4-(aminomethyl)phenol;hydrobromide

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

実験手順: 4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated at reflux for 10 hours. The cooled reaction mixture was filtered to give the sub-title compound (2.25 g). at reflux for 10 hours The cooled reaction mixture was filtered

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

実験手順: A mixture of 40.0 g (0.29 mole) of 4-methoxybenzylamine (98%, Aldrich) and 150 mL of 48% hydrobromic acid (Baker) was stirred and heated at reflux for 18 hr, then stirred at ambient temperature for 72 hr. The precipitate was collected by filtration, washed with ethyl ether (300 mL) and dried to give 21.0 g (35%) of the title compound as an off-white solid, mp 215°-217° C. heated at reflux for 18 hr stirred at ambient temperature for 72 hr The precipitate was collected by filtration washed with ethyl ether (300 mL) dried

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

実験手順: 4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated at reflux for 10 hours. The cooled reaction mixture was filtered to give the sub-title compound (2.25 g). at reflux for 10 hours The cooled reaction mixture was filtered

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

実験手順: 4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated at reflux for 10 hours. The cooled reaction mixture was filtered to give the sub-title compound (2.25 g). at reflux for 10 hours The cooled reaction mixture was filtered

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

実験手順: A mixture of 40.0 g (0.29 mole) of 4-methoxybenzylamine (98%, Aldrich) and 150 mL of 48% hydrobromic acid (Baker) was stirred and heated at reflux for 18 hr, then stirred at ambient temperature for 72 hr. The precipitate was collected by filtration, washed with ethyl ether (300 mL) and dried to give 21.0 g (35%) of the title compound as an off-white solid, mp 215°-217° C. heated at reflux for 18 hr stirred at ambient temperature for 72 hr The precipitate was collected by filtration washed with ethyl ether (300 mL) dried

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Biphenyl-2-ylcarbamic acid 1-{3-[3-(3-hydroxylpropyl)-2-oxoimidazolidin-1-yl]propyl}piperidin-4-yl ester (5.2 g, 10.8 mmol, 1.0 eq; prepared as described in Preparation 4) was dissolved in DCM (120 mL) and cooled to −15° C. DMSO (7.6 mL, 108.3 mmol, 10 eq) was added, followed by DIPEA (9.4 mL, 54.1 mmol, 5 eq). After 5 minutes of stirring, pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid. The reaction was stirred for two hours, during which it was permitted to warm slowly to 0° C. After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel and washed with saturated solution of sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate, and filtered. To the filtrate was added anhydrous MeOH (120 mL), and cooled to 0° C. for 15 minutes. p-Hydroxybenzylamine-hydrobromide (4.18 g, 20.5 mmol, 1.9 eq) was added as a solid and the reaction was stirred for 30 minutes at 0° C. Solid Na(OAc)3BH (6.86 g, 32.4 mmol, 3.0 eq) was added in one portion, and the reaction was removed from the ice bath and stirred for 1 hour. Aqueous HCl (1N, 500 mL) was added to the reaction, and the solution was transferred to a separatory funnel. The DCM layer was removed and EtOAc (300 mL) was added. The layers were well mixed and separated. Solid NaOH was added to the aqueous acid layer to adjust the pH to 12-14. The aqueous base layer was then extracted with EtOAc (2×250 mL). The extracted organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps). The crude material was dissolved in DCM (˜1 g/50 mL) and with vigorous stirring was added 0.5 M NaH2PO4 (3×250 mL). The acidic washes were combined and brought to pH=6.5 using 6N NaOH. The aqueous layer was then washed using DCM (300 mL). The aqueous layer was then removed and brought to pH=˜11 using 6N NaOH. The aqueous layer was extracted with EtOAc (3×250 mL). The extracted organic layers were combined, washed with water (2×200 ml) and saturated brine (250 mL), and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated. The final purification was conducted via silica gel chromatography (eluent: 11% MeOH in DCM with 1% NH3(25% aq)) to afford the title compound (2.5 g, 4.32 mmol, 40% yield). MS m/z: [M+H+] calcd for C34H43N5O4, 586.3; found, 586.4. pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid The reaction was stirred for two hours, during which it to warm slowly to 0° C After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel washed with saturated solution of sodium bicarbonate and brine The organic phase was then dried over anhydrous sodium sulfate filtered To the filtrate was added anhydrous MeOH (120 mL) cooled to 0° C. for 15 minutes the reaction was stirred for 30 minutes at 0° C the reaction was removed from the ice bath stirred for 1 hour Aqueous HCl (1N, 500 mL) was added to the reaction the solution was transferred to a separatory funnel The DCM layer was removed EtOAc (300 mL) was added The layers were well mixed separated Solid NaOH was added to the aqueous acid layer The aqueous base layer was then extracted with EtOAc (2×250 mL) washed with saturated brine dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps) with vigorous stirring The aqueous layer was then washed The aqueous layer was then removed The aqueous layer was extracted with EtOAc (3×250 mL) washed with water (2×200 ml) and saturated brine (250 mL) dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated The final purification

