Hydrochloric Acid → N-(6-Maleimidocaproyloxy)succinimide

HRID 991400Notes

Reaction equation

HRID 991400 reaction equation
[O:1]=[C:2]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])/[CH:3]=[CH:4]\[C:5](O)=[O:6].C(O[C:21](=[O:23])[CH3:22])(=O)C.C1[C:37]2[NH:36]C3C(=CC=CC=3)S[C:28]=2C=CC=1.Cl.[OH2:39]>C1COCC1.C(N(CC)CC)C>[CH2:22]1[C:21](=[O:23])[N:36]([O:16][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]2=[O:6])=[O:15])[C:37](=[O:39])[CH2:28]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 962WaterHCID 7108PhenothiazineHCID 7918Acetic AnhydrideHCID 5384149(Z)-6-(3-Carboxyacrylamido)hexanoic acid

Product 1

HCID 5091655N-(6-Maleimidocaproyloxy)succinimide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

(Z)-4-Oxo-5-aza-2-undecendioic acid, 150.0 g (0.654 moles), acetic anhydride, 68 ml (73.5 g, 0.721 moles), and phenothiazine, 500 mg, were added to a 2 liter three-neck round bottom flask equipped with an overhead stirrer. Triethylamine, 91 ml (0.653 moles), and 600 ml of THF were added and the mixture was heated to reflux while stirring. After a total of 4 hours of reflux, the dark mixture was cooled to <60° C. and poured into a solution of 250 ml of 12 N HCl in 3 liters of water. The mixture was stirred 3 hours at room temperature and then was filtered through a filtration pad (Celite 545, J. T. Baker, Jackson, Tenn.) to remove solids. The filtrate was extracted with 4×500 ml of chloroform and the combined extracts were dried over sodium sulfate. After adding 15 mg of phenothiazine to prevent polymerization, the solvent was removed under reduced pressure. The 6-maleimidohexanoic acid was recrystallized from 2:1 hexane:chloroform to give typical yields of 76-83 g (55-60%) with a melting point of 81-85° C. Analysis on a NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) maleimide protons 6.55 (s, 2H), methylene adjacent to nitrogen 3.40 (t, 2H), methylene adjacent to carbonyl 2.30 (t, 2H), and remaining methylenes 1.05-1.85 (m, 6H).

Workup

  1. customequipped with an overhead stirrer
  2. temperaturethe mixture was heated
  3. temperatureto reflux
  4. temperatureAfter a total of 4 hours of reflux
  5. temperaturethe dark mixture was cooled to <60° C.
  6. stirringThe mixture was stirred 3 hours at room temperature
  7. filtrationwas filtered through a filtration pad (Celite 545, J. T. Baker, Jackson, Tenn.)
  8. customto remove solids
  9. extractionThe filtrate was extracted with 4×500 ml of chloroform
  10. dry with materialthe combined extracts were dried over sodium sulfate
  11. additionAfter adding 15 mg of phenothiazine
  12. custompolymerization
  13. customthe solvent was removed under reduced pressure
  14. customThe 6-maleimidohexanoic acid was recrystallized from 2:1 hexane
  15. customchloroform to give typical
  16. customyields of 76-83 g (55-60%) with a melting point of 81-85° C

Sources & evidence

ORD record
ord-beb963afe7c444928f19391f0a69316e
Source dataset
uspto-grants-2002_10
Patent number
US06465178B2

Reaction notes

Loading…