Triethylamine → 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

HRID 331619Notes

Reaction equation

HRID 331619 reaction equation
CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C=O)C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 22031079Methyl 4-bromo-2-(bromomethyl)benzoate

Product 1

HCID 690490113-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dioneYield 20.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J=17.7 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 5.11 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.89 (d, J=0.9 Hz, 1H), 11.00 (s, 1H).

Workup

  1. additionAfter the addition
  2. customThe mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL)
  3. additiona 1:1 mixture of ethyl acetate and hexanes (600 mL)
  4. stirringAfter stirring the mixture for 20 minutes
  5. filtrationthe solid was filtered
  6. washwashed with water and air
  7. customdried overnight
  8. stirringThe solid was stirred in acetic acid (200 mL)
  9. temperaturerefluxed for 2 hours
  10. temperatureThe mixture was cooled to room temperature
  11. filtrationfiltered
  12. washThe solid was washed with additional acetic acid, hexanes and air
  13. customdried overnight

Sources & evidence

ORD record
ord-85cc139306cf404ab5d32cb02872dc20
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

Loading…