tert-butyl N-[(3S)-2-oxoazepan-3-yl]carbamate

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

実験手順: (S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoazepan-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% ethyl acetate/hexanes, to provide compound (2f) in 48% yield. The crude product was purified by column chromatography eluting with 25% ethyl acetate/hexanes

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

実験手順: (S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2e) in 48% yield. The crude product was purified by column chromatography eluting with 50% ethyl acetate/hexanes

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

実験手順: (S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2e) in 48% yield. The crude product was purified by column chromatography eluting with 50% ethyl acetate/hexanes

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

実験手順: To a solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (116 mg, 0.510 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60% in oil, 23 mg, 0.57 mmol) in 2 portions. After stirring for 5 min, isobutyl bromide (175 mg, 1.28 mmol) was added to the reaction mixture and the mixture was stirred at rt for 20 h. Saturated aqueous NH4Cl (2 mL) was added to the mixture and crude product was extracted with methylene chloride (3 mL) and the combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified using silica gel chromatography to afford (S)-tert-Butyl 1-isobutyl-2-oxoazepan-3-ylcarbamate (46.4 mg, 0.247 mmol, 49% yield). Anal. Calcd. for C15H28N2O3 m/z 284.2. found: 285.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.44 (d, J=6.64 Hz, 1H), 4.26 (t, J=9 Hz, 1H), 3.57-3.50 (m, 1H), 3.26-3.17 (m, 2H), 3.10-3.05 (m, 1H), 1.84-1.62 (m, 5H), 1.37 (s, 9H), 1.34-1.24 (m, 2H), 0.84-0.80 (m, 6H). the mixture was stirred at rt for 20 h was extracted with methylene chloride (3 mL) the combined organic layers were dried (Na2SO4) concentrated The crude product was purified

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

実験手順: To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (400 mg, 1.75 mmol) in DCM (7.5 mL) was added TEA (0.488 mL, 3.50 mmol) followed by copper (II) acetate (477 mg, 2.63 mmol) and 3-chlorophenylboronic acid (548 mg, 3.50 mmol) at rt under argon. Then, activated molecular sieves (˜1 gm) were added. The reaction mixture was stirred at rt for 36 hr. The reaction mixture was filtered through CELITE®. The filtrate was concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)-tert-butyl 1-(3-chlorophenyl)-2-oxoazepan-3-ylcarbamate (60.0 mg, 0.177 mmol, 10.1% yield) as white solid. Anal. Calcd. for C17H23ClN2O3 m/z 338.8. found: 339.1 (M+H)+. Then, activated molecular sieves (˜1 gm) were added The reaction mixture was filtered through CELITE® The filtrate was concentrated The residue was purified eluting with a gradient of 0-100% EtOAc/Hex

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirring solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (250 mg, 1.10 mmol) in DMF (1 mL) was added a solution of 20 weight % LiHMDS in THF (870 mg, 1.04 mmol) at −70° C. under argon. The reaction mixture was stirred at −70° C. for 10 min followed by the addition of (bromomethyl)benzene (0.137 mL, 1.15 mmol) at the same temperature. Then the reaction was allowed to stir at rt for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (300 mg, 0.942 mmol, 86% yield) as a colorless oil. Anal. Calcd. for C18H26N2O3 m/z 318.4. found: 319.3 (M+H)+. to stir at rt for 30 min The reaction was quenched with water extracted with EtOAc The organic layer was washed with water, saturated aqueous NaCl dried over MgSO4 filtered concentrated The crude product was purified eluting with a gradient of 0-80% EtOAc/Hex

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

実験手順: To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (230 mg, 1.01 mmol) in DMF (1 mL) was added sodium hydride (129 mg, 3.22 mmol) at rt under argon. The reaction mixture was stirred at rt for 10 min followed by the addition of 3-(chloromethyl)pyridine hydrochloride (197 mg, 1.54 mmol) at rt. The reaction was allowed to stir at rt for an additional 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylcarbamate (155 mg, 0.485 mmol, 48.2% yield) as colorless oil. Anal. Calcd. for C17H25N3O3 m/z 319.4. found: 320.2 (M+H)+. to stir at rt for an additional 30 min The reaction was quenched with water extracted with EtOAc The organic layer was washed with water, saturated aqueous NaCl dried over MgSO4 filtered concentrated The crude product was purified eluting with a gradient of 0-80% EtOAc/Hex

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

実験手順: To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (130 mg, 0.569 mmol), THF (10 mL) and LiHMDS (0.190 mL, 1.14 mmol). The reaction was stirred at rt for 30 min. Then methyl 2-bromoacetate (0.079 mL, 0.85 mmol) was added to the reaction and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by RP prep-HPLC to give (S)-methyl 2-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)acetate (60 mg, 0.20 mmol, 35% yield) as a clear oil. Anal. Calcd. for C14H24N2O5 m/z 300.3. found: 301.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.89 (br. s., 1H), 4.40 (d, J=4.4 Hz, 1H), 4.13 (br. s., 2H), 3.79-3.56 (m, 4H), 3.15 (d, J=12.1 Hz, 1H), 2.07-1.87 (m, 2H), 1.75 (d, J=10.4 Hz, 2H), 1.62-1.49 (m, 2H), 1.39 (br. s., 9H); 13C NMR (126 MHz, CDCl3) δ ppm 173.82, 169.55, 155.20, 79.55, 53.36, 52.17, 50.71, 50.63, 32.21, 28.31, 27.80, 26.87. the reaction mixture was stirred at rt overnight The reaction mixture was concentrated purified by RP prep-HPLC

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

実験手順: To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (500 mg, 2.19 mmol), THF (10 mL) and a 6 M solution of LiHMDS in THF (0.475 mL, 2.85 mmol). The reaction was stirred at rt for 1 hr before it was cooled to 0° C. Then, methyl acrylate (0.237 mL, 2.63 mmol) was added to the reaction and the reaction was slowly warmed up to rt and stirred at rt overnight. The reaction was concentrated and purified using RP prep-HPLC (Method A) to give (S)-methyl 3-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)propanoate (140 mg, 0.445 mmol, 20.3% yield) as a white solid. Anal. Calcd. for C15H26N2O5 m/z 314.3. found: 315.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.96 (d, J=5.5 Hz, 1H), 4.34 (dd, J=11.0, 6.0 Hz, 1H), 3.77 (ddd, J=13.6, 6.7, 6.6 Hz, 1H), 3.69 (s, 3H), 3.61 (ddd, J=13.9, 7.1, 7.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.33 (dd, J=14.8, 4.4 Hz, 1H), 2.65-2.50 (m, 2H), 2.04 (d, J=13.2 Hz, 1H), 1.94 (d, J=13.7 Hz, 1H), 1.88-1.74 (m, 2H), 1.50-1.40 (m, 9H), 1.41-1.25 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 173.15, 172.24, 155.16, 79.35, 53.34, 51.80, 49.88, 45.50, 32.51, 28.39, 27.86, 27.74. was cooled to 0° C the reaction was slowly warmed up to rt stirred at rt overnight The reaction was concentrated purified

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

実験手順: To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (500 mg, 2.19 mmol), THF (10 mL) and a 6 M solution of LiHMDS in THF (0.475 mL, 2.85 mmol). The reaction was stirred at rt for 1 hr before it was cooled to 0° C. Then, methyl acrylate (0.237 mL, 2.63 mmol) was added to the reaction and the reaction was slowly warmed up to rt and stirred at rt overnight. The reaction was concentrated and purified using RP prep-HPLC (Method A) to give (S)-methyl 3-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)propanoate (140 mg, 0.445 mmol, 20.3% yield) as a white solid. Anal. Calcd. for C15H26N2O5 m/z 314.3. found: 315.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.96 (d, J=5.5 Hz, 1H), 4.34 (dd, J=11.0, 6.0 Hz, 1H), 3.77 (ddd, J=13.6, 6.7, 6.6 Hz, 1H), 3.69 (s, 3H), 3.61 (ddd, J=13.9, 7.1, 7.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.33 (dd, J=14.8, 4.4 Hz, 1H), 2.65-2.50 (m, 2H), 2.04 (d, J=13.2 Hz, 1H), 1.94 (d, J=13.7 Hz, 1H), 1.88-1.74 (m, 2H), 1.50-1.40 (m, 9H), 1.41-1.25 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 173.15, 172.24, 155.16, 79.35, 53.34, 51.80, 49.88, 45.50, 32.51, 28.39, 27.86, 27.74. was cooled to 0° C the reaction was slowly warmed up to rt stirred at rt overnight The reaction was concentrated purified

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

実験手順: Following the procedure of example 1h) except ((S)-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester and bromo-acetic acid benzyl ester is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 base to give ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. Removal of the Boc group by procedure 2d) gives ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester.

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

実験手順: Following the procedure of example 1h) except ((S)-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester and bromo-acetic acid benzyl ester is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 base to give ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. Removal of the Boc group by procedure 2d) gives ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester.