N-[2-(5-bromo-1-indolinyl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide → 4,9-Dibromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine

HRID 4095Notes

Reaction equation

HRID 4095 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=O)[CH2:6][CH2:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[N:18][C:12]1[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=13

Participants

3

Reactant 1

HCID 13823368N-[2-(5-bromo-1-indolinyl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide

Product 1

HCID 138233094,9-Dibromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepineYield 70.3%

Reagents, catalysts & solvents 1

HCID 24813Phosphorus oxychlorideSolvent

Procedure

A solution of N-[2-(5-bromo-1-indolinyl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide (12.3 g, 24.8 mmoles) and phosphorus oxychloride (250 ml) was heated under reflux for 1 hour. The reaction mixture was cooled and then concentrated at 50°-60° C. under vacuum. Ice-chilled sodium hydroxide solution (15%, 500 ml) and dichloromethane (500 ml) was added to the reaction mixture. The mixture was stirred for 20 minutes. The organic phase was separated and the aqueous phase was extracted once with dichloromethane (250 ml). The combined dichloromethane solutions were washed with 1N sodium hydroxide solution (350 ml) and brine (2×350 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The residue was purified on a silica gel column (250 gm), eluted with 2% and then 3% methanol:dichloromethane. The appropriate fractions were combined and concentrated to give 8.3 g (70%) of product. Recrystallization from isopropanol gave the analytical sample, mp 215°-216° C.

Workup

  1. temperatureunder reflux for 1 hour
  2. temperatureThe reaction mixture was cooled
  3. concentrationconcentrated at 50°-60° C. under vacuum
  4. temperatureIce-chilled sodium hydroxide solution (15%, 500 ml) and dichloromethane (500 ml)
  5. additionwas added to the reaction mixture
  6. customThe organic phase was separated
  7. extractionthe aqueous phase was extracted once with dichloromethane (250 ml)
  8. washThe combined dichloromethane solutions were washed with 1N sodium hydroxide solution (350 ml) and brine (2×350 ml)
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. customThe filtrate was evaporated
  12. customThe residue was purified on a silica gel column (250 gm)
  13. washeluted with 2%
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-1577a09d549645cab8527ad89e92fb7a
Source dataset
uspto-grants-1988_02
Patent number
US04723003

Reaction notes

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