25% |
In acetonitrile; at 80.0℃; under 14441.0 Torr; for 10.0h;Inert atmosphere; Microwave irradiation; |
General procedure: The reaction was conducted under Argon atmosphere. To a solution of <strong>[131986-45-3]Xanomeline</strong> 3 (1 equiv) in dry CH3CN (0.1M) a solution of functionalized tacrine bromide (9) (1 equiv) in dry CH3CN (0.1M) was added. The mixture was reacted for 10h at 80C in a microwave apparatus (pressure: 19atm, power of 500W). The crude reaction mixtures were submitted to silica gel column chromatography (eluent: DCM/MeOH 99:1?9:1), providing the pure target derivatives 8-C8, 8-C10 and 8-C12. 4.7.1 5-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-1-methyl-1-(8-((1,2,3,4-tetrahydroacridin-9-yl)amino)octyl)-1,2,3,6-tetrahydropyridin-1-ium bromide (8-C8) The title compound was prepared by reacting 3 (150mg, 0.533mmol) and 9a (228mg, 0.586mmol) in CH3CN (10mL). After standard workup, 8-C8 was obtained as a beige solid (90mg, 25%): Rf=0.36 (DCM/MeOH 9:1). mp=96-98C. 1H NMR (400MHz, CD3OD): delta 8.43 (d, J=8.7Hz, 1H; H9), 7.87 (ddd, J=8.5, 7.0, 1.1Hz, 1H; H6), 7.81 (dd, J=8.5, 1.2Hz, 1H; H7), 7.61 (ddd, J=8.4, 6.8, 1.4Hz, 1H; H8), 7.32 (dd, J=4.8, 3.3Hz, 1H; H4?), 4.56-4.48 (m, 4H; CH2-O, 2×H2?), 3.99 (d, J=7.3Hz, 2H; HN-CH2), 3.72-3.62 (m, 2H; CH2-N+), 3.52 (t, J=8.3Hz, 2H; H6?), 3.21 (s, 3H; CH3-N+), 3.05 (t, J=5.6Hz, 2H; H4), 2.83 (s, 2H; H1), 2.74 (t, J=5.4Hz, 2H; H5?), 2.05-1.80 (m, 10H; 2×H2, 2×H3, CH2CH2O, CH2CH2N+, NHCH2CH2), 1.56-1.33 (m, 14H; HN-(CH2)2-CH2-CH2-CH2-CH2-(CH2)2-N+, CH3-CH2-CH2-CH2-(CH2)2-O), 0.95 (t, J=7.1Hz, 3H; CH3-(CH2)5-O). 13C NMR (101MHz, CD3OD): delta 163.94, 157.91, 151.69, 145.53, 139.82, 134.03, 127.67, 126.50, 126.29, 124.34, 120.17, 117.07, 112.87, 72.63, 65.60, 60.25, 57.26, 49,14, 48.37, 32.58, 31.53, 30.57, 30.28, 29.86, 29.38, 27.70, 27.42, 26.75, 24.97, 23.59, 23.12, 23.00, 22.60, 21.87, 14.37. MS (ESI) m/z [M+H]+ calcd for C35H53BrN5OS+: 590,39, found: 590.25. HPLC analysis: retention time=8.2min, purity 97.8%. |