(R)-3-氨基-2,3,4,5-四氢-1H-苯并氮杂-2-酮

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

实验步骤: Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step I. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 (d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H).

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

实验步骤: Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step I. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 (d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H).

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

实验步骤: A solution of 8.70 g (49.4 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mL of methylene chloride was treated with 10.73 g (49.4 mmol) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL of triethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersed in an ambient temperature water bath then 26 g of benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (59 mmol, 1.2 eq) was added all at once and the mixtrue stirred at room temperature for 2 hours. The reaction mixture was added to 300 mL of ethyl acetate and washed three times with 5% aqueous citric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (4:1), to afford 17.42 g (46.4 mmol, 94%) of the product as a white solid. 1H NMR (200 MHz, CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d, 15 Hz, 1H), 2.59 (d, 15 Hz, 1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s, 1H), 6.72 (d, 7 Hz, 1H), 6.98 (d, 8 Hz, 1H), 7.1-7.3 (m,3H), 7.82 (br s, 1H), FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H, 70%). was immersed in an ambient temperature washed three times with 5% aqueous citric acid The organic layer was removed dried over magnesium sulfate filtered the filtrate concentrated under vacuum The residue was purified by preparative high pressure liquid chromatography on silica eluting with ethyl acetate/hexane (4:1)

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

实验步骤: A suspension of 98.31 g (0.530 mol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in 1600 mL of methanol at room temperature was treated with 155 mL (1.112 mol) of triethylamine. The resulting suspension was cooled to 0° C. and treated with a solution of 110.01 g (0.557 mol) of N-chlorosulfonyl-4,4-dimethylazetidin-2-one in 960 mL of methanol over 20 minutes maintaining the internal temperature below 10° C. Additional methanol (100 mL) was used to rinse the flask and the rinse was transferred into the reaction vessel. The reaction mixture was warmed to room temperature and stirred for 90 minutes. maintaining the internal temperature below 10° C to rinse the flask The reaction mixture was warmed to room temperature

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

实验步骤: To a solution of 200 mg (1.13 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 8 mL of dry methylene chloride was added 0.206 mL (1.48 mmol) of triethylamine, 553 mg (1.25 mmol) of BOC-D-serine t-butyl ether followed by 602 mg (1.36 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours then diluted with 100 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexane (55:45) to afford 480 mg (200%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.20 (s,9H), 1.47 (s,9H), 1.92 (m,1H), 2.55-3.02 (m,3H), 3.38 (t,8 Hz,1H), 3.78 (m,1H), 4.15 (m,1H), 4.52 (m,1H), 5.45 (s,1H), 7.00 (m,1H), 7.10-7.35 (m,3H), 7.68 (d,4 Hz,1H), 8.05 (s,1H). FAB-MS: calculated for C22H33N3O5 419; found 420 (M+H,205), 426 (M+Li,40%). washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine The organic layer was dried over magnesium sulfate filtered the solvents removed under vacuum The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (55:45)

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

实验步骤: To a solution of 200 mg (1.13 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 8 mL of dry methylene chloride was added 0.206 mL (1.48 mmol) of triethylamine, 553 mg (1.25 mmol) of BOC-D-serine t-butyl ether followed by 602 mg (1.36 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours then diluted with 100 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexane (55:45) to afford 480 mg (200%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.20 (s,9H), 1.47 (s,9H), 1.92 (m,1H), 2.55-3.02 (m,3H), 3.38 (t,8 Hz,1H), 3.78 (m,1H), 4.15 (m,1H), 4.52 (m,1H), 5.45 (s,1H), 7.00 (m,1H), 7.10-7.35 (m,3H), 7.68 (d,4 Hz,1H), 8.05 (s,1H). FAB-MS: calculated for C22H33N3O5 419; found 420 (M+H,205), 426 (M+Li,40%). washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine The organic layer was dried over magnesium sulfate filtered the solvents removed under vacuum The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (55:45)

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

实验步骤: Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (n,3H), 3.26 (d,6Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7Hz,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).

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

实验步骤: Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (n,3H), 3.26 (d,6Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7Hz,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).

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

实验步骤: Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.42 (s,12H), 1.46 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.48 (m,1H), 5.01 (br s,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.9 (br s,1H). FAB=MS: calculated for C19H27N3O4 361; found 362 (M+H,30%).

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

实验步骤: A solution of 528 mg (3.0 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 45 mL of absolute methanol at room temperature was treated with 4.5 g of powdered 3A molecular sieves followed by dropwise addition of a solution of 954 mg (9.0 mmol, 3 eq.) of benzaldehyde in 15 mL of methanol. The pH of the mixture was adjusted to 7 by addition of trifluoroacetic acid then stirred at room temperature for 2 hours. Sodium cynaoborohydride (18 mL of 1.0M THF solution: 18 mmol, 6 eq.) was added and the mixture stirred at room temperature for 18 hours. The mixture was filtered and the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours, then all volatiles removed under vacuum and the residue dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by chromatography on silica, eluting with ethyl acetate/hexane (70:30), to afford 410 mg (1.54 mmol, 51%) of the product. 1H NMR (200MHz,CDCl3): 2.05 (m,1H), 2.5-3.0 (m,3H), 3.37 (dd;7.11Hz;1H), 3.57 (d,12Hz,1H), 3.90 (d,12Hz,1H), 7.05 (d,8Hz,1H), 7.1-7.4 (m,8H), 7.75 (br s,1H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+H,75%). the mixture stirred at room temperature for 18 hours The mixture was filtered the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours all volatiles removed under vacuum the residue dissolved in 50 mL of ethyl acetate The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate filtered solvents removed under vacuum The residue was purified by chromatography on silica eluting with ethyl acetate/hexane (70:30)

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

实验步骤: A solution of 528 mg (3.0 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 45 mL of absolute methanol at room temperature was treated with 4.5 g of powdered 3A molecular sieves followed by dropwise addition of a solution of 954 mg (9.0 mmol, 3 eq.) of benzaldehyde in 15 mL of methanol. The pH of the mixture was adjusted to 7 by addition of trifluoroacetic acid then stirred at room temperature for 2 hours. Sodium cynaoborohydride (18 mL of 1.0M THF solution: 18 mmol, 6 eq.) was added and the mixture stirred at room temperature for 18 hours. The mixture was filtered and the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours, then all volatiles removed under vacuum and the residue dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by chromatography on silica, eluting with ethyl acetate/hexane (70:30), to afford 410 mg (1.54 mmol, 51%) of the product. 1H NMR (200MHz,CDCl3): 2.05 (m,1H), 2.5-3.0 (m,3H), 3.37 (dd;7.11Hz;1H), 3.57 (d,12Hz,1H), 3.90 (d,12Hz,1H), 7.05 (d,8Hz,1H), 7.1-7.4 (m,8H), 7.75 (br s,1H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+H,75%). the mixture stirred at room temperature for 18 hours The mixture was filtered the filtrate treated with 3 mL of trifluoroacetic acid with stirring for 3 hours all volatiles removed under vacuum the residue dissolved in 50 mL of ethyl acetate The ethyl acetate solution was washed with water (3×15 mL), saturated aqueous sodium bicarbonate (2×15 mL) and 15 mL of brine then dried over magnesium sulfate filtered solvents removed under vacuum The residue was purified by chromatography on silica eluting with ethyl acetate/hexane (70:30)

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

实验步骤: Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.37 (s,6H), 1.44 (s,9H), 1.95 (m,1H), 2.46 (d,15 Hz, 1H), 2.59 (d,15 Hz, 1H), 2.6-3.0, (m,3H), 4.53 (m,1H), 5.30 (br s,1H), 6.72 (d,7 Hz, 1H), 6.98 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.82 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,70%).