Methanol → 3-tert-Butoxycarbonyl-7-chloro-6-(1-cyano-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 911749

반응식

HRID 911749 반응식
[OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][C:23](=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].BrC(C)[C:32]#[N:33].[CH3:35]O>CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH:23]([C:32]#[N:33])[CH3:35])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]

참가 물질

7

반응물 5

HCID 887MethanolHCID 14797Potassium HydroxideHCID 24758Sodium hydrideHCID 1405382-BromopropionitrileHCID 576559793-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

생성물 1

HCID 667072883-tert-Butoxycarbonyl-7-chloro-6-(1-cyano-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine수율 89%

시약·촉매·용매 1

HCID 8857Ethyl Acetate용매

반응 조건

온도
80 °C

실험 절차

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)+.

후처리

  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)

출처 및 근거

ORD 기록
ord-eff8b36f4f564fa5be74ab1532ce8f1b
출처 데이터셋
uspto-grants-2011_09
특허 번호
US08022062B2

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