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draculic acid69
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[*] posted on 1-3-2023 at 07:38
Can't figure out synthesis


So recently read a paper on cannabinoid synthesis (THC's not spice analogs) and can't imagine how one would synthesize the olivetol (1,3dihydroxy 5pentyl benzene)
Usually I can look at a basic molecule and I can visualise a pathway to get to
it or at least really close. I just can't figure whether one starts with benzene,
alkyl benzene, resorcinol,phenol and what goes next is a bit of a mystery to me too.
Google is no help here either.1,3,5 pattern got me stumped. Anyone know how this could (theoretically) be made? Do u alkylate resorcinol with a Friedel craft rxn or nitrate alkyl benzene followed by reducing to aniline then diazotizing? I just can't figure out a possibility.
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blogfast25
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[*] posted on 1-3-2023 at 10:44


Quote: Originally posted by draculic acid69  
So recently read a paper on cannabinoid synthesis.


Which paper? (link)




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[*] posted on 1-3-2023 at 14:48


Here’s an interesting route published in an open-access journal: https://www.thieme-connect.de/products/ejournals/html/10.105...

Attachment: a-1440-9732.pdf (409kB)
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clearly_not_atara
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[*] posted on 2-3-2023 at 05:37


While I agree that the route posted by Texium is very nice, I had the same question once and I wondered if there should be a synthetic route via phloroglucinol, that typical representative of the 1,3,5 pattern. Indeed, from Wikipedia:

Quote:
Phloroglucinol readily forms 5-aminoresorcinol (aka Phloramine) in aqueous ammonia at low temperatures.[7][8]


With a suitable protection strategy, it should be possible in a few steps to substitute the amine for alkyl.




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[*] posted on 2-3-2023 at 05:54


Quote: Originally posted by clearly_not_atara  
While I agree that the route posted by Texium is very nice, I had the same question once and I wondered if there should be a synthetic route via phloroglucinol, that typical representative of the 1,3,5 pattern. Indeed, from Wikipedia:

Quote:
Phloroglucinol readily forms 5-aminoresorcinol (aka Phloramine) in aqueous ammonia at low temperatures.[7][8]


With a suitable protection strategy, it should be possible in a few steps to substitute the amine for alkyl.


And how would 5-aminoresorcinol lead to THC?




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[*] posted on 2-3-2023 at 10:59


Olivetol is found in some biological materials naturally, so hard to make it cheaper than just buying it from extracted material, although that is not trivial. But CBD is dirt cheap now, due to glut on the market, so it makes a much better starting material than olivetol for many compounds, and much easier to control reaction, as olivetol condensation makes a mixture of products. There are several ways to convert CBD to other useful materials in good yields. Anyway, you would really want a longer chain and more substitutions on the R group if you are doing synthetic work.
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[*] posted on 2-3-2023 at 13:26


Quote: Originally posted by Dr.Bob  
Olivetol is found in some biological materials naturally, so hard to make it cheaper than just buying it from extracted material, although that is not trivial. But CBD is dirt cheap now, due to glut on the market, so it makes a much better starting material than olivetol for many compounds, and much easier to control reaction, as olivetol condensation makes a mixture of products. There are several ways to convert CBD to other useful materials in good yields. Anyway, you would really want a longer chain and more substitutions on the R group if you are doing synthetic work.


So what would be a plausible route from CBD to THC? :o:o




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[*] posted on 2-3-2023 at 15:13


Alpha-resorcylic acid, which gives you the 5-substituted resorcinol part, can be made from benzoic acid and fuming sulphuric acid.
http://orgsyn.org/demo.aspx?prep=cv3p0288

A slightly longer route would be to make it from 3,5-dinitrobenzoic acid, by reducing the nitro groups to amines, then converting them to hydroxyls via the diazonium ions.
http://www.orgsyn.org/demo.aspx?prep=CV3P0337

Direct aromatic substitution at the 5 position is pretty much impossible with resorcinol itself, as the hydroxyl groups direct substitution to the 2, 4 or 6 positions.

[Edited on 2-3-2023 by Lionel Spanner]




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[*] posted on 3-3-2023 at 01:03


Quote: Originally posted by blogfast25  
Quote: Originally posted by Dr.Bob  
Olivetol is found in some biological materials naturally, so hard to make it cheaper than just buying it from extracted material, although that is not trivial. But CBD is dirt cheap now, due to glut on the market, so it makes a much better starting material than olivetol for many compounds, and much easier to control reaction, as olivetol condensation makes a mixture of products. There are several ways to convert CBD to other useful materials in good yields. Anyway, you would really want a longer chain and more substitutions on the R group if you are doing synthetic work.


