反应详情

Heat the mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 0.807 mmol) and potassium hydroxide (1.45 g, 25.83 mmol) in methanol (5 mL) at 50° C. for 3 h. Cool the reaction mixture to room temperature and dilute with saturated aqueous NH4Cl and EtOAc. Separate the layers and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous DMF (2 mL) and cool at 0° C. Add sodium hydride (21 mg, 0.888 mmol) and a solution of (R)-1-[4-(1-bromoethyl)-phenyl]-3,3-dimethylbutan-1-one {prepared by the mixture of (S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one (213 mg, 0.969 mmol), triphenylphosphine (296 mg, 1.130 mmol) and NBS (201 mg, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. and then room temperature}. Stir the mixture at 0° C. for 30 min and quench with water. Dilute with EtOAc and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (85:15) to give (S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine as yellow oil (197 mg, 47%).

1. temperatureHeat
2. customSeparate the layers
3. extractionextract the aqueous layer three times with EtOAc
4. dry with materialDry the combined organic extracts over Na2SO4
5. filtrationfilter
6. concentrationconcentrate in vacuo
7. dissolutionDissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous DMF (2 mL)
8. temperaturecool at 0° C
9. customroom temperature}
10. customquench with water
11. additionDilute with EtOAc
12. extractionextract the aqueous layer three times with EtOAc
13. dry with materialDry the combined organic extracts over Na2SO4
14. filtrationfilter
15. concentrationconcentrate in vacuo
16. customPurify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (85:15)