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466-97-7Relevant articles and documents
Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants
K?teles, István,Mazák, Károly,Tóth, Gerg?,T?z, Boglárka,Hosztafi, Sándor
, (2020/09/17)
Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.
Efficient iron-catalyzed n-demethylation of tertiary amine-N-oxides under oxidative conditions
Kok, Gaik B.,Scammells, Peter J.
, p. 1515 - 1521 (2012/02/04)
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.
Two-step iron(0)-mediated N-demethylation of N -methyl alkaloids
Kok, Gaik B.,Pye, Cory C.,Singer, Robert D.,Scammells, Peter J.
experimental part, p. 4806 - 4811 (2010/10/19)
(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.
N-Demethylation of N-methyl alkaloids with ferrocene
Kok, Gaik B.,Scammells, Peter J.
supporting information; experimental part, p. 4499 - 4502 (2010/09/15)
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.
Therapeutic compounds
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Page/Page column 13, (2008/06/13)
This invention relates to novel structural analogues and derivatives of compounds with general analgesic or related pharmacological activity. In particular the invention relates to derivatives of opioid compounds, particularly morphine and related compounds, in which an opioid compound is linked via the nitrogen at position 17 to a spacer group, which in turn is linked to a charged group, or a pharmaceutically acceptable salt thereof. In particularly preferred embodiments the opioid compound is morphine, codeine, or buprenorphine.
L-Selectride as a general reagent for the O-demethylation and N- decarbomethoxylation of opium alkaloids and derivatives
Coop,Janetka,Lewis,Rice
, p. 4392 - 4396 (2007/10/03)
L-Selectride was shown to be an efficient and general O-demethylating agent for the opium alkaloids and their derivatives and also an efficient reagent for the cleavage of methyl carbamates, thus offering a convenient method for the N-demethylation of opioids. Further, it was shown that by choice of reaction conditions it is possible to achieve both N- decarbomethoxylation and O-demethylation in one pot, or only render N- decarbomethoxylation in high yield without accompanying O-demethylation.
Synthesis of a Morphine-6-Glucuronide Hapten, N-(4-Aminobutyl)normorphine-6-Glucuronide, and Related Haptens
Brown, Richard T.,Carter, Neil E.,Lumbard, Keith W.,Scheinmann, Feodor
, p. 8661 - 8664 (2007/10/02)
For use as a hapten in the radioimmunoassay of morphine-6-glucuronide (2) (M6G), N-(4-aminobutyl)normorphine-6-glucuronide 12 has been prepared, together with related haptens, using the imidate coupling method developed for synthesis of M6G; a rebuttal of recent critical comments on our synthesis of M6G is included.
Diastereoisomeric quaternary morphinium salts: Synthesis, stereochemistry and analgesic properties
Iorio,Disciullo,Mazzeo Farina,Frigeni
, p. 11 - 16 (2007/10/02)
Diastereoisomeric quaternary morphinium salts were prepared by alkylation of morphine with alkyl halides or by alkylation of N-alkylnormorphines with methyl iodide. Nitrogen configuration of diastereoisomeric pairs was assigned by means of 1H NMR chemical shifts of corresponding N-methyl protons. These compounds were evaluated for analgesic activity by the guinea pig ileum assay and by the hot-plate test after icv administration in mice. The correlation between N-substituent orientation and narcotic agonist/antagonist activity is discussed.