Diphosgene → 8-Fluoro-4-methyl-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 4-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzylamide

HRID 558977Notes

Reaction equation

HRID 558977 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:13])[N:7]2[CH3:12].ClC([O:17][C:18](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([N:41]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[CH2:45][N:44]3[CH:52]=[CH:53][CH:54]=[C:43]3[CH2:42]2)=[O:40])=[CH:35][C:34]=1[CH3:55]>C1(C)C=CC=CC=1.C1COCC1>[CH:54]1[CH:53]=[CH:52][N:44]2[CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N:41]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:18]([N:4]4[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[F:1])[N:7]([CH3:12])[C:6](=[O:13])[CH2:5]4)=[O:17])=[C:34]([CH3:55])[CH:35]=3)=[O:40])[CH2:42][C:43]=12

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 81531Diisopropylethylamine2×HCID 231111055-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-oneHCID 25178381(4-aminomethyl-3-methylphenyl)-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)methanone

Product 1

HCID 115556308-Fluoro-4-methyl-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 4-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzylamide

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-fluoro-1-methyl-3,4-dihydro-1H-quinoxalin-2-one from Example 18A (72 mg, 0.40 mmol) in toluene (4.0 ml) were added trichloromethyl chloroformate (48 μl, 0.40 mmol), diisopropylethylamine (72 μl, 0.40 mmol) and a spatula full of activated carbon. The mixture was heated at reflux for 2 h. The mixture was cooled to room temperature, filtered through Celite® and evaporated. The residue was taken up in THF (3.0 ml) and added to a solution of (4-aminomethyl-3-methyl-phenyl)-(5H,11H-benzo[e]pyrrolo[ 1,2-a][1,4]diazepin-10-yl)methanone from Example G (119 mg, 0.36 mmol) in THF (5.0 ml) and diisopropylethylamine (72 μl, 0.40 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 1.5 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 85:15) to give a pale yellow solid; yield 112 mg, 58%.

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 2 h
  3. filtrationfiltered through Celite®
  4. customevaporated
  5. temperaturewhile cooling in an ice/water bath
  6. temperatureto warm to room temperature
  7. customevaporated in vacuo
  8. customThe residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 85:15)
  9. customto give a pale yellow solid

Sources & evidence

ORD record
ord-dbea09db78654a98920535f0b7cdd047
Source dataset
uspto-grants-2011_11
Patent number
US08063038B2

Reaction notes

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