Thebaine bromination

As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16). Catalytic reduction... 

Synthesis (Krauli (E. Merck), 1925, Juby et al., 1968, Ehrhart and Ruschig 1972) Thebaine is oxidized with hydrogene peroxide to 14-hydroxycodeinone (Bentley 1954, Hauser 1974), which is hydrogenated directly or via its oxime, or its bromination products to oxycodone. The reduction of 14-hydroxycodeinone can also be carried out with sodium hydrosulfite. Alternatively 14-hydroxycodeinone is prepared by oxidation of codeine. 

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

A study(206) of the ketalization of 14-hydroxycodeinone resulted in the insertion of a hydroxyl function at C-7. Contrary to the 14-position halogena-tion seen with bromine and chlorine, iodination of thebaine occurred at C-7.(207)... 

Dihydrothebaine- was originally given the structure [n], which was in accord with most of its chemical properties [3-4] except its failure to condense with benzoquinone or maleic anhydride and its failure to yield a derivative of 14-bromothebainone [iii] on treatment with bromine [5], However, the production of a conjugated diene as final product in a sodium-alcohol or sodium-ammonia reduction is contrary to general experience and examination of the infra-red and ultra-violet absorption spectra of dihydrothebaine-, thebaine, /3-dihydrothebaine, several 1 4-dihydroanisole derivatives, and 1-alkoxy-l 3-dienes led to modification of the structure of dihydrothebaine- to [iv] [6], which structure is more in accord with its properties than is [n], and in particular explains why the hydrogenation of this base proceeds with absorption of only one mole of hydrogen (see Chap. XIV). 

Whereas total syntheses of alkaloids have been few, a great deal of attention has been given to the modification of alkaloid skeletons and to the synthesis of alkaloid analogues in an effort to prepare new pharmacologically active compounds. To begin, the bromination product of thebaine (137), 14-bromocodein-one (138 R1 + R2 = O), has been the subject of a number of reports.147-154... 

In contrast to bromination of thebaine (137), which gave 14-bromocodeinone (138 R1 + R2 = O), iodination in methanol-chloroform solution produced the 7-iodo-derivative (141 R1 = H, R2 = I).156 The latter was transformed into the indolinocodeine (147 X = OAc) by treatment with silver acetate in acetic acid, thus offering an alternative route to those derivatives which had been previously prepared by solvolysis of 14-bromocodeine (138 R1 = OH, R2 = H). Similarly, treatment of (141 R = H, R2 = I) with silver cyanide and sodium azide afforded compounds (147 X = NC) and (147 X = N3) respectively. This report should stimulate further investigation of the factors involved in yielding predominantly C(14)- or C(7)-substituted products in electrophilic reactions on thebaine.156... 

These investigators succeeded in preparing codeinone dimethyl ketal (CCCLXXXV) starting with A -dihydrothebaine, which can itself be prepared by methylation of dihydrocodeinone with sodium <-butoxide and dimethyl sulfate (426). Addition of bromine in methanol to the enol ether gave a bromoketal which was dehydrobrominated to CCCLXXXV with potassium i-amyloxide. Direct preparation of codeinone dimethyl ketal from codeinone was not successful. Thebaine was obtained by warming CCCLXXXV with p-toluenesulfonic acid in chloroform. 

Bromocodeinone, which is readily obtained from the treatment of thebaine with brominating agents, can be reduced to the j8,y-unsaturated ketone, neopinone, and this gives neopine (CCCLXXXVII) on reduction with sodium borohydride (409). 

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