tert-butyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate

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

実験手順: Combine methanol (5000 mL) and 5N aqueous hydrogen chloride solution (1393 mL, 5.57 mol) and heat to 35° C. for 15 minutes. Add tert-butyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (Armstrong III, Joseph D, et al, Tetrahedron Let. 35(20) pp. 3239-3242 (1994) (770 g, mmol and commercially available) portionwise over 1 hour. Concentrate the mixture under reduced pressure to a white solid. Combine this solid with additional (3R)-3-amino-1,3,4,5-tetrahydro-1-benzazepin-2-one (different lot, same method; 660 g, 3.78 mol) and dissolve in water (2.5 L). To the resulting solution add sodium carbonate (3.17 kg, 3.18 mol) and acetonitrile (7.5 L). Add benzyl chloroformate (7.14 mol, 1.21 Kg) dropwise over 2 hours. After 2 hours at ambient temperature, add ethyl acetate (8 L) and filter. Wash the wet cake with water (4.0 L), acetonitrile (2.0 L), and ethyl acetate (3.0 L). Dry the solid under reduced pressure for 48 hours to give the title compound (2.14 kg, 105%): MS (m/z): 310.8 (M+1). Concentrate the mixture under reduced pressure to a white solid After 2 hours at ambient temperature filter Wash the wet cake with water (4.0 L), acetonitrile (2.0 L), and ethyl acetate (3.0 L) Dry the solid under reduced pressure for 48 hours

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

実験手順: Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m, 1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H), 7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz, 1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C29H29N3O3 467; found 468 (M+H, 15%), 368 (M-BOC, 100%). prepared by the method of M

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

実験手順: Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m, 1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H), 7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz, 1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C29H29N3 O3 467; found 468 (M+H, 15%), 368 (M-BOC, 100%). prepared by the method of M

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

実験手順: A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (0.338 g, 1.20 mmol) was fitted with a stirbar and septa. Acetic acid (glacial, 5 mL) and bromine (0.37 g, 2.3 mmol) were added, in that order, giving a solution that was stirred at room temperature for 1.5 hours. The reaction was then poured into ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (10% to 50% ethyl acetate/hexanes linear gradient) to give the desired product. was fitted with a stirbar and septa giving a solution that washed with saturated aqueous NaHCO3 solution (2×50 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (10% to 50% ethyl acetate/hexanes linear gradient)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (3.09 g, 11.2 mmol) was fitted with a stirbar and septa and flushed with nitrogen. N,N-Dimethylformamide (30 mL) was added, giving a solution that was cooled to 0° C. N-Chlorosuccinimide (2.20 g, 16.5 mmol) was then added, and stirring was continued for 24 hours. The reaction was then poured into ethyl acetate (200 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a solid that was purified via flash chromatography on silica gel (5% to 30% ethyl acetate/hexanes linear gradient) to give the desired product. was fitted with a stirbar and septa flushed with nitrogen N,N-Dimethylformamide (30 mL) was added giving a solution that washed with 1:1 H2O The organic layer was dried over MgSO4 filtered concentrated in vacuo to give a solid that was purified via flash chromatography on silica gel (5% to 30% ethyl acetate/hexanes linear gradient)