- AN IMPROVED PROCESS FOR O-DEMETHYLATING METHOXY SUBSTITUTED MORPHINAN-6-ONE DERIVATIVES USING BORON-BASED COMPLEXES
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The present invention discloses an improved process for O-demethylation of methoxy-substituted morphinan-6-one derivatives using boron-based complex as a demethylating boron complex in an inert reaction solvent.
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Page/Page column 19-20
(2020/10/09)
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- PROCESS FOR IMPROVED OXYMORPHONE SYNTHESIS
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Processes for preparing oxymorphone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxymorphinone salt in the presence of trifluoroacetic acid and/or a glycol.
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Paragraph 0644-0655; 0703-0717
(2017/02/24)
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- PROCESS FOR OBTAINING 3,14-DIACETYLOXYMORPHONE FROM ORIPAVINE
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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.
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Page/Page column 20; 21
(2018/01/17)
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- Design and Development of Pd-Catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode
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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.
- Gutmann, Bernhard,Cantillo, David,Weigl, Ulrich,Cox, D. Phillip,Kappe, C. Oliver
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supporting information
p. 914 - 927
(2017/02/15)
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- PROCESS FOR THE PREPARATION OF OXYMORPHONE FREEBASE
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The present invention is directed to a process for the preparation oxymorphone freebase, comprising hydrogenation of 14-hydroxymorphinone in DMF, to yield oxymorphone freebase, preferably oxymorphone freebase of improved appearance, purity and / or yield. The present invention is further directed to oxymorphone freebase with improved impurity profile. The present invention is further directed to an HPLC or UPLC system/method for analysis of opioid compounds.
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Page/Page column 51
(2016/12/12)
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- Processes for Making Opioids Including 14-Hydroxycodeinone and 14-hydroxymorphinone
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Improved processes for making opioid products having low impurity levels including making 14-hydroxycodeinone and 14-hydroxymorphinone from thebaine and oripavine, respectively.
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Paragraph 0120; 0121
(2016/03/14)
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- Synthesis of Nororipavine and Noroxymorphone via N- and O-Demethylation of Iron Tricarbonyl Complex of Thebaine
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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.
- Machara, Ale?,Endoma-Arias, Mary Ann A.,Císa?ova, Ivana,Cox, D. Phillip,Hudlicky, Tomá?
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p. 1803 - 1813
(2016/07/06)
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- PROCESS FOR IMPROVED OXYMORPHONE SYNTHESIS
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Processes for preparing oxymorphone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxymorphinone salt in the presence of trifluoroacetic acid and/or a glycol.
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Paragraph 00505-00512
(2015/08/03)
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- O-DEMETHYLATING PROCESS OF METHOXY SUBSTITUTED MORPHINAN-6-ONE DERIVATIVES
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The present invention relates to an improved process for O-demethylating methoxy substituted morphinan-6-one derivatives using AlCl3 as a demethylating agent in a reaction-inert solvent having a water content ranging from 0.1 %wt to 0.8 %wt.10
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Page/Page column 6; 7
(2015/11/03)
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- PROCESS FOR IMPROVED OPIOID SYNTHESIS
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Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxymorphone base and/or an oxymorphone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.
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Paragraph 00565 - 00573
(2014/02/15)
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- IMPROVED METHOD OF PREPARING OXYMORPHONE
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The invention relates to an improved method of preparing oxymorphone or a salt thereof from oripavine. In particular, the invention relates to a method of preparing oxymorphone with a content of alpha-beta- unsaturated ketones (ABUK) 10 ppm.
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Page/Page column 19
(2014/01/08)
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- PROCESS FOR N-DEALKYLATION OF TERTIARY AMINES
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The present disclosure provides improved methods for N-dealkylation of tertiary amines, including methods for N-demethylation of alkaloids and opioids, in which the dealkylation reaction is carried out in a solvent comprising a tertiary alcohol. The present disclosure also provides improved processes for preparing semi-synthetic opioids that incorporate the disclosed methods for N-dealkylation of tertiary amines.
