Triphenylphosphine → (S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041588노트

반응식

HRID 2041588 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[H-].[Na+].Br[C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=1)[CH3:32].O[C@H](C1C=CC(C(=O)CC(C)(C)C)=CC=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N(Br)C(=O)C1>CO.[NH4+].[Cl-].CCOC(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C@H:31]([C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=3)[CH3:32])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

참가 물질

12

반응물 7

HCID 11776TriphenylphosphineHCID 14797Potassium HydroxideHCID 24758Sodium hydrideHCID 67184N-bromobutanimideHCID 576559793-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 57656522(S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-oneHCID 66706665(R)-1-[4-(1-bromoethyl)-phenyl]-3,3-dimethylbutan-1-one

생성물 1

HCID 66707511(S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine수율 47%

시약·촉매·용매 4

HCID 887Methanol용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매HCID 25517Ammonium Chloride용매

실험 절차

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%).

후처리

  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)

출처 및 근거

ORD 기록
ord-721ec46579ee40e4bc99fb36ec778d59
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08580780B2

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