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

HRID 448387Notes

Reaction equation

HRID 448387 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([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)=[C:5]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.Cl.[NH2:30][CH:31]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:32]1=[O:33]>N1C=CC=CC=1>[O:33]=[C:32]1[CH:31]([N:30]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]2=[O:15])[CH2:37][CH2:36][C:35](=[O:38])[NH:34]1

Participants

4

Reactant 2

HCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 583071663-(4-Methoxy-2-phenoxy-phenylamino)-phthalic acid

Product 1

HCID 588272502-(2,6-Dioxo-piperidin-3-yl)-4-(4-methoxy-2-phenoxy-phenylamino)-isoindole-1,3-dioneYield 89%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

A mixture of 3-(4-methoxy-2-phenoxy-phenylamino)-phthalic acid (0.60 g, 1.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.26 g, 1.6 mmol) in pyridine (10 mL) were heated to reflux for 20 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (3×100 mL) and water (100 mL), and then evaporated under vacuum. The residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 0.66 g of the product, an orange solid, at 95:5 methylene chloride-methanol, in 89% yield: mp 142-144° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 4.71 min (96.79%); 1H NMR (DMSO-d6) δ 1.98-2.04 (m, 1H), 2.49-2.61 (m, 2H), 2.81-2.90 (m, 1H), 3.73 (s, 3H), 5.06 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 6.84 (dd, J=8.8, J=2.8 Hz, 1H), 6.90-6.94 (m, 2H), 7.04-7.10 (m, 2H), 7.16 (d, J=7.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.3 Hz, J=7.4 Hz, 1H), 7.95 (s, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 30.9, 48.6, 55.5, 105.9, 109.6, 110.7, 112.6, 117.9, 118.7, 122.8, 123.5, 127.2, 129.9, 132.0, 136.0, 144.0, 151.1, 156.2, 157.8, 167.1, 168.5, 169.9, 172.8; Anal. calcd For C26H21N3O6.0.3H2O: C, 65.49; H, 4.55; N, 8.84. Found: C, 65.43; H, 4.29; N, 8.73.

Workup

  1. temperaturewere heated
  2. temperatureto reflux for 20 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 (3×100 mL) and water (100 mL)
  7. customevaporated under vacuum
  8. customThe residue was purified by ISCO silica gel flash chromatography
  9. washeluting 0.66 g of the product
  10. customHPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 4.71 min (96.79%)

Sources & evidence

ORD record
ord-6ed9306b2913429fb03570f83d3e76f6
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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