反应详情

温度

80 °C

Add potassium hydroxide (10.8 g, 192 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3 g, 7.8 mmol) in degassed methanol (150 mL) under a nitrogen atmosphere. Heat the mixture at 80° C. for 6 h. Cool the mixture to ambient temperature, then concentrate in vacuo to an oil. Dissolve the oil in EtOAc (50 mL), wash with aqueous saturated ammonium chloride (30 mL). Separate the organic layer and extract the aqueous layer with EtOAc (3×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to an oil (2.4 g). Dissolve the oil in anhydrous DMF (50 mL). Slowly add sodium hydride (470 mg, 11.7 mmol) portionwise over 5 min followed by 2-bromopropionitrile (1 mL, 11.7 mmol). Stir the mixture under nitrogen at ambient temperature for 16 h. Dilute the mixture slowly with EtOAc (100 mL) and wash with cold aqueous saturated ammonium chloride (50 mL). Separate the organic layer and extract the aqueous-layer with EtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient) to obtain the desired intermediate (2.5 g, 89%). MS (ES+) m/z: 267.2 (M-Boc)+.

1. temperatureCool the mixture to ambient temperature
2. concentrationconcentrate in vacuo to an oil
3. dissolutionDissolve the oil in EtOAc (50 mL)
4. washwash with aqueous saturated ammonium chloride (30 mL)
5. customSeparate the organic layer
6. extractionextract the aqueous layer with EtOAc (3×50 mL)
7. dry with materialDry the combined organic extracts over Na2SO4
8. filtrationfilter
9. concentrationconcentrate in vacuo to an oil (2.4 g)
10. dissolutionDissolve the oil in anhydrous DMF (50 mL)
11. washwash with cold aqueous saturated ammonium chloride (50 mL)
12. customSeparate the organic layer
13. extractionextract the aqueous-layer with EtOAc (3×50 mL)
14. concentrationCombine the organic extracts and concentrate in vacuo
15. customPurify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient)