- Perchloric acid induced epimerisation of the thevinones: An improved synthesis of 7β-dihydrothevinones
-
The region above and away from C7 in the orvinols is known to be of particular importance in determining the μ-opioid receptor profile of this important class of opioids. However it has been difficult to explore this site due to the relative inaccessibility of 7β-substituted compounds. Here we report that perchloric acid induced epimerisation of the 7α-ketones (dihydrothevinones) allows considerably improved access to a series of β-ketones (β-dihydrothevinones). The extent of epimerisation of the 7α-ketone is determined by the degree of steric bulk in both the 6,14-bridge and in the ketone side chain. (C) 2000 Elsevier Science Ltd.
- Derrick,Coop,Al-Mousawi,Husbands,Lewis
-
-
Read Online
- Photooxidation of Thebaine. A Route to 14-Hydroxymorphinones and Hydrodibenzofuran Analogs of Methadone.
-
The photooxidation of thebaine (1) produces a highly functionalized hydrodibenzofuran 2 via formation of the endoperoxide and a tert-amine radical cation.Photooxidation of the quaternary ammonium salt of thebaine 6, allows the isolation of the endoperoxide 7.Photooxidation of thebaine 1 in acidic medium (TFA), yields 14-hydroxycodeinone salt 3 via the corresponding endoperoxide.
- Lopez, Dolores,Quinoa, Emilio,Riguera, Ricardo
-
-
Read Online
- The [4 + 2] Addition of Singlet Oxygen to Thebaine: New Access to Highly Functionalized Morphine Derivatives via Opioid Endoperoxides
-
The photooxidation of thebaine (3) with a sun lamp affords two main products: hydrodibenzofuran 10 (major) and benzofuran 11 (minor). The latter compound becomes predominant if a Hg lamp is used instead of a sun lamp. The formation of 10 proceeds via an endoperoxide intermediate that undergoes oxidation at the nitrogen atom. Protection of the nitrogen either by protonation or quaternization prevents its oxidation and thus the photooxidation of 3 in acid media constitutes a one-pot procedure for the preparation of 14-hydroxycodeinone 35. Photooxidation of the thebaine ammonium salt 31 allows the isolation in good yields of the corresponding to thebaine endoperoxide 32. The selective protection and reduction of the keto, aldehyde, and olefinic groups of hydrodibenzofuran 10 allowed the preparation of several diol and keto alcohol derivatives. This is the first report on the use of photooxidation to functionalize thebaine at C(6) and C(14) and also the first on the isolation of opioid endoperoxides.
- Lopez, Dolores,Quinoa, Emilio,Riguera, Ricardo
-
-
Read Online
- PROCESS FOR THE SYNTHESIS OF BUPRENORPHINE
-
The present invention relates to a novel route of synthesis for the opioid receptor antagonist Buprenorphine or a pharmaceutically acceptable salt thereof, starting from thebaine, wherein the route comprises the reaction of the baine with a dienophile; forming an alkylated reaction product by reaction with a Grignard-reagent; formation of an cyanamide; deprotection of the cyanamide- and the phenolic-oxygen-moiety, wherein the cleavage of one or both groups is performed in the presence of an alkali or alkaline earth sulfide; followed by derivatization with a cyclopropyl-halogen and hydrogenation to yield Buprenorphine.
- -
-
Page/Page column 13
(2021/08/06)
-
- DEUTERATED COMPOUND AND MEDICAL USE THEREOF
-
The present invention relates to a compound represented by formula I and a non-toxic pharmaceutically acceptable salt thereof. In formula (I), R1 is H, CH3 or deuterated methyl (CD3); R2 is CH3 or CH2CH3; R3, R4 and R5 are each independently H or deuterium (D); when R1 is H or CH3, at least one of R3, R4 and R5 is D.
- -
-
Paragraph 0017
(2020/01/12)
-
- Photoredox Imino Functionalizations of Olefins
-
Shown herein is that polyfunctionalized nitrogen heterocycles can be easily prepared by a visible-light-mediated radical cascade process. This divergent strategy features the oxidative generation of iminyl radicals and subsequent cyclization/radical trapping, which allows the effective construction of highly functionalized heterocycles. The reactions proceed efficiently at room temperature, utilize an organic photocatalyst, use simple and readily available materials, and generate, in a single step, valuable building blocks that would be difficult to prepare by other methods.
- Davies, Jacob,Sheikh, Nadeem S.,Leonori, Daniele
-
supporting information
p. 13361 - 13365
(2017/10/17)
-
- PROCESS FOR THE PREPARATION OF (S)-2-((4R,4AS, 6R,7AR,12BS)-7,9-DIMETHOXY-1,2,3,4,5,6,7,7A-OCTAHYDRO-4A,7-ETHANO-4, 12-METHANOBENZOFURO[3,2-E] ISOQUINOLIN-6-YL)-3,3-DIMETHYLBUTAN-2-OL
-
An invention includes a process for the preparation of (S)-2((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol.
- -
-
Paragraph 00142-00147
(2017/05/02)
-
- PROCESS FOR THE PREPARATION OF OPIOID COMPOUNDS
-
The present invention is directed to a process for the preparation of opioid compounds such as buprenorphine, naltrexone, naloxone, nalbuphone, nalbuphine, and the like.
- -
-
Paragraph 0159; 0160
(2015/11/27)
-
- Industrial process for the preparation of buprenorphine and its intermediates
-
There is provided an efficient industrial process for the preparation of 21-cyclopropyl-7a-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro-oripavine,i.e. buprenorphine of Formula- I in high yield and purity, with enhanced safety and eco-friendly norms. The invention further relates to an improved process for preparation of intermediates thereof in high yield and purity.
