反应详情

DIAD (7.78 mL, 39.53 mmol) was added dropwise to 4-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)phenol (12 g, 32.94 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (6.23 g, 49.41 mmol) and triphenylphosphine (12.96 g, 49.41 mmol) in THF (250 mL). The resulting solution was stirred at ambient temperature for 18 hours then split and added to a series of SCX columns (6). The crude product was eluted from the columns using 2M NH3/MeOH and the solvents evaporated. The crude product was diluted with DCM (200 mL) and washed with 2M NaOH (200 mL×2). The organic layer was dried over MgSO4, filtered and evaporated then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness giving a yellow solid, which was triturated with ether then dried to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (9.18 g, 59.0%) as a cream solid.

1. customthen split
2. additionadded to a series of SCX columns (6)
3. washThe crude product was eluted from the columns
4. customthe solvents evaporated
5. additionThe crude product was diluted with DCM (200 mL)
6. washwashed with 2M NaOH (200 mL×2)
7. dry with materialThe organic layer was dried over MgSO4
8. filtrationfiltered
9. customevaporated
10. customthen purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM
11. customPure fractions were evaporated to dryness
12. customgiving a yellow solid, which
13. customwas triturated with ether
14. customthen dried