反应详情

Add (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine dihydroiodide (650 g, 1.43 mol), 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (427 g, 1.71 mol), and 1-hydroxybenzotriazole hydrate (262.5 g. 1.71 mol) to dichloromethane (3 L). Stir the mixture in an ice water bath and slowly add diisopropylethylamine (797 ml, 4.57 mol). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (333.6 g, 1.71 mol) over 10 minutes. Remove the ice water bath and allow the mixture to stir for approximately 16 hours at ambient temperature. Wash the reaction mixture with water (3×4 L). Dry the organic phase over sodium sulfate. Filter and concentrate the mixture under reduced pressure to approximately 1 L volume. Dilute the residue with ethyl acetate (4 L). Remove 2 L of solvent under reduced pressure. Allow mixture to stand 1 hour at ambient temperature. Isolate the resulting precipitate by filtration and wash the cake with hexanes (2×2 L) to give the title compound (569.9 g, 93%) as a pale tan solid: MS (m/z): 431 (M+1). H1 NMR (399.81 MHz, DMSO): 8.91 (s, 1H), 7.95-7.93 (d, J=7.5 Hz, 1H), 7.87-7.83 (d, J=8.7 Hz, 2H), 7.49 (d, J=1.4 Hz, 1H), 7.44-7.43 (d, J=7.6 Hz, 1H), 7.38 (m, 2H), 7.34-7.29 (m, 1H), 7.00-6.96 (d, J=8.7 Hz, 2H), 6.95 (d, J=1.3 Hz, 1H), 4.65-4.60 (m, 1H), 4.08 (q, J=7.0 Hz, 2H), 2.70-2.65 (m, 1H), 2.59-2.56 (m, 1H), 2.33-2.28 (m, 1H), 2.04-2.00 (m, 1H), 1.34-1.31 (m, 4H), 1.27-1.25 (m, 1H), 1.03-0.98 (m, 1H), 0.96-0.90 (m, 1H).

1. customRemove the ice water bath
2. stirringto stir for approximately 16 hours at ambient temperature
3. washWash the reaction mixture with water (3×4 L)
4. dry with materialDry the organic phase over sodium sulfate
5. filtrationFilter
6. concentrationconcentrate the mixture under reduced pressure to approximately 1 L volume
7. additionDilute the residue with ethyl acetate (4 L)
8. customRemove 2 L of solvent under reduced pressure
9. customIsolate the resulting precipitate
10. filtrationby filtration
11. washwash the cake with hexanes (2×2 L)