Imidazole → 3-[4-(1-Amino-cyclobutyl)-phenyl]-6-imidazol-1-yl-2-phenyl-chromen-4-one

HRID 1037207Notes

Reaction equation

HRID 1037207 reaction equation
C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CO.S1C=CC=C1C([O-])=O.[Cu+]>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:37]5[CH:41]=[CH:40][N:39]=[CH:38]5)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1

Participants

7

Reactant 3

HCID 795ImidazoleHCID 10796Cesium carbonateHCID 67067709{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester

Product 1

HCID 510308823-[4-(1-Amino-cyclobutyl)-phenyl]-6-imidazol-1-yl-2-phenyl-chromen-4-oneYield 14%

Reagents, catalysts & solvents 3

HCID 11194830Cuprous 2-thiophenecarboxylateCatalystHCID 887MethanolSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
110 °C

Procedure

{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (55 mg, 0.1 mmol), imidazole (9 mg, 0.12 mmol), cesium carbonate (49 mg, 0.15 mmol) and copper (I)thiophene-2-carboxylate (4 mg, 0.02 mmol) were suspended in NMP (1.0 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated conventionally at 110° C. for 24 hours. Due to incomplete reaction, the temperature was increased to 130° C. After a further 24 hours, the reaction mixture was allowed to cool to RT, dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2 M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was dissolved in DCM (2 mL) and TFA (500 μL) and stirred at RT for 1.5 hours. The mixture was dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2 M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was purified on reverse phase HPLC (gradient 5% 20 mM TEA in acetonitrile/20 mM TEA in water to 98% 20 mM TEA in acetonitrile/20 mM TEA in water) to give the title compound as a white solid (6 mg, 14%). 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.42 (m, 1H), 8.23 (d, J=3 Hz, 1H), 8.18 (dd, J=3 and 9 Hz, 1H), 7.94 (d, J=9 Hz, 1H), 7.93-7.92 (m, 1H), 7.47-7.33 (m, 7H), 7.16-7.13 (m, 3H), 2.40-2.32 (m, 2H), 2.11-2.02 (m, 2H), 2.02-1.95 (m, 1H), 1.70-1.61 (m, 1H). LCMS (Method F): RT=6.40 min, [M+H]+=434.

Workup

  1. customThe vial was sealed
  2. customevacuated
  3. customflushed twice with nitrogen
  4. customDue to incomplete reaction
  5. temperaturethe temperature was increased to 130° C
  6. temperatureto cool to RT
  7. washThe cartridge was washed repeatedly with methanol
  8. washbefore eluting with 2 M ammonia in methanol solution
  9. customThe eluent was collected
  10. concentrationconcentrated in vacuo
  11. dissolutionThe resulting residue was dissolved in DCM (2 mL)
  12. dissolutionThe mixture was dissolved in methanol
  13. washThe cartridge was washed repeatedly with methanol
  14. washbefore eluting with 2 M ammonia in methanol solution
  15. customThe eluent was collected
  16. concentrationconcentrated in vacuo
  17. customThe resulting residue was purified on reverse phase HPLC (gradient 5% 20 mM TEA in acetonitrile/20 mM TEA in water to 98% 20 mM TEA in acetonitrile/20 mM TEA in water)

Sources & evidence

ORD record
ord-7f262b9794634a4bb1506c56a6f1df28
Source dataset
uspto-grants-2013_10
Patent number
US08546376B2

Reaction notes

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