• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio | someguyontheinternet

6,14-Endoethenotetrahydrooripavine: parent molecule from which all Bentley's are made

serotonin2A said:
It is a broad interpretation but it has appeared in the Federal Register many times. Technically it would have to be litigated by a court but courts generally grant federal agencies wide latitude to interpret statutory language.

In your example, how would they prove the CO2 was derived from thebaine? Apomorphine, which is derived from morphine, is a much better example. Apomorphine was listed as a schedule II morphine derivative until 1976 when it was explicitly removed from control.

http://www.ncbi.nlm.nih.gov/pubmed/23949903
Click to expand...

My example was a bit of an extreme one, but what I was trying to say is that in 1 instance you can take a controlled substance, say thebaine, and obliterate it, producing nothing of use (for example CO2); in another instance you can take something really simple and unrelated, say benzene, and produce a "thebaine derivative", which itself is not illegal, in a number of steps (which can be unreasonably big) without actually starting from, using or having thebaine as an intermediate. So according to the logic I understand that the first product (CO2) would be illegal, while the second product would be legal, since it never involved a controlled substance.

If, as they say, the number of steps is irrelevant, then it can really get out of hand, which I'm sure you can see. Laws need to be strict and clear, there should be no room left for interpretation. Theoretically any known substance can be converted into any known/unknown stable substance in a finite number of reactions, so saying that "number of steps is irrelevant" and "all derivatives of controlled substances are also illegal" means that basically they've given themselves the freedom to name any substance illegal/controlled, as it theoretically can be derived from a controlled one.
 
Last edited:
blowpipe said:
My example was a bit of an extreme one, but what I was trying to say is that in 1 instance you can take a controlled substance, say thebaine, and obliterate it, producing nothing of use (for example CO2); in another instance you can take something really simple and unrelated, say benzene, and produce a "thebaine derivative", which itself is not illegal, in a number of steps (which can be unreasonably big) without actually starting from, using or having thebaine as an intermediate. So according to the logic I understand that the first product (CO2) would be illegal, while the second product would be legal, since it never involved a controlled substance.

If, as they say, the number of steps is irrelevant, then it can really get out of hand, which I'm sure you can see. Laws need to be strict and clear, there should be no room left for interpretation. Theoretically any known substance can be converted into any known/unknown stable substance in a finite number of reactions, so saying that "number of steps is irrelevant" and "all derivatives of controlled substances are also illegal" means that basically they've given themselves the freedom to name any substance illegal/controlled, as it theoretically can be derived from a controlled one.
Click to expand...

I don't think the interpretation is quite as broad as you are saying ("free to name any substance illegal"). This isn't a theoretical exercise. They are not classifying benzene as a opium alkaloid derivative because benzene has never, and will never, be synthesized through the route you are describing. Buprenorphine, the example they have actually litigated, is actually derived from thebaine, although several steps are required. A reasonable person, informed of the regulation and how buprenorphine is made, would likely understand that buprenorphine is controlled.
 
serotonin2A said:
I don't think the interpretation is quite as broad as you are saying ("free to name any substance illegal"). This isn't a theoretical exercise. They are not classifying benzene as a opium alkaloid derivative because benzene has never, and will never, be synthesized through the route you are describing. Buprenorphine, the example they have actually litigated, is actually derived from thebaine, although several steps are required. A reasonable person, informed of the regulation and how buprenorphine is made, would likely understand that buprenorphine is controlled.
Click to expand...

You're right about the reality of this law, it's not as broad as I made it out to be. Nevertheless, I'm still uncomfortable with the degree of freedom they're given and I hope you agree with me that theoretically it is very broad; what happens in practice is a whole other story of course. I apologize for going off-topic.
 
blowpipe said:
You're right about the reality of this law, it's not as broad as I made it out to be. Nevertheless, I'm still uncomfortable with the degree of freedom they're given and I hope you agree with me that theoretically it is very broad; what happens in practice is a whole other story of course. I apologize for going off-topic.
Click to expand...

I agree that it is more restrictive than is necessary. But I don't think it really matters all that much because there are plenty of other chemical classes that one can tinker around with if so inclined.
 
