Imidazole → 2-(2-Chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

Participants

Reaction Conditions

Reaction Steps

DMF (0.75 mL) was added to a nitrogen flushed flask containing copper(I) iodide (13 mg, 0.067 mmol), 2-(2-pyridyl)benzimidazole (13 mg, 0.067 mmol) and cesium carbonate (273 mg, 0.839 mmol). The resulting suspension was heated at 60° C. for 1 hour. 1H-Imidazole (23 mg, 0.336 mmol) and 2-(2-chloro-4-iodophenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole (150 mg, 0.336 mmol) were added and the mixture was heated at 90° C. for ˜18 hours. The reaction mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford a green oil. The crude material was taken up in MeOH (30 mL) and SiliaMetS-DMT (0.61 mmol/g, 1.098 g, 0.67 mmol) was added. The resulting suspension was stirred at room temperature for 72 hours then the SiliaMetS-DMT was removed by vacuum filtration and the filtrate was concentrated in vacuo to afford the crude product as a yellow oil. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified). The product containing fractions were combined, loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a white solid (22 mg, 17% yield). LC-MS: Rt 0.52 min; MS m/z 387.0 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.15 (d, J=8.59 Hz, 1H), 8.06 (d, J=2.02 Hz, 1H), 7.91 (s, 1H), 7.83 (dd, J=8.59, 2.53 Hz, 1H), 7.15 (s, 1H), 3.72 (dd, J=10.36, 8.34 Hz, 2H), 3.37 (dd, J=10.36, 2.78 Hz, 2H), 3.00 (br. s., 2H), 2.56 (br. s., 4H), 2.26 (s, 3H).

Provenance & Evidence