- Efficient iron-catalyzed n-demethylation of tertiary amine-N-oxides under oxidative conditions
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An investigation into the influence of oxidative conditions on the efficiency of opiate N-demethylation using iron powder has been carried out under non-classical Polonovski conditions. This approach involves a two-step process of N-oxidation and subsequent treatment of the intermediate N-oxide hydrochloride with the redox catalyst. Significant improvements in rate and yield have been realized for these reactions in the presence of molecular oxygen. In this context, further rate enhancement was achieved by the judicious addition of small amounts of ferric ions, leading to a concomitant reduction in the amount of the zero-valent iron primary catalyst that is required. This has led to a generalized improved methodology for the N-demethylation of oripavine, codeine, morphine, and thebaine. This protocol can also be carried out in one-pot without the need to isolate the intermediate N-oxide.
- Kok, Gaik B.,Scammells, Peter J.
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experimental part
p. 1515 - 1521
(2012/02/04)
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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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- 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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experimental part
p. 4806 - 4811
(2010/10/19)
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- Opioids and efflux transporters. Part 2: P-glycoprotein substrate activity of 3- and 6-substituted morphine analogs
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Continuing our studies investigating opioids with reduced P-glycoprotein (P-gp) substrate activity, a series of known 3- and 6-hydroxy, -methoxy, and -desoxymorphine analogs was synthesized and analyzed for P-gp substrate activity and opioid binding affinity. 6-Desoxymorphine (7) showed high affinity for opioid receptors and did not induce P-gp-mediated ATP hydrolysis. Additionally, 7 demonstrated morphine-like antinociceptive potency in mice, indicating this compound as an ideal lead to further evaluate the role of P-gp in opioid analgesic tolerance development.
- Cunningham, Christopher W.,Mercer, Susan L.,Hassan, Hazem E.,Traynor, John R.,Eddington, Natalie D.,Coop, Andrew
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p. 2316 - 2320
(2008/12/22)
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- Studies on regioselective hydrogenation of thebaine and its conversion to hydrocodone
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Thebaine was subjected to catalytic hydrogenation under a variety of conditions in order to determine the regioselectivity for C-6/C-7 versus C-8/C-14 olefin saturation.
- Leisch, Hannes,Carroll, Robert J.,Hudlicky, Tomas,Cox, D. Phillip
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p. 3979 - 3981
(2008/02/04)
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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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- Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and efficient syntheses of (8S)-8-bromomorphide
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A practical method for the conversion of tetrahydrothebaine to dihydromorphine in 92% yield is described. The procedure should allow more efficient production of opium products and may be easily modified for large-scale synthesis. The conversion of codeine to (8S)-8-bromomorphide, a potentially valuable intermediate to 6-demethoxyoripavine and derivatives, is also described. The absolute configuration of (8S)-8-bromomorphide was determined by a single-crystal X-ray diffraction study of the hydrobromide salt.
- Przybyl, Anna K.,Flippen-Anderson, Judith L.,Jacobson, Arthur E.,Rice, Kenner C.
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p. 2010 - 2013
(2007/10/03)
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