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Biphenyl-2-ylcarbamic acid 1-{3-[3-(3-hydroxylpropyl)-2-oxoimidazolidin-1-yl]propyl}piperidin-4-yl ester (5.2 g, 10.8 mmol, 1.0 eq; prepared as described in Preparation 4) was dissolved in DCM (120 mL) and cooled to −15° C. DMSO (7.6 mL, 108.3 mmol, 10 eq) was added, followed by DIPEA (9.4 mL, 54.1 mmol, 5 eq). After 5 minutes of stirring, pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid. The reaction was stirred for two hours, during which it was permitted to warm slowly to 0° C. After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel and washed with saturated solution of sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate, and filtered. To the filtrate was added anhydrous MeOH (120 mL), and cooled to 0° C. for 15 minutes. p-Hydroxybenzylamine-hydrobromide (4.18 g, 20.5 mmol, 1.9 eq) was added as a solid and the reaction was stirred for 30 minutes at 0° C. Solid Na(OAc)3BH (6.86 g, 32.4 mmol, 3.0 eq) was added in one portion, and the reaction was removed from the ice bath and stirred for 1 hour. Aqueous HCl (1N, 500 mL) was added to the reaction, and the solution was transferred to a separatory funnel. The DCM layer was removed and EtOAc (300 mL) was added. The layers were well mixed and separated. Solid NaOH was added to the aqueous acid layer to adjust the pH to 12-14. The aqueous base layer was then extracted with EtOAc (2×250 mL). The extracted organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps). The crude material was dissolved in DCM (˜1 g/50 mL) and with vigorous stirring was added 0.5 M NaH2PO4 (3×250 mL). The acidic washes were combined and brought to pH=6.5 using 6N NaOH. The aqueous layer was then washed using DCM (300 mL). The aqueous layer was then removed and brought to pH=˜11 using 6N NaOH. The aqueous layer was extracted with EtOAc (3×250 mL). The extracted organic layers were combined, washed with water (2×200 ml) and saturated brine (250 mL), and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated. The final purification was conducted via silica gel chromatography (eluent: 11% MeOH in DCM with 1% NH3(25% aq)) to afford the title compound (2.5 g, 4.32 mmol, 40% yield). MS m/z: [M+H+] calcd for C34H43N5O4, 586.3; found, 586.4. pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid The reaction was stirred for two hours, during which it to warm slowly to 0° C After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel washed with saturated solution of sodium bicarbonate and brine The organic phase was then dried over anhydrous sodium sulfate filtered To the filtrate was added anhydrous MeOH (120 mL) cooled to 0° C. for 15 minutes the reaction was stirred for 30 minutes at 0° C the reaction was removed from the ice bath stirred for 1 hour Aqueous HCl (1N, 500 mL) was added to the reaction the solution was transferred to a separatory funnel The DCM layer was removed EtOAc (300 mL) was added The layers were well mixed separated Solid NaOH was added to the aqueous acid layer The aqueous base layer was then extracted with EtOAc (2×250 mL) washed with saturated brine dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps) with vigorous stirring The aqueous layer was then washed The aqueous layer was then removed The aqueous layer was extracted with EtOAc (3×250 mL) washed with water (2×200 ml) and saturated brine (250 mL) dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated The final purification

