Ethylene carbonate → 2-(4-{1-[3-(Trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol

HRID 2381099Notes

Reaction equation

HRID 2381099 reaction equation
[C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1

Participants

5

Reactant 3

HCID 7303Ethylene carbonateHCID 11430Potassium CarbonateHCID 367300784-(1-(3-(Trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol

Product 1

HCID 667882562-(4-{1-[3-(Trifluoromethyl) [1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of ethylene carbonate (121 g, 1376.13 mmol) in DMF (200 mL) was added dropwise to a stirred suspension of 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (100 g, 275.23 mmol) and potassium carbonate (76 g, 550.45 mmol) in DMF (200 mL) at 80° C. over a period of 15 minutes under nitrogen. The resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, then concentrated and diluted with DCM (2 L), and washed sequentially with water (1 L) and saturated brine (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with EtOAc (150 mL). The resulting solid was washed with further EtOAc (50 mL) and ether then dried to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol. The filtrate was evaporated and further purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with ether, dried and combined with the material previously collected to afford 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 79%) as a solid.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated
  3. additiondiluted with DCM (2 L)
  4. washwashed sequentially with water (1 L) and saturated brine (500 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. customto afford crude product
  9. customThe crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane
  10. additionFractions containing the desired product
  11. customwere evaporated to dryness
  12. customthen triturated with EtOAc (150 mL)
  13. washThe resulting solid was washed with further EtOAc (50 mL) and ether
  14. customthen dried

Sources & evidence

ORD record
ord-dc7814b8aa7c48f3a53b4c61e8122112
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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