Water → 1,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

HRID 241179Notes

Reaction equation

HRID 241179 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:27]([N:29]=[C:30]=S)[CH3:28].O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:27]([NH:29][C:30]1[NH:1][C:2]2[CH:3]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=4[CH:26]=3)[CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:28]

Participants

6

Reactant 4

HCID 962Water2×HCID 10966Ethyl isothiocyanateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 668201741,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

Product 1

HCID 668204081,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateYield 39.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (750 mg, 2.10 mmol) in ethyl acetate (20 mL) was treated with ethyl isothiocyanate (184 uL, 2.10 mmol). The mixture was heated to 60° C. for 4.25 h. After cooling to rt, water was added and the layers were partitioned. The organic phase was washed once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was then dissolved in ethyl acetate (20 mL), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (403 mg, 2.10 mmol) was added. The mixture was heated to 60° C. for 50 minutes before cooling to rt. Water was added, and the biphasic mixture was partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient: 98:2 dichloromethane:methanol to 90:10 dichloromethane:methanol) to provide 1,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (337 mg, 0.83 mmol, 39% yield) as an orange film. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.47-7.38 (m, 2H), 7.32 (s, 1H), 7.20-7.08 (m, 2H), 7.05-6.96 (m, 1H), 6.68-6.58 (m, 1H), 4.55-4.40 (m, 2H), 4.09-3.98 (m, 2H), 3.77-3.65 (m, 2H), 3.33-3.26 (m, 2H), 1.41-1.28 (m, 9H), 1.18 (t, 3H); MS (EI) for C23H28N4O3: 409 (MH+).

Workup

  1. temperatureAfter cooling to rt
  2. customthe layers were partitioned
  3. washThe organic phase was washed once with saturated sodium bicarbonate
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe residue was then dissolved in ethyl acetate (20 mL)
  8. temperatureThe mixture was heated to 60° C. for 50 minutes
  9. temperaturebefore cooling to rt
  10. customthe biphasic mixture was partitioned
  11. extractionThe aqueous phase was extracted with ethyl acetate
  12. dry with materialThe combined organic extracts were dried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe residue was purified by silica gel chromatography (gradient: 98:2 dichloromethane:methanol to 90:10 dichloromethane:methanol)

Sources & evidence

ORD record
ord-21074d0f39754ee985c6a5b0f6d7e8d4
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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