Citric Acid → 1,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

HRID 473902Notes

Reaction equation

HRID 473902 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](C(OC(C)(C)C)=O)[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]([O:24][C:25]([N:27]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO.O1CCOCC1>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH2:29][CH2:28][N:27]([C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:26])[CH2:33][C:32]=3[CH:34]=2)=[CH:7][CH:6]=1

Participants

9

Reactant 5

HCID 311Citric AcidHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 57225088tert-butyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylateHCID 59604707(4-(Tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)boronic acid

Product 1

HCID 675152711,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateYield 89%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

1,1-Dimethylethyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (457 mg, 1.41 mmol) and (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (456 mg, 1.55 mmol) were taken into dioxane (5 mL) and water (1 mL) followed by addition of DIPEA (1.1 mL, 6.2 mmol) and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (58 mg) then the mixture was heated at 80° C. over 12 h. The mixture was cooled then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue thus obtained was taken into methanol (10 mL) followed by addition of sodium hydroxide (180 mg, 4.5 mmol) in water (1 mL). The mixture was stirred at room temperature for 30 minutes then neutralized by addition of 10% aqueous citric acid then concentrated. The aqueous residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 1,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (490 mg, 89% yield). MS (EI) for C23H25N3O3: 392 (MH+).

Workup

  1. temperatureThe mixture was cooled
  2. customthen partitioned with ethyl acetate and 10% aqueous citric acid
  3. washThe organic solution was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationthen filtered
  6. concentrationconcentrated
  7. customThe residue thus obtained
  8. concentrationthen concentrated
  9. customThe aqueous residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate
  10. washthe organic solution was washed with brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. filtrationthen filtered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-0b9d2554dcbe461092a28d9744f7ab47
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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