反应详情

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.737 g, 2.263 mmol) and 7-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography using 5-15% [9:1 methanol:ammonium hydroxide] in ethyl acetate. The desired fractions were concentrated and further purified using 5-15% [9.5:0.5 methanol:ammonium hydroxide] in ethyl acetate to afford ((R)—N-(7-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.061 g, 0.156 mmol, 17% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s), 8.12 (1H, s), 7.66 (2H, s), 7.32 (1H, s), 4.01 (1H, d), 3.73 (1H, d), 3.35-3.42 (1H, m), 3.22-3.29 (1H, m), 2.84-3.17 (4H, m), 2.13-2.35 (2H, m), 1.62-1.96 (3H, m). LCMS:R.T.=1.76; [M+]+=387.21.

1. stirringthe mixture was stirred at room temperature for 18 hours
2. concentrationThe mixture was concentrated
3. custompurified by silica gel chromatography
4. concentrationThe desired fractions were concentrated
5. customfurther purified