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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

HRID 2381101
Notes
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Reaction equation

HRID 2381101 reaction equation
CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].[OH-].[Na+]>CC(N(C)C)=O>[C:43]([N:46]1[CH2:51][CH2:50][N:49]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:48][CH2:47]1)(=[O:45])[CH3:44]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 837951-AcetylpiperazineHCID 866466942-(4-{1-[3-(Trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate

Product 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
Yield 77%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
110 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-9932a0dc2329484ca10d50c0aff7ee53
Source dataset
uspto-grants-2012_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08258140B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes