Bromoacetonitrile → 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041609Notes

Reaction equation

HRID 2041609 reaction equation
[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:32]#[N:33]>CO.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:23][C:32]#[N:33])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:4])([CH3:6])[CH3:5]

Participants

7

Reactant 4

HCID 11534BromoacetonitrileHCID 14797Potassium HydroxideHCID 24758Sodium hydrideHCID 576559793-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 667072373-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 81%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Add potassium hydroxide (5.4 g, 96.2 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 4.7 mmol) in degassed methanol (75 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) and wash with saturated aqueous 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 (1.4 g). Dissolve the oil in anhydrous DMF (25 mL), then slowly add sodium hydride (282 mg, 7.1 mmol) and bromoacetonitrile (470 7.1 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 (40 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 residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 7:3 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.34 g, 81%). MS (ES+) m/z: 253.2 (M-Boc)+.

Workup

  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 saturated aqueous 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 (1.4 g)
  10. dissolutionDissolve the oil in anhydrous DMF (25 mL)
  11. washwash with cold aqueous saturated ammonium chloride (40 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 residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 7:3 gradient)

Sources & evidence

ORD record
ord-2ad38492bbe84c6aa68b66fee595003f
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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