- Enantioselective synthesis of (-)-codeine and (-)-morphine
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A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine. Copyright
- Trost, Barry M.,Tang, Weiping
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- BIOTRANSFORMATION OF CODEINONE TO CODEINE BY IMMOBILIZED CELLS OF PAPAVER SOMNIFERUM
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Papaver somniferum (opium poppy) cells were immobilized in calcium alginate, where they continued to live with their biological activity for 6 months.The immobilized living cells performed the biotransformation of (-)-codeinone to (-)-codeine in both a shake flask and a column bioreactor.The biotransformation ratio in the shake flask (70.4percent) was higher than that in the cell suspension (60.8percent).Furthermore, 88percent of the codeine converted was extracted in the medium.The column bioreactor was functional for 30 days under optimal conditions (20 deg C, 3,75 vvm in aeration), whereas the ratio was 41.7percent.Key Word Index - Papaver somniferum; Papaveraceae; immobilized cell; biotransformation; bioreactor; codeinone; codeine; GC/MS; SIM.
- Furuya, Tsutomu,Yoshikawa, Takafumi,Taira, Megumi
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- Total Synthesis of Codeine
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In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.
- Li, Qilin,Zhang, Hongbin
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p. 16379 - 16382
(2015/11/09)
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- On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships
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Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.
- Musazzi, Umberto M.,Matera, Carlo,Dallanoce, Clelia,Vacondio, Federica,De Amici, Marco,Vistoli, Giulio,Cilurzo, Francesco,Minghetti, Paola
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p. 177 - 185
(2015/05/20)
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- Transformation of codeine and codeine-6-glucuronide to opioid analogues by urine adulteration with pyridinium chlorochromate: Potential issue for urine drug testing
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Rationale: Pyridinium chlorochromate (PCC) is the active ingredient of 'Urine Luck', a commercially available in vitro adulterating agent used to conceal the presence of drugs in a urine specimen. The exposure of codeine and its major glucuronide metabolite codeine-6-glucuronide (C6G) to PCC was investigated to determine whether PCC is an effective masking agent for these opiate compounds. Methods: Following the addition of PCC to both spiked and authentic codeine and C6G-positive urine specimens, the samples were monitored using liquid chromatography/mass spectrometry (LC/MS). Stable reaction products were identified and characterized using high-resolution MS analysis and, where possible, nuclear magnetic resonance (NMR) analysis. Results: It was determined that PCC effectively oxidizes codeine and C6G, thus altering the original codeine-to-C6G ratio in the urine specimen. Four reaction products were identified for codeine: codeinone, 14-hydroxycodeinone, 6-O-methylcodeine and 8-hydroxy-7,8-dihydrocodeinone. Similarly, three reaction products were identified for C6G: codeinone, codeine and a lactone of C6G (tentative assignment). Conclusions: Besides addressing the complications added to interpretation, more investigation is warranted to further determine their potential for use as markers for monitoring the presence of codeine and C6G in urine specimens adulterated with PCC. Copyright
- Luong, Susan,Ung, Alison T.,Kalman, John,Fu, Shanlin
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p. 1609 - 1620
(2014/06/23)
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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 total synthesis of (±)-codeine by 1,3-dipolar cycloaddition
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Nitrone cycloaddition on a dearomatized bicyclic phenol enabled the facile construction of the correctly configured phenanthrene skeleton of codeine. Further steps yielded allopseudocodeine in a completely diastereoselective manner and finally (±)-codeine by allylic transposition through the hydrolysis of chlorocodides.
- Erhard, Thomas,Ehrlich, Gunnar,Metz, Peter
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supporting information; experimental part
p. 3892 - 3894
(2011/06/24)
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- Total synthesis of (-)-morphine
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We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNsamide moiety.
- Koizumi, Hifumi,Yokoshima, Satoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 2192 - 2198
(2011/06/19)
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- SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES
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The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.
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Page/Page column 84-85
(2010/12/17)
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- Further investigation of the N-demethylation of tertiary amine alkaloids using the non-classical Polonovski reaction
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The iron salt-mediated Polonovski reaction efficiently N-demethylates certain opiate alkaloids. In this process, the use of the hydrochloride salt of the tertiary N-methyl amine oxide was reported to give better yields of the desired N-demethylated product. Herein, we report further investigation into the use of N-oxide salts in the iron salt-mediated Polonovski reaction. An efficient approach for the removal of iron salts that greatly facilitates isolation and purification of the N-nor product is also described.
- Thavaneswaran, Shanti,Scammells, Peter J.
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p. 2868 - 2871
(2007/10/03)
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- Process for the production of opiates
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A morphine component, e.g., a concentrate of poppy straw, is converted into codeine in high yield and high purity and in a highly controlled manner. The conversion process involves the following steps: (a) providing a solution or suspension of a morphine component in an inert solvent or a mixture of solvents; (b) methylating the resultant solution or suspension with a methylating agent in the presence of an alkaline ingredient; and (c) recovering the resultant codeine as the free base or as a salt.
