(+-)-3-Quinuclidinol → (Rac.)-3-[6-(4-fluorophenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane

HRID 1471456Notes

Reaction equation

HRID 1471456 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[N:14][C:13]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1

Participants

5

Reactant 3

HCID 15381(+-)-3-QuinuclidinolHCID 24758Sodium hydrideHCID 64224443-chloro-6-(4-fluorophenyl)pyridazine

Product 1

HCID 9817766(Rac.)-3-[6-(4-fluorophenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of (rac.)-3-quinuclidinol (0.007 mole) in dry THF under nitrogen is treated with sodium hydride (60% in mineral oil; 1.1 equiv.). After 1 hr at room temperature, a solution of 3-chloro-6-(4-fluoro-phenyl)pyridazine (1.0 equiv.) in THF (30 ml) is added, and the reaction mixture heated to reflux for 6 hrs. After cooling to rt, the THF is evaporated and the residue dissolved in ethyl acetate (100 ml) and then washed with water (3×20 ml), followed by sodium chloride solution (20 ml). The ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: ethyl acetate-methanol-triethylamine (50:10:2) to afford (rac.)-3-[6-(4-fluorophenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane as a colourless solid. 1H-NMR (400 MHz, CDCl3): δ=8.00 (m, 2H), 7.75 (d, 1H), 7.17 (m, 2H), 7.1 (d, 1H), 5.35 (m, 1H), 3.5 (m, 1H), 2.99-2.83 (m, 5H), 2.32 (m, 1H), 1.98 (m, 1H), 1.76-1.68 (m, 2H), 1.46 (m, 1H).

Workup

  1. temperaturethe reaction mixture heated
  2. temperatureto reflux for 6 hrs
  3. customthe THF is evaporated
  4. dissolutionthe residue dissolved in ethyl acetate (100 ml)
  5. washwashed with water (3×20 ml)
  6. dry with materialThe ethyl acetate is dried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. customevaporated to dryness
  9. customthe residual oil purified by silica gel column chromatography (eluent

Sources & evidence

ORD record
ord-ec57df046bf74d28beb8ee711030c415
Source dataset
uspto-grants-2015_04
Patent number
US09012451B2

Reaction notes

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