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MrMario
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Synthesis of Hydroxynorketamine
Today I read an article about the working mechanism of Ketamine on depression. They discovered that (S-/R- Ketamine) is not the cause of the
anti-depressive effect but its metabolite hydroxynorketamine, which has no psychoactive/sedating or anesthethic effects. Link to article: https://www.sciencedaily.com/releases/2014/06/140617093820.h...
Quoted from Wikipedia:
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Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a metabolite of ketamine which is formed by hydroxylation of its metabolite norketamine.[1] In
contrast to ketamine and norketamine, hydroxynorketamine is inactive as an anesthetic and psychostimulant.[2][3] In accordance, it has only very weak
affinity for the NMDA receptor (Ki = 21.19 µM and > 100 μM for (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine, respectively).[4]
However, hydroxynorketamine does still show biological activity, having been found to act as a potent and selective negative allosteric modulator of
the α7-nicotinic acetylcholine receptor (IC50 < 1 µM).[4] Moreover, (2S,6S)-hydroxynorketamine was tested and was found to increase the function
of the mammalian target of rapamycin (mTOR), a marker of the antidepressant activity of ketamine, far more potently than ketamine itself (0.05 nM for
(2S,6S)-hydroxynorketamine, 10 nM for (S)-norketamine, and 1,000 nM for (S)-ketamine (esketamine), respectively), an action that was observed to
correlate closely with their ability to inhibit the α7-nicotinic acetylcholine receptor.[5][6][7] This finding has led to a call of reassessment of
the understanding of the rapid antidepressant effects of ketamine and their mechanisms.[8] However, subsequent research has found that
dehydronorketamine, which is a potent and select antagonist of the α7-nicotinic acetylcholine receptor similarly to hydroxynorketamine, is inactive
in the forced swim test at doses up to 50 mg/kg in mice, and this is in contrast to ketamine and norketamine, which are effective at doses of 10 mg/kg
and 50 mg/kg, respectively.[9] This is likely due to the far lower potency of dehydronorketamine as an NMDA receptor antagonist in comparison.
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Hydroxynorketamine (2-Amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one):
Ketamine ((RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone):
Because this substance is not psychoactive or has any anesthetic effects it's legal to synthesis right? If legal what would the procedure look like
during the synthesis of this compound. I want to learn about different reactions/mechanisms and this would be a challenging and fun way to learn more.
I will never make something illegal, so if anyone knows more about its legal status that would be nice!
[Edited on 6-5-2016 by MrMario]
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Metacelsus
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I was just thinking about this myself, after reading the same article. You could probably make it by heating this:
which you might be able to make indirectly from 2-chlorobenzonitrile and an appropriate cyclopentyl Grignard reagent (additional steps needed to add
hydroxyl groups).
[Edited on 5-6-2016 by Metacelsus]
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Nicodem
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The psychoactivity of a substance has no relation to its legal status. Most psychoactive compounds are legal to manufacture, posses and trade without
any limitations, or only regulatory limitations (like transportation, chemical safety or sales regulations). Only a small fraction of them is
controlled by the law and even this is highly jurisdiction specific.
Even if a compound is not psychoactive, it can still be controlled and illegal to manufacture, posses and trade. For example, in United States of
America, bufotenin is a "Schedule I" controlled substance (same class as heroin) even though it is not psychoactive by any standard definition. It was
scheduled by an ironic mistake in 1967 due to political hysteria, yet nobody removed it from the schedule after the error has been realized. Similar
things happen today with the so called "research chemicals" related hysteria where politicians "scheduled" several non-psychoactive compounds along
the real ones due to administrative errors (prohibition is a poorly regulated industry, and as such it produces bizarre errors often resulting in
human suffering).
Anyway, one thing is obvious. Nobody can answer whether this particular compound is legal in your jurisdiction, because you did not say which
jurisdiction you live in.
Quote: Originally posted by MrMario  | | If legal what would the procedure look like during the synthesis of this compound. I want to learn about different reactions/mechanisms and this would
be a challenging and fun way to learn more. |
Have you considered doing it by prior art? It looks doable to me.
Edit: Ketamine is a widely used active pharmaceutic ingredient (API) and is given the status of essential medicine by the World Health Organization. As such it is legal in most jurisdictions. Its human use is however regulated as it is an
API.
[Edited on 6/5/2016 by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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MrMario
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I'm from Europe, Netherlands. I thought some countries passed a law that scheduled all psychoactives (analogues) illegal.
I'm thinking of a grignard reaction of O-chlorobenzonitrile and 2,3-dihydroxy-1-Magnesiumbromide-cyclopentyl. The o-chlorobenzonitrile can be made
from o-chlorobenzoic acid, but I don't know how one should make the dihydroxycyclopentyl magnesiumbromide and if this would work in a grignard.
