Triethylamine → Naloxone

HRID 2275310Notes

Reaction equation

HRID 2275310 reaction equation
[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:23](N(CC)CC)[CH3:24].C(OCC=C)(=O)C>C1(C)C=CC=CC=1>[CH2:23]=[CH:24][CH2:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 11584Allyl acetateHCID 1528625314-Hydroxymorphine-6-one

Product 1

HCID 5284596Naloxone

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Into a round bottom flask equipped with a stir bar was charged noroxymorphone (2.89 g, 10.1 mmol), triethylamine (4.20 mL, 30.1 mmol), toluene (50 mL), tetrakis(triphenylphosphine)palladium[0](1.15 g, 1.00 mmol), and allyl acetate (1.40 mL, 12.9 mmol). The flask was equipped with a reflux condenser and the resulting reaction mixture was stirred and heated at 80° C. for 64 hours. The mixture was cooled to a temperature of about 20° C. and filtered through a plug of CELITE. The filtrate was concentrated under reduced pressure. The concentrated material was dissolved in a mixture of ethyl acetate (150 mL) and 0.75N aqueous hydrochloric acid (100 mL) and allowed to stir at a temperature of about 20° C. for 20 minutes. The layers were separated and the aqueous layer was washed with an additional 150 mL of ethyl acetate. The aqueous layer was basified to a pH of 9.05 with 28% ammonium hydroxide and extracted twice with dichloromethane (100 mL for each extraction). The organic portions were combined and concentrated under reduced pressure. Naloxone (HPLC purity of 76%) was isolated as an oil, contaminated with triphenylphosphine and 3-allyl-naloxone (isolated 2.78 g crude of 76% purity containing about 6.37 mmol of naloxone)).

Workup

  1. customInto a round bottom flask equipped with a stir bar
  2. customThe flask was equipped with a reflux condenser
  3. customthe resulting reaction mixture
  4. temperatureThe mixture was cooled to a temperature of about 20° C.
  5. filtrationfiltered through a plug of CELITE
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. dissolutionThe concentrated material was dissolved in a mixture of ethyl acetate (150 mL) and 0.75N aqueous hydrochloric acid (100 mL)
  8. stirringto stir at a temperature of about 20° C. for 20 minutes
  9. customThe layers were separated
  10. washthe aqueous layer was washed with an additional 150 mL of ethyl acetate
  11. extractionextracted twice with dichloromethane (100 mL
  12. extractionfor each extraction)
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-626d6b343ba244198f9bc21da5c4aeab
Source dataset
uspto-grants-2015_09
Patent number
US09127014B2

Reaction notes

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