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

Temperature

110 °C

{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.

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)

ORD record

ord-7f262b9794634a4bb1506c56a6f1df28

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08546376B2