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

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence