- Alternative methods for the MnO2 oxidation of codeine methyl ether to thebaine utilizing ionic liquids
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The MnO2 oxidation of codeine methyl ether, CME, to thebaine has been accomplished via the use of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, bmimBF4. The ionic liquid has been used to remove or extract excess MnO
- Singer, Robert D,Scammells, Peter J
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- A novel synthesis of thebaine from codeine
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Codeine was converted into thebaine through methylation of the enolate of codeinone.
- Coop, Andrew,Rice, Kenner C.
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- Rearrangement of 5-trimethylsilylthebaine on treatment with L-selectride: An efficient synthesis of (+)-bractazonine
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Treatment of 5-trimethylsilylthebaine with L-Selectride gave rise to a rearrangement to 10trimethylsilylbractazonine through migration of the phenyl group, whereas treatment of thebaine with strong Lewis acids is known to lead to a similar rearrangement through migration of the alkyl bridge to give, after reduction, (+)-neodihydrothebaine. It is suggested that the rearrangement of the alkyl group of thebaine is favored due to the formation of a tertiary benzylic cation. However, for 5-trimethylsilylthebaine, the lithium ion of L-Selectride acts as the Lewis acid and the β-silyl effect dominates in the stabilization of any positive charge. This rearrangement provides a clear example of the greater relative migratory aptitude of phenyl groups over alkyl groups, and provides an efficient synthesis of (+)-bractazonine from thebaine.
- Chen, Weibin,Wu, Huifang,Bernard, Denzil,Metcalf, Matthew D.,Deschamps, Jeffrey R.,Flippen-Anderson, Judith L.,MacKerell Jr., Alexander D.,Coop, Andrew
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- Relationship of pharmacokinetic and metabolic parameters to the absence of physical dependence liability with thebaine 3H
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The rapid metabolism, excretion and elimination of thebaine from rat brain produces no biochemical changes in the cells of the central nervous system, which could be the reason for its low physiological tolerance.
- Misra,Pontani,Mule
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- Two-step iron(0)-mediated N-demethylation of N -methyl alkaloids
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(Figure Presented) A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.
- Kok, Gaik B.,Pye, Cory C.,Singer, Robert D.,Scammells, Peter J.
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- ESR ANALYSIS OF THE KINETIC ALKALINITY OF PSEUDOEPHEDRINE
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The kinetics of protonation of pseudoephedrine by 3,6-di-tert-butyl-2-hydroxyphenoxyl have been analyzed by the ESR technique.It was shown that protolysis of the radical produced closed ionic pairs with the pseudoephedrine cation in a dimer state. Keywords: ESR, pseudoephedrine, 3,6-di-tert-butyl-2-hydroxyphenoxyl, ion pairs.
- Masalimov, A. S.,Nikol'skii, S. N.,Abdykarimova, A. P.,Prokof'ev, A. I.,Muldakhmetov, Z. M.
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- Manganese dioxide allylic and benzylic oxidation reactions in ionic liquids
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Ionic liquids 1-butyl-3-methylimidazolium tetrafluoroborate [bmIm][BF4] and 1-butyl-3-methylimidazolium hexafluorophosphate [bmIm][PF6] were evaluated as reaction media for allylic and benzylic oxidation reactions using manganese dioxide. The use of ionic liquids as an extractant in the reaction work-up was also investigated. Procedures for recycling of the [bmIm][PF6] ionic liquids used in these MnO2 oxidation reactions were also developed.
- Hemeon, Ivan,Barnett, Neil W.,Gathergood, Nicholas,Scammells, Peter J.,Singer, Robert D.
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- Closure of the oxide bridge in morphine biosynthesis
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A highly substrate specific enzyme has been discovered and purified to homogeneity, which transfers the acetyl-moiety from acetyl-coenzyme A to the 7-OH group of salutaridinol. The formed 7-O-acetyl-salutaridinol spontaneously closes the oxide bridge at pH 8-9 by allylic elimination furnishing the morphine precursor thebaine.
- Lenz, Rainer,Zenk, Meinhart H.
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- A Regio- and Diastereoselective Anodic Aryl–Aryl Coupling in the Biomimetic Total Synthesis of (?)-Thebaine
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The biosynthesis of thebaine is based on the regioselective, intramolecular, oxidative coupling of (R)-reticuline. For decades, chemists have sought to mimic this coupling by using stoichiometric oxidants. However, all approaches to date have suffered from low yields or the formation of undesired regioisomers. Electrochemistry would represent a sustainable alternative in this respect but all attempts to accomplish an electrochemical synthesis of thebaine have failed so far. Herein, a regio- and diastereoselective anodic coupling of 3′,4′,5′-trioxygenated laudanosine derivatives is presented, which finally enables electrochemical access to (?)-thebaine.
