Phosphoric Acid → Oxycodone

HRID 1790727Notes

Reaction equation

HRID 1790727 reaction equation
[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].P(=O)(O)(O)O.[OH-].[Na+].NC(N)=S.[H][H]>[Pd].C1COCC1>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]

Participants

8

Reactant 5

HCID 1004Phosphoric AcidHCID 14798Sodium HydroxideHCID 2723790ThioureaHCID 5359420(4R,4aS,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one2×HCID 178418361HCID 178418361, compound2×

Product 1

HCID 5284603OxycodoneYield 91.2%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A known amount of THF (26.7 g) is charged into a 0.5 L RBF, and 3.05 g of 14-hydroxycodeinone is added into it. With stirring 120 g of aqueous phosphoric acid (1M, 9.8%) is added. The mixture is stirred until the entire solid dissolved. While stirring 40% aqueous sodium hydroxide is added (12.5 g) dropwise over a 30-minute period until the pH of the solution reaches 6.20–6.30. An aqueous thiourea solution (0.001% w/w, 20.0 g) is then added to the reaction flask. This buffered solution is charged into a stainless hydrogenation vessel, followed by the addition of 0.150 g of 5% palladium on barium sulfate (dry basis). The vessel is sealed, pressurized to 15 psi with nitrogen, and then ventilated. This operation is repeated 3 times with nitrogen, and then with hydrogen. The reaction vessel is finally pressurized to 15 psi with hydrogen, and is stirred at this pressure until the reaction is completed (6 hours, residual 14-hydroxycodeinone<0.5 a/a % by HPLC). The hydrogenated solution is taken out from the stainless vessel. The catalyst is vacuum filtered off through a pad of Celite. The autoclave is rinsed with water (2×5 g) and the rinses are used to wash the catalyst cake on the filter. The filtrates are combined in a 0.5 L beaker with a magnetic stirrer. The solution is cooled in an ice-bath for 30 minutes and 15.5 g of ammonium hydroxide is added dropwise over a period of 30 minutes while cooling and brisk stirring continued. The addition of aqueous ammonia is mildly exothermic, so the rate of addition should be controlled such that the temperature does not exceed 30° C. A fine white precipitate formed during the basification process. The final pH of the suspension is 10–12. The precipitate is continuously cooled and stirred for 1 hour. It is then filtered, washed with water (3×10 g), and vacuum-dried for 3 h. A white solid of oxycodone (2.80 g, 91%) is obtained.

Workup

  1. additionis added into it
  2. additionis added
  3. dissolutiondissolved
  4. additionis added (12.5 g) dropwise over a 30-minute period until the pH of the solution
  5. additionThis buffered solution is charged into a stainless hydrogenation vessel
  6. customThe vessel is sealed
  7. stirringis stirred at this pressure until the reaction
  8. filtrationfiltered off through a pad of Celite
  9. washThe autoclave is rinsed with water (2×5 g)
  10. washto wash the catalyst cake on the filter
  11. customThe filtrates are combined in a 0.5 L beaker with a magnetic stirrer
  12. temperatureThe solution is cooled in an ice-bath for 30 minutes
  13. addition15.5 g of ammonium hydroxide is added dropwise over a period of 30 minutes
  14. temperaturewhile cooling
  15. stirringbrisk stirring
  16. additionThe addition of aqueous ammonia
  17. additionis mildly exothermic, so the rate of addition
  18. customdoes not exceed 30° C
  19. customA fine white precipitate formed during the basification process
  20. temperatureThe precipitate is continuously cooled
  21. stirringstirred for 1 hour
  22. filtrationIt is then filtered
  23. washwashed with water (3×10 g)
  24. customvacuum-dried for 3 h

Sources & evidence

ORD record
ord-1fa2ba475a8c427c8914a6f9aa3a427b
Source dataset
uspto-grants-2006_07
Patent number
US07071336B2

Reaction notes

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