Hydrogen Bromide → Codeine

HRID 1390815Notes

Reaction equation

HRID 1390815 reaction equation
[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.Br>C(O)(=O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1

Participants

4

Reactant 2

HCID 260Hydrogen BromideHCID 5324289Thebaine

Product 1

HCID 5284371Codeine

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent2×

Conditions

Temperature
10 °C

Procedure

Thebaine (2.0 g) was dissolved in warm glacial acetic acid (10 ml) then chilled in an ice/water bath. A 45% w/v solution of anhydrous hydrogen bromide in glacial acetic acid (6 ml, 2.7 g HBr) was added dropwise with stirring over 9 minutes. Stirring was continued for 20 minutes during which time a fine precipitate separated. Methanol (75 ml) was added to a solution of sodium hydroxide (12.72 g) in water (75 ml). This solution was chilled (10° C.) and sodium borohydride (247 mg) added. The above slurry of 8-bromodihydrocodeinone hydrobromide in acetic acid was added portionwise to the sodium hydroxide-sodium borohydride mixture with vigorous stirring over 34 minutes keeping the temperature below 10° C. by means of an ice bath. After the addition, the mixture was allowed to stir for 30 minutes. Chloroform (50 ml) was added, the mixture stirred vigorously, allowed to settle and the layers separated. The aqueous phase was extracted with fresh chloroform (2 × 20 ml). The combined chloroform extracts were washed with brine (3 × 50 ml), dried (Na2SO4) and evaporated under reduced pressure. Final traces of solvent were removed under high vacuum. The fluffy off-white solid (1.85 g) displayed one major spot on TLC and one major peak on GLC, both of which corresponded to codeine. Codeinone was absent, and only minor amounts of other alkaloidal substances were present.

Workup

  1. temperaturethen chilled in an ice/water bath
  2. additionwas added dropwise
  3. stirringStirring
  4. waitwas continued for 20 minutes during which time
  5. customa fine precipitate separated
  6. additionMethanol (75 ml) was added to a solution of sodium hydroxide (12.72 g) in water (75 ml)
  7. additionadded
  8. additionThe above slurry of 8-bromodihydrocodeinone hydrobromide in acetic acid was added portionwise to the sodium hydroxide-sodium borohydride mixture
  9. stirringwith vigorous stirring over 34 minutes
  10. customthe temperature below 10° C.
  11. additionAfter the addition
  12. stirringto stir for 30 minutes
  13. additionChloroform (50 ml) was added
  14. stirringthe mixture stirred vigorously
  15. customthe layers separated
  16. extractionThe aqueous phase was extracted with fresh chloroform (2 × 20 ml)
  17. washThe combined chloroform extracts were washed with brine (3 × 50 ml)
  18. dry with materialdried (Na2SO4)
  19. customevaporated under reduced pressure
  20. customwere removed under high vacuum

Sources & evidence

ORD record
ord-fb7fc1945ab749718c0361d9d4385cc8
Source dataset
uspto-grants-1979_02
Patent number
US04140687

Reaction notes

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