Ammonium formate → 6-[4-[4-[3-(4-Acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine

HRID 2381088Notes

Reaction equation

HRID 2381088 reaction equation
[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:36])([F:37])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]

Participants

6

Reactant 2

HCID 2723923Ammonium formate2×HCID 591496936-[4-[4-[3-(4-Acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine

Product 1

HCID 468935846-[4-[4-[3-(4-Acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazineYield 71.5%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
76 °C

Procedure

10% Palladium on carbon (0.276 g, 0.26 mmol) was added to 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 25.96 mmol) and ammonium formate (16.37 g, 259.61 mmol) in ethanol (300 mL) at 20° C. The resulting slurry was stirred at 76° C. for 32 hours, regularly adding more ammonium formate and catalyst to force the reaction to completion. The cooled reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give a colourless gum which was dissolved in DCM (1 L) and the solution washed with water (1 L). The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% MeOH in DCM. Pure fractions were evaporated to dryness and the resulting oil was triturated with ether to give 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (9.90 g, 71.4%) as a white solid.

Workup

  1. customthe reaction to completion
  2. customThe cooled reaction mixture
  3. filtrationwas filtered through diatomaceous earth
  4. concentrationthe filtrate was concentrated under vacuum
  5. customto give a colourless gum which
  6. washthe solution washed with water (1 L)
  7. washThe organic layer was washed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated to dryness
  11. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 8% MeOH in DCM
  12. customPure fractions were evaporated to dryness
  13. customthe resulting oil was triturated with ether

Sources & evidence

ORD record
ord-e142b8a8ab504b009c3e7a6fd4641502
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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