HTML by Rhodium
Codeinone is prepared by reacting thebaine with a halohydric acid in an anhydrous medium in the presence of a catalyst at not more than 10°C. and hydrolysing the resulting halogenated product in an alkaline medium. The preferred halohydric acid is hydrobromic acid preferably dissolved in an ether, the thebaine is preferably dissolved in a chlorinated compound, and the catalyst is preferably iodine.
1. Field of the Invention
This invention relates to a process for preparing codeinone from thebaine at a virtually quantitative yield.
2. Description of the Prior Art
The transformation of thebaine to codeinone can be carried out by a variety of different procedures. Knorr and Horlein, Ber. 39, 1409 (1906), on the one hand, and Schopf and Hirsch, Ann. Chem. 489, 224 (1931), on the other hand, performed the hydrolysis of thebaine in an aqueous acid medium obtaining codeinone and methanol, but with very low yields. The conversion of .thebaine to codeinone via 14-bromocodeinone and neopinone was also attempted by Conroy and Krausz, J. Am. Chem. Soc., 77, 5960 (1955) and Bull, Soc. Chim. France 2148 (1960), but the number of steps required and the yield in each step make this method of little practical value. This transformation was carried out with some success by several authors such as Gavard et al., Bull, Soc. Chim. France 1486 (1965), and has been the subject of different patents. The yields obtained are found to be between 50% and 75%.
This invention relates to a process for transforming thebaine to codeinone by treating thebaine dissolved in an inert halogenated hydrocarbon solvent, with a hydrogen halide dissolved in an inert hydrocarbon ether solvent, particularly alkyl ethers having from one to 4 carbon atoms in the alkyl groups, under anhydrous conditions, in the presence of a catalyst, preferably iodine, and the subsequent hydrolysis of the halogenated compound thus formed in an aqueous alkaline medium at working temperatures lower than 10°C. The hydrogen halide is preferably hydrogen bromide or hydrogen chloride, and hydrogen bromide is especially preferred.
Yields of higher than 95% are obtained by the process of the invention.
To a 3-liter flask equipped with an agitator, a thermometer and a gas outlet tube containing calcium chloride, which flask contains a solution of 150 g of anhydrous hydrogen bromide dissolved in 550 ml of n-dibutyl ether and is externally cooled at -15°C, there is added a solution of 2 g of iodine dissolved in 100 ml of anhydrous methylene chloride, and the temperature is then reduced to -20°C.
When this temperature is reached, a solution of 100 g of thebaine (purity: 92.5%) dissolved in 1000ml anhydrous methylene chloride previously cooled at -15°C is rapidly added with vigorous agitation to the former solution. As a consequence of this addition, the temperature rises to +10°C. It is reduced to 0°C in a short time by external cooling and this temperature is maintained for 7 minutes. At the end of this period the content of the flask is poured with vigorous agitation into a 5-liter flask containing a suspension of 180 g sodium bicarbonate in 1000mL of water and 450 g of ice.
The agitation is maintained for one hour. the hydrolysis reaction product separates into two layers. The aqueous layer is adjusted to pH 8 with dilute soda and is extracted three times, each time with 200 ml methylene chloride. The combined extracts are added to the organic layer, and the organic mixture is washed with water and dried with anhydrous sodium sulfate. From the resulting solution, the methylene chloride solvent is evaporated under vacuum until its volume is reduced to 1/100 of the original volume.
The codeinone which precipitates during concentration of the organic solution, which exhibits a clear pink color, is then filtered and washed with diethyl ether. There is obtained 96 g codeinone of mp 165-7°C and with a purity of 90.36%. The yield was 98%.
Thebaine → Codeinone:
Facile synthesis of codeine precursors from thebaine
US Patent 4,277,604
Abstract
Thebaine is converted to a mixture of codeinone and neopinone in aqueous formic acid solution containing as catalyst a mercuric salt. Thebaine is converted to a neopinone ketal by irradiation in an alkanol or to a mixture of neopinone and codeinone in an acidic aqueous solution. Neopinone ketals, codeinone and neopinone can be converted to codeine.
Method for the preparation of codeinone from thebaine
British Patent 937,128
Abstract
Codeinone is prepared by reacting thebaine or a salt thereof with a hydrohalic acid in an anhydrous organic medium and adjusting the pH of the reaction mixture to 8-12 by treatment (preferably in an aqueous medium) with a basic agent selected from alkali and alkaline-earth metal hydroxides, carbonates and bicarbonates, ammonia, salts having an alkaline action, an organic bases.
Process for the preparation of codeinone
Swiss Patent 619,227
Abstract
Codeinone is prepared by reacting thebaine, which is dissolved in an inert halogenated hydrocarbon, with a hydrogen halide, which is dissolved in an inert hydrocarbon ether solvent, in the presence of iodine as catalyst under anhydrous conditions. A halogenated reaction product is obtained. This reaction product is hydrolysed using an aqueous sodium bicarbonate solution to give codeinone. The conversion and hydrolysis steps are carried out at temperatures of below 10°C, and the codeinone is isolated from the hydrolysis product.
Thebaine → Dehydrothebaine → Dihydrocodeinone:
Reduction of Thebaine
US Patent 3,812,132
Abstract
A process for the preparation of 8,14-dihydrothebaine from thebaine, in which the thebaine is reduced by heating it with a thermally decomposable hydrazide, or with disodium azodicarboxylate and a proton donor. The 8,14-dihydrothebaine may be hydrolyzed to dihydrocodeinone.