3-Aminopiperidine-2,6-dione hydrochloride → 2-(2,6-Dioxo-3-piperidyl)-4-(2-methoxyethylamino)isoindoline-1,3-dione

HRID 2103501Notes

Reaction equation

HRID 2103501 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]=1[C:15]([OH:17])=O.Cl.[NH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:21]1[CH:20]([N:19]2[C:15](=[O:17])[C:7]3[C:8](=[CH:12][CH:13]=[CH:14][C:6]=3[NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]2=[O:11])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1

Participants

4

Reactant 2

HCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 219885193-(2-Methoxy-ethylamino)-phthalic acid

Product 1

HCID 99236092-(2,6-Dioxo-3-piperidyl)-4-(2-methoxyethylamino)isoindoline-1,3-dioneYield 64%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a stirred solution of 3-(2-methoxy-ethylamino)-phthalic acid (8.38 mmol) in pyridine (40 ml) was added 3-amino-piperidine-2,6-dione hydrochloride (1.39 g, 8.42 mmol). The reaction mixture was heated to reflux for 5 hours. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride (125 ml). The methylene chloride mixture was treated with Norit (2 g), washed with water (2×100 ml), 0.1N HCl (1×100 ml), brine (1×100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the residue (oil) crystallized from a minimal amount of ethanol to give a yellow solid that was purified by preparative HPLC to give 1.71 g (64%) of product as a yellow solid: mp 182-1184° C.; 1H NMR (DMSO-d6) d 11.12 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.04 (d, J=6-9 Hz, 1H), 6.59 (bs, 1H), 5.07 (dd, J=4.7 and 12.1 Hz, 1H), 3.54-3.30 (m, 7H), 2.95-2.85 (m, 1H), 2.64-2.52 (m, 2H), 2.07-2.02 (m, 1H); 3C NMR (DMSO-d6) d 172.79, 170.06, 168.98, 167.27, 146.38, 136.21, 132.07, 117.33, 110.67, 109.24, 70.39, 58.12, 48.58, 41.50, 30.99, 22.15; Anal. Calcd. For C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found: C, 58.06; H, 5.12; N, 12.76.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux for 5 hours
  3. customThe solvent was evaporated in vacuo
  4. dissolutionthe residue dissolved in methylene chloride (125 ml)
  5. additionThe methylene chloride mixture was treated with Norit (2 g)
  6. washwashed with water (2×100 ml), 0.1N HCl (1×100 ml), brine (1×100 ml)
  7. dry with materialdried (MgSO4)
  8. customThe solvent was evaporated in vacuo
  9. customthe residue (oil) crystallized from a minimal amount of ethanol
  10. customto give a yellow solid
  11. customthat was purified by preparative HPLC

Sources & evidence

ORD record
ord-b6d24e00008342c79abe234c877e3405
Source dataset
uspto-grants-2009_08
Patent number
US07576104B2

Reaction notes

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