3-Aminopiperidine-2,6-dione hydrochloride → [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl ester

HRID 240671Notes

Reaction equation

HRID 240671 reaction equation
[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]2[C:12]=1[C:20](=[O:22])[N:24]([CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27])[C:14]2=[O:16])[CH3:9])([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 2

HCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 670196793-[(t-Butoxycarbonyl-methyl-amino)-methyl]phthalic acid

Product 1

HCID 24755597[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl esterYield 60%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

A stirred mixture of 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid (2.3 g, 7.1 mmol) from above and α-aminoglutarimide hydrochloride (1.3 g, 7.8 mmol) in pyridine (40 mL) was refluxed for 5 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and water (50 mL). The EtOAc solution was separated and washed with water (40 mL), IN citric acid (2×40 mL), water (2×40 mL), and brine (40 mL), and then dried (MgSO4). Solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, CH2Cl2: EtOAc 8:2) to give [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl ester (1.7 g, 60%): mp 138-140° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.91-7.81 (m, 2H), 7.57 (b, 1H), 5.19-5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.85 (s, 2H), 2.97-2.83 (m, 1H), 2.89 (s, 3H), 2.63-2.50 (m, 2H), 2.07-2.03 (m, 1H), 1.44-1.29 (d, 9H); 13CNMR (DMSO-d6) δ 172.70, 169.74, 167.48, 166.87, 154.75, 138.31, 134.99, 132.31, 131.74, 127.42, 121.98, 79.13, 48.86, 47.32, 34.84, 30.90, 27.93, 21.94; Anal. Calcd. for C20H23N3O6: C, 59.84; H, 5.78; N, 10.47. Found: C, 59.51; H, 5.68; N, 10.31.

Workup

  1. temperaturewas refluxed for 5 hours
  2. temperatureThe mixture was cooled
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in EtOAc (100 mL)
  5. customThe EtOAc solution was separated
  6. washwashed with water (40 mL), IN citric acid (2×40 mL)
  7. dry with materialwater (2×40 mL), and brine (40 mL), and then dried (MgSO4)
  8. customSolvent was removed in vacuo
  9. customthe residue was purified by flash chromatography (SiO2, CH2Cl2: EtOAc 8:2)

Sources & evidence

ORD record
ord-01403058b3864d85bfd79a45f2402b4e
Source dataset
uspto-grants-2014_02
Patent number
US08648096B2

Reaction notes

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