反应详情

Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combined extracts with brine (50 mL), dry over MgSO4, filter and concentrate in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum oven to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (481 mg) that was used without further purification. MS (ES+) m/z: 537 (M+Na)÷.

1. temperatureHeat
2. temperatureunder reflux for 2 h
3. temperaturecontinue heating
4. temperatureunder reflux for another 6 h
5. temperatureCool the reaction mixture
6. temperaturethen heat at 50° C. for 5 h
7. temperatureunder reflux for 5 h
8. concentrationConcentrate in vacuo
9. custompartition the residue between water (100 mL) and EtOAc (50 mL)
10. extractionExtract the aqueous phase with EtOAc (2×50 mL)
11. washWash the combined extracts with brine (50 mL)
12. dry with materialdry over MgSO4
13. filtrationfilter
14. concentrationconcentrate in vacuo
15. customto obtain the crude mixture as a yellow oil
16. concentrationthen re-concentrate in vacuo and repeat until a solid remains
17. customDry the solid in a vacuum oven