- -
-
Paragraph 0055
(2015/01/18)
-
- Polonovski-type N-demethylation of N-methyl alkaloids using substituted ferrocene redox catalysts
-
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.
-
experimental part
p. 2587 - 2594
(2012/09/22)
-
- A facile synthesis and structural verification of etorphine and dihydroetorphine from codeine
-
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
-
p. 101 - 107
(2011/11/28)
-
- Processes for the synthesis of opiates alkaloids with reduced impurity formation
-
The invention provides processes for the production of opiate alkaloids. In particular, the present invention provides processes for the formation of opiate alkaloids that minimizes the formation of impurities.
- -
-
Page/Page column 7
(2010/04/25)
-
- Two-step iron(0)-mediated N-demethylation of N -methyl alkaloids
-
(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.
-
experimental part
p. 4806 - 4811
(2010/10/19)
-
- N-Demethylation of N-methyl alkaloids with ferrocene
-
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.
-
supporting information; experimental part
p. 4499 - 4502
(2010/09/15)
-
- PROCESSES FOR THE PRODUCTION OF BUPRENORPHINE WITH REDUCED IMPURITY FORMATION
-
The present invention provides process for the production of opiate alkaloids. In particular, the present invention provides processes for the production of buprenorphine or a derivative of buprenorphine that minimizes the formation of impurities.
- -
-
Page/Page column 23
(2010/04/27)
-
- Processes for synthesis of opiate alkaloid derivatives
-
The present invention provides processes for the synthesis of opiate alkaloids. In particular, the opiate alkaloids produced by the process of the invention are typically intermediate compounds that may be utilized to produce a variety of biologically active alkaloids including buprenorphine and diprenorphine.
- -
-
Page/Page column 8
(2010/04/25)
-
- Synthesis and opioid activity of novel 6-substituted-6-demethoxy-ethenomorphinans
-
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
-
experimental part
p. 3535 - 3542
(2010/07/17)
-
- Synthesis and evaluation of a full-agonist orvinol for PET-imaging of opioid receptors: [11C]PEO
-
Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [11C]PEO binds with high affinity to μ and κ-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the μ-OR after intravenous injection. Blocking studies with μ and κ-OR selective compounds demonstrated that the binding of [11C]PEO is saturable and selective to the μ-OR in rat brain.
- Marton, János,Schoultz, Bent W.,Hjoernevik, Trine,Drzezga, Alexander,Yousefi, Behrooz H.,Wester, Hans-Jurgen,Willoch, Frode,Henriksen, Gjermund
-
supporting information; experimental part
p. 5586 - 5589
(2010/03/24)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF MORPHINANE ANALOGUES
-
The present invention relates to an improved process for preparing morphinane analogues of formula (1) wherein the substituents R1, R2, R2a, R3, R4, R5 and Y have the meanings as defined in the specifications.
- -
-
Page/Page column 18; 27-28
(2009/10/30)
-
- BUPRENORPHINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
The present invention relates to a buprenorphine derivative or a pharmaceutically acceptable salt thereof which is an effective analgesic having a much reduced level of addictiveness and an analgesic composition comprising same as an active ingredient.
- -
-
Page/Page column 6
(2008/06/13)
-
- Oripavine derivatives and their uses as medicines
-
The present invention relates to oripavine derivatives of formula (I), wherein R1 is hydrogen or methyl, R2 is methyl, cyclopropyl methyl, cyclobutyl methyl or allyl, R3 is thiophenyl ethyl or cycloalkyl methyl where the cycloalkyl has 3 to 6 carbon atoms, or nontoxic pharmaceutically acceptable salts thereof. These compounds can be used for the preparation of analgesics or abstinence agents of opium habit-forming drugs.
- -
-
Page/Page column 2-4
(2008/06/13)
-
- NEW ORIPAVINE DERIVATIVES AND THEIR USES AS MEDICINES
-
The present invention relates to oripavine derivatives of formula (I), ???wherein R1 is hydrogen or methyl, R2 is methyl, cyclopropyl methyl, cyclobutyl methyl or allyl, R3 is thiophenyl ethyl or cycloalkyl methyl where the cycloalkyl has 3 to 6 carbon atoms, or non-toxic pharmaceutically acceptable salts thereof. These compounds can be used for the preparation of analgesics or abstinence agents of opium habit-forming drugs.
- -
-
-
- Isomerization reactions of 7-substituted 6,14-bridged thebaine derivatives (Bentley compounds)
-
Equilibration of the 7α→7β isomers of 7-subslituted 6,14-ethenomorphinanes has been accomplished, for the first time, in dipolar aprotic solvents by the application of bases with weak nucleophilic character. Transformation of the 7β-nitrile with phenylmagnesium bromide led to a new type of 6,6′-dimeric compound. Acta Chemica Scandinavica 1998.
- Marton, Janos,Garadnay, Sandor,Szabo, Zoltan,Hosztafi, Sandor,Makleit, Sandor
-
p. 1234 - 1238
(2007/10/03)
-
- Synthesis of N-substituted 7β-diprenorphine derivatives
-
The separation of thevinone (2a) and β-thevinone (2b), as well as that of dihydrothevinone (3a) and β-dihydrothevinone (3b) was accomplished. By the application of various procedures numerous new N-substituted Diprenorphine analogues (8a-f) with 7R absolute configuration were synthesized. Detailed pharmacological investigation of the prepared compounds may contribute to a better understanding of the structure-activity relationship of morphine alkaloids.
- Marton,Miklos,Hosztafi,Makleit
-
p. 829 - 848
(2007/10/02)
-