Maybe nitration of Cyclopentyl Bromide and then treatment via diazonium salt?
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AvBaeyer
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A very SIMPLE Google search turns up the following reference which contains further references to synthesis of various ketamine analogs including your
desired compound.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948022/
I did not look at the references- I leave that to anyone interested.
AvB
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Polverone
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It's probably spitting into the wind but I would like to remind everyone that the legal restrictions (or lack thereof) on possessing/manufacturing a
substance has never been a reason for me to shut down discussions here. Hence the large, flourishing Energetic Materials section. I
would actually enjoy more discussion of novel psychoactive substances here, or novel routes to popular materials. Much how I enjoy new substances or
synthetic routes to energetic materials when they're discussed in the EM section. The USA has some of the most overbearing synthetic drug laws but
some of the most permissive free speech laws in the world, so there is no risk to the forum or myself from discussing any chemistry here no matter how
great the legal penalties might be if you get caught trying to implement said chemistry in your own home.
I don't like low-effort threads started by people who are apparently just looking for a quick way to get high or get rich. Nor do I like low-effort
threads started by people who just want to make a big, impressive explosion without too much work. But I am never going to lock a thread just because
it might be a felony to do the chemistry where I live, or where some other members live. Everything is fine to write about and some members may be
more risk-tolerant or lucky enough to live in less legally uptight jurisdictions. The legal considerations, like the personal safety risks, are the
responsibility and choice of the individual contemplating doing some chemistry.
So please, feel free to discuss synthetic routes to this ketamine metabolite or any other interesting molecule that crosses your mind.
PGP Key and corresponding e-mail address
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Tsjerk
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In the Netherlands a compound is only illegal when it is specifically mentioned on the opiumlist. See 4-fluoro-amphetamine which is legal at the
moment.
Good luck with your synth!
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CuReUS
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Here is my method:
1.make 2-nitrocyclohexanone
a) from cyclohexen-1-yl acetate https://www.thieme-connect.com/products/ejournals/abstract/1...
( cylcohexen-1-yl acetate can be made from cyclohexanone and acetic anhydride - http://www.tandfonline.com/doi/full/10.1081/SCC-120013734 )
b)from cyclohexene
http://pubs.acs.org/doi/abs/10.1021/jo980167z
2.react it with 1-chlorobromobenzene in the presence of sodium methoxide to arylate the carbanion formed between the keto and the nitro group (maybe
the diazonium salt of o-chloroaniline could be used instead ? )
3.convert the ketone to alpha hydroxy ketone to get the desired product
a) in one step - http://www.sciencedirect.com/science/article/pii/S0022328X02...
b) the longer route would be to alpha bromination of the ketone followed by substituting with OH(being careful to avoid a favoriskii rearrangement).
4.reduce the nitro group to amine.
another way would be to start of with cyclohexanone with a COOMe/Et group at the alpha position,( instead of nitro),this can be arylated
similarly,then alpha hydroylated and finally the COOMe/Et can be converted to amide,then a hoffman- rearrangement can be done to get the amine (would
the alpha -OH react with the isocyanate to form a carbamate ? ).
In that case the rearrangement has to be done first and then the alpha hdyroxylation has to be done,but 2 questions arise-
1.would the bromine react with the NH2 during the alpha bromination ?
2.would there be a chance of N-alkylation between the Br of one molecule and the NH2 of another before the Br was substituted with OH ?
if the palladium catalyst was used for the alpha hydroxylation after the ester was converted to amine, the NH2 group would definitely
poison it 
and if the OH group is protected(by acetylation) before the rearrangement is done,there might be some dehydration during the deprotection step.
In step 2,the arylation might go via a benzyne intermediate, if I am not wrong
in that case I have a doubt https://en.wikipedia.org/wiki/Aryne#Regiochemistry_of_the_ad...
so would it give the desired arylated product if 1-chlorobromobenzene was used since Cl is an EDG
the problem could be avoided if the diazonium coupling is possible.
[Edited on 7-5-2016 by CuReUS]
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hissingnoise
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| Quote: |
The USA has some of the most overbearing synthetic drug laws but some of the most permissive free speech laws in the world, so there is no risk to the
forum or myself from discussing any chemistry here no matter how great the legal penalties might be if you get caught trying to implement said
chemistry in your own home. |
Ohhh, my G-a-a-a-d! The siteowner's just revealed himself to be a Trotskyite, commie libtard? 
