Direct Synthesis of Naltrexone by Palladium‐Catalyzed <i>N</i>‐Demethylation/Acylation of Oxymorphone: The Benefit of CH Activation and the Intramolecular Acyl Transfer from C‐14 Hydroxy

Machara, Aleš; Cox, D. Phillip; Hudlický, Tomáš

doi:10.1002/adsc.201200677

Cited by 28 publications

(30 citation statements)

References 76 publications

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“…However, they were also highly dependent on the substituent present at C6, with more electron withdrawing substituents giving lower product yields. Overall, oxidations of opioids are challenging and almost exclusive to the production of 14-hydroxy derivatives from thebaine (6) and oripavine (7), in route to the preparation of drugs such as naloxone (4) and naltrexone (5) (Figure 1) [19,29]. Nonetheless, some oxidized products of opioids, namely 7,8-epoxides, have been suggested to bear less liability to dependence, with activity comparable to the parent compounds both in vitro and in vivo [23,24].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

Ahonen

Rinne

Grutschreiber

et al. 2018

European Journal of Medicinal Chemistry

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Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron(II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

Ahonen

Rinne

Grutschreiber

et al. 2018

European Journal of Medicinal Chemistry

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“…[5][6][7] The residence time is kept constant by using higher flow rates, which involves ap otential change in superficial velocity. [45] Based on the pioneering work of Hudlicky, [46] the aforementioned consortium has developed environmentally friendly continuous-flow procedures for catalytic N-demethylation methods (11!12)t hat rely on the use of molecular oxygen ast erminal oxidant (Scheme 8). One approach to overcome this problem is to apply "smartd imensioning" by using the appropriate reactor modules at the right locations.…”

Section: Ideal Solventsmentioning

confidence: 99%

The Use of Molecular Oxygen in Pharmaceutical Manufacturing: Is Flow the Way to Go?

2016

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Molecular oxygen is arguably the greenest reagent available to the organic chemist. Most commonly, a diluted form of oxygen gas, consisting of less than 10 % O in N ("synthetic air"), is used in pharmaceutical and fine chemical batch manufacturing to effectively address safety concerns when handling molecular oxygen. Concentrations of O in N below 10 % are generally required to prevent the risk of combustions in the presence of flammable organic solvents ("limiting oxygen concentration"). Nonetheless, the use of pure oxygen is more efficient than using O diluted with N and can often provide enhanced reaction rates, resulting in significant improvements in product quality and process efficiency. This Concept takes into account recent studies to make the argument that, for liquid-phase aerobic oxidations, pure oxygen can indeed be handled safely on large scale by employing continuous-flow reactors, while also providing highly convincing synthetic and manufacturing benefits.

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“…With 10 mol‐% Pd(OAc) 2 as catalyst and dioxane/acetic anhydride as solvent, N ‐acetylnorhydrocodone was obtained after 15 h at 80 °C. In subsequent publications, the Hudlicky group showed that the reaction can be extended to certain other morphine alkaloids, such as 3,14‐diacetyloxymorphone, by using oxygen under atmospheric pressure ( 5 ; Scheme ) , . The demethylation of diacetyloxymorphone is accompanied by intramolecular 14‐ O ‐ to 17‐ N ‐acetyl migration to form the 3,17‐diacetylnoroxy derivative as the immediate product ( 7 ; Scheme ) .…”

Section: Introductionmentioning

confidence: 99%

“…In subsequent publications, the Hudlicky group showed that the reaction can be extended to certain other morphine alkaloids, such as 3,14‐diacetyloxymorphone, by using oxygen under atmospheric pressure ( 5 ; Scheme ) , . The demethylation of diacetyloxymorphone is accompanied by intramolecular 14‐ O ‐ to 17‐ N ‐acetyl migration to form the 3,17‐diacetylnoroxy derivative as the immediate product ( 7 ; Scheme ) . Subsequent hydrolysis with 6 m HCl finally yields the desired noroxymorphone ( 3a ; Scheme ) …”

Section: Introductionmentioning

confidence: 99%

Design and Development of Pd‐Catalyzed Aerobic N‐Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

Gutmann

Cantillo

Weigl³

et al. 2017

Eur J Org Chem

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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.

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Direct Synthesis of Naltrexone by Palladium‐Catalyzed N‐Demethylation/Acylation of Oxymorphone: The Benefit of CH Activation and the Intramolecular Acyl Transfer from C‐14 Hydroxy

Cited by 28 publications

References 76 publications

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

The Use of Molecular Oxygen in Pharmaceutical Manufacturing: Is Flow the Way to Go?

Design and Development of Pd‐Catalyzed Aerobic N‐Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

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