Sodium hydride → ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo [1,5-a][1,4]benzodiazepine-1-carboxylate

HRID 1378162Notes

Reaction equation

HRID 1378162 reaction equation
[Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C-:37]>CN(C)C=O.C(O)(=O)C.CCCCCC>[Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11]3[N:12]([CH:37]=[N:36][C:38]=3[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 75654Diphenyl chlorophosphateHCID 533707Ethyl isocyanoacetate2×HCID 54191878(S)-5-bromo-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione

Product 1

HCID 53712300ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo [1,5-a][1,4]benzodiazepine-1-carboxylateYield 59%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent3×HCID 8058HexaneSolvent

Procedure

30 g (106.7 mmol) of (S)-5-bromo-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 50 ml of N,N-dimethylformamide, treated at -20° with 5.6 g (128 mmol) of sodium hydride dispersion (55% in oil) (washed with hexane) and deprotonized at -30° to -20° for 30 minutes. A solution of 43 g (160 mmol) of diphenyl chlorophosphate in 25 ml of N,N-dimethylformamide was added thereto at -60° and the mixture was stirred at max. -45° for 35 minutes. In the meanwhile and separately, 12 g (107 mmol) of potassium tert.-butylate were dissolved in 20 ml of N,N-dimethylformamide and treated at -60° with 12.1 g (107 mmol) of ethyl isocyanoacetate. The reaction mixture is added dropwise to the deprotonized ethyl isocyanoacetate at max. -65° within 11/4 hours. The mixture was stirred for 1 hour in an acetone/dry-ice bath, neutralized with 10 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.21), dried over magnesium sulfate and evaporated to dryness. By recrystallization of the residue from ethanol and ether there were obtained 23.7 g (49%) of ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]-benzodiazepine-1-carboxylate of m.p. 184°-185°.

Workup

  1. wait-45° for 35 minutes
  2. custom-65°
  3. custom4 hours
  4. stirringThe mixture was stirred for 1 hour in an acetone/dry-ice bath
  5. extractionThe mixture was extracted five times with methylene chloride (a total of 1.21),
  6. dry with materialdried over magnesium sulfate
  7. customevaporated to dryness
  8. customBy recrystallization of the residue from ethanol

Sources & evidence

ORD record
ord-f6ec588888884219954af1701a9076d6
Source dataset
uspto-grants-1997_09
Patent number
US05665718

Reaction notes

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