Acetic Acid → 14-Hydroxydihydrocodeine

HRID 1406627Notes

Reaction equation

HRID 1406627 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].C(O)(=O)C>[Pd].O>[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@@H:7]([OH:8])[CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1

Participants

5

Reactant 2

HCID 176Acetic AcidHCID 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×

Product 1

HCID 536024114-Hydroxydihydrocodeine

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 962WaterSolvent

Procedure

A mixture of dry 14-hydroxycodeinone (9.5 g dry) and damp 14-hydroxycodeinone (8.5 g by LOD) was charged to a reactor and triturated with water (150 g) (to enable blending) for 15 min. The resulting slurry was filtered and a sample of the cake dried at 50° C. under vacuum (0.39 g) for analysis. The remaining wet cake (assumed 17.5 g) was charged to a stainless steel Parr pressure vessel followed by water (48.37 g to give a total water of 54.84 g accounting for the water in the starting material) and acetic acid (7.21 g, 2.15 equivalents) forming a solution. Pd/C (10%, dry, 0.16 g, ˜0.01 g Pd/C per gram of 14-hydroxycodeinone) was then added under nitrogen, rinsing the sides of the flask with water (1.16 g, 0.07 g/g of 14-hydroxycodeinone). The resulting mixture was evacuated and the vacuum released with nitrogen three times. It was again evacuated and hydrogen was added with the mixture at 17° C. (target 20±5° C.) up to 40 psi (target 40±2 psi). There was a one degree change in temperature after 2 minutes. The temperature gradually crept up to 28° C. over 50 minutes. Heating was applied to the mixture after reaching 28° C., getting to 80±5° C., over 2 h. The reaction was held at 80±5° C./40 psi for approximately 18 h (total time of 21 h after hydrogen addition) and sampled (see table) showing 4.60 area % of 6α-oxycodol. Thus, it can be seen that the addition of hydrogen at low temperature gives relatively higher levels of 6α-oxycodol compared to adding hydrogen at a higher temperature.

Workup

  1. additionwas charged to a reactor
  2. customtriturated with water (150 g) (to enable blending) for 15 min
  3. filtrationThe resulting slurry was filtered
  4. customa sample of the cake dried at 50° C. under vacuum (0.39 g) for analysis
  5. additionThe remaining wet cake (assumed 17.5 g) was charged to a stainless steel Parr pressure vessel
  6. customto give a total water of 54.84 g
  7. customforming a solution
  8. washrinsing the sides of the flask with water (1.16 g, 0.07 g/g of 14-hydroxycodeinone)
  9. customThe resulting mixture was evacuated
  10. customIt was again evacuated
  11. additionhydrogen was added with the mixture at 17° C. (target 20±5° C.) up to 40 psi (target 40±2 psi)
  12. customwas a one degree
  13. customafter 2 minutes
  14. temperatureHeating
  15. customafter reaching 28° C.
  16. waitgetting to 80±5° C., over 2 h
  17. customwas held at 80±5° C.
  18. customfor approximately 18 h
  19. addition(total time of 21 h after hydrogen addition)
  20. aliquotsampled (see table)
  21. additionThus, it can be seen that the addition of hydrogen at low temperature

Sources & evidence

ORD record
ord-ae4e7ad697cd4a178544fabecf3c0d67
Source dataset
uspto-grants-2014_12
Patent number
US08916707B2

Reaction notes

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