Thebaine oxidation

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

Singer and Scammells have investigated the y-Mn02 oxidation of codeine methyl ether (CME) to thebaine in the ionic liquid [BMIM][BF4] [63]. The ionic liquid was used in different ways and with mixed results (Scheme 5.1-35). For example, the oxidation of CME in the ionic liquid gave 38 % yield after 120 hours. A similar reaction under biphasic conditions (with diethyl ether) gave a 36 % yield of thebaine. This reaction gave a 25 % yield of thebaine when carried out in tetrahydrofuran... 

Finally, it should be mentioned that ionic liquids have successfully been used in classical, stoichiometric oxidation reactions as well. Singer et al., for example, described the application of [BMIM][Bp4] in the oxidation of codeine methyl ether to thebaine [64]. The ionic liquid was used here as a very convenient solvent to extract excess Mn02 and associated impurities from the reaction mixture. 

Thallium metal, 24 627—629 Thallium nitrates, 24 633 Thallium organometallics, 24 633—635 Thallium oxides, 24 632—633 Thallium poisonings, 24 637, 638-639 Thallium stress test, 24 629 Thallium sulfates, 24 628, 633 Thaumatin, 72 43, 24 241-242 Thaumatin II, 24 242 Theaspiranes, 24 572 Thebaine, 2 89 Thenardite, 22 863, 5 785t Thenoyltrifluoroacetone molecular formula, 5 712t Theobroma cacao, 6 350 Theobromine, 2 105-106... 

The transient C-nitrosoimine 193 (Ar = 4-CIC6H4) is formed by the action of ethyl cyanoformate on the sulfimide 191 and also by the oxidation of the amidoxime 192 with lead tetraacetate. In the presence of thebaine, both reactions yield an identical dihydrooxazine101. 

It was postulated [152, 153] that the aryl amine is oxidized by direct oxygen transfer from Compound I to the substrate. In contrast, for the oxidation of alkaloids, e.g. morphine, codeine and thebaine (Eq. 12), to the corresponding N-oxi-des by hydrogen peroxide in the presence of HRP or crude enzyme preparation from poppy seedlings, a radical mechanism was proposed [154]. 

Oxymorphone Oxymorphone, 4,5-epoxy-3,14-dihydroxy-N-methyl-6-oxyomorphinane (3.1.26), is chemically similar to hydromorphone. It differs from hydromorphone in that it contains a hydroxyl group on C13. The drug is synthesized from thebaine (3.1.23), which during oxidation with hydrogen peroxide in formic acid changes into 14-hydroxycodeinone... 

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). 

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. 

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]. 

Two isomeric IV-oxides of morphine, of codeine, and of thebaine have been isolated from P. somniferum, and the thebaine V-oxides are also present in P. bracteatum. The oxides have, in each case, also been prepared by the N-oxidation of the free bases. N.m.r. spectroscopic studies suggest that the nitrogen-oxygen bond is axial in the major isomer and equatorial in the minor.146... 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

Circumstantial evidence suggested that levorphanol ((-) 49, R = OH R = Me), because its pharmacodynamic profile is similar to that of morphine, has the same absolute configuration. Proof of absolute configuration came from Hellerbach s group,<35) who subjected it to Hofmann degradation, followed by oxidative steps to the dicarboxylic acid, 52, identical to that obtained from thebaine and abietic acid. 

Acetylthebaol [i, R = Ac] can be oxidized to a quinone [n] without loss of groups, showing that the 9 10 positions are free from substituents [07-68], and methylthebaol [i, R = Me] [72] was shown to be identical with 3 4 6-trimethoxyphenanthrene by synthesis of the latter [73]. In this way the positions of the oxygen functions in thebaine were established and the base identified as a derivative of a partially hydrogenated phenanthrene. 

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