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

HRID 2381134Notes

Reaction equation

HRID 2381134 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)ethanolYield 71.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of ethylene carbonate (18.18 g, 206.42 mmol) in DMF (30 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 (obtained as described in Example 4.2, preparation of starting materials) (15 g, 41.28 mmol) and potassium carbonate (11.41 g, 82.57 mmol) in DMF (30 mL) at 80° C. over a period of 10 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 (500 mL), and washed sequentially with water (500 mL) and saturated brine (250 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. Pure fractions were evaporated to dryness to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (12.04 g, 71.6%) as a solid.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationthen concentrated
  3. additiondiluted with DCM (500 mL)
  4. washwashed sequentially with water (500 mL) and saturated brine (250 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. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-9ed5854d24a049e3866e88be66ea9d59
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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