Diisopropylethylamine → N-[1-[[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamoyl]cyclopropyl]-4-ethoxy-benzamide

HRID 2068533Notes

Reaction equation

HRID 2068533 reaction equation
I.I.[CH:3]1[N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH2:13])[C:6]2=[N:5][CH:4]=1.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][C:28]2([C:31](O)=[O:32])[CH2:30][CH2:29]2)=[O:26])=[CH:23][CH:22]=1)[CH3:19].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:3]1[N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:31]([C:28]3([NH:27][C:25](=[O:26])[C:24]4[CH:34]=[CH:35][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=4)[CH2:30][CH2:29]3)=[O:32])[C:6]2=[N:5][CH:4]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 583041121-[(4-Ethoxybenzoyl)amino]cyclopropanecarboxylic acidHCID 67234232(4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine dihydroiodide

Product 1

HCID 53242014N-[1-[[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamoyl]cyclopropyl]-4-ethoxy-benzamideYield 93%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-4a70dee6a15541ceaa3c01aa90eed47b
Source dataset
uspto-grants-2012_10
Patent number
US08299061B2

Reaction notes

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