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

Temperature

60 °C

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).

1. temperaturethe mixture was heated at 90° C. for ˜18 hours
2. filtrationfiltered through celite
3. concentrationThe filtrate was concentrated in vacuo
4. customto afford a green oil
5. additionSiliaMetS-DMT (0.61 mmol/g, 1.098 g, 0.67 mmol) was added
6. customthe SiliaMetS-DMT was removed by vacuum filtration
7. concentrationthe filtrate was concentrated in vacuo
8. customto afford the crude product as a yellow oil
9. customThe crude material was purified by mass
10. additionThe product containing fractions
11. washthe cartridge washed with MeOH (10 mL)
12. customthen flushed with 7M NH3 in MeOH (10 mL)
13. customThe MeOH/NH3 was removed in vacuo

ORD record

ord-2ac68cf11f6442c78be73a1a18eb26ee

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040712B2