AlsoTapered
Bluelighter
- Joined
- Apr 1, 2023
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While the N-allyl and N-methylcyclopropyl homologues of oxymorphone have shown their utility as opiate antagonists, their remains a serious problem regarding their duration of action.
I note this supplement to WO2008096046A1. To be clear - noroxymorphone does not notably cross the blood-brain barrier so the analgesic activity demonstrated merely shows that peripheral (non-psychoactive) opioids can still act as analgesics. In many ways this provides great advantages. Psychological addiction does not represent a risk and with all psychoactivity absent, the level of physical dependence will be significantly reduced and the remaining symptoms amenable to treatment.
It merely represents a simple methodology to use a freely available precursor to develop novel antagonists,
But in spite of the fact that the following information does not in any way produce 'drugs of abuse;, I am aware that it could be considered a synthesis. NOT discussion. I am merely pointing to an existing patent.
I should add that the 6-carbonyl moiety can be converted to an ethenyl moiety via the Wittig reaction and the derivatives of such are used to treat alcohol dependence (nalmefene - Revex) and the replacement of the 3-hydroxy moiety with a carboxamide has produced a long-acting series of compounds used in the treatment of cocaine dependence.
.SUPPLEMENT
Synthesis of noroxymorphone hydrochloride.
Noroxymorphone has previously been synthesized from other opiates, such as morphine (1), codeine (2), or thebaine (3) in good overall yields. However, several synthetic steps are required and, as previously stated by Iijima et al. (4), noroxymorphone is difficult to purify. Although noroxymorphone is used in the manufacturing of naloxone, it is not commercially readily available for research purposes. Naloxone, however, is readily available and differs from noroxymorphone only by having an allyl group in the nitrogen. We reasoned that direct N-deallylation of naloxone would provide an easy access to a small-scale synthesis of pure noroxymorphone for research purposes.
A practical method for the N-deallylation of naloxone hydrochloride to afford noroxymorphone hydrochloride is presented. The N-deallylation was accomplished by rhodium-catalyzed (Wilkinson’s catalyst) isomerization of N-allyl to enamine, followed by hydrolysis of the enamine under the reaction conditions. The catalyst is not soluble in water under normal conditions and therefore such deallylations are typically done in a mixture of water and an organic solvent such as acetonitrile. However, the catalyst seems to be soluble in water, to some extent, at very high temperatures because when a heterogeneous mixture of naloxone in water and 5 to 10 mole percent of the catalyst was stirred at 200 °C for 30-60 min, a complete N-deallylation was observed (as determined by the complete disappearance of the olefinic protons between 5.50 and 6.00 ppm in the 1H NMR spectrum). When the reaction was performed at 150 °C or without the catalyst, no N-deallylation was observed at all. The developed microwave-assisted and rhodium-catalyzed N-deallylation method for preparing noroxymorphone is facile and robust.
I note this supplement to WO2008096046A1. To be clear - noroxymorphone does not notably cross the blood-brain barrier so the analgesic activity demonstrated merely shows that peripheral (non-psychoactive) opioids can still act as analgesics. In many ways this provides great advantages. Psychological addiction does not represent a risk and with all psychoactivity absent, the level of physical dependence will be significantly reduced and the remaining symptoms amenable to treatment.
It merely represents a simple methodology to use a freely available precursor to develop novel antagonists,
But in spite of the fact that the following information does not in any way produce 'drugs of abuse;, I am aware that it could be considered a synthesis. NOT discussion. I am merely pointing to an existing patent.
I should add that the 6-carbonyl moiety can be converted to an ethenyl moiety via the Wittig reaction and the derivatives of such are used to treat alcohol dependence (nalmefene - Revex) and the replacement of the 3-hydroxy moiety with a carboxamide has produced a long-acting series of compounds used in the treatment of cocaine dependence.
.SUPPLEMENT
Synthesis of noroxymorphone hydrochloride.
Noroxymorphone has previously been synthesized from other opiates, such as morphine (1), codeine (2), or thebaine (3) in good overall yields. However, several synthetic steps are required and, as previously stated by Iijima et al. (4), noroxymorphone is difficult to purify. Although noroxymorphone is used in the manufacturing of naloxone, it is not commercially readily available for research purposes. Naloxone, however, is readily available and differs from noroxymorphone only by having an allyl group in the nitrogen. We reasoned that direct N-deallylation of naloxone would provide an easy access to a small-scale synthesis of pure noroxymorphone for research purposes.
A practical method for the N-deallylation of naloxone hydrochloride to afford noroxymorphone hydrochloride is presented. The N-deallylation was accomplished by rhodium-catalyzed (Wilkinson’s catalyst) isomerization of N-allyl to enamine, followed by hydrolysis of the enamine under the reaction conditions. The catalyst is not soluble in water under normal conditions and therefore such deallylations are typically done in a mixture of water and an organic solvent such as acetonitrile. However, the catalyst seems to be soluble in water, to some extent, at very high temperatures because when a heterogeneous mixture of naloxone in water and 5 to 10 mole percent of the catalyst was stirred at 200 °C for 30-60 min, a complete N-deallylation was observed (as determined by the complete disappearance of the olefinic protons between 5.50 and 6.00 ppm in the 1H NMR spectrum). When the reaction was performed at 150 °C or without the catalyst, no N-deallylation was observed at all. The developed microwave-assisted and rhodium-catalyzed N-deallylation method for preparing noroxymorphone is facile and robust.