Naltrexone is n-cyclopropylmethylnoroxycodone. My inspiration for what follows is based on the knowledge that cyclopropanes reactivity is similar to alkenes. Cyclopropane carbon-carbon bonds are relatively short in length and yet have low disassociation energies. Also, the carbon-hydrogen bonds have similar characteristics those in ethylene.
So for instance, with electrophyllic additions they give Markonikov products. Therefore, N-cyclopropylmethyl should yield predominantly N-(2-bromo)butane (unless someone can comment on how the protonated nitrogen might contribute to further reactivity?).
Most excitingly though, cyclopropanes undergo hydrogenolysis with cission of the bond between the least substituted carbons. So..... hydrogenolylsis of the N-cyclopropylmethyl group in naltrexone yields N-isobutylnoroxymorphone which just so happens to be an agonist! (ED50 for s.c. N-isobutylnorlevorphanol HBr was 5.0 in mice, N-butyl tartrate was 4.9, and N-propyl was surprisingly inactive (Synthetic Analgesics, Part II A -Morphinans)) During my searching I found that someone had already done this: Bioorg Med Chem Lett. 2008 Sep 15;18(18):4978-81. "in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl (noroxymorphone)". "The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11-17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure-activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED(50): 5.05 mg/kg, sc), indicating it was an opioid agonist."
So, in one step a chemist can obtain a material which I believe is roughly equal to morphine in potency. In all likelihood one would want to further improve action via modification at that 14-OH position, ideally placing a cinnamoyl, hydrocinnamoyl, or phenylpropoxy, any of which should get potency well up into the hundreds times morphine in potency. Also, when looking at various potent N substituents of 14-phenylpropoxynoroxymorphone (J. Med. Chem. 2003, 46, 1758-1763), of all of the various structures tested, while all were potent agonists, none of them showed selectivity to the mu receptor except for N-propyl. They did not test the N-isobutyl material but I would venture to say that of the compounds tested N-propyl would give the best estimate of our N-(2-methyl)propyl group. My only possible concern with the estimated activity above would be if sterics came into play as in the case of N-phenethyl-14-phenylpropoxynormorphone, which was only 17x Morphine. I'm not sure how dimethyl-ethyl compares to phenyl-ethyl spacially. Maybe someone with the knowledge and/or tools could comment on this? If this were a significant issue then we could just forget the N-isobutyl and make the N-butyl-14-hydroxymorphone via electrophyllic addition using HBr followed by a dehalogenation.
14-phenylpropoxy-N-propylnoroxymorphone:
-400x Morphine in PPQ, 400x M in HP, 950x M in TF
-mu receptor preference: 4x kappa, 10x sigma
But back to that initial reaction of making the N-isobutyl material- platinum (IV) oxide, hydrobromic acid and a hydrogen atmosphere- this is not the most convenient set of reaction materials and conditions that I would imagine. But chemists have their hydrogenation set-ups (old habits) and so they stick with what they know rather than trying a more modern approach that may be much more convenient to accomplish while the job done in high yield and purity. What I propose is Catalytic Transfer Hydrogenolysis, or at the very least a more convenient catalytic hydrogenolysis (such as with the use of Pd/C). As far as I can tell CTH cission of cyclopropane bonds are not in the literature, but there appears to be a great Chemical Reviews article titled The Catalytic Hydrogenolysis of Small Carbon Rings where the main focus is on cyclopropanes. I do truly believe that after a thorough reading of this review, I will be able to refine a CTH route to the desired N-isobutyl materials.
Now, I beg for your help! Please, if you have the ability to provide the review articles listed below, either privately or on this thread, or if you can point out where free full versions of theses articles are on the web, I would be ever so grateful!!!
To continue this research I need access to:
Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic compounds
Robert A. W. Johnstone, Anna H. Wilby, Ian D. Entwistle
Chem. Rev., 1985, 85 (2), pp 129–170
DOI: 10.1021/cr00066a003
AND MOST IMPORTANTLY:
The Catalytic Hydrogenolysis of Small Carbon Rings.
J. Newham
Chem. Rev., 1963, 63 (2), pp 123–137
DOI: 10.1021/cr60222a003
Thanks for reading this post. Thank you for your insightful commentary and especially for any help with the needed references!!!
P.S. Yes, I am aware that there is a recently developed route to noroxymorphone from naloxone. But considering that amassing even just a few grams of naloxone can be extremely difficult for a number of reasons (small dosage, comes in injection solution for OD's) naloxone is not a viable starting material in my opinion.
