反应详情

温度

55 °C

To a solution of 188 mg (0.45 mmol) 4-(cyclohexylammonio)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride (5-2) and 136 mg (0.473 mmol) tert-butyl 5-(bromomethyl)pyridin-2-ylcarbamate (prepared in a manner similar to that described in PCT application WO 00/0665570, substituting Methanesulfonicanhydredl/lutidine/LiBr/THF 0-55° C. in the bromination step) in 2.5 mL DMF was added 399 mg (2.89 mmol) granular potassium carbonate and the mixture stirred vigorously at 55° C. overnight. The reaction mixture was treated with 30 mL H2O and extracted with EtOAc (3×25 mL). The combined extracts were washed with H2O (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered, and concentrated to dryness in vacuo to give a crude oily solid (390 mg). Purification by automated flash chromatography (0-6% MeOH in CH2Cl2 over 20 m) afforded tert-butyl 5-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}pyridin-2-ylcarbamate as a white solid. 1H NMR (DMSO, 400 MHz): δ 9.67 (s, 1H), 8.09 (d, J=7.78 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J=8.42 Hz 1H), 7.46 (dd, J=8.52, 2.10 Hz 1H), 7.36 (m, 1H), 7.14 (m, 2H), 7.07 (d, J=8.15 Hz 1H), 3.68 (m, 1H), 3.22 (s, 2H), 2.53 (m, 2H), 2.09 (m, 2H), 1.82 (m, 4H), 1.73 (m, 1H), 1.61 (m, 1H), 1.47 (s, 9H), 1.29 (m, 5H), 1.12 (m, 1H). High resolution mass spec (FT/ICR): calc M+H=551.3141. found 551.3157

1. extractionextracted with EtOAc (3×25 mL)
2. washThe combined extracts were washed with H2O (1×20 mL), brine (1×20 mL)
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated to dryness in vacuo
6. customto give a crude oily solid (390 mg)
7. customPurification by automated flash chromatography (0-6% MeOH in CH2Cl2 over 20 m)