A practical synthesis of codeine from dihydrothebainone.
The conversion of dihydrothebainone to codeine or thebaine has been achieved in high yield. Bromination and dehydrobromination constructs the 4,5-oxide bridge to give 1-bromo- and 1,7-dibromodihydrocodeinone which yield dihydrocodeinone practically quantitatively after catalytic debromination. Ketalization and acid-catalyzed elimination of methanol give excellent yields of delta6-dihydrothebaine to which is added methyl hypobromite using N-bromoacetamide in methanol. The action of potassium tert-butoxide in Me2SO on the resulting 7-bromodihydrocodeinone dimethyl ketal gives codeinone dimethyl ketal selectivity at 60 degrees while at 120 degrees thebaine is the exclusive product. Hydrolysis to codeinone and borohydride reduction give codeine in 70% overall yield. The bromo intermediates in the formation of the 4,5-oxide bridge have been examined. 1,5beta, 7alpha-Tribromodihydrothebainone has been identified as the main product in the tribromination of dihydrothebainone.
D003061:Codeine / Q000138:chemical synthesis*; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008722:Methods; D008968:Molecular Conformation; D013797:Thebaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D013797:Thebaine; D003061:Codeine