33522-95-1Relevant academic research and scientific papers
Batch- and Continuous-Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines—A Concise Synthesis of Noroxymorphone
Gutmann, Bernhard,Weigl, Ulrich,Cox, D. Phillip,Kappe, C. Oliver
, p. 10393 - 10398 (2016)
14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas–liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.
Direct Synthesis of Noroxymorphone from Thebaine: Unusual CeIV Oxidation of a Methoxydiene-Iron Complex to an Enone-γ-Nitrate
Machara, Ales,Endoma-Arias, Mary Ann A.,Císa?ová, Ivana,Cox, D. Phillip,Hudlicky, Tomas
, p. 1500 - 1503 (2016)
Noroxymorphone was prepared from thebaine in seven operations. The key steps involved the successive N- A nd O-demethylations of an iron tricarbonyl complex of thebaine followed by the unusual ceric ammonium nitrate oxidation of the methoxydiene moiety to the corresponding enone-γ-nitrate during the decomplexation of the iron tricarbonyl functionality. A protocol for the conversion of thebaine to noroxymorphone via C-14 oxidation is described.
Efficient Synthesis of 14-Hydroxymorphinans from Codeine
Schwartz, Martin A.,Wallace, Rebecca A.
, p. 1525 - 1528 (1981)
Codeine is converted to 7,8-dihydro-14-hydroxynorcodeinone (noroxycodone) in six steps and 52percent overall yield or to noroxymorphone in seven steps and 43percent overall yield.N-Demethylation and oxidation of codeine afford N-(ethoxycarbonyl)norcodeinone, which is converted to its dienol acetate derivative and oxidized with singlet oxygen to give N-(ethoxycarbonyl)-14-hydroxynorcodeinone in the key step.Hydrogenation of the latter affords N-(ethoxycarbonyl)noroxycodone, which upon acid hydrolysis yields noroxycodone.Alternatively, O-demethylation of N-(ethoxycarbonyl)noroxycodone with boron tribromide and subsequent acid hydrolysis gives noroxymorphone.The results of the singlet oxygen oxidation of the pyrrolidine dienamine derived from N-(ethoxycarbonyl)norcodeinone are also described.
Design and Development of Pd-Catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode
Gutmann, Bernhard,Cantillo, David,Weigl, Ulrich,Cox, D. Phillip,Kappe, C. Oliver
, p. 914 - 927 (2017)
Strategies for the generation of noroxymorphone from 14-hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone, and nalmefene, as well as mixed agonists-antagonists such as nalbuphine. The transformation requires removal of the N-methyl group from the naturally occurring opiates and double-bond hydrogenation. The pivotal reaction step thereby is an N-methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3-oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and the use of various phenol protecting groups were explored. The most direct route consumes only H2, O2, and H2O as stoichiometric reagents and produces only H2O as a byproduct. Challenges inherent to gas/liquid reactions with oxygen as oxidant have been addressed by developing a continuous flow process.
An improved synthesis of noroxymorphone
Ninan,Sainsbury
, p. 6709 - 6716 (1992)
A brief synthesis of noroxymorphone is described which involves the oxidation of 3-O-(t)butyldimethylsilylmorphine by manganese dioxide. The initial product is the corresponding morphinone which is further oxidised to the 14-hydroxymorphinone. After hydrogenation the 7,8-dihydro-14-hydroxymorphinone is acetylated and N-demethylation of the 14-O-acetylated product is achieved using vinyl chloroformate as the reagent. The overall yield from morphine is 40-45%.
Synthesis of Nororipavine and Noroxymorphone via N- and O-Demethylation of Iron Tricarbonyl Complex of Thebaine
Machara, Ale?,Endoma-Arias, Mary Ann A.,Císa?ova, Ivana,Cox, D. Phillip,Hudlicky, Tomá?
, p. 1803 - 1813 (2016)
Thebaine was converted into its iron tricarbonyl complex, which underwent successive N- and O-demethylation with BrCN and BBr3, respectively. Decomplexation of the iron tricarbonyl moiety was accomplished with ammonium cerium(IV) nitrate (CAN) and base-catalyzed hydrolysis furnished nororipavine. When excess CAN was used the methoxydiene unit was converted into its C-14 nitrate that on hydrogenation and further hydrolysis furnished noroxymorphone. Full experimental and spectral data are provided for all key compounds.
Synthesis and Characterization of Azido Aryl Analogs of IBNtxA for Radio-Photoaffinity Labeling Opioid Receptors in Cell Lines and in Mouse Brain
Grinnell, Steven G.,Uprety, Rajendra,Varadi, Andras,Subrath, Joan,Hunkele, Amanda,Pan, Ying Xian,Pasternak, Gavril W.,Majumdar, Susruta
, p. 977 - 993 (2020/05/29)
Mu opioid receptors (MOR-1) mediate the biological actions of clinically used opioids such as morphine, oxycodone, and fentanyl. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating multiple splice variants. One type of splice variants are truncated variants containing only six transmembrane domains (6TM) that mediate the analgesic action of novel opioid drugs such as 3′-iodobenzoylnaltrexamide (IBNtxA). Previously, we have shown that IBNtxA is a potent analgesic effective in a spectrum of pain models but lacks many side-effects associated with traditional opiates. In order to investigate the targets labeled by IBNtxA, we synthesized two arylazido analogs of IBNtxA that allow photolabeling of mouse mu opioid receptors (mMOR-1) in transfected cell lines and mMOR-1 protein complexes that may comprise the 6TM sites in mouse brain. We demonstrate that both allyl and alkyne arylazido derivatives of IBNtxA efficiently radio-photolabeled mMOR-1 in cell lines and MOR-1 protein complexes expressed either exogenously or endogenously, as well as found in mouse brain. In future, design and application of such radio-photolabeling ligands with a conjugated handle will provide useful tools for further isolating or purifying MOR-1 to investigate site specific ligand–protein contacts and its signaling complexes.
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.
PROCESS FOR THE PREPARATION OF MORPHINANE COMPOUNDS
-
Page/Page column 9, (2019/01/21)
The invention describes the process of catalytic O-demethylation of 3-methoxy-morphinane compounds using boron tribromide. Addition of catalysts reduces the reaction time, improves reacting the substrate to give the product in very good purity and yield. The said approach can be used, for example, for the preparation of oxymorphone, naltrexone, naloxone and nalbuphine from their respective O-methyl derivatives.
PROCESS FOR OBTAINING 3,14-DIACETYLOXYMORPHONE FROM ORIPAVINE
-
, (2018/01/17)
The present invention relates to a new process for obtaining 3,14-diacetyloxymorphone from oripavine, a process to transform the obtained 3,14-diacetyloxymorphone into a noroxymorphone and a process to transform said noroxymorphone into naloxone, naltrexone, nalbuphine, nalfurafine or nalmefene.
