Carbon Dioxide → ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate

HRID 1377987Notes

Reaction equation

HRID 1377987 reaction equation
[Cl: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][C:3]=1[F:17].[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[N+:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])#[C-:39].C(=O)=O>CN(C)C=O.C(O)(=O)C.CCCCCC>[Cl: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:39]=[N:38][C:40]=3[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:17]

Participants

9

Reactant 5

HCID 280Carbon DioxideHCID 24758Sodium hydrideHCID 533707Ethyl isocyanoacetate2×HCID 20976795Phosphoric acid diphenyl ester chlorideHCID 53739015(S)-5-chloro-6-fluoro-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione

Product 1

HCID 54090463ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylateYield 41.2%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent3×HCID 8058HexaneSolvent

Procedure

25.4 g (100 mmol) of (S)-5-chloro-6-fluoro-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 125 ml of N,N-dimethylformamide, treated at -30° with 4.8 g (110 mmol) of sodium hydride dispersion (55-65% in oil, washed with n-hexane) and deprotonated for 40 min. at -30° to -18°. A solution of 26.86 g (100 mmol) of phosphoric acid diphenyl ester chloride in 5 ml of N,N-dimethylformamide was added at -60° and the mixture was stirred at max. -45° for 35 min. In the meanwhile and separately, 12.3 g (110 mmol) of potassium tert.-butylate were dissolved in 30 ml of N,N-dimethylformamide and treated at -60° C. with 12.2 g (107 mmol) of ethyl isocyanoacetate. The deprotonated ethyl isocyanoacetate was cooled to -70° and the reaction mixture was added dropwise using a dropping funnel cooled with dry ice at max. -65° within 5/4 hours. The mixture was stirred in an acetone/dry ice bath for 1 hour, neutralized with 12 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.2 l), dried over magnesium sulfate and evaporated to dryness. By chromatography of the residue on 1.5 kg of silica gel while eluting with ethyl acetate there were obtained 14.4 g (41%) of ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate of m.p. 161°-163°.

Workup

  1. wait-45° for 35 min
  2. additionthe reaction mixture was added dropwise
  3. custom-65°
  4. custom4 hours
  5. stirringThe mixture was stirred in an acetone/dry ice bath for 1 hour
  6. extractionThe mixture was extracted five times with methylene chloride (a total of 1.2 l),
  7. dry with materialdried over magnesium sulfate
  8. customevaporated to dryness
  9. washBy chromatography of the residue on 1.5 kg of silica gel while eluting with ethyl acetate

Sources & evidence

ORD record
ord-80c2d750b904416296e1f6926e12459c
Source dataset
uspto-grants-1997_09
Patent number
US05665718

Reaction notes

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