Naloxone, Naltrexone & Nalmefene are all derivatives.

You can make from oripavine that is NOT found in opium. It does occur in other strains of poppy, but not opium poppy. Take a look at Tazmanian Alkaloids. If the junk pushers in Mexico got their act together, they could obtain the Norman Strain, extract the oripavine and make 14-methoxymorphone - Some interesting chemistry in their. Which superbase for the final step and so on (I hope this is vague enough) because it isn't NaH like the patent. I forget the German guys name but I had quite a long exchange of E-mails concerning this factor as applied to buprenorphine. Of course, I presume he hadn't found the papers on N-dealkylation of buprenorphine.
 
Last edited:
clubcard said:
Naloxone, Naltrexone & Nalmefene are all derivatives.

You can make from oripavine that is NOT found in opium. It does occur in other strains of poppy, but not opium poppy. Take a look at Tazmanian Alkaloids. If the junk pushers in Mexico got their act together, they could obtain the Norman Strain, extract the oripavine and make 14-methoxymorphone - Some interesting chemistry in their. Which superbase for the final step and so on (I hope this is vague enough) because it isn't NaH like the patent. I forget the German guys name but I had quite a long exchange of E-mails concerning this factor as applied to buprenorphine. Of course, I presume he hadn't found the papers on N-dealkylation of buprenorphine.
Click to expand...

All three of those antagonists were origionally controlled by the DEA under the controlled substance act but were then explicitly removed from control. I think that happened in the 1970s. In the Canadian regulatory system, control of opiates is based on the exact synthesis route, so a particular opiate may or may not be controlled depending on how it is made (whether or not it is actually derived from a controlled opiate). But in the USA, it only matters if you CAN derive an opiate from a controlled precursor. Oripavine is controlled in the USA as a thebaine derivative, and so anything synthesized from it would be controlled as a "derivative of a derivative". That is the same logic they used to control buprenorphine. I guess the determining factor would be whether a particular conversion has appeared in the literature or is used commercially.

I'm not saying I agree with their logic, but that is the argument they have made, and courts have upheld it.
 
So, again, any literature that you guys could site for me that explicitly covers 14-methoxydihydromorphinone, 14-OH-morphine or 14-OH-morphinone? Doesn't have to be online, just a source and it's DOI# would be fine.
 
Synthesis of 14-alkoxymorphinan derivatives and their pharmacological actions.
In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel mu opioid analgesic with reduced propensity to alter motor function.

These articles contain binding affinity values and in vivo tests for 14-methoxydihydromorphinone compared to similar compounds and morphine. I don't think there is as much information about 14-hydroxymorphine and 14-hydroxymorphinone, in the past I searched for articles on the former and I couldn't find much useful information in papers from recent years. Perhaps they are described in more detail in older literature.
 
J; Schmidhammer has a patent with the synthesis of 14-methoxymorphone and another paper in which it's Ki values are compared with oxymorphone & 14-methoxymetopon. It's Ki is just under 1, if I recall correctly. ALL of the data IS in his patents but I'm not going to search dozens and dozens. My point was really concerning the choice of superbase. He used NaH so it's insoluble - the reaction has to take place on the interface of the NaH. Other superbases are soluble but he just said that they just used the simplest system. CH3I was the alkylating agent. It would be interesting to compare superbases in the protection of tertiary hydroxyls.
It's certainly all listed in Reaxys.
 
Abstracts of the papers you're talking about are linked in my previous post. ;)

According to the articles 14-methoxydihydromorphinone (14-OMO) has a Ki of 0.10 nM and 14-methoxymetopon (14-MM) 0.15 nM with oxymorphone having a Ki of 0.97 nM and morphine 6.55 nM (all at mu receptors). Both 14-OMO and 14-MM have a higher mu/kappa selectivity than oxymorphone.
 
Adder -

Getting the methyl onto the tertiary alcohol is big fun. You have to deprotonate it (cue superbase) with something with a Ph>30. I talked to the original chemist, Helmut Schmidhammer (search for dozens of related patents) and his attitude was 'well, NaH + CH3I was OK for the small samples we needed'. Anyone care to try with magic methyl ;-)
 
Last edited:
You must log in or register to reply here.
Top