3-Aminopiperidine-2,6-dione hydrochloride → 2-(2,6-Dioxo-piperidin-3-yl)-4-(3-methoxy-phenylamino)-isoindole-1,3-dione

HRID 448411Notes

Reaction equation

HRID 448411 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]2=[O:15])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1

Participants

4

Reactant 2

HCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 58307244HCID 58307244, compound

Product 1

HCID 588272712-(2,6-Dioxo-piperidin-3-yl)-4-(3-methoxy-phenylamino)-isoindole-1,3-dioneYield 76.7%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

A mixture of 3-(3-methoxy-phenylamino)-phthalic acid (0.32 g, 1.1 mmol) and rac-α-aminoglutarimide hydrochloride (0.18 g, 1.1 mmol) in pyridine (10 mL) was heated to reflux for 15 hours. The reaction mixture was cooled, and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL). Solvent was evaporated in vacuo. The residue was purified by ISCO silica gel flash chromatography using a methanol-methylene chloride gradient, eluting the product at 5:95 methanol-methylene chloride to give the title product (0.32 g, 76% yield): mp 210-212° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.70 (97.39%); 1H NMR (DMSO-d6) δ 2.04-2.08 (m, 1H), 2.49-2.64 (m, 2H), 2.84-2.94 (m, 1H), 3.75 (s, 3H), 5.13 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 6.71 (dd, J=8.4 Hz, J=2.2 Hz, 1H), 6.90-6.92 (m, 2H), 7.25-7.32 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.60-7.66 (m, 1H), 8.42 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.1, 107.3, 109.6, 112.2, 113.6, 119.9, 130.2, 132.5, 136.2, 140.7, 142.6, 160.2, 167.0, 168.2, 170.0, 172.8; Anal. calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C, 63.22; H, 4.51; N, 10.78.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 15 hours
  3. temperatureThe reaction mixture was cooled
  4. customthe solvent was evaporated in vacuo
  5. washwashed with dilute aqueous HCl (2×100 mL) and water (2×100 mL)
  6. customSolvent was evaporated in vacuo
  7. customThe residue was purified by ISCO silica gel flash chromatography
  8. washeluting the product at 5:95 methanol-methylene chloride

Sources & evidence

ORD record
ord-4f108d453da6468c873951de43837489
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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