So what would be a plausible route from CBD to THC? :o:o
get the weed seeds from anywhere is smartshop, smoke your cbd peacefully while plant is growing



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draculic acid69
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[*] posted on 3-3-2023 at 08:40


Quote: Originally posted by clearly_not_atara  
While I agree that the route posted by Texium is very nice, I had the same question once and I wondered if there should be a synthetic route via phloroglucinol, that typical representative of the 1,3,5 pattern. Indeed, from Wikipedia:

Quote:
Phloroglucinol readily forms 5-aminoresorcinol (aka Phloramine) in aqueous ammonia at low temperatures.[7][8]


With a suitable protection strategy, it should be possible in a few steps to substitute the amine for alkyl.


That seems like a feasible starting point. Would you then diazotize the amine to a ???
How would u proceed? If the aminophlorglucinol had its OH's etherified to methyls then diazotize to a halide then grignard + long alky aldehyde (like propanal or pentanal) or nitrile to a ketone or alcohol then reduce OH to the alkane followed by remaining Omethyls removed to yeild the olivetol compound. Were U thinking something different?
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draculic acid69
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[*] posted on 3-3-2023 at 08:43


Quote: Originally posted by blogfast25  
[

Which paper? (link)


It's the one off the erowid/rhodium archive
It's old nothing new in there
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[*] posted on 3-3-2023 at 13:03


Quote: Originally posted by blogfast25  
Quote: Originally posted by Dr.Bob  
Olivetol is found in some biological materials naturally, so hard to make it cheaper than just buying it from extracted material, although that is not trivial. But CBD is dirt cheap now, due to glut on the market, so it makes a much better starting material than olivetol for many compounds, and much easier to control reaction, as olivetol condensation makes a mixture of products. There are several ways to convert CBD to other useful materials in good yields. Anyway, you would really want a longer chain and more substitutions on the R group if you are doing synthetic work.


So what would be a plausible route from CBD to THC? :o:o






I believe the route most commonly used is a reflux of CBD in toluene with p-toluene sulfonic acid.


It looks like a ring closure in which an alkene group reacts with an alcohol group to produce a closed ring.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357058/



[Edited on 3-3-2023 by Elemental Phosphorus]
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[*] posted on 3-3-2023 at 14:01


Quote: Originally posted by Elemental Phosphorus  
So what would be a plausible route from CBD to THC? :o:o[/rquote]





I believe the route most commonly used is a reflux of CBD in toluene with p-toluene sulfonic acid.


It looks like a ring closure in which an alkene group reacts with an alcohol group to produce a closed ring.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357058/





That looks like an interersting route and paper.




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[*] posted on 3-3-2023 at 17:40


That (acidic reflux in toluene) indeed is the way that most places make delta-8 THC, which has been largely ignored by the DEA due to the wording of the Hemp products law. With other acidic catalysts and solvents you can also get more delta-9, but that is illegal in many states.

Since delta 8 is ~50-90% as active as delta 9, and less illegal, most people go that route. That route is cheaper than any other way to make THC that I have everr seen. CBD can be bought wholesale for about $1/g, so there is no other way to make it that comes close to that price. Only some of the spice/K2 type indoles are cheaper per dose, as some are quite potent.
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[*] posted on 3-3-2023 at 22:49


Quote: Originally posted by draculic acid69  

That seems like a feasible starting point. Would you then diazotize the amine to a ???
How would u proceed? If the aminophlorglucinol had its OH's etherified to methyls then diazotize to a halide then grignard + long alky aldehyde (like propanal or pentanal) or nitrile to a ketone or alcohol then reduce OH to the alkane followed by remaining Omethyls removed to yeild the olivetol compound. Were U thinking something different?

I was thinking diazotization, yeah. Dimethyl carbonate gives the methyls and a carboxyl group on the nitrogen which can be removed by base. Substitution with cyanide is probably better since it avoids a Grignard. There's a thread somewhere on here about the prep of CuCN from ferrocyanide without using HCN. Avoids the sensitivity of a Grignard.

For subsequent alkylation may consider e.g. aldol or Claisen condensations or organomanganese. In particular benzyl manganese compounds are readily formed with activated Mn and considerably more stable (r.t.) than the usual Grignards.




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[*] posted on 4-3-2023 at 05:24


Quote: Originally posted by Dr.Bob  
That (acidic reflux in toluene) indeed is the way that most places make delta-8 THC, which has been largely ignored by the DEA due to the wording of the Hemp products law. With other acidic catalysts and solvents you can also get more delta-9, but that is illegal in many states.