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clearly_not_atara
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CuReUS: can you arylate the anion of an alpha-nitroketone with a mere haloarene? Two EWGs would seem to make that carbon atom a very weak nucleophile,
and aryl halides are already unreliable at carbanions, without very advanced catalysts, at least. It might be better to react 2-chlorocyclohexanone
with phthalimide and use 2-phthalimidocyclohexanone as your nucleophile. A diaryliodonium or a good ligand/metal catalyst is probably still necessary.
Nitro compounds have some frustrating instabilities, but using a different amine synthon and o-iodochlorobenzene should make it doable. I guess.
I tried to find a route that can't be used to make ketamine itself -- might as well keep the OP honest. Here goes:
From cyclopentanone cyanohydrin, dehydrate with P2O5 to 1-cyanocyclopentene.
Ortho-acylation of phenol may be achieved in two ways:
*by acylating phenol and separating the products with chromatography
*by acylating paracetamol, and removing the acetamide group with 1. N2O3; 2. hv in a reducing solvent (isopropanol); this may be difficult, but
N-nitrosoarylacetamides are known precursors to aryl radicals.
Ortho-acylation of phenol via cyanocyclopentene gives o-hydroxybenzoylcyclopentene. This is converted to o-chlorobenzoylcyclopentene with SOCl2,
Ph3P/Cl2 or possibly HOBt/SO2Cl2 (the latter reaction has only been tested on aliphatic alcohols, but it's a very similar idea).
From o-chlorobenzoylcyclopentene, the alkene is converted to a diol with cold alkaline KMnO4 (1. CH2Cl2, BnEt3NCl, KMnO4; 2. H2O/NaOAc; see [1], [2])
or with OsO4. The hydroxyketone functionality thus generated undergoes an alpha-ketol rearrangement with tritylamine, and is selectively deprotected
with a poisoned palladium catalyst.
[1]: https://www.thevespiary.org/rhodium/Rhodium/chemistry/alkene...
[2]: http://chemistry.mdma.ch/hiveboard/palladium/piperine/oxidn.PTC-DCM-MnO4_Chem.Lett.pp443-6(1979).mht
[Edited on 9-5-2016 by clearly_not_atara]
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Darkstar
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Not only that, but the nitroketone will also act as a bidentate ligand and coordinate with the sodium ions after being deprotonated by the
NaOCH3. This would result in an extremely stable chelate complex and a rather poor nucleophile, as the enolate's negative charge would be
significantly stabilized through both electrostatic forces as well as electron delocalization/resonance:
And while I'm not entirely sure to what extent (if any) this would happen given the strongly basic conditions, cyclic alpha-nitroketones can also
undergo a ring opening on reaction with alcohols and other similar nucleophiles. I'm guessing it works something like this (using ethanol instead of
methanol):
[Edited on 5-10-2016 by Darkstar]
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CuReUS
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first of all I thank you atara for replying to my post,your comments are invaluable
It is well known that b-keto esters can be arylated using haloarenes
http://matematicas.udea.edu.co/~carlopez/Organic_Name_Reacti...
Instead of an ester group I used nitro because it is even more electron pulling and I could convert it to amine later easily. If the reaction did
fail however,due to reasons you and darkstar pointed out,one could easily substitute the nitro group for a COOR which would make it a b-keto
ester.Then the arylation would definitely work.
| Quote: | | Two EWGs would seem to make that carbon atom a very weak nucleophile |
that's one way to look at it .The other way would be to think how acidic the alpha
H between these two EWG's would become and how easily a H-abstraction would be possible.(I am sure the nitro group would be enough on its own,the
ketone is there just for decoration )
| Quote: | | and aryl halides are already unreliable at carbanions |
I think you meant carbocations ? I am guessing the intermediate formed would be either that or benzyne,but I am not sure
| Quote: | | It might be better to react 2-chlorocyclohexanone with phthalimide and use 2-phthalimidocyclohexanone as your nucleophile. |
that's not a bad idea.You could decompose the phthalimide in the last step using a mild reaction to liberate the amine after alpha- hydroxylating the
ketone so that the NH2 does not interfere in the preceding reactions.The question is - "Is there a mild reaction for decomposing
pthalimide,while not dehydrating the a-hydroxyketone" ?
| Quote: | | Ortho-acylation of phenol via cyanocyclopentene gives o-hydroxybenzoylcyclopentene. |
I don't understand,How
can you acylate using CN ?
