Reaction Steps
To a solution of 30 ml of pentanol that had reacted with 0.5 g of Na (0.022 mol) was added 1.7 g of (7) (0.0071 mol). The reaction was heated to 70° C. for 2 h, the reaction cooled to ambient temperature, and 30 ml of 1 N HCl was added. The excess pentanol was azeotroped off with water and the residue made basic with 5 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% N and then with 10% ethanol-1% NH4OH-CHCl3 to give 1.68 g of 3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol. NMR ppm (CDCl3) 0.97 (3H, t), 1.2 (1H, m), 1.45 (6H, m), 1.87 (2H, m), 2.3 (1H, m), 2.4 (1H, t), 2.8 (1H, m), 2.93 (3H, m), 3.1 (1H, m), 3.98 (1H, s), 4.28 (1H, d), 4.42 (2H, m), 8.01 (1H, d), 8.11 (1H, d). A solution of 1.48 g of this alcohol (0.0051 mol) in 50 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred 1.5 h and then heated to reflux for 45 min. After cooling to ambient temperature, ice-water was added to the reaction and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol- 0.5% N4OH-CHCl3 to give 1.27 g of 3-chloro-3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octane. NMR ppm (CDCl3) 0.99 (3H, t), 1.35-1.8 (7H, m), 1.9 (2H, m) 2.37 (1H, m), 2.6-2.82 (2H, m), 3.0 (1H, t), 3.15 (2H, m), 3.6-4.1 (2H, m), 4.42 (2H, t), 8.06 (2H, m). A mixture of 1.05 g of this chloride (0.0034 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated 1 h at 60 psi of H2. The catalyst was filtered off, 25 ml of isopropanolic HCl was added, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.28 g of (25), mp 166°-167° C. NMR ppm (CDCl3) 0.95 (3H, t), 1.41 (4H, m), 1.57-1.9 (5H, m), 2.13 (2H, m), 2.45 (1H, m), 3.12 (1H, m), 3.3-4.46 (3H, m), 3.55 (1H, m), 3.7 (1H, m), 4.3 (1H, q), 4.37 (2H, t), 8.03 (1H, d), 8.1 (1H, d). Anal. C16H25N3O-HCl requires C: 61.62; H: 8.40; N: 13.47%. Found C: 61.39; H: 8.07; N: 13.48%.
