Sodium hydride → (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-one

HRID 963455Notes

Reaction equation

HRID 963455 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.Br[CH2:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[O:41][C:40](=[O:45])[CH:39]=[CH:38]2.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[O:41][C:40](=[O:45])[CH:39]=[CH:38][C:37]=3[CH:36]=2)[C:13](=[O:21])[CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[N:11]=1

Participants

9

Reactant 4

HCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 105141316-Bromomethyl-chromen-2-oneHCID 19081136(3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one

Product 1

HCID 19081262(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-oneYield 93.1%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of sodium hydride (0.11 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (20 ml) was added gradually (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. The mixture was cooled in an ice-bath and a solution of 6-bromomethyl coumarin (0.66 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto. The mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture was added acetic acid (0.5 g) under cooling in an ice-bath. The resultant mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) under stirring. The mixture was adjusted to pH 7.5 with sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with a brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel (eluent : CHCL3) to afford (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-one as a colorless crystalline solid (1.30 g).

Workup

  1. temperatureat cooling in an ice-bath
  2. temperatureThe mixture was cooled in an ice-bath
  3. stirringThe mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight
  4. temperatureunder cooling in an ice-bath
  5. stirringunder stirring
  6. customThe organic layer was separated
  7. extractionThe aqueous layer was extracted with ethyl acetate (50 ml)
  8. washThe combined organic layer was washed with a brine (30 ml)
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto afford a crude product
  13. customThe crude product was purified by column chromatography on silica gel (eluent : CHCL3)

Sources & evidence

ORD record
ord-ab2329a58a6e443498f2a06e4b816a3a
Source dataset
uspto-grants-1998_06
Patent number
US05763437

Reaction notes

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