I think an easier way to o-chlorobenzoylcyclopentene would be to start of with o-chlorobenzoyl chloride and acylate the enamine formed from morpholine
and cyclopentanone.
preparation of the enamine - https://www.thieme-connect.com/products/ejournals/abstract/1...
the acylation - http://www.tandfonline.com/doi/abs/10.1080/00397918608077298
the yield is shitty though ( 46%)
| Quote: | | The hydroxyketone functionality thus generated undergoes an alpha-ketol rearrangement with tritylamine, and is selectively deprotected with a poisoned
palladium catalyst. |
In the NCBI paper that AvBayer linked above,the authors used liquid NH3(instead of using NH4OH) to make the imine which they
heated to to do the alpha-ketol rearrangement to get the amino-ketone.But their compound did not have the other OH group which could have got
dehydrated during the heating.Is that why you go via the tritylamine route ? Is that a milder approach ? Or is it because of the shitty yield in the
NH3 method(22% imine formed) ? Also,how do you plan on doing the rearrangement ? by heating ?
NH4OH approach - http://onlinelibrary.wiley.com/doi/10.1002/jps.2600710818/ab...
Attachment: sythesis of norketamine(NCBI method).doc (29kB)
This file has been downloaded 699 times
[Edited on 11-5-2016 by CuReUS]
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sushipizza
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1. Synthesis of norketamine
http://dx.doi.org/10.1016/j.tetlet.2015.04.050
2. Synthesis of hydroxynorketamine from norketamine
http://pubs.acs.org/doi/abs/10.1021/jm00161a043
Both articles are available for download in the usual places.
No synthesis of ketamine itself seems to be involved in this process, nor does any other (as far as I am aware) controlled substance.
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CuReUS
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I am surprised that the other OH group didn't get ripped out(dehydrated) or form condensation products(ethers) during the ritter reaction.There is
also a chance for a pinacol-pinacolone rearrangement to take place.It is also surprising that the dichromate didn't oxidise the NH2 as
well.
[Edited on 14-5-2016 by CuReUS]
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hnk55
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Could anyone synthesize hydroxynorketamine from ketamine for a group?
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Texium
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No. That would require making or otherwise obtaining ketamine which I'm sure would not be something any reputable member here would be willing to do.
Also, no spoonfeeding requests please.
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zed
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hnk55....
That would depend on your legal status. Got a permit? Doing research?
I'm sure someone here could whip up some ketamines for you, if it were legal to supply them to you.
It's just that, if you aren't licensed, it might appear......that you are soliciting members to commit a felony.
[Edited on 27-11-2016 by zed]
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loststar0
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It's not a classified substance. Assuming that you don't use ketamine, it's legal.
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zed
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Don't know where you are loststar0, but where most of us reside, Ketamine is not legal.
https://www.justice.gov/archive/ndic/pubs4/4769/#illegal
As always: "It is important for a gentleman, to avoids the appearance of impropriety."
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Aztral
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Plz don't message me with this nonsense about making you some ketamine (or derivative/synthetic).
If you're that hard-up, (and can maintain focus long enough) I suggest you pick up some books and make it yourself.
Beyond all that - no idea why you would message a complete newbie here. The very few posts I've made here have to do with deep eutectic solvents
and/or graphene production. I wouldn't even rate my chems skill/knowledge as college level just yet - although I learn fast 
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Texium
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They have sent that message out to many members here, new and old. Their U2U privileges have been revoked, and they will likely be banned.
https://www.sciencemadness.org/whisper/viewthread.php?tid=71...
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Dr.Bob
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Darn, I never got an email, I feel slighted. Even worse since I have made bioorganic molecules for 3 decades. Not that I would make drugs for
unknown parties, but it feels bad not to have been asked. Oh well.
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The Volatile Chemist
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| Quote: Originally posted by Dr.Bob | | Darn, I never got an email, I feel slighted. Even worse since I have made bioorganic molecules for 3 decades. Not that I would make drugs for
unknown parties, but it feels bad not to have been asked. Oh well. |
*Secretly cons the local idiots out of their cash by offering to do business and requiring an up-front fee*
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Dr.Bob
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No I just worked for a big pharma company that raised your prices often. That is a legal form of organized crime, nowadays. But I was RIF'd a
while back and now work for a non-profit. I would not try to con drug dealers, they are not the forgiving types. But I did watch Breaking Bad, so
now I know all about making illicit drugs... One of my favorite parts was getting red phosphorus from a road flare...
But the hydroxynorketamine synthesis does look challenging, and there is a clear need for a good route, so I would say that of all of the topics on
the forum, this is one that is ripe for someone to find a better route to. You could actually patent it and make some money, or get your PhD if you
could find a really good route to it. Maybe I will have to think about this in my (non-existant) spare time.
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Metacelsus
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I actually figured out a route (which I might post soon in the future), and am now trying to design an enantioselective one.
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