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Biphenyl-2-ylcarbamic acid 1-{3-[3-(3-hydroxylpropyl)-2-oxoimidazolidin-1-yl]propyl}piperidin-4-yl ester (5.2 g, 10.8 mmol, 1.0 eq; prepared as described in Preparation 4) was dissolved in DCM (120 mL) and cooled to −15° C. DMSO (7.6 mL, 108.3 mmol, 10 eq) was added, followed by DIPEA (9.4 mL, 54.1 mmol, 5 eq). After 5 minutes of stirring, pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid. The reaction was stirred for two hours, during which it was permitted to warm slowly to 0° C. After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel and washed with saturated solution of sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate, and filtered. To the filtrate was added anhydrous MeOH (120 mL), and cooled to 0° C. for 15 minutes. p-Hydroxybenzylamine-hydrobromide (4.18 g, 20.5 mmol, 1.9 eq) was added as a solid and the reaction was stirred for 30 minutes at 0° C. Solid Na(OAc)3BH (6.86 g, 32.4 mmol, 3.0 eq) was added in one portion, and the reaction was removed from the ice bath and stirred for 1 hour. Aqueous HCl (1N, 500 mL) was added to the reaction, and the solution was transferred to a separatory funnel. The DCM layer was removed and EtOAc (300 mL) was added. The layers were well mixed and separated. Solid NaOH was added to the aqueous acid layer to adjust the pH to ˜12-14. The aqueous base layer was then extracted with EtOAc (2×250 mL). The extracted organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps). The crude material was dissolved in DCM (˜1 g/50 mL) and with vigorous stirring was added 0.5 M NaH2PO4 (3×250 mL). The acidic washes were combined and brought to pH=6.5 using 6N NaOH. The aqueous layer was then washed using DCM (300 mL). The aqueous layer was then removed and brought to pH=˜11 using 6N NaOH. The aqueous layer was extracted with EtOAc (3×250 mL). The extracted organic layers were combined, washed with water (2×200 ml) and saturated brine (250 mL), and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated. The final purification was conducted via silica gel chromatography (eluent: 11% MeOH in DCM with 1% NH3(25% aq)) to afford the title compound (2.5 g, 4.32 mmol, 40% yield). MS m/z: [M+H+] calcd for C34H43N5O4, 586.3; found, 586.4. pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid The reaction was stirred for two hours, during which it to warm slowly to 0° C After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel washed with saturated solution of sodium bicarbonate and brine The organic phase was then dried over anhydrous sodium sulfate filtered To the filtrate was added anhydrous MeOH (120 mL) cooled to 0° C. for 15 minutes the reaction was stirred for 30 minutes at 0° C the reaction was removed from the ice bath stirred for 1 hour Aqueous HCl (1N, 500 mL) was added to the reaction the solution was transferred to a separatory funnel The DCM layer was removed EtOAc (300 mL) was added The layers were well mixed separated Solid NaOH was added to the aqueous acid layer The aqueous base layer was then extracted with EtOAc (2×250 mL) washed with saturated brine dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps) with vigorous stirring The aqueous layer was then washed The aqueous layer was then removed The aqueous layer was extracted with EtOAc (3×250 mL) washed with water (2×200 ml) and saturated brine (250 mL) dried over sodium sulfate The drying agent was removed via filtration the organic solution was concentrated The final purification

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

実験手順: 4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated at reflux for 10 hours. The cooled reaction mixture was filtered to give the sub-title compound (2.25 g). at reflux for 10 hours The cooled reaction mixture was filtered

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

実験手順: A mixture of 40.0 g (0.29 mole) of 4-methoxybenzylamine (98%, Aldrich) and 150 mL of 48% hydrobromic acid (Baker) was stirred and heated at reflux for 18 hr, then stirred at ambient temperature for 72 hr. The precipitate was collected by filtration, washed with ethyl ether (300 mL) and dried to give 21.0 g (35%) of the title compound as an off-white solid, mp 215°-217° C. heated at reflux for 18 hr stirred at ambient temperature for 72 hr The precipitate was collected by filtration washed with ethyl ether (300 mL) dried