Sodium hydride → (S)-1-(m-chlorophenyl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one

HRID 2290243Notes

Reaction equation

HRID 2290243 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[C@@H:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1.[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[CH2:42][N+:43]#[C-:44]>CN(C)C=O.O.C(O)(=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([C:42]2[N:43]=[CH:44][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=4[C:7](=[O:16])[N:8]4[CH2:15][CH2:14][CH2:13][C@H:9]4[C:10]=23)[CH:45]=[CH:46][CH:47]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 27574083-ChlorobenzylisocyanideHCID 20976795Phosphoric acid diphenyl ester chlorideHCID 54064345(S)-7-fluoro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione

Product 1

HCID 54000153(S)-1-(m-chlorophenyl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent4×

Procedure

A suspension of 8.20 g (35 mmol) of (S)-7-fluoro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione in 40 ml of dry N,N-dimethylformamide is treated at -30° to -20° with 1.53 g (35 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at the above temperature for a further 35 minutes, and then at -60° there are added dropwise 7.25 ml (35 mmol) of phosphoric acid diphenyl ester chloride in 7 ml of dry N,N-dimethylformamide. The temperature is allowed to rise to -35°, the mixture is then again cooled to -70° and there is added a solution of 5.03 g (35 mmol) of 3-chlorobenzyl isocyanide in 5 ml of dry N,N-dimethylformamide, and subsequently there is added a solution of 3.92 g (35 mmol) of potassium t-butylate in 7 ml of dry N,N-dimethylformamide. After completion of the addition, the mixture is left to warm to 20°, neutralized by the addition of 1.5 ml of glacial acetic acid and poured into 250 ml of water. The mixture is extracted five times with methylene chloride, the combined organic extracts are washed three times with water, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and recrystallized from ethyl acetate and n-hexane. There is obtained (S)-1-(m-chlorophenyl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one having a melting point of 182°-183°.

Workup

  1. customto rise to -35°
  2. temperaturethe mixture is then again cooled to -70°
  3. additionAfter completion of the addition
  4. waitthe mixture is left
  5. temperatureto warm to 20°
  6. extractionThe mixture is extracted five times with methylene chloride
  7. washthe combined organic extracts are washed three times with water
  8. dry with materialdried over magnesium sulfate
  9. customevaporated
  10. customThe residue is chromatographed on silica gel
  11. washwhile eluting with ethyl acetate
  12. customrecrystallized from ethyl acetate and n-hexane

Sources & evidence

ORD record
ord-c8227d49b42b49e383502e55adb28b82
Source dataset
uspto-grants-1986_10
Patent number
US04616010

Reaction notes

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