Sodium hydride → N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea

HRID 1596368Notes

Reaction equation

HRID 1596368 reaction equation
[H-].[Na+].[CH:3]([C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1)([CH3:5])[CH3:4].Br[CH2:30][C:31]([N:33]1[CH2:39][CH:38]2[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]2)[CH2:34]1)=[O:32]>CN(C)C=O>[CH:38]12[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]1)[CH2:34][N:33]([C:31]([CH2:30][N:10]1[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:8]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:20])[C:9]1=[O:17])=[O:32])[CH2:39]2

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 21701395N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonaneHCID 136035713N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea

Product 1

HCID 53838314N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)ureaYield 43.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a suspension of sodium hydride (0.030 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added gradually N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.250 g) at 5˜10° C. in an ice-bath for 30 minutes. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. To the above mixture was added dropwise a solution of N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.200 g) in dry N,N-dimethylformamide (5 ml) for 10 minutes and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was separated, washed with a brine (50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a crude product. The product was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (10:1) as an eluent. The fractions containing the desired compound were combined and evaporated in vacuo to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.160 g).

Workup

  1. waitat room temperature for 2 hours
  2. stirringstirred at ambient temperature overnight
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. customThe organic layer was separated
  5. washwashed with a brine (50 ml)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customevaporated in vacuo
  8. customto give a crude product
  9. customThe product was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (10:1) as an eluent
  10. additionThe fractions containing the desired compound
  11. customevaporated in vacuo

Sources & evidence

ORD record
ord-5096c69da9bb44f6a666d6664ec13ec0
Source dataset
uspto-grants-2001_09
Patent number
US06291452B1

Reaction notes

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