[1-(氧杂-4-基甲基)哌啶-4-基]甲胺

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of piperidine-4-carboxamide (1.28 g, 10 mmol), tetrahydro-2H-pyran-4-carboxylic acid (1.43 g, 11 mmol) and diisopropylethylamine (2.09 mL, 11 mmol) in N,N-dimethylformamide was added HBTU (N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate, 4.14 g, 11 mmol) at 0° C. After being stirred for 0.5 h at 0° C., the mixture was stirred for 3 h at ambient temperature. Then, the mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic extract was washed with brine, dried over magnesium sulfate and concentrated. This crude material was dissolved in tetrahydrofuran (50 mL) and added to the mixture of lithium aluminum hydride (1.90 g, 50 mmol) in tetrahydrofuran (50 mL) at 0° C. Then, the mixture was heated at 40° C. and stirred for 5 h. The mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g). After vigorous stirring for 0.5 h, the insoluble materials were filtered off. The filtrate was concentrated to give 2.19 g (99%) of the title compound as a colorless viscous oil. the mixture was stirred for 3 h at ambient temperature Then, the mixture was partitioned between ethyl acetate and water After extraction with ethyl acetate the combined organic extract was washed with brine dried over magnesium sulfate concentrated This crude material was dissolved in tetrahydrofuran (50 mL) Then, the mixture was heated at 40° C. stirred for 5 h The mixture was cooled to 0° C. quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g) After vigorous stirring for 0.5 h the insoluble materials were filtered off The filtrate was concentrated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of tetrahydrofuran, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 1 hour. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. Dichloromethane and water are added to the residue; the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.73 g of white solid. Yield 85%. The resulting solution is maintained does not exceed 5° C The solution is maintained under stirring at 0° C. for 1 hour at ambient temperature for 1 hour the tetrahydrofuran is evaporated at low pressure Dichloromethane and water are added to the residue the two phases are separated the organic phase is washed with water (2×) after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of dichloromethane, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 2 hours. 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.64 g of white solid. Yield 85%. The resulting solution is maintained does not exceed 5° C The solution is maintained under stirring at 0° C. for 1 hour at ambient temperature for 2 hours the two phases are separated the organic phase is washed with water (2×) after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of tetrahydrofuran and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of tetrahydrofuran cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 0.5 hours. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. The residue is taken up with dichloromethane and water; the organic phase is washed with water (2×), and after a solvent change with ethyl acetate at low pressure, compound (12) is crystallised from ethyl acetate to obtain 15 g of white solid. Yield 87%. does not exceed 5° C The resulting mixture is maintained does not exceed 5° C The solution is maintained under stirring at 0° C. for 1 hour at ambient temperature for 5 hours the tetrahydrofuran is evaporated at low pressure the organic phase is washed with water (2×) after a solvent change with ethyl acetate at low pressure, compound (12) is crystallised from ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of dichloromethane and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of dichloromethane cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. After a process control, 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate, to obtain 14.29 g of white solid. Yield 83%. does not exceed 5° C The resulting mixture is maintained does not exceed 5° C The solution is maintained under stirring at 0° C. for 1 hour at ambient temperature for 5 hours the two phases are separated the organic phase is washed with water (2×) after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of piperidine-4-carboxamide (1.28 g, 10 mmol), tetrahydro-2H-pyran-4-carboxylic acid (1.43 g, 11 mmol) and diisopropylethylamine (2.09 mL, 11 mmol) in N,N-dimethylformamide was added HBTU (N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate, 4.14 g, 11 mmol) at 0° C. After being stirred for 0.5 h at 0° C., the mixture was stirred for 3 h at ambient temperature. Then, the mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic extract was washed with brine, dried over magnesium sulfate and concentrated. This crude material was dissolved in tetrahydrofuran (50 mL) and added to the mixture of lithium aluminum hydride (1.90 g, 50 mmol) in tetrahydrofuran (50 mL) at 0° C. Then, the mixture was heated at 40° C. and stirred for 5 h. The mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g). After vigorous stirring for 0.5 h, the insoluble materials were filtered off. The filtrate was concentrated to give 2.19 g (99%) of the title compound as a colorless viscous oil. the mixture was stirred for 3 h at ambient temperature Then, the mixture was partitioned between ethyl acetate and water After extraction with ethyl acetate the combined organic extract was washed with brine dried over magnesium sulfate concentrated This crude material was dissolved in tetrahydrofuran (50 mL) Then, the mixture was heated at 40° C. stirred for 5 h The mixture was cooled to 0° C. quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g) After vigorous stirring for 0.5 h the insoluble materials were filtered off The filtrate was concentrated