Water → 3-[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-azabicyclo[2.2.2]octane

HRID 2168636Notes

Reaction equation

HRID 2168636 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+].[CH2:12]([C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH3:15].O>C1COCC1.C(OCC)(=O)C>[CH2:12]([C:16]1[N:17]=[N:18][C:19]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[CH:20][C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:13][CH2:14][CH3:15]

Participants

7

Reactant 4

HCID 962WaterHCID 15381(+-)-3-QuinuclidinolHCID 24758Sodium hydrideHCID 866577793-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine

Product 1

HCID 584383533-[6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-azabicyclo[2.2.2]octane

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 1-aza-bicyclo[2.2.2]octan-3-ol (0.44 mmol, 0.055 g) in THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.58 mmol, 0.023 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.29 mmol, 0.1 g) in THF (1 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 1 h. LCMS showed the reaction was about 50% complete, so the temperature was raised to 68° C. and the reaction was stirred over night. The reaction was poured into a mixture of water (3 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge using 4-6% (2N NH3 in MeOH) in DCM to provide 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-azabicyclo[2.2.2]octane. The amine was treated with 2N HCl in diethyl ether (2 mL) and DCM (2 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 437 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.92 (1H, s), 7.51-7.49 (2H, m), 7.10-7.17 (2H, m), 5.49-5.56 (1H, m), 4.41-4.50 (1H, m), 3.99-3.93 (1H, m), 3.61 (1H, d), 3.35-3.51 (4H, m), 3.14-3.21 (2H, m), 2.64-2.71 (1H, m), 2.41-2.34 (1H, m), 1.94-2.25 (5H, m), 1.77-1.87 (2H, m), 1.25-1.65 (10H, m), 0.82 (3H, t).

Workup

  1. additionAfter completion of addition
  2. temperaturethe reaction mixture was warmed to 50° C. for 1 h
  3. temperatureso the temperature was raised to 68° C.
  4. stirringthe reaction was stirred over night
  5. stirringThe mixture was shaken
  6. customseparated
  7. washThe ethyl acetate layer was washed with brine (2 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified on a 4 g SiO2 cartridge

Sources & evidence

ORD record
ord-411765b3100342c6b8cc7b3f7e2ced0c
Source dataset
uspto-grants-2015_06
Patent number
US09045461B2

Reaction notes

Loading…