反应详情

温度

120 °C

A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H).

1. washwashed with saturated NaHCO3(aq) (20 mL)
2. customThe organic phase was separated
3. extractionthe aqueous phase was re-extracted with DCM (20 mL)
4. concentrationThe combined organic phases were concentrated in vacuo
5. customto afford the crude product as a dark brown oily residue
6. customThe crude material was purified by mass
7. additionthe product containing fractions
8. washThe cartridge was washed with MeOH (15 mL)
9. customthen flushed with 7M NH3 in MeOH (10 mL)
10. customThe MeOH/NH3 was removed in vacuo