3-(2,4-Dimethoxyphenylamino)phthalic acid → 4-(2,4-Dimethoxy-phenylamino)-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-YL]-isoindole-1,3-dione

HRID 448407Notes

Reaction equation

HRID 448407 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Br.[NH2:25][C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:15]2=[O:17]

Participants

4

Reactant 2

HCID 583073283-(2,4-Dimethoxyphenylamino)phthalic acidHCID 66643102(S)-3-amino-3-methylpiperidine-2,6-dione hydrobromide

Product 1

HCID 588273534-(2,4-Dimethoxy-phenylamino)-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-YL]-isoindole-1,3-dioneYield 41%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid (0.37 g, 1.2 mmol) and (3S)-3-amino-3-methyl-piperidine-2,6-dione hydrobromide (0.28 g, 1.2 mmol) in pyridine (10 mL) was heated to reflux for 24 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting 0.20 g of the product, an orange solid, at 50:50 hexanes-ethyl acetate, in 41% yield: mp 255-257° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 65/35 (CH3CN/0.1% H3PO4): tR=2.72 (97.30%); 1H NMR (DMSO-d6) δ 1.91 (s, 3H), 2.05-2.08 (m, 1H), 2.59-2.73 (m, 3H), 3.79 (s, 6H), 6.57 (d, J=7.5 Hz, 1H), 6.71 (s, 1H), 6.97-7.08 (m, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.52 (m, 1H), 7.94 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.6, 29.2, 55.4, 55.7, 58.5, 99.5, 104.7, 110.2, 111.8, 118.1, 120.1, 125.0, 131.9, 136.0, 144.0, 153.6, 157.9, 167.8, 169.8, 172.1, 172.4; Anal. calcd for C22H21N3O6.0.2H2O: C, 61.88; H, 5.05; N, 9.84. Found: C, 61.91; H, 5.01; N, 8.52.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 24 hours
  3. temperatureThe mixture was cooled
  4. customevaporated under vacuum
  5. dissolutionThe residue was dissolved in ethyl acetate (100 mL)
  6. washwashed with dilute aqueous HCl (2×100 mL) and water (2×100 mL)
  7. customevaporated
  8. customThe residue was purified by ISCO silica gel flash chromatography
  9. washeluting 0.20 g of the product

Sources & evidence

ORD record
ord-b91ea1c141f94e0cbc5d52f46c5ebe62
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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