Water → HCID 56925083, compound

HRID 661982Notes

Reaction equation

HRID 661982 reaction equation
[NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[C:25]5=[O:33])[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].[H-].[Na+].O>C1COCC1.C(Cl)Cl>[CH3:34][C:19]1[C:20]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:33])=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1

Participants

7

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 702254-Bromobutyryl chlorideHCID 66606434HCID 66606434, compound

Product 1

HCID 56925083HCID 56925083, compoundYield 72.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 7-amino-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 54-14, 60 mg, 0.134 mmol) in THF (3 mL) was treated with TEA (0.019 mL, 0.134 mmol) and a solution of 4-bromobutanoyl chloride (24.92 mg, 0.134 mmol) in DCM (1 mL). The mixture was stirred at rt for 40 min, then was diluted with DCM, washed with water, dried and concentrated. The residue was dissolved in THF (5 mL) and added to a suspension of sodium hydride (60% oil dispersion, 40 mg, 1.000 mmol, pre-washed with hexane) in THF (5 mL). The mixture was stirred at rt overnight, then was heated at 65° C. for 30 min. The mixture was cooled to rt, poured into water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 99:0.9:0.1 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide (50 mg, 66%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 10.67 (1H, s), 7.96 (1H, d, J=7.47 Hz), 7.91 (1H, s), 7.74 (1H, d, J=7.91 Hz), 7.62-7.67 (1H, m), 7.52-7.58 (2H, m), 7.45-7.48 (2H, m), 7.38-7.42 (1H, m), 7.22 (1H, dd, J=8.79, 1.76 Hz), 7.11 (2H, d, J=7.91 Hz), 4.86 (2H, s), 3.90-4.02 (2H, m), 2.66 (2H, t, J=8.13 Hz), 2.16-2.25 (2H, m), 1.94 (3H, s). Mass spectrum m/z 515.3 (M+H)+.

Workup

  1. washwashed with water
  2. customdried
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in THF (5 mL)
  5. stirringThe mixture was stirred at rt overnight
  6. temperaturewas heated at 65° C. for 30 min
  7. temperatureThe mixture was cooled to rt
  8. extractionextracted with EtOAc
  9. customThe organic phase was dried
  10. concentrationconcentrated
  11. customthe residue was purified by column chromatography (
  12. washeluting with a gradient from 99:0.9:0.1 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide)

Sources & evidence

ORD record
ord-b5ac843e6de0423fa44a578ad827d6f4
Source dataset
uspto-grants-2011_12
Patent number
US08084620B2

Reaction notes

Loading…