反应详情

温度

120 °C

To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (Intermediate 1) (297 mg, 0.990 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (300 mg, 0.900 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (52 mg, 0.045 mmol) followed by a solution of Na2CO3 (191 mg, 1.800 mmol) in water (1 mL). The resulting mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow oil. The crude material was pre-absorbed onto silica gel and purified by flash chromatography over silica using 2.5% [7M NH3 in MeOH]/DCM as the eluent to afford a pale brown glass-like solid which was re-dissolved in MeOH (10 mL) and SiliaMetS DMT (0.52 mmol/g, 433 mg) was added. The resulting suspension was placed in a shaker for 2.5 hours then the SiliaMetS DMT removed by filtration and the filtrate concentrated in vacuo to afford an orange/brown oil. The crude oil was re-dissolved in MeOH and loaded onto a 10 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (40 mL) then flushed with 7M NH3 in MeOH (40 mL). The MeOH/NH3 was removed in vacuo to afford a pale orange/brown glass-like solid. The crude glass-like solid was re-purified by mass directed preparative HPLC under basic conditions (5 mM NH4OH) to afford the title compound as a pale pink glass-like solid (0.185 g, 48% yield). LC-MS: Rt 1.53 min; MS m/z 427.3 [M+H]+ [Method B]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=2.53 Hz, 1H), 8.19 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.65 (d, J=2.02 Hz, 1H), 7.59 (dd, J=8.59, 2.02 Hz, 1H), 6.60 (dd, J=2.53, 1.52 Hz, 1H), 4.36 (tt, J=12.38, 3.28 Hz, 1H), 4.04 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=12.38 Hz, 2H), 1.29 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H). HR-MS: Rt 1.54 mins; MS m/z 427.2260 [M+H]+ [Method C].

1. customThe resulting mixture was purged with nitrogen
2. customsealed
3. additionThe reaction mixture was diluted with EtOAc (100 mL)
4. washwashed with water (50 mL)
5. customThe organic phase was separated
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationThe filtrate was concentrated in vacuo
9. customto afford the crude product as a yellow oil
10. customThe crude material was pre-absorbed onto silica gel
11. custompurified by flash chromatography over silica using 2.5% [7M NH3 in MeOH]/DCM as the eluent
12. customto afford a pale brown glass-like solid which
13. additionSiliaMetS DMT (0.52 mmol/g, 433 mg) was added
14. customthe SiliaMetS DMT removed by filtration
15. concentrationthe filtrate concentrated in vacuo
16. customto afford an orange/brown oil
17. washThe cartridge was washed with MeOH (40 mL)
18. customthen flushed with 7M NH3 in MeOH (40 mL)
19. customThe MeOH/NH3 was removed in vacuo
20. customto afford a pale orange/brown glass-like solid
21. customThe crude glass-like solid was re-purified by mass