1-(2-羟乙基)-4-羟基哌啶

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

实验步骤: DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s). then partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H)

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

实验步骤: DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s). then partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H)

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

实验步骤: Piperidin-4-yl-carbamic acid tert-butyl ester 3 (5 g, 25 mmol), 1-(2-Hydroxy-ethyl)-piperidin-4-ol 22 (4 g, 27.5 mmol) and DIEA (5.6 ml, 32.5 mmol) are suspended in 25 ml of propionitril. Cyanomethyl-trimethyl-phosphonium iodide (4 g, 30 mmol) is added and the reaction mixture is refluxed. Additional portions of cyanomethyl-trimethyl-phosphonium iodide (1.5 g, 11.25 mmol) are added after 90 minutes and after 3 hours. After cooling to room temperature, a solution of potassium carbonate (4 g) in 250 ml of water is added and the product is isolated by extraction with DCM. Evaporation under reduced pressure gave 6.9 g of a red oil which could be crystallized from ether. the reaction mixture is refluxed Evaporation under reduced pressure

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

实验步骤: Piperidin-4-ol (5 g, 49.4 mmol) is dissolved in 200 ml of ethanol and anhydrous sodium carbonate (21 g, 197.6 mmol) is added. 2-Bromo-ethanol (6.9 ml, 98.8 mmol) is added dropwise and the reaction mixture is refluxed for 16 hours. After evaporation under reduced pressure the mixture is stirred with 200 ml of DCM and filtered. The clear filtrate is evaporated under reduced pressure and dried at high vacuum. the reaction mixture is refluxed for 16 hours After evaporation under reduced pressure the mixture filtered The clear filtrate is evaporated under reduced pressure dried at high vacuum

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

实验步骤: Piperidin-4-yl-carbamic acid tert-butyl ester 3 (5 g, 25 mmol), 1-(2-Hydroxy-ethyl)-piperidin-4-ol 22 (4 g, 27.5 mmol) and DIEA (5.6 ml, 32.5 mmol) are suspended in 25 ml of propionitril. Cyanomethyl-trimethyl-phosphonium iodide (4 g, 30 mmol) is added and the reaction mixture is refluxed. Additional portions of cyanomethyl-trimethyl-phosphonium iodide (1.5 g, 11.25 mmol) are added after 90 minutes and after 3 hours. After cooling to room temperature, a solution of potassium carbonate (4 g) in 250 ml of water is added and the product is isolated by extraction with DCM. Evaporation under reduced pressure gave 6.9 g of a red oil which could be crystallized from ether. the reaction mixture is refluxed Evaporation under reduced pressure

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

实验步骤: Piperidin-4-ol (5 g, 49.4 mmol) is dissolved in 200 ml of ethanol and anhydrous sodium carbonate (21 g, 197.6 mmol) is added. 2-Bromo-ethanol (6.9 ml, 98.8 mmol) is added dropwise and the reaction mixture is refluxed for 16 hours. After evaporation under reduced pressure the mixture is stirred with 200 ml of DCM and filtered. The clear filtrate is evaporated under reduced pressure and dried at high vacuum. the reaction mixture is refluxed for 16 hours After evaporation under reduced pressure the mixture filtered The clear filtrate is evaporated under reduced pressure dried at high vacuum

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

实验步骤: DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s). then partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H)