Sodium Hydroxide → 6-[4-[4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine

温度

110 °C

DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basified to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (1 L), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid.

1. temperatureThe reaction mixture was cooled to room temperature
2. customthe solvents were evaporated
3. dissolutionThe residue was dissolved in ethyl acetate (1 L)
4. washthe solution was washed with water (1 L)
5. extractionThe aqueous was re-extracted with ethyl acetate (1 L)
6. washthe combined organics were washed with brine (1 L)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. customevaporated
10. customto give crude product
11. extractionextracted with ethyl acetate (1 L)
12. washwashed with brine (1 L)
13. dry with materialdried over MgSO4
14. filtrationfiltered
15. customevaporated
16. customto give further crude product
17. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM
18. customPure fractions were evaporated

ORDレコード

ord-9932a0dc2329484ca10d50c0aff7ee53

出典データセット

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08258140B2