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

Participants

Reaction Conditions

Reaction Steps

{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.

Provenance & Evidence