So for instance, with electrophyllic additions they give Markonikov products. Therefore, N-cyclopropylmethyl should yield predominantly N-(2-bromo)butane (unless someone can comment on how the protonated nitrogen might contribute to further reactivity?).
Most excitingly though, cyclopropanes undergo hydrogenolysis with cission of the bond between the least substituted carbons. So..... hydrogenolylsis of the N-cyclopropylmethyl group in naltrexone yields N-isobutylnoroxymorphone which just so happens to be an agonist! (ED50 for s.c. N-isobutylnorlevorphanol HBr was 5.0 in mice, N-butyl tartrate was 4.9, and N-propyl was surprisingly inactive (Synthetic Analgesics, Part II A -Morphinans)) During my searching I found that someone had already done this: Bioorg Med Chem Lett. 2008 Sep 15;18(18):4978-81. "in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl (noroxymorphone)". "The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11-17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure-activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED(50): 5.05 mg/kg, sc), indicating it was an opioid agonist."
So, in one step a chemist can obtain a material which I believe is roughly equal to morphine in potency. In all likelihood one would want to further improve action via modification at that 14-OH position, ideally placing a cinnamoyl, hydrocinnamoyl, or phenylpropoxy, any of which should get potency well up into the hundreds times morphine in potency. Also, when looking at various potent N substituents of 14-phenylpropoxynoroxymorphone (J. Med. Chem. 2003, 46, 1758-1763), of all of the various structures tested, while all were potent agonists, none of them showed selectivity to the mu receptor except for N-propyl. They did not test the N-isobutyl material but I would venture to say that of the compounds tested N-propyl would give the best estimate of our N-(2-methyl)propyl group. My only possible concern with the estimated activity above would be if sterics came into play as in the case of N-phenethyl-14-phenylpropoxynormorphone, which was only 17x Morphine. I'm not sure how dimethyl-ethyl compares to phenyl-ethyl spacially. Maybe someone with the knowledge and/or tools could comment on this? If this were a significant issue then we could just forget the N-isobutyl and make the N-butyl-14-hydroxymorphone via electrophyllic addition using HBr followed by a dehalogenation.
14-phenylpropoxy-N-propylnoroxymorphone:
-400x Morphine in PPQ, 400x M in HP, 950x M in TF
-mu receptor preference: 4x kappa, 10x sigma
But back to that initial reaction of making the N-isobutyl material- platinum (IV) oxide, hydrobromic acid and a hydrogen atmosphere- this is not the most convenient set of reaction materials and conditions that I would imagine. But chemists have their hydrogenation set-ups (old habits) and so they stick with what they know rather than trying a more modern approach that may be much more convenient to accomplish while the job done in high yield and purity. What I propose is Catalytic Transfer Hydrogenolysis, or at the very least a more convenient catalytic hydrogenolysis (such as with the use of Pd/C). As far as I can tell CTH cission of cyclopropane bonds are not in the literature, but there appears to be a great Chemical Reviews article titled The Catalytic Hydrogenolysis of Small Carbon Rings where the main focus is on cyclopropanes. I do truly believe that after a thorough reading of this review, I will be able to refine a CTH route to the desired N-isobutyl materials.
Now, I beg for your help! Please, if you have the ability to provide the review articles listed below, either privately or on this thread, or if you can point out where free full versions of theses articles are on the web, I would be ever so grateful!!!
To continue this research I need access to:
Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic compounds
Robert A. W. Johnstone, Anna H. Wilby, Ian D. Entwistle
Chem. Rev., 1985, 85 (2), pp 129–170
DOI: 10.1021/cr00066a003
AND MOST IMPORTANTLY:
The Catalytic Hydrogenolysis of Small Carbon Rings.
J. Newham
Chem. Rev., 1963, 63 (2), pp 123–137
DOI: 10.1021/cr60222a003
Thanks for reading this post. Thank you for your insightful commentary and especially for any help with the needed references!!!
P.S. Yes, I am aware that there is a recently developed route to noroxymorphone from naloxone. But considering that amassing even just a few grams of naloxone can be extremely difficult for a number of reasons (small dosage, comes in injection solution for OD's) naloxone is not a viable starting material in my opinion.
CHEMREV 1985.pdf
Not that naltrexone is exactly easy to get however 
