Thebaine hydrolysis

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... 

The product (6-2) from the reaction of thebaine with hydrogen peroxide can be viewed as the result from fromal 1,4 addition of two hydroxyl groups across the diene. The perspective depiction of thebaine reveals that the addition in fact occurs at the far more open face of the molecule. The product from this oxidation incorporates a new hydroxyl group at the 14(3 position and a hemiacetal at the 6 position. Treatment with a nuld acid leads to the hydrolysis of this last function and the formation of enone (6-3). 

A new method for the demethylation of codeine to morphine, previously a capricious reaction, has been reported, the product being obtained in good yield. Demethylation by boron tribromide in chloroform gives 90—91%150 and by potassium t-butoxide in propanethiol gives 80% morphine.151 A patent describes an improved method for the preparation of codeinone from thebaine, by adding the alkaloid to anhydrous hydrogen bromide in solution in methylene chloride and dibutyl ether at -20 °C, in the presence of small quantities of iodine, followed by hydrolysis with aqueous sodium bicarbonate. The claimed yields of codeinone are 95% crude and 90% after purification.152 Codeinohe is an intermediate in the conversion of thebaine into codeine. An overall yield of 85% of codeine from thebaine, without purification of any of the intermediates, has been claimed for an... 

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... 

Thebaine has been shown to react with lithium dimethylcuprate to give 7/j-methyldihydro- -thebaine (97),187,188 acid hydrolysis of which gives 7-methyl-thebainone-A (98) and its B/c-trans-isomer, which can be catalytically reduced to 7a- and 7/ -dihydrothebainone (99) and their B/c-trans-isomers. The la- and 7/j-dihydrothebainones are also obtained by the action of lithium dimethylcuprate on dihydrothebaine and on dihydrocodeinone enol acetate and subsequent hydrolysis of the products.187 The phenol (97) can be converted into the... 

The acetylation of morphine and of codeine by aspirin202 and the enzymatic hydrolysis of heroin203 and the reduction of codeinone204 have been studied. Dihydronorcodeine and dihydromorphine have been isolated from urine as metabolites of dihydrocodeine.205 Patents have been published covering the preparation of -(cyclopropylmethyOnormorphine,206 the conversion of thebaine into codeinone,207 and the preparation of nalorphine 6-sulphate.208 Salts of codeine and ethylmorphine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one have been prepared.209 The circular dichroism210,211 and fluorescence characteristics212 of morphine and related bases have been studied. 

Diethylazodicarboxylate may be employed as a reagent for the N-demethylation of thebaine to northebaine via an N-Me addition product. However, when thebaine was dissolved in diethylazodicarboxylate and allowed to stand, the hexacyclic product 251 was isolated,<9a) presumably from the Diels-Alder intermediate 249, and after hydrolysis gave 250. The putative intermediates 249 and 250 defied isolation. 

The oxidation of thebaine with manganic acetate first gives [xvi], which on hydrolysis with 20 per cent, hydrochloric acid affords after three minutes at 100° C. the dihydroxyketone [xvrr], and 14-hydroxy-codeinone [xvm] after twenty minutes [98]. The 14-substituted codeinones are discussed in Chapter XVIII. 

Catalytic reduction of thebaine in 2-2-5N hydrochloric acid results in hydrolysis of the dihydrothebaine [xi] first formed, the product being a mixture of dihydrothebainone [xn] and dihydrocodeinone [xv] [19-21] in 5N hydrochloric acid migration of the side-chain occurs and metathebainone [xvi] is formed [19] (see below). 

When thebaine [i] is reduced by sodium and boiling alcohol [1-3], or best by sodium in liquid ammonia [4-5], scission of the 4 5-oxygen bridge occurs with the addition of two atoms of hydrogen and production of a phenolic dihydrothebaine, for which the name dihydrothe-baine-< has now been adopted [5]. The sodium-ammonia reduction is rapid, simple, and results in excellent yields of product. Reduction of thebaine with lithium aluminium hydride also yields a phenolic base, /3-dihydrothebaine, which is isomeric with dihydrothebaine- [6], Dihydrothebaine- was first allotted the structure [n] on the basis of its reactions [3], and 3-dihydrothebaine the structure [m] with the abnormal configuration at C-14 on the basis of its hydrolysis to ]S-thebainone-A [iv] [6] thebainone-A enol methyl ether [m] with the normal configuration at C-14, which results from the isomerization of codeine methyl ether [v] under the influence of hot sodium ethoxide, is known to give thebainone-A [rv, C-14 epimer] on hydrolysis [3]. 

Dihydro thebaine-< absorbs only one mole of hydrogen on catalytic reduction, yielding dihydrothebainone AB-enol methyl ether [ix], which is identical with the product of sodium and liquid ammonia reduction of the non-phenolic dihydrothebaine [x] [5]. (A compound of different melting-point and specific rotation was prepared by Small and Brown-ing [3] by the catalytic reduction of dihydrothebaine-< and allotted the structure [xi] owing to a misconception of the structure of the latter. It is probably a mixture [5].) Dihydrothebainone [xn] is produced by the hydrolysis of [ix] showing that no rearrangement of the thebaine skeleton occurs during sodium and alcohol reduction [5]. 

The cause of the isomerism is the asymmetric carbon atom C-14, which in thebainone-A and its derivatives is configured as in codeine but has the opposite configuration in /3-thebainone-A. Although the latter could arise from /3-dihydrothebaine [nr] by a 1 4-hydrolysis of the system MeO C=C—C=C, such a mechanism seems unlikely as it cannot be operative in the hydrolysis of dihydrothebaine- cf> [iv] during which /3-thebainone-A must be formed by the isomerization of thebain-one-B, a reaction that has been independently realized [13] (see below). 

This isomer is obtained in erratic yield by the hydrolysis of dihydro-thebaine- by sulphurous acid. It was initially allotted the structure [xm] [3], but has since been shown to have the structure [xxv], which is allotted to the base on account of the ultra-violet absorption spectrum, which indicates a highly conjugated system (Figs. 8 and 9), and the infra-red absorption, which indicates that the compound is a /3 y-unsaturated ketone [13]. It is apparently formed during the hydrolysis... 

Dihydrothebainone [ix], obtained by the catalytic reduction of thebainone-A [v] [1] and thebainone-B [xm] [13], can be most conveniently prepared by the catalytic reduction of thebaine in acid solution [9-12, 25], and it can also be obtained by the hydrolysis of its two enol ethers (see below). It is a phenolic, ketonic, base, that shows the diazo-reaction in dilutions up to 1 in 2,000,000 [26-27], gives a methyl ether [28], oxime [9], semicarbazone [29], and a benzylidene [30] and piperonylidene [25] derivative. The optical antipode is produced by the sodium amalgam reduction of sinomenine [xxvi] and is known as desmethoxydihydrosinomenine [31]. 

This enol ether [xxxi] is the product of catalytic or sodium amalgam reduction of thebainone-A enol methyl ether [vn] [3], from which it arises by 1 4-addition of hydrogen to the conjugated system, and it can also be prepared by the hydrogenation of thebaine in neutral solution [3]. It is very readily hydrolysed to dihydrothebainone, which doubtless arises from this during the reduction of thebaine in acid solution. (Dihydrothebainone was prepared by Speyer and Ereunds [10] by the reduction of thebaine in neutral solution and no doubt arose from the enol ether by hydrolysis during the isolation of the product.)... 

Schopf and Borkowsky [25] postulated the 1 4-addition of water to the dienoid system of thebaine [1] to give [xxi], which could then undergo hydrolysis and t/r-codeine transformation to [xxn]. The ether bridge was then beliovod to break with introduction of a C-5 14 double bond, neoossitating migration of the side-chain from C-14 to C-5,... 

The first indication that derivatives of 14-aminocodeinone and 14-aminomorphi-none could be accessible came from the reaction of thebaine with nitrosobenzene to yield a cyclic adduct (10a) which yielded 14p-phenylaminodihydrocodeinone (11a) on sequential hydrolysis and reduction (Scheme 1) [5]. Schwab then utilised this chemistry for the synthesis of a small series of 14-phenylaminodihydrocodei-nones and derivatives (11) [6]. Some codeinone derivatives produced by these reactions were evaluated in antinociceptive assays, showing that the (V-methyl derivatives (11a,b) had substantial activity in the writhing assay but only weak... 

Further improvements in the synthesis of 13, using in situ generated nitrosofor-mates, were made by the Kirby group (Scheme 3) [13]. This method has proven both more convenient and higher yielding than the earlier methods. In brief, 2,2,2-trichloroethyl /V-hydroxycarbamate was oxidised by sodium periodate in the presence of thebaine to yield adduct (17) which was converted into (18) before zinc powder mediated reduction to an amino acetal and hydrolysis to 14-aminocodeinone (13). 

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