6-[4-[4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine → Azd 3514

HRID 2381102Notes

Reaction equation

HRID 2381102 reaction equation
[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:35])([F:36])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]

Participants

4

Reactant 1

HCID 591497636-[4-[4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine

Product 1

HCID 46893585Azd 3514Yield 88.9%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

Methanol (375.0 mL) was added to 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (25.0 g, 48 m mol) in a 2.0 L autoclave reactor and to this was added 10% Pd/C (12.5 g, 50% w/w) paste at 22-25° C. under nitrogen gas atmosphere. The reaction was performed under hydrogen pressure (5.0 bar) at 50° C. temperature for 10.0 h. The reaction mass was cooled to room temperature and the catalyst removed by filtration. Filtered cake was washed with methanol. The solvent was evaporated and the residue was azeotropically distilled by is ethylacetate (2×125.0 mL) at 40° C. under reduced pressure to 3.0 rel vol (75.0 mL). Drop wise addition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass resulted in solid material, which was collected by filtration and washed with MTBE (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (22.3 g, 88%) as a white color free flowing solid. The isolated material was confirmed by XRPD as Form A.

Workup

  1. customat 50° C.
  2. customfor 10.0 h
  3. customthe catalyst removed by filtration
  4. filtrationFiltered cake
  5. washwas washed with methanol
  6. customThe solvent was evaporated
  7. distillationthe residue was azeotropically distilled
  8. customat 40° C.
  9. additionaddition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass
  10. customresulted in solid material, which
  11. filtrationwas collected by filtration
  12. washwashed with MTBE (50.0 mL)
  13. customThe material was dried under reduced pressure with nitrogen gas
  14. custombleed at 50° C.

Sources & evidence

ORD record
ord-a85ebd9dd9f6433a9e708283dd07af20
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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