Sodium hydride → N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide

HRID 914681Notes

Reaction equation

HRID 914681 reaction equation
[C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:35]([CH3:37])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C=O)C.[Cl-].[Na+].O>[CH:35]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:37])[CH3:36]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 103560791-Phenyl-4h-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5(6h)-oneHCID 152160012-bromo-N-isopropyl-N-phenyl-acetamide

Product 1

HCID 58957944N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamideYield 72.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (2.5 g, 9.05 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol). The reaction was warmed to room temperature and was stirred for 40 minutes. The reaction was cooled to −6° C. and a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A)) (2.55 g, 9.95 mmol) in DMF (20 mL) was added to the reaction mixture dropwise over 0.5 hour, maintaining the internal reaction temperature below −3° C. The reaction mixture was stirred for 105 minutes below −3° C. and brine (200 mL) was added. The aqueous solution was washed with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to ⅓ volume. Hexanes were slowly added until a solid crashed out. The white solid was collected by filtration and was rinsed with ether and hexanes to give 2.96 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide. MS 452 (M+1). This intermediate was carried forward according to Example 3(B), Steps A and B above to afford 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture.

Workup

  1. temperatureThe reaction was cooled to −6° C.
  2. temperaturemaintaining the internal reaction temperature below −3° C
  3. stirringThe reaction mixture was stirred for 105 minutes below −3° C.
  4. washThe aqueous solution was washed with ethyl acetate (200 mL)
  5. washThe organic layer was washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. additionHexanes were slowly added until a solid
  9. filtrationThe white solid was collected by filtration
  10. washwas rinsed with ether and hexanes

Sources & evidence

ORD record
ord-fd06d01af70547028e2914a0ffee4b2f
Source dataset
uspto-grants-2007_09
Patent number
US07265104B2

Reaction notes

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