Diphosgene → {4-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzylcarbamoyl]-5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}acetic acid methyl ester

HRID 558975Notes

Reaction equation

HRID 558975 reaction equation
[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7][C:6]1=[O:16].ClC([O:21][C:22](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]2[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[CH2:49][N:48]3[CH:56]=[CH:57][CH:58]=[C:47]3[CH2:46]2)=[O:44])=[CH:39][C:38]=1[CH3:59]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]([C:22](=[O:21])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([N:45]3[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=4[CH2:49][N:48]4[CH:56]=[CH:57][CH:58]=[C:47]4[CH2:46]3)=[O:44])=[CH:39][C:38]=2[CH3:59])[CH2:7][C:6]1=[O:16]

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 81531Diisopropylethylamine2×HCID 25178381(4-aminomethyl-3-methylphenyl)-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)methanoneHCID 57470783(5-Fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetic acid methyl ester

Product 1

HCID 11599657{4-[4-(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzylcarbamoyl]-5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}acetic acid methyl ester

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetic acid methyl ester from Example 17A (72 mg, 0.30 mmol) in toluene (5.0 ml) were added trichloromethyl chloroformate (36 μl, 0.30 mmol), diisopropylethylamine (54 μl, 0.30 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 (4.0 ml) and added to a solution of (4-aminomethyl-3-methylphenyl)-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)methanone from Example G (9 9mg, 0.30 mmol) in THF (4.0 ml) and diisopropylethylamine (54 μl, 0.30 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 18 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 75:25) to give a white solid; yield 61 mg, 34%.

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 75:25)
  9. customto give a white solid

Sources & evidence

ORD record
ord-37f35e53ce9f422ebdecbf019d091cdf
Source dataset
uspto-grants-2011_11
Patent number
US08063038B2

Reaction notes

Loading…