3-(4-溴苯基)-1-吗啉代丙烷-1-酮

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

实验步骤: A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%). heated to reflux for 1 hour partitioned between ethyl acetate and 1N NaOH The aqueous layer was extracted with ethyl acetate (3×50 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane

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

实验步骤: A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%). heated to reflux for 1 hour partitioned between ethyl acetate and 1N NaOH The aqueous layer was extracted with ethyl acetate (3×50 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane

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

实验步骤: A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL) at room temperature was treated with 1-tert-butoxycarbonylpiperazine (300 mg, 1.611 mmol), Pd2(dba)3 (61 mg, 0.0671 mmol), bis-tert-butyl biphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg, 2.013 mmol), degassed three times by freeze-thaw cycle, stirred overnight and partitioned between ethyl acetate and saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane to provide the desired product (317 mg, 59%). 1H NMR (300 MHz, CD3OD) δ 7.12 (2H, m), 6.91 (2H, br), 3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t), 2.58 (1H, t), 1.48 (9H, s). degassed three times by freeze-thaw cycle partitioned between ethyl acetate and saturated NH4Cl The aqueous layer was extracted with ethyl acetate (3×30 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane

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

实验步骤: A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL) at room temperature was treated with 1-tert-butoxycarbonylpiperazine (300 mg, 1.611 mmol), Pd2(dba)3 (61 mg, 0.0671 mmol), bis-tert-butyl biphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg, 2.013 mmol), degassed three times by freeze-thaw cycle, stirred overnight and partitioned between ethyl acetate and saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane to provide the desired product (317 mg, 59%). 1H NMR (300 MHz, CD3OD) δ 7.12 (2H, m), 6.91 (2H, br), 3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t), 2.58 (1H, t), 1.48 (9H, s). degassed three times by freeze-thaw cycle partitioned between ethyl acetate and saturated NH4Cl The aqueous layer was extracted with ethyl acetate (3×30 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane

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

实验步骤: A solution of Example 4A (4.405 mmol) in 1:1 ethyl acetate/ethanol (50 mL) was treated with Wilkinson's catalyst (815 mg, 0.880 mmol), degassed three times by freeze-thaw cycle, heated to reflux under nitrogen atmosphere for 2 days, and cooled to room temperature. The solution was adsorbed onto silica gel and purified by flash column chromatography with 50% ethyl acetate in hexane to provide the desired product (1.024 g, 78%). 1H NMR (300 MHz, CD3OD) δ 7.40 (2H, d), 7.10 (2H, d), 3.62 (4H, m), 3.57 (2H, t), 3.38 (2H, t), 2.94 (2H, t), 2.58 (2H, t). degassed three times by freeze-thaw cycle heated to reflux under nitrogen atmosphere for 2 days purified by flash column chromatography with 50% ethyl acetate in hexane

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

实验步骤: A solution of Example 4A (4.405 mmol) in 1:1 ethyl acetate/ethanol (50 mL) was treated with Wilkinson's catalyst (815 mg, 0.880 mmol), degassed three times by freeze-thaw cycle, heated to reflux under nitrogen atmosphere for 2 days, and cooled to room temperature. The solution was adsorbed onto silica gel and purified by flash column chromatography with 50% ethyl acetate in hexane to provide the desired product (1.024 g, 78%). 1H NMR (300 MHz, CD3OD) δ 7.40 (2H, d), 7.10 (2H, d), 3.62 (4H, m), 3.57 (2H, t), 3.38 (2H, t), 2.94 (2H, t), 2.58 (2H, t). degassed three times by freeze-thaw cycle heated to reflux under nitrogen atmosphere for 2 days purified by flash column chromatography with 50% ethyl acetate in hexane

反应条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of lithium aluminum hydride (4.4 g, 115.79 mmol, 2.00 equiv) in tetrahydrofuran (120 mL) maintained under nitrogen at −30° C. was added a solution of 3-(4-bromophenyl)-1-morpholinopropan-1-one (17.2 g, 57.91 mmol, 1.00 equiv) in tetrahydrofuran (80 mL) dropwise with stirring. The resulting solution was stirred at −30° C. for 30 min and at room temperature for 2 h. The reaction was quenched by the sequential addition of 4.4 mL of water, 13 mL of 15% aqueous sodium hydroxide solution and 4.4 mL of water. The solid was removed by filtration and the filtrate was extracted with 1×350 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 13.5 g (82%) of 4-(3-(4-bromophenyl)propyl)morpholine as a light yellow oil. The resulting solution was stirred at −30° C. for 30 min and at room temperature for 2 h The reaction was quenched by the sequential addition of 4.4 mL of water, 13 mL of 15% aqueous sodium hydroxide solution and 4.4 mL of water The solid was removed by filtration the filtrate was extracted with 1×350 mL of ethyl acetate The organic layer was washed with 2×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

实验步骤: To a solution of morpholine (11 g, 126.44 mmol, 2.01 equiv) in dichloromethane (60 mL) 0˜5° C. was added a solution of 3-(4-bromophenyl)propanoyl chloride (15.5 g, 63.01 mmol, 1.00 equiv) in dichloromethane (30 mL) dropwise with stirring. The resulting solution was stirred at 0˜5° C. for 1 h. The reaction mixture was warmed to room temperature. The resulting solution was diluted with 40 mL of water. The mixture was extracted with dichloromethane 2×100 mL. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 17.4 g (93%) of 3-(4-bromophenyl)-1-morpholinopropan-1-one as a white solid. The resulting solution was stirred at 0˜5° C. for 1 h The mixture was extracted with dichloromethane 2×100 mL The combined organic layers was washed with 3×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

实验步骤: To a solution of morpholine (11 g, 126.44 mmol, 2.01 equiv) in dichloromethane (60 mL) 0˜5° C. was added a solution of 3-(4-bromophenyl)propanoyl chloride (15.5 g, 63.01 mmol, 1.00 equiv) in dichloromethane (30 mL) dropwise with stirring. The resulting solution was stirred at 0˜5° C. for 1 h. The reaction mixture was warmed to room temperature. The resulting solution was diluted with 40 mL of water. The mixture was extracted with dichloromethane 2×100 mL. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 17.4 g (93%) of 3-(4-bromophenyl)-1-morpholinopropan-1-one as a white solid. The resulting solution was stirred at 0˜5° C. for 1 h The mixture was extracted with dichloromethane 2×100 mL The combined organic layers was washed with 3×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

实验步骤: A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%). heated to reflux for 1 hour partitioned between ethyl acetate and 1N NaOH The aqueous layer was extracted with ethyl acetate (3×50 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane

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

实验步骤: A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%). heated to reflux for 1 hour partitioned between ethyl acetate and 1N NaOH The aqueous layer was extracted with ethyl acetate (3×50 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane

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

实验步骤: A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL) at room temperature was treated with 1-tert-butoxycarbonylpiperazine (300 mg, 1.611 mmol), Pd2(dba)3 (61 mg, 0.0671 mmol), bis-tert-butyl biphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg, 2.013 mmol), degassed three times by freeze-thaw cycle, stirred overnight and partitioned between ethyl acetate and saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane to provide the desired product (317 mg, 59%). 1H NMR (300 MHz, CD3OD) δ 7.12 (2H, m), 6.91 (2H, br), 3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t), 2.58 (1H, t), 1.48 (9H, s). degassed three times by freeze-thaw cycle partitioned between ethyl acetate and saturated NH4Cl The aqueous layer was extracted with ethyl acetate (3×30 mL) the combined extracts were dried (MgSO4) filtered concentrated The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane