反应详情

A mixture of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.126 g, 0.380 mmol), potassium fluoride (0.067 g, 1.15 mmol) and 18-crown-6 (0.050 g, 0.19 mmol) in benzene (10 mL) was heated at reflux overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with 20-30% ethyl acetate in hexanes, to obtain the cis isomer (0.022 g), trans isomer (0.030 g), and a mixture of cis/trans 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone (0.040 g), as oils. The separated isomers were de-protected and converted into their trifluoroacetate salts by reaction with trifluoroacetic acid in dichloromethane (5 mL) (ambient temperature, 1 h). The solvent was evaporated, and the products were dried by vacuum to obtain 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone trifluoroacetate as cis and trans isomers (0.025 g and 0.032 g, respectively) (1H NMR of trans isomer (CD3OD, 300 MHz): δ 5.08 (s, 1H), 4.93 (s, 1H), 3.37-3.29 (m, 2H), 3.24-3.16 (m, 3H), 3.00-2.95 9m, 2H), 2.34-2.22 (m, 2H), 1.69-1.58 (m, 2H); MS (m/z): 172 (M+1); 1H-NMR of cis isomer (CD3OD, 300 MHz): δ 5.13 (s, 1H), 4.98 (s, 1H), 3.60-3.52 (m, 2H), 3.78-3.67 (m, 2H), 3.12-2.96 (m, 3H), 2.38-2.15 (m, 2H), 1.91-1.64 (m, 2H); MS (m/z): 172 (M+1)). The cis isomer exhibited Ki values at rat and human α4β2 of 6.8 nM and 6.3 nM respectively and did not pass HTS for α7. The trans isomer exhibited a Ki value at rat and human α4β2 of 154 nM and 176 nM respectively and exhibited a Ki value at α7 of >10.000 nM.

1. temperaturewas heated
2. temperatureat reflux overnight
3. filtrationThe mixture was filtered
4. concentrationthe filtrate was concentrated
5. custompurified by silica gel column chromatography
6. washeluting with 20-30% ethyl acetate in hexanes
7. customto obtain the cis isomer (0.022 g)
8. customThe solvent was evaporated
9. customthe products were dried by vacuum