-MS m/z 262, 264 (M+H)+ Concentrated in vacuo

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

实验步骤: Hunig's base (1.3 eq) and 3-aminopropan-1-ol (1.3 eq) were added to a solution of 2-bromo-5-fluoro-benzyl bromide (1 eq) in acetonitrile (0.6 M) and the resulting mixture stirred at RT under nitrogen for 12 h. Concentrated in vacuo to give 3-(((2-bromo-5-fluorophenyl)methyl)amino)propan-1-ol as a clear oil. EI-MS m/z 262, 264 (M+H)+ Concentrated in vacuo

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

实验步骤: A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-fluorobenzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (160 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.10 (br. s., 1 H), 7.69 (dd, J=8.59, 5.31 Hz, 1 H), 7.11 (ddd, J=8.53, 3.16 Hz, 1 H), 7.05 (dd, J=9.60, 2.78 Hz, 1 H), 4.95 (s, 2H), 4.63 (t, J=12.38 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.52-1.74 (m, J=27.54, 11.62 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.10 (q, J=12.97 Hz, 1 H). extracted with ethyl acetate (×2) The combined organic solutions were washed with 1 molar hydrochloric acid evaporated The residue was purified by flash chromatography (10-50% ethyl acetate in hexane) the required fractions evaporated dissolved in ethanol (5 mL) 1 molar sodium hydroxide solution (3.0 mL) added extracted with ethyl acetate (×2) the combined extracts washed with 1 molar hydrochloric acid dried evaporated Recrystallization from acetic acid-water

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

实验步骤: To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 mL) at 0° C., NaH (285 mg, 60 w/w % in mineral oil, 7.13 mmol, 1.1 eq.) was added in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (50 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to ambient. The reaction was completed in 3 h, monitored by LC-MS. The reaction was quenched with saturated aq. NH4Cl (80 mL). Volatiles were removed in vacuo. Crude mixture was extracted with EtOAc, and dried over Na2SO4. The resulting clear gel was purified by SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient). The titled compound was obtained as a clear oil. LC-MS: 500.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H). The mixture was stirred at 0° C. for 30 min The resulting mixture was stirred cold for 30 min to warm to ambient The reaction was quenched with saturated aq. NH4Cl (80 mL) Volatiles were removed in vacuo Crude mixture was extracted with EtOAc dried over Na2SO4 The resulting clear gel was purified by SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient)

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

实验步骤: To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 mL) at 0° C., NaH (285 mg, 60 w/w % in mineral oil, 7.13 mmol, 1.1 eq.) was added in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (50 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to ambient. The reaction was completed in 3 h, monitored by LC-MS. The reaction was quenched with saturated aq. NH4Cl (80 mL). Volatiles were removed in vacuo. Crude mixture was extracted with EtOAc, and dried over Na2SO4. The resulting clear gel was purified by SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient). The titled compound was obtained as a clear oil. LC-MS: 500.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H). The mixture was stirred at 0° C. for 30 min The resulting mixture was stirred cold for 30 min to warm to ambient The reaction was quenched with saturated aq. NH4Cl (80 mL) Volatiles were removed in vacuo Crude mixture was extracted with EtOAc dried over Na2SO4 The resulting clear gel was purified by SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient)

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

实验步骤: Sodium hydride (60% oil dispersion, 0.24 g) was added to a stirred solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (0.935 g) in THF (15 mL) and the mixture was stirred for 5 minutes. 2-Bromo-5-fluorobenzyl bromide (1.608 g) was added and stirring was continued for 20 hours. The resultant suspension was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl (S)-3-(2-bromo-5-fluorobenzyloxy)-pyrrolidine-1-carboxylate (1.88 g) as a colourless oil. stirring was continued for 20 hours The resultant suspension was filtered the filtrate was evaporated to dryness The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15%

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

实验步骤: Sodium hydride (60% oil dispersion, 0.24 g) was added to a stirred solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (0.935 g) in THF (15 mL) and the mixture was stirred for 5 minutes. 2-Bromo-5-fluorobenzyl bromide (1.608 g) was added and stirring was continued for 20 hours. The resultant suspension was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl (S)-3-(2-bromo-5-fluorobenzyloxy)-pyrrolidine-1-carboxylate (1.88 g) as a colourless oil. stirring was continued for 20 hours The resultant suspension was filtered the filtrate was evaporated to dryness The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15%

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

实验步骤: To a solution of 2-bromo-5-fluorobenzyl bromide (1 g, 3.73 mmol) in THF (15 mL) was added allylmagnesium bromide (5.60 mL, 5.60 mmol) at 0° C. It was warmed to rt and then refluxed for 5 h. The reaction mixture was quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOac/hexane to isolate 1-bromo-2-(but-3-en-1-yl)-4-fluorobenzene (0.7 g, 3.06 mmol, 82% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.53-7.45 (m, 1H), 6.99-6.94 (m, 1H), 6.82 (td, J=8.3, 2.9 Hz, 1H), 5.89 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.14-4.98 (m, 2H), 2.89-2.76 (m, 2H), 2.45-2.33 (m, 2H). refluxed for 5 h The reaction mixture was quenched with NH4Cl extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil It was then purified by 5% EtOac/hexane