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

HRID 1596339Notes

Reaction equation

HRID 1596339 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[NH:13][C:12]1=[O:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34]Br)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34][N:13]1[C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([CH:18]([CH3:19])[CH3:20])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:9])[C:12]1=[O:25])(=[O:28])[CH3:27]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 217012741-[3-(Bromomethyl)thiophen-2-yl]ethan-1-oneHCID 136152314(3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one

Product 1

HCID 21701415(3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-oneYield 52.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

To a suspension of sodium hydride (0.065 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1, 4-benzodiazepin-2-one (0.508 g) in dry N,N-dimethylformamide (5 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature for 2 hours. To the mixture was added dropwise a solution of 2-acetyl-3-bromomethylthiophene (0.420 g) in dry N,N-dimethylformamide under cooling in an ice-bath. After completion of the addition, the mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnight. The resultant mixture was concentrated in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (50 ml) and dried over anhydrous sodium sulfate. Filtration and evaporation gave a crude product. The product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1) to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.380 g).

Workup

  1. temperatureunder cooling in an ice-bath
  2. waitat ambient temperature for 2 hours
  3. temperatureunder cooling in an ice-bath
  4. additionAfter completion of the addition
  5. stirringthe mixture was stirred under the same condition for 30 minutes
  6. customat ambient temperature
  7. customovernight
  8. concentrationThe resultant mixture was concentrated in vacuo
  9. additionThe residue was treated with ethyl acetate (100 ml)
  10. washwashed with water (50 ml)
  11. dry with materialdried over anhydrous sodium sulfate
  12. filtrationFiltration and evaporation
  13. customgave a crude product
  14. customThe product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1)

Sources & evidence

ORD record
ord-29ad3d4183584d67a6cb7e750acaab03
Source dataset
uspto-grants-2001_09
Patent number
US06291452B1

Reaction notes

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