2-氨基-2-甲基-3-苯基丙-1-醇

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H). The reaction mixture was stirred at 0° C. for 0.5 h purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA

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

实验步骤: To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H). The reaction mixture was stirred at 0° C. for 0.5 h purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA

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

实验步骤: To a solution of rac-α-methyl-phenylalanine (1.74 g, 9.71 mmol) in 30 mL THF at rt was added NaBH4 (0.92 g 24.27 mmol) in one portion. The solution was cooled to 0° C. Iodine (2.46 g, 9.71 mmol) in 5 mL THF was added dropwise over 30 min. After the addition was complete, the reaction was heated to reflux for 2 days. The reaction was then cooled to 0° C. and quenched by the addition of methanol until the bubbling subsided. The reaction mixture was acidified by the addition of 6N HCl until pH 1, stirred at 50° C. for 30 min and concentrated in vacuo. Purification using ion exchange chromatography (SCX cartridge) afforded 2-amino-2-methyl-3-phenylpropan-1-ol I as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4 Hz, 1H), 3.31 (B of AB, d, J=10.4 Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H). After the addition the reaction was heated to reflux for 2 days The reaction was then cooled to 0° C. quenched by the addition of methanol until the bubbling The reaction mixture was acidified by the addition of 6N HCl until pH 1 concentrated in vacuo Purification

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

实验步骤: To a solution of rac-α-methyl-phenylalanine (1.74 g, 9.71 mmol) in 30 mL THF at rt was added NaBH4 (0.92 g 24.27 mmol) in one portion. The solution was cooled to 0° C. Iodine (2.46 g, 9.71 mmol) in 5 mL THF was added dropwise over 30 min. After the addition was complete, the reaction was heated to reflux for 2 days. The reaction was then cooled to 0° C. and quenched by the addition of methanol until the bubbling subsided. The reaction mixture was acidified by the addition of 6N HCl until pH 1, stirred at 50° C. for 30 min and concentrated in vacuo. Purification using ion exchange chromatography (SCX cartridge) afforded 2-amino-2-methyl-3-phenylpropan-1-ol I as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4 Hz, 1H), 3.31 (B of AB, d, J=10.4 Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H). After the addition the reaction was heated to reflux for 2 days The reaction was then cooled to 0° C. quenched by the addition of methanol until the bubbling The reaction mixture was acidified by the addition of 6N HCl until pH 1 concentrated in vacuo Purification

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H). The reaction mixture was stirred at 0° C. for 0.5 h purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA

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

实验步骤: To a solution of rac-α-methyl-phenylalanine (1.74 g, 9.71 mmol) in 30 mL THF at rt was added NaBH4 (0.92 g 24.27 mmol) in one portion. The solution was cooled to 0° C. Iodine (2.46 g, 9.71 mmol) in 5 mL THF was added dropwise over 30 min. After the addition was complete, the reaction was heated to reflux for 2 days. The reaction was then cooled to 0° C. and quenched by the addition of methanol until the bubbling subsided. The reaction mixture was acidified by the addition of 6N HCl until pH 1, stirred at 50° C. for 30 min and concentrated in vacuo. Purification using ion exchange chromatography (SCX cartridge) afforded 2-amino-2-methyl-3-phenylpropan-1-ol I as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4 Hz, 1H), 3.31 (B of AB, d, J=10.4 Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H). After the addition the reaction was heated to reflux for 2 days The reaction was then cooled to 0° C. quenched by the addition of methanol until the bubbling The reaction mixture was acidified by the addition of 6N HCl until pH 1 concentrated in vacuo Purification