Synthesis of N-Demethyl-N-Substituted-14-Hydroxycodeine and Morphine Derivatives<sup>+</sup>

Hosztafi, Sándor; Simon, Csaba; Makleit, S.

doi:10.1080/00397919208021649

Cited by 9 publications

(8 citation statements)

References 9 publications

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“…The improved yields of the N-nor products achieved using this reagent have been attributed to the enhanced electrophilicity of the acyl carbon, which is activated by its attachment to a vinyl ether moiety. Vinyl chloroformate (26) has been applied to opiates to give various N-noropiates in yields of greater than 90% [10,39]. An example is the conversion of oxymorphone 33 α-Chloroethyl chloroformate (ACE-Cl, 27) is an alternative to vinyl chloroformate, which has been applied to N-demethylate certain tertiary amines in near quantitative yield under mild conditions.…”

Section: The Von Braun Reactionmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

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The removal of an N-methyl group, or N-demethylation, is a useful chemical transformation in organic synthesis which has particular importance in the field of alkaloid chemistry. Historically, tertiary N-methyl alkaloids have been N-demethylated using the same methods as for N-dealkylating tertiary amines. Such methodologies have included the von Braun reaction, the use of chloroformate and azodicarboxylate reagents and the Polonovski reaction, amongst others. Photochemical and biochemical procedures have also been successfully employed. This review will examine these N-demethylation procedures, with special emphasis on their application to opiate alkaloids.

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Section: The Von Braun Reactionmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

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“…Sodium borohydride reduction of 14-hydroxymorphinone in ethanol yielded 14-hydroxymorphine ( 3 ) as previously described [18] . N -Phenethyl-14-hydroxynormorphine ( 4 ) was prepared in several steps from N -phenethylnorthebaine as earlier described [28] . N -Benzylnoroxymorphone ( 5 ) [31] and N -phenethylnoroxymorphone ( 6 ) [21] were synthesized by a new route via noroxymorphone ethylene ketal.…”

Section: Methodsmentioning

confidence: 99%

“…SAR studies were performed on a series comprising of four derivatives of morphine ( 1–4 ) and two derivatives of oxymorphone ( 5 and 6 ) ( Figure 1 ). Although the synthesis of compounds 1 [26] , [27] and 3 [18] has been reported about fifty years ago, and derivative 4 was prepared twenty years ago [28] , there is only spare data on their biological activities, with binding affinities and selectivities at MOP, DOP and KOP receptors not yet reported. Herein, we also describe the synthesis and biological characterization of a new N-substituted derivative of morphine, N -phenylpropylnormorphine ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

et al. 2014

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Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.

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“…Intramolecular nucleophilic attack of the amine was used to form unstable enaminone 24 , which was then trapped using CbzCl as a dienamide 25 in 72 % yield. Various oxidation conditions, including H 2 O 2 /HCO 2 H, MoO 5 ⋅ pyridine complex, and PhNO, were tested, but compound 25 did not react at all under these conditions. Furthermore, using 3‐chloroperoxybenzoic acid ( m CPBA) or NBS resulted in the decomposition of starting material 25 .…”

Section: Figurementioning

confidence: 99%

“…Consideringt he yield andr eaction time, DABCO was employed as ab ase for further investigations.C ombining DABCO with acetic acid instead of TFAr esulted in al ower yield (entry 13). Various oxidation conditions, including H 2 O 2 / HCO 2 H, [18] MoO 5 ·pyridine complex, [19] and PhNO, [20] were tested, but compound 25 did not react at all under these conditions. These results indicated that the bulkiness and basicity of the amine werei mportant for this [5+ +2] cycloaddition.N otably, this established sequence including a[5+ +2] cycloaddition readily furnished the ADE ring core bearingt he spiro structure and vicinal quaternary carbon centers from commerciallya vailable materialt hrough eight steps and three purifications using silica gel chromatography.…”

mentioning

confidence: 99%

Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition

Nakamura

Kawakami

Tsukano

et al. 2019

Chemistry A European J

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Ac oncise route for construction of the ACDE ring skeleton in calyciphyllineA type alkaloids was developed using an intramolecular [5+ +2] cycloaddition reaction of an oxidopyrylium species bearing at etrasubstituted olefin. Key to the successo ft his reactionw as the combination of acid and base, which accelerated the construction of this skeleton containing as piro ring and vicinal quaternaryc arbon centers. The resultant tricyclicA DE ring compound was converted to an ACDE ring model through CÀHo xidation anda na za-Wittig reaction.

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Synthesis of N-Demethyl-N-Substituted-14-Hydroxycodeine and Morphine Derivatives⁺

Cited by 9 publications

References 9 publications

N-Demethylation of Alkaloids

N-Demethylation of Alkaloids

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition

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Synthesis of N-Demethyl-N-Substituted-14-Hydroxycodeine and Morphine Derivatives+

Cited by 9 publications

References 9 publications

N-Demethylation of Alkaloids

N-Demethylation of Alkaloids

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

Concise Construction of the ACDE Ring System of Calyciphylline A Type Alkaloids by a [5+2] Cycloaddition

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Synthesis of N-Demethyl-N-Substituted-14-Hydroxycodeine and Morphine Derivatives⁺