Benzophenone → Hydrocodone

HRID 496802Notes

Reaction equation

HRID 496802 reaction equation
C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:15][N:16]1[C@@H:32]2[CH2:33][C:21]3[CH:22]=[CH:23][C:24]([O:35][CH3:36])=[C:25]4[O:26][C@H:27]5[C@@H:28]([OH:34])[CH:29]=[CH:30][C@@H:31]2[C@:19]5([C:20]=34)[CH2:18][CH2:17]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1CCCCC1>[CH3:15][N:16]1[C@@H:32]2[CH2:33][C:21]3[CH:22]=[CH:23][C:24]([O:35][CH3:36])=[C:25]4[O:26][C@H:27]5[C:28]([CH2:29][CH2:30][C@@H:31]2[C@:19]5([C:20]=34)[CH2:18][CH2:17]1)=[O:34]

Participants

5

Reactant 2

HCID 3102BenzophenoneHCID 5284371Codeine

Product 1

HCID 5284569HydrocodoneYield 94%

Reagents, catalysts & solvents 2

HCID 84599Chlorotris(triphenylphosphine)rhodium(I)CatalystHCID 8078CyclohexaneSolvent

Procedure

Benzophenone (6.22 g), cyclohexane (22 mL), dried codeine (1.38 g) and chlorotris(triphenylphosphine)rhodium (I) (Wilkinson's catalyst) (0.22 g) were charged into a glass hydrogenation bottle. The bottle was evacuated and filled with hydrogen. The mixture was magnetically agitated at ambient temperature (24–28° C.) while the hydrogen pressure was maintained at 5–15 psi until the pressure drop caused by the hydrogen consumption stopped. A solution of potassium tert-amylate in cyclohexane (12 mL, 15.4% w/w) was charged into the bottle with the reaction mixture in one portion, the mixture was magnetically agitated under nitrogen at ambient temperature for 4 hours and quenched by adding 1.5N acetic acid (13 mL) to the solution with mixing and cooling in an ice bath. Alternatively, in another embodiment the solution may be quenched by adding the solution to 1.5N acetic acid with mixing and cooling in an ice bath. The mixture was filtered, aqueous layer was separated and the organic layer was extracted with 1.5N acetic acid (2 mL). Combined aqueous layer (14.5 mL) according to the assay by HPLC contains 89.7 mg/mL hydrocodone (94% yield), purity 95 area %.

Workup

  1. customThe bottle was evacuated
  2. additionfilled with hydrogen
  3. temperaturewas maintained at 5–15 psi until the pressure drop
  4. customcaused by the hydrogen consumption
  5. additionA solution of potassium tert-amylate in cyclohexane (12 mL, 15.4% w/w) was charged into the bottle with the reaction mixture in one portion
  6. stirringthe mixture was magnetically agitated under nitrogen at ambient temperature for 4 hours
  7. customquenched
  8. additionby adding 1.5N acetic acid (13 mL) to the solution
  9. additionwith mixing
  10. temperaturecooling in an ice bath
  11. customAlternatively, in another embodiment the solution may be quenched
  12. additionby adding the solution to 1.5N acetic acid
  13. additionwith mixing
  14. temperaturecooling in an ice bath
  15. filtrationThe mixture was filtered
  16. customaqueous layer was separated
  17. extractionthe organic layer was extracted with 1.5N acetic acid (2 mL)

Sources & evidence

ORD record
ord-861d9c9908bb4782b3a2cfa08acb21e2
Source dataset
uspto-grants-2005_09
Patent number
US06946556B1

Reaction notes

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