Triethylamine → 4-Hydroxy thalidomide

HRID 1915140Notes

Reaction equation

HRID 1915140 reaction equation
C(N(CC)CC)C.[OH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([O:14][C:15](=[O:16])[C:10]=12)=O.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>CN(C=O)C>[O:24]=[C:23]1[CH:22]([N:21]2[C:15](=[O:16])[C:10]3[C:11](=[CH:17][CH:18]=[CH:19][C:9]=3[OH:8])[C:12]2=[O:14])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 965803-Hydroxyphthalic anhydrideHCID 1345483-Aminopiperidine-2,6-dione hydrochloride

Product 1

HCID 117780874-Hydroxy thalidomideYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3-hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and rac-α-aminoglutarimide hydrochloride (3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90° C. overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50° C., the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.45-2.61 (m, 2H), 2.82-2.96 (m, 1H), 5.08 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.23-7.33 (m, 2H), 7.66 (dd, J=8.2 Hz, J=7.2 Hz, 1H), 11.10 (s, 1H), 11.19 (s, 1H).

Workup

  1. temperaturecooled to room temperature
  2. customthe solvent was evaporated under vacuum
  3. customthe solvent was removed under vacuum
  4. stirringThe residue was stirred in water (120 mL) for 2 h
  5. filtrationthe resulting solid was filtered
  6. washwashed with water (50 mL)
  7. customdried
  8. addition1,4-Dioxane (200 mL) was added
  9. stirringthe resulting suspension was stirred for 16 h
  10. filtrationfiltered
  11. additionThe filtrate was treated with decolorizing carbon (2 g)
  12. temperatureheated
  13. temperatureto reflux for 1 h
  14. temperatureAfter cooling to 50° C.
  15. filtrationthe reaction mixture was filtered through Celite
  16. washthe filter was washed with additional 1,4-dioxane (50 mL)
  17. customevaporated to dryness
  18. customThe resulting solid was triturated with ethyl acetate (100 mL)
  19. filtrationfiltered
  20. customdried

Sources & evidence

ORD record
ord-afc5ddb1fa8c4e608665da9dce5c6414
Source dataset
uspto-grants-2013_12
Patent number
US08614328B2

Reaction notes

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