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Page/Page column 43; 56-57
(2012/01/05)
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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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- 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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- IMPROVED PREPARATION OF OXYMORPHONE FROM ORIPAVINE
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An improved method for the preparation of oxymorphone from oripavine is provided. Oripavine is oxidized to form 14-hydroxymorphinone after which the oxidation reaction is quenched to prevent the formation of 1-1'-dimer side products. The 14-hydroxymorphinone is then reduced, typically by catalytic hydrogenation to form oxymorphone. The inventive method disclosed is further applicable to the production of morphinan derivatives.
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Page/Page column 12
(2008/12/04)
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- PROCESS FOR PREPARING OXYMORPHONE
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Methods are provided which include converting oripavine to other opiates, including converting oripavine to 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone. Purification and salt formation are optionally included.
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Page/Page column 4; 7-8
(2008/12/05)
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- METHOD FOR MAKING ANALGESICS
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Improved analgesic oxymorphone hydrochloride contains less than 10 ppm of alpha, beta unsaturated ketones and pharmaceutical preparations comprising such oxymorphone hydrochloride. The oxymorphone hydrochloride is produced by reducing a starting material oxymorphone hydrochloride using gaseous hydrogen and under specified acidity, solvent system and temperature conditions. A specific polymorph of oxymorphone hydrochloride may be obtained by hydration.
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Page/Page column 9; 10
(2008/12/06)
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- NOVEL OPIATE REDUCTION UTILIZING CATALYTIC HYDROGEN TRANSFER REACTION
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An improved opiate synthesis scheme is provided. An improvement to the oxidation of oripavine and oripavine derivatives comprises the in-situ formation of the peroxacids required to oxidize the oripavine and oripavine derivatives to form an intermediate. An improvement to the reduction of the intermediate to form oxycodone and oxycodone derivatives comprises reduction utilizing a hydrogen transfer reagent. These improvements allow the production of oxycodone and oxycodone derivatives without isolation of the intermediate, providing a one-pot synthesis method.
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Page/Page column 9-10
(2008/12/08)
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- Synthesis of 2-fluoro-11-hydroxy-N-propylnoraporphine: A potential dopamine D2 agonist
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(Chemical Equation Presented) 2-Fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-11 -OH-NPa) was synthesized from thebaine in 13 steps with an overall yield of 1.35%. The key steps included the Pd-catalyzed 3-dehydroxylation of 14-hydroxymorphine, SN2 substitution of Ts- by F -, and CH3SO2OH-promoted rearrangement of the substituted morphinandiene. The dopamine binding affinity of this compound was also investigated on rat brain membranes, and as expected, this compound displayed high affinity and selectivity at the D2 receptor.
- Zhang, Ao,Csutoras, Csaba,Zong, Rushi,Neumeyer, John L.
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p. 3239 - 3242
(2007/10/03)
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- Transformations of morphine, codeine and their analogues by Bacillus sp
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A bacterial strain belonging to the genus Bacillus islolated by enrichment culture technique using morphine as a sole source of carbon transforms morphine and codeine into 14-hydroxymorphinone and 14-hydroxycodeinone as major and 14-hydroxymorphine and 14-hydroxycodeine as minor metabolites, respectively. When the N-methyl group in morphine and codeine are replaced by higher alkyl groups, the organism still retains its ability to carry out 14-hydroxylation as well as oxidation of the C6-hydroxyl group in these N-variants, although the level of metabolites formed are considerably low. The organism readily transforms dihydromorphine and dihydrocodeine into only dihydromorphinone and dihydrocodeinone, respectively, suggesting that the 7,8-double bond is a necessary structural feature to carry out 14-hydroxylation reaction. The cell free extract (20,000 × g supernatant), prepared from morphine grown cells, transforms morphine into 14-hydroxymorphinone in the presence of NAD+, but fails to show activity against testosterone. However, the cell free extract prepared from testosterone grown cells contains significant levels of 17β- hydroxysteroid dehydrogenase but shows no activity against morphine.
- Madyastha,Reddy,Sridhar
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p. 749 - 753
(2007/10/03)
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- L-Selectride as a general reagent for the O-demethylation and N- decarbomethoxylation of opium alkaloids and derivatives
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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.
- Coop,Janetka,Lewis,Rice
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p. 4392 - 4396
(2007/10/03)
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