2-(4-((1-(2,5-Difluorophenyl)propan-2-yl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione → 2-(4-(1-(2,5-Difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one

HRID 69393Notes

Reaction equation

HRID 69393 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:40][C:23]2=[CH:24][C:25]3[C:26](=[O:39])[N:27]([CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:28](=O)[C:29]=3[CH:30]=[C:22]2[N:21]=1)[CH3:11]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:21][C:22]2=[CH:30][C:29]3[CH2:28][N:27]([CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:26](=[O:39])[C:25]=3[CH:24]=[C:23]2[N:40]=1)[CH3:11]

Participants

4

Reactant 1

HCID 1363406422-(4-((1-(2,5-Difluorophenyl)propan-2-yl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione

Product 1

HCID 1363406412-(4-(1-(2,5-Difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-oneYield 74.6%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 176Acetic AcidSolvent

Procedure

2-(4-((1-(2,5-Difluorophenyl)propan-2-yl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.40 g, 0.74 mmol) and zinc powder (1.16 g, 17.7 mmol) were suspended in acetic acid-(30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.29 g, 74.6% yield. MS: 527 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.06 (s, 1H), 11.18 (s, 1H), 11.06-11.05 (m, 1H), 7.96 (s, 0.5H), 7.86 (s, 0.5H), 7.81 (s, 0.5H), 7.70 (s, 0.5H), 7.29-7.28 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.12 (m, 1H), 6.89-6.85 (m, 1H), 6.14-6.11 (m, 1H), 4.48 (s, 2H), 4.17-4.13 (m, 1H), 4.03-3.99 (m, 1H), 3.01-2.98 (m, 2H), 2.88-2.85 (m, 2H), 2.35 (d, 3H, J=4.5 Hz), 2.20 (s, 3H), 2.03-1.99 (m, 2H), 1.86-1.83 (m, 3H), 1.70-1.68 (m, 2H), 1.33 (d, 3H, J=6.5 Hz).

Workup

  1. temperatureheated
  2. temperatureto reflux overnight under argon
  3. customThen, the solvent was removed under reduced pressure
  4. stirringThe residue solid was stirred in 100 mL of saturated K2CO3 solution
  5. filtrationThe white solid was filtered out
  6. customdried under vacuum
  7. extractionextracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL)
  8. concentrationThe extracts were concentrated to dryness
  9. customThe residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v)
  10. customto give a white solid product, 0.29 g, 74.6% yield

Sources & evidence

ORD record
ord-3508649d5d684e52af734014a008f7ab
Source dataset
uspto-grants-2014_09
Patent number
US08822500B2

Reaction notes

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