Ethyl Acetate → Tivantinib

HRID 388324Notes

Reaction equation

HRID 388324 reaction equation
[Mg].[C:2]1([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3[CH:3]=1.C(OCC)(=O)C>CO>[C:2]1([C@H:14]2[C@H:18]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[C:17](=[O:28])[NH:16][C:15]2=[O:29])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3[CH:3]=1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 5462224MagnesiumHCID 99692093-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione

Product 1

HCID 11494412TivantinibYield 89.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Magnesium turnings (3.05 g, 0.125 mol) were added to a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (2.56 g, 6.97 mmol) in anhydrous methanol (100 ml) and heated to reflux under an atmosphere of nitrogen for 40 minutes. After cooling to room temperature the mixture was poured into ethyl acetate (300 ml), washed with 1M hydrochloric acid (300 ml) and water (500 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then purified by silica gel chromatography using 40-50% ethyl acetate in hexanes to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione as a pale pink solid (2.3 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 11.03 (s, 1H), 7.32-7.4 (m, 4H), 7.17 (d, 1H, J=7.2 Hz), 7.07 (t, 1H, J=7.6 Hz), 6.96 (t, 1H, J=7.6 Hz), 6.82-6.89 (m, 2H), 4.5 (dd, 2H, J=7.2 and 20 Hz), 4.07 (t, 2H, J=5.2 Hz), 2.87 (t, 2H, J=6 Hz), 2.08 (m, 2H).

Workup

  1. temperatureheated
  2. temperatureto reflux under an atmosphere of nitrogen for 40 minutes
  3. washwashed with 1M hydrochloric acid (300 ml) and water (500 ml)
  4. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  5. customevaporated to dryness
  6. customThe residue was then purified by silica gel chromatography

Sources & evidence

ORD record
ord-e85cba53a0904e248459c9ff77ec6fd3
Source dataset
uspto-grants-2013_02
Patent number
US08377927B2

Reaction notes

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