Hydroxy thebaine

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 starting material for these 14-hydroxy compounds is the opium alkaloid thebaine (9). Although present in only small amounts in the alkaloid fraction from Papaver somniferum, it constitutes the major component (as much as 26% of the dried latex) from a... 

After 10 years of intensive research, no significant dissociation of potent analgesia and dependence liability was accomplished. As an indirect result of the systematic program the identification of the 17-hydroxy-7,8-dihydro compounds oxycodone (patented in 1925 by E. Merck AG, Germany) and oxymorphone, derived from thebaine, are of particular note. 

The TPP-sensitized photo-oxidation of thebaine 101 as ammonium salts (entries ii and iii) affords the endoperoxide 104 and the 14-hydroxy-codeinone 105, stereoselectively and in high yields. Instead, product 103 is the main product under neutral conditions and its formation has been rationalized via an endoperoxide intermediate 102 that undergoes oxidation at the nitrogen atom (Sch. 61) [103]. 

Naloxone and naltrexone are prepared from thebaine in several steps. The first of these is the introduction of the 14-hydroxy group which can be accomplished by peroxy acid treatment of thebaine to yield 14/ -hydroxycodei-none (3) [42, 43], Catalytic hydrogenation affords 14/i-hydroxydihydroco-... 

Diels-Alder adducts of thebaine may exhibit exceptionally high levels of opioid activity. The crystal structure of 7a-(l-(i )-hydroxy-l-methylbutyl)-6,14-endo-ethenotetrahydrothebaine hydrobromide (Etorphine 221) was determined 00 and the C-ring cage structure was found to be severely distorted relative to the idealized Dreiding model. 

Chlorphenesin Hexamine Acetylcodeine Bephenium Hydroxy-naphthoate Oxypertine Thebaine Thiambutosine Hydrastinine... 

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. 

The reduction of thebaine methiodide with sodium in liquid ammonia leads to dihydrothebaine- dihydromethine [xxx], also accessible by the reduction of dihydrothebaine- methiodide the methyl ether can be prepared in the same way from dihydrothebaine methyl ether methiodide. [xxx] can be hydrolysed by mineral acids to the-bainone-B dihydromethine [xxxi], and reduced with difficulty to dihydrothebainone dihydromethine AB-enol methyl ether. Its methiodide on reduction with sodium and ammonia yields 4-hydroxy-3 6-dimethoxy-13-ethyl-7 13 9 10-tetrahydrophenanthrene [Xxxii] and on alkaline degradation gives A6,8-6-methoxythebendiene [xxxm] [11],... 

The synthesis of 10-hydroxymorphine has also been reported (392). Here it was necessary to protect the phenolic hydroxyl, and the ingenious device of preparing the allyl ether, followed after oxidation by removal of the allyl group with sodium and liquid ammonia, was used with success. Neopine, the A " isomer of codeine, was also transformed to the 10-hydroxy derivative, but thebaine (CCCXLIII) merely gave the known 14-hydroxycodeinone (CCCXLIV) by attack of the enol ether system (392). 

Thebainone, 7,S-Didehydro-4-hydroxy-3-meth-oxy-l7-nteihvlmorphinan-6-one thebainone-A. C.gHj.NO, mol wt 299 36. C 72.21%, H 7.07%, N 4.68%, O 16.03%. Prepn from thebaine. codeinone Or 0-ethylthiocodide Morris, Small, J. Am. Chem. Soc. 56, 2159(1934). Earlier references and discussion of structure Small, Lutz, Chemistry of the Opium Alkaloids, U.S. Public Health Reports Suppt. No. 103, Washington (1932). About anomalies in nomenclature and difference from metathebaioone see Henry. Plant Alkaloids (London, 1939) p 249. Description of all thebainones K. W. Bentley, The Chemistry of I he Morphine Alkaloids (Oxford, 1954) p 219-... 

The opium aikaioid thebaine can be syntheticaiiy converted to 14a-hydroxy-6-keto derivatives of... 

Lopez D, Quinoa E, Riguera R (1994) Photooxidation of thebaine - a route to 14-hydroxy-morphinones and hydrodibenzofuran analogs of methadone. Tetrahedron Lett 35 5727-5730... 

Oxidation of thebaine with m-chloroperbenzoic acid has been shown to give a mixture of 14-hydroxycodeinone and 8-acetoxy-14-hydroxy-dihydro thebaine (143), which can be hydrolysed to 8,14-dihydroxy-dihydrocodeinone and hydrolysed and dehydrated to 14-hydroxy-dihydrocodeinone. ... 

An improved rapid procedure for the preparation of normorphine and norcodeine by A/-demethylation with phenyl chloroformate followed by hydrazine has been reported.An efficient synthesis of N-cyclobutylmethylnoroxymorphone (naltrexone) from thebaine, via 14-hydroxy-codeinone, has been described,as have preparations of A/-tetrahydrofurfuryl-noroxymorphone and of N-s-alkyl- and N-t-alkyl-normorphines. ° N-Demethylation and O-de-ethylation of 3-O-ethylmorphine by rat hepatic microsomes has been observed.A patent has been published covering the... 

Reticuline (25) is also the key precursor for isoboldine (33), which is a minor alkaloid of Papaver somniferum (Brochmann-Hanssen et al. 1973) (the hydrophenan-threne alkaloids of this plant, e.g. thebaine (35) also derive from reticuline). Orienta-line (36) with a methylation pattern different to that in reticuline (25) was not incorporated into (33). Coupling of the two rings in reticuline (25) is thus ortho to a hydroxy-group on one ring and para on the other. 

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