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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 2041588
Notes
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Reaction equation

HRID 2041588 reaction equation
[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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

12

Reactant 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-one
HCID 66706665
(R)-1-[4-(1-bromoethyl)-phenyl]-3,3-dimethylbutan-1-one

Product 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]azepineYield 47%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Procedure

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%).

Workup

  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)

Sources & evidence

ORD record
ord-721ec46579ee40e4bc99fb36ec778d59
Source dataset
uspto-grants-2013_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08580780B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes