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 69343Notes

Reaction equation

HRID 69343 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 13.8%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 176Acetic AcidSolvent

Procedure

To a solution of 2-(4-(1-(2,5-difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.30 g, 0.53 mmol) in 50 mL of acetic acid was added zinc powder (0.64 g, 9.78 mmol). The mixture was heated to reflux for 16 h and filtered through Celite. Acetic acid was removed under vacuum and the residue was taken up with 10 mL of MeOH. Reverse phase chromatography purification yielded the title compound as a white solid (39 mg, 13.8%). 1H NMR δ (500 MHz, DMSO-d6) 13.05 (d, J=3.5 Hz, 1H), 11.23 (t, J=6.5 Hz, 1H), 11.10 (d, J=7.5 Hz, 1H), 7.96 (s, 0.5H, conformational isomer), 7.85 (s, 0.5H), 7.81 (s, 0.5H), 7.68 (s, 0.5H), 7.44-7.30 (m, 2H), 7.22-7.14 (m, 1H), 7.11-7.02 (m, 1H), 6.17 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.18-4.08 (m, 1H), 4.08-3.98 (m, 1H), 3.08-3.02 (m, 1H), 3.02-2.94 (m, 1H), 2.91 (d, J=10.5 Hz, 2H), 2.23 (s, 3H), 2.11-2.02 (m, 2H), 1.90-1.78 (m, 2H), 1.74-1.66 (m, 2H), 1.34-1.29 (m, 3H). ESI MS: m/z 533.02 (M+1).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 16 h
  3. filtrationfiltered through Celite
  4. customAcetic acid was removed under vacuum
  5. customReverse phase chromatography purification

Sources & evidence

ORD record
ord-5aed537fdd7348f2b3b0aa7c15826bd8
Source dataset
uspto-grants-2014_09
Patent number
US08822500B2

Reaction notes

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