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Sodium hydride → (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

HRID 963479
Notes
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Reaction equation

HRID 963479 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[NH:13][C:12]1=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38][N:13]1[C:14]2[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]1=[O:29])(=[O:32])[CH3:31]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 19081122(3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-oneHCID 217012741-[3-(Bromomethyl)thiophen-2-yl]ethan-1-one

Product 1

HCID 19081290(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-oneYield 57.9%

Reagents, catalysts & solvents 1

HCID 6228
Dimethylformamide
Solvent
3×

Procedure

To a suspension of sodium hydride (0.119 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (8 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5- (2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.005 g) in dry N,N-dimethylformamide (5 ml) under stirring at cooling in an ice-bath. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.5 hours. To the mixture was added a solution of 2-acetyl-3-bromomethylthiophen (0.82 g) in N,N-dimethylformamide (3 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnignt. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer seas washed with water and a brine, and dried over sodium sulfate. Removal of the solvent at reduced pressure gave a crude product. The crude product was purified by column chromatography on silica gel with chloroform as an eluent to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.80 g).

Workup

  1. temperatureat cooling in an ice-bath
  2. stirringThe mixture was stirred at the same temperature for 30 minutes
  3. temperatureunder cooling in an ice-bath
  4. stirringThe mixture was stirred under the same condition for 30 minutes
  5. customat ambient temperature
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. additionThe residue was treated with ethyl acetate and water
  8. washThe organic layer seas washed with water
  9. dry with materiala brine, and dried over sodium sulfate
  10. customRemoval of the solvent at reduced pressure
  11. customgave a crude product
  12. customThe crude product was purified by column chromatography on silica gel with chloroform as an eluent

Sources & evidence

ORD record
ord-dcf21717d8424a5693bd1aff678fe16d
Source dataset
uspto-grants-1998_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05763437

Reaction notes

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