- Lipp, Alexander,Ferenc, Dorota,Gütz, Christoph,Geffe, Mario,Vierengel, Nina,Schollmeyer, Dieter,Sch?fer, Hans J.,Waldvogel, Siegfried R.,Opatz, Till
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supporting information
p. 11055 - 11059
(2018/08/21)
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- Polonovski-type N-demethylation of N-methyl alkaloids using substituted ferrocene redox catalysts
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Various substituted ferrocenes have been trialed as catalysts in the nonclassical Polonovski reaction for N-demethylation of N-methyl alkaloids. Earlier studies suggest that conditions facilitating a higher ferrocenium ion concentration lead to superior outcomes. In this regard, the bifunctional ferrocene FcCH2CO2H, with electron donor and acceptor moieties in the same molecule, has been shown to be advantageous for use as a catalyst in the N-demethylation of a number of tertiary N-methylamines such as codeine, thebaine, and oripavine. These substrates are readily N-demethylated under mild conditions, employing sub-stoichiometric amounts of the substituted ferrocene at ambient temperature. These reactions are equally efficient in air and may also be carried out in one pot. Georg Thieme Verlag Stuttgart · New York.
- Kok, Gaik B.,Scammells, Peter J.
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experimental part
p. 2587 - 2594
(2012/09/22)
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- A facile synthesis and structural verification of etorphine and dihydroetorphine from codeine
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In this study, an improved process for the synthesis of etorphine and dihydroetorphine from codeine with an overall yield of 2.7% and 1.5% respectively is described. The structure of 19-propylthevinol 7 was verfied by X-ray structure analysis. This result is promising for synthesizing various morphine-based drugs.
- Huang, Xin-Ren,Srimurugan, Sankareswaran,Lee, Gene-Hsiang,Chena, Chinpiao
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p. 101 - 107
(2011/11/28)
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- On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives
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An improved method for the synthesis of 8-[(1E)-2-phenylethenyl]codeinone dimethyl ketal was described. The ability of [(1E)-2-phenylethenyl] substituent to stabilize effectively the π-system of the ring C is responsible for the essential difference in both the reactivity and the compositions of products formed in the reactions of the corresponding substituted and unsubstituted codeinone and thebaine derivatives.
- Moiseev,Shishkov,Kalinin
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body text
p. 557 - 560
(2011/11/05)
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- Synthesis and opioid activity of novel 6-substituted-6-demethoxy-ethenomorphinans
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A set of novel 6-substituted orvinols was synthesized and pharmacologically characterized in order to explore the effect of the polarity and steric effects of these new moieties on the opioid activity. It was revealed that longer 6-O-alkyl chains led to increased agonistic activities, while the lack of C6-etheral oxygen gave rise to an antagonistic profile at the opioid receptors in the mouse ileum.
- Czakó, Barbara,Marton, János,Berényi, Sándor,Gach, Katarzyna,Fichna, Jakub,Storr, Martin,Tóth, Géza,Sipos, Attila,Janecka, Anna
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scheme or table
p. 3535 - 3542
(2010/07/17)
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- N-Demethylation of N-methyl alkaloids with ferrocene
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Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.
- Kok, Gaik B.,Scammells, Peter J.
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supporting information; experimental part
p. 4499 - 4502
(2010/09/15)
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- Combination of benzyl-4, 5-dihydro-1H-imidazole derivative and an opioid receptor ligand
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The present invention refers to a combination of a Compound A, a benzyl-4,5-dihydro-1 H-imidazole derivative according to formula (I) and a Compound B, an opioid receptor ligand; especially of xylometazoline or oxymetazoline and a μ-opioid receptor agonist, most preferably of xylometazoline or oxymetazoline and morphine; a medicament comprising this combination; a pharmaceutical formulation for nasal application comprising this combination; or the use of this combination for the treatment of the symptoms of pain, or the prevention or the prophylaxis of the symptoms of pain, whereas pain particularily encompasses visceral pain, chronic pain, cancer pain, acute pain or neuropathic pain, specifically involving also breakthrough pain.
