- One-Pot Process for Synthesis of Nalbuphine Hydrochloride and Impurity Control Strategy
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An improved kilogram-scale process of synthesis of nalbuphine was developed by investigating the critical parameters. Ten process-related impurities were identified, of which the source and control strategy was elucidated. Moreover, tetramethylammonium triacetoxyborohydride (Me4NBH(OAc)3) was developed to reduce the imine and ketone in one pot. As a result, 6-β-epimer was significantly controlled to only 0.08% in the crude nalbuphine. The improved process was robust at kilogram scale in 60.4% overall yield with 99.95% high-performance liquid chromatography (HPLC) purity.
- Chen, Yibo,Wu, Zenong,Yang, Zhezhou,Zhang, Fuli,Zhang, Tao,Zhao, Weili
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p. 1707 - 1717
(2020/12/01)
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- SYNTHESIS OF NOROXYMORPHONE
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The present invention relates to the improved synthesis of noroxymorphone of formula (III). Particularly, the invention shows a way how to reduce the impurity level in the product avoiding lengthy purification steps.
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Page/Page column 6; 7; 26
(2019/06/23)
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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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- PROCESSES AND OXAZOLIDINE-CONTAINING INTERMEDIATES FOR THE PREPARATION OF MORPHINE ANALOGS AND DERIVATIVES
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The present invention relates to processes useful in the preparation of morphine analogs and derivatives, such as naltrexone, naloxone and nalbuphine and intermediates in the synthesis of said morphine analogs and derivatives. In a particular example, the process begins with for example oxymorphone, oxycodone, 14-hydroxycodeinone or 14- hydroxymorphinone, and includes the formation of an oxazolidine-containing intermediate using catalytic oxidation.
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Paragraph 00277-00281
(2017/11/15)
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- Batch- and Continuous-Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines—A Concise Synthesis of Noroxymorphone
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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.
- Gutmann, Bernhard,Weigl, Ulrich,Cox, D. Phillip,Kappe, C. Oliver
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supporting information
p. 10393 - 10398
(2016/07/21)
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- REDUCTION OF ALPHA, BETA-UNSATURATED KETONE LEVELS IN MORPHINAN DERIVATIVE COMPOSITIONS
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The disclosure relates to processes for reducing the amount of a compound of formula (I) or a salt or a solvate thereof present in a composition comprising compounds of formulae (I) and (II) or a salt or a solvate thereof.
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Paragraph 00526; 00527
(2016/04/26)
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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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