1-[3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one → 4-(3-Fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol

HRID 1675009Notes

Reaction equation

HRID 1675009 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:29])([F:28])[F:10])=[N:13][N:14]=4)[N:17]=3)[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1

Participants

4

Reactant 2

HCID 595783691-[3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-oneHCID 178505773HCID 178505773, compound

Product 1

HCID 591498264-(3-Fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-olYield 18%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

3-Fluorophenylmagnesium bromide (1.0M in THF, 1.68 mL, 1.68 mmol) was added dropwise to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (400 mg, 1.40 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting mixture was stirred at 0° C. for 20 minutes, then quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO4 and evaporated to a pale orange oil which was triturated with DCM to give a beige solid. The solid was filtered, washed with DCM and dried, then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(3-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (96 mg, 18%) as a colourless solid.

Workup

  1. customquenched with saturated ammonium chloride solution (20 mL)
  2. extractionextracted with ethyl acetate
  3. washThe extract was washed with saturated brine
  4. dry with materialdried over MgSO4
  5. customevaporated to a pale orange oil which
  6. customwas triturated with DCM
  7. customto give a beige solid
  8. filtrationThe solid was filtered
  9. washwashed with DCM
  10. customdried
  11. custompurified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length)
  12. additionFractions containing the desired compound
  13. customwere evaporated to dryness

Sources & evidence

ORD record
ord-ec9a99b90bee4b7c9e8ca2242f4963a6
Source dataset
uspto-grants-2011_08
Patent number
US08003649B2

Reaction notes

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