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Page/Page column 3-4; 9-10
(2008/06/13)
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- Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine
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An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.
- Trost, Barry M.,Tang, Weiping,Toste, F. Dean
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p. 14785 - 14803
(2007/10/03)
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- Synthesis of (-)-morphine
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The preparation of the diastereomerically pure β-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1. Copyright
- Taber, Douglass F.,Neubert, Timothy D.,Rheingold, Arnold L.
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p. 12416 - 12417
(2007/10/03)
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- Improved process for the preparation of codeine from morphine
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Codeine is prepared by reacting morphine with trimethyl phenyl ammonium chloride in the presence of an alkali metal carbonate and a hydrocarbon solvent at a temperature of from 40° to l20°C. Codeine is recovered from the reaction mixture. Codeine is useful as an analgesic and antitussive drug.
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- NEODIHYDROTHEBAINE AND BRACTAZONINE, TWO DIBENZAZONINE ALKALOIDS OF PAPAVER BRACTEATUM
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Two new dibenzazonine alkaloids, neodihydrothebaine and bractazonine were isolated from Papaver bracteatum.Their possible biosynthesis from thebaine is discussed.The structures of both new alkaloids are proven by synthesis.An isomeric dibenzazonine compound was also prepared. - Keywords: Papaver bracteatum; Papaveraceae; alkaloids; dibenzazonines; neodihydrothebaine; bractazonine; biosynthetic pathway; synthesis; 5,6,8,9-tetrahydro-2-methoxy-7-methyl-dibenzazonin-1,12-diol; 5,6,8,9-tetrahydro-2,10-dimethoxy-7-methyl-dibenzazonin-1-ol; 5,6,8,9-tetrahydro-2,11-dimethoxy-7-methyl-dibenz-azonin-1-ol; 5,6,8,9-tetrahydro-2,12-dimethoxy-7-methyl-dibenzazonin-1-ol.
- Theuns, Hubert G.,Lenting, Herman B. M.,Salemink, Cornelis A.,Tanaka, Hitoshi,Shibata, Masayoshi,et al.
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p. 1157 - 1166
(2007/10/02)
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- BIOTRANSFORMATION OF THEBAINE BY CELL SUSPENSION CULTURES OF PAPAVER SOMNIFERUM CV. MARIANNE
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Thebaine is biotransformed to neopine by cell suspension cultures of Papaver somniferum cv.Marianne grown in O-B5 medium.Results of precursor studies on these cell suspension cultures are also described.Key Word Index - Papaver somniferum; Papaveraceae; cell suspension culture; biotransformation; thebaine; neopine; morphinan alkaloids.
- Tam, W. H. John,Kurz, Wolfgang G. W.,Constabel, Friedrich,Chatson, Kenneth B.
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p. 253 - 255
(2007/10/02)
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- Facile synthesis of codeine precursors from thebaine
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Thebaine is converted to a mixture of codeinone and neopinone in aqueous formic acid solution containing as catalyst a mercuric salt. Thebaine is converted to a neopinone ketal by irradiation in an alkanol or to a mixture of neopinone and codeinone in an acidic aqueous solution. Neopinone ketals, codeinone and neopinone can be converted to codeine.
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- Claisen Reactions on Codeins. 8-Alkyl-8,14-dihydro-6-demethoxythebaines and -oripavines
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Claisen Eschenmoser reaction of 1a leads to 2a, which is transformed to 2c, e, and f by especially adopted reduction conditions.Reduction of 2i with LiAlH4 gives 2g.Catalytic hydrogenation of 2 results in ether bridge opening and formation of 4.Reaction of 2e with 4 N HCl yields the cyclic phenol 7a.Orthoester Claisen rearrangement of 1a leads to orthoacetate 10 and 11.Claisen Eschenmoser reaction on codeine isomers 1b and 12c gives the amides 12a and 1f.
- Fleischhacker, Wilhelm,Richter, Bernd
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p. 3866 - 3880
(2007/10/02)
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- Process for the preparation of 8-halodihydrocodeinone hydrohalides and codeine
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Compounds of the general formula STR1 in which X represents halogen. These compounds are useful in the production of codeinone and codeine substantially free from impurities.
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- Dehydrohalogenation of a 7-halodihydrocodeinone dialkyl ketal
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A process for the dehydrohalogenation of a 7-halo- or a 1,7-dihalodihydrocodeinone dialkyl ketal of the general formula (I): STR1 in which R represents an alkyl group containing from 1 to 6 carbon atoms, X represents hydrogen or chlorine or bromine and Y represents chlorine or bromine which comprises subjecting the ketal to the action of a base in the presence of a polar aprotic solvent. The process has utility in facilitating the production of codeine.
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- Process for converting neopinone to codeinone
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A process for converting neopinone alkaloid to codeinone alkaloid which involves treating neopinone with a hydrohalic acid in a suitable solvent under anhydrous conditions. It also relates to the compound 8-halodihydrocodeinone hydrohalide.
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