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- PROCESS FOR THE SYNTHESIS OF N-DEMETHYLATED MORPHINANE COMPOUNDS
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The present invention relates to a process for the preparation of an N-demethyl morphinane or a protected form thereof. In one form the preparation of the N-demethyl morphinane or a protected form thereof involves the N-demethylation of an N-methyl morphinane or protected form thereof. In particular the present process is useful in the preparation N-demethyl morphinane or a protected form thereof by N-demethylation of N-methyl morphinanes or protected forms thereof extracted from plants of the genus Papaver of the family Papaveraceae. An example of a suitable N-methyl morphinane that may be usefully subjected to the process of the present invention is thebaine.
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(2010/01/12)
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- Methods for making thebaine or its acid salts
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Methods for making thebaine and an acid salt of thebaine are disclosed herein. In one embodiment, an acid salt of thebaine is made from codeinone or an acid salt of one or more of the following: 8-methoxy-Δ6-dihydrothebaine, codeinone dimethyl ketal, and neopinone dimethyl ketal.
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- Preparation of opiates, intermediates and uses of salts
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A process for the preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of analogous 14-hydroxymorphinones.
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- Preparation of opiates, intermediates and uses of salts
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A process for the preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of analogous 14-hydroxymorphinones.
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- Formation and Reactions of C-Nitrosoformate Esters, A New Class of Transient Dienophiles
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Oxidation of N-hydroxycarbamic esters, ROCONHOH, with tetraethylammonium or sodium periodate in the presence of conjugated dienes gave N-alkoxycarbonyl-3,6-dihydro-2H-1,2-oxazines, formed apparently by cycloaddition of transient C-nitrosoformate esters, ROCONO, with the dienes.Cleavage of various N-alkoxycarbonyl derivatives under mild conditions is exemplified.The cycloadduct (10a) of benzyl nitrosoformate and 9,10-dimethylanthracene decomposed in benzene at 80 deg C in the presence of thebaine (3) to give the corresponding adduct (4a) of thebaine, together with 9,10-dimethylanthracene.Similarly, the adduct (6b) of 2,2,2-trichloroethyl nitrosoformate and cyclopentadiene, when heated with ergosteryl acetate, gave the corrresponding adduct (8b) of the steroid.Benzyl and t-butyl azidoformates decomposed in dimethyl sulphoxide at 115-130 deg C in the presence of thebaine to give the adducts (4a) and (4c) of benzyl and t-butyl nitrosoformate and the alkaloid.The other, major products were the sulphoximides (20a) and (20c).Alkoxycarbonylnitrenes, therefore, attack dimethyl sulphoxide either on sulphur, to give sulphoximides, or on oxygen, to give nitrosoformates.Benzyl nitrosoformate, generated thermally from either the adduct (10a) or (6a), reacted with triphenylphosphine to give, apparently, benzyloxycarbonylnitrene which attacked the solvent, benzene, to form N-benzyloxycarbonylazepine (24a).The adduct (6c) of t-butyl nitrosoformate and cyclopentadiene behaved likewise to give the azepine (24c).The reaction of (6c) with triphenylphosphine in benzene or dichloromethane gave a small quantity of 5,5-dimethyloxazolidin-2-one (26), a known cyclisation product of t-butyloxy-carbonylnitrene.
- Kirby, Gordon W.,McGuigan, Henry,Mackinnon, John W. M.,McLean, David,Sharma, Ram Prakash
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p. 1437 - 1442
(2007/10/02)
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- Method of producing thebaine from codeine and oripavine from morphine
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A method of producing thebaine from codeine and oripavine from morphine which comprises (a) producing the 0-6 methyl ethers from codeine and morphine using potassium hydride and methyl iodide as the O-alkylation agents and (b) subsequently oxidizing the respective 0-6 methyl ethers of codeine and morphine to shift from allylic structure to a dienol ether structure using an oxidizing amount of MnO2 in tetrahydrofuran to produce thebaine from codeine and oripavine from morphine. In the case of morphine, it is preferable to protect the 0-3 position by acetylation prior to the oxidizing step. Both the etherification and oxidizing steps are carried out under a protecting blanket such as nitrogen and the reactions are carried out preferably under atmospheric pressure and ambient temperature with the exception of the etherification affecting the 0-6 position which may be commenced by cooling with ice.
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- N-acyl-N-norsalutaridines and process for making them
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N-acyl-N-norsalutaridines can be made by oxidative coupling of N-acyl-N-norreticulines using thallium tristrifluoroacetate or a coordinating agent and an oxidizing agent. The N-acyl-N-norsalutaridines can be converted to thebaine, N-northebaine, and N-substituted-N-northebaines, which can be converted to opium alkaloids and related compounds.
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