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Conversion of Thebaine to Codeine
Randy B. Barber and Henry Rapoport
Journal of Medicinal Chemistry, 19, 1176-11 (1976)
Abstract
An improved conversion of thebaine to codeine has been developed. Oxymercuration of thebaine with mercuric acetate in refluxing methanol, followed by hydrolysis of the intermediate 7-acetomercurineopinone dimethyl ketal with 3 N acetic acid, or, alternatively, reduction of the organomercury compound with sodium borohydride and mild acid hydrolysis of the resulting neopinone dimethyl ketal, gives neopinone in 95-100% yields. Either acid or alkali-catalyzed isomerization to codeinone leads to the equilibrium mixture consisting of codeinoneneopinone, 3:1. Complete conversion to codeinone in 85-90% yield results from treatment of neopinone with anhydrous hydrogen chloride or hydrogen bromide in ether-methylene chloride, followed by elimination of hydrogen halide from the intermediate 8-halodihydrocodeinone. The known borohydride reduction of codeinone then gives codeine in 85% overall yield from thebaine.
A solution of 1.17 g (3.75 mmol) of thebaine and 79.8 mg (0.25 mmol, 6.7 mol%) of Hg(OAc)2 in 100 ml of 3N formic acid was stirred under nitrogen, for 6.5 hr. The solution was diluted with 100 ml of saturated aqueous K2CO3 and extracted with CHCl3. The organic layer was washed with water, dried over Na2SO4, and evaporated in a rotary evaporator.
The residue was dissolved in 5.3 ml of CHCl3 and allowed to react with 5.3 ml of a solution of 1.1 g of hydrogen chloride in 10 ml of ether. A precipitate formed immediately, but the reaction was allowed to continue for 30 min before the reaction mixture was diluted with 2.5 ml of CH2Cl2 and 2.5 ml of the above solution of hydrogen chloride in ether. The reaction was allowed to continue for 15 min more, whereupon 250 ml of cold 0.2 N NaOH solution and 50 ml of CHCl3were added to the mixture. After separation of the layers, the aqueous layer was re-extracted with CHCl3. The combined organic extracts were washed with water, dried over Na2SO4, and evaporated using a rotary evaporator.
To the residue, dissolved in 60 ml of methanol, was added 3.02 g (79 mmol) of NaBH4 in 73 ml of methanol. Under nitrogen, the reduction was allowed to proceed for 15 hr. The resulting solution was concentrated to a volume of 60 ml, diluted with 60 ml of 10% NaOH solution, and heated to reflux. The reaction mixture was further diluted with 50 ml of water and extracted with CHCl3. The organic extract was washed with water, dried over Na2SO4, and evaporated using a rotary evaporator to yield 890 mg (79%) of crude white codeine, GC analysis of which indicated 90% purity. The crude product was sublimed (100°C/0.03 mmHg) to give codeine in 80% yield, mp 151-154°C.
Mercury concentration of codeine prepared as above was of the order of 22 ppm, according to atomic absorption determination.