Since delta 8 is ~50-90% as active as delta 9, and less illegal, most people go that route. That route is cheaper than any other way to make THC that I have everr seen. CBD can be bought wholesale for about $1/g, so there is no other way to make it that comes close to that price. Only some of the spice/K2 type indoles are cheaper per dose, as some are quite potent.


What would the work up to 'pure' delta-8 look like?

[Edited on 5-3-2023 by blogfast25]




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[*] posted on 4-3-2023 at 13:05


Quote: Originally posted by blogfast25  
Quote: Originally posted by Dr.Bob  
That (acidic reflux in toluene) indeed is the way that most places make delta-8 THC, which has been largely ignored by the DEA due to the wording of the Hemp products law. With other acidic catalysts and solvents you can also get more delta-9, but that is illegal in many states.

Since delta 8 is ~50-90% as active as delta 9, and less illegal, most people go that route. That route is cheaper than any other way to make THC that I have everr seen. CBD can be bought wholesale for about $1/g, so there is no other way to make it that comes close to that price. Only some of the spice/K2 type indoles are cheaper per dose, as some are quite potent.


What would the work up to 'pure' delta-9 look like?


From the paper I linked: "Higher product yields of either Δ8-THC or Δ9-THC can be gained by means of the improved conditions presented by Webster et al. [76]. The conversion of CBD to Δ8-THC is enhanced, if a CBD solution in toluene is boiled in the presence of a Lewis acid (p-toluenesulfonic acid or boron trifluoride, BF3), while Δ9-THC is preferably formed when CBD is dissolved in dichloromethane (DCM) and stirred at 0 °C in the presence of boron trifluoride etherate (BF3Et2O). To avoid the formation of oxidized side products, Webster et al. [76] further recommended conducting the conversion of CBD to Δ8-THC or Δ9-THC under nitrogen atmosphere."

I didn't see whether or not it yields 100% delta-9 THC, but evidently it produces mostly delta-9. I believe somewhere stated that the yield was around 70%, though.
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draculic acid69
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[*] posted on 4-3-2023 at 21:08


Quote: Originally posted by Dr.Bob  
Olivetol is found in some biological materials naturally, so hard to make it cheaper than just buying it from extracted material, although that is not trivial. But CBD is dirt cheap now, due to glut on the market, so it makes a much better starting material than olivetol for many compounds, and much easier to control reaction, as olivetol condensation makes a mixture of products. There are several ways to convert CBD to other useful materials in good yields. Anyway, you would really want a longer chain and more substitutions on the R group if you are doing synthetic work.


I've noticed 10% cbd in mct oil everywhere but cbd on its own is rare
also it's not cheap and usually it's the same price as thc
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[*] posted on 4-3-2023 at 21:17


Quote: Originally posted by Dr.Bob  
That (acidic reflux in toluene) indeed is the way that most places make delta-8 THC, which has been largely ignored by the DEA due to the wording of the Hemp products law. With other acidic catalysts and solvents you can also get more delta-9, but that is illegal in many states.

Since delta 8 is ~50-90% as active as delta 9, and less illegal, most people go that route. That route is cheaper than any other way to make THC that I have everr seen. CBD can be bought wholesale for about $1/g, so there is no other way to make it that comes close to that price. Only some of the spice/K2 type indoles are cheaper per dose, as some are quite potent.


Those jwh indoles would be cheaper and easier to make but I highly doubt they are as benign/harmless/anti carcinogenic as the real THC's
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[*] posted on 4-3-2023 at 21:21


Quote: Originally posted by Texium  
Here’s an interesting route published in an open-access journal: https://www.thieme-connect.de/products/ejournals/html/10.105...



This method is something I never would have thought of.way outside my thought
process.for something so simple it's a long way round.
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[*] posted on 4-3-2023 at 21:28


Quote: Originally posted by clearly_not_atara  
While I agree that the route posted by Texium is very nice, I had the same question once and I wondered if there should be a synthetic route via phloroglucinol, that typical representative of the 1,3,5 pattern. Indeed, from Wikipedia:

Quote:
Phloroglucinol readily forms 5-aminoresorcinol (aka Phloramine) in aqueous ammonia at low temperatures.[7][8]


With a suitable protection strategy, it should be possible in a few steps to substitute the amine for alkyl.


One possible thing to consider is the amine could be alkylated with alkyl halides as the nitrogen might not eliminate activity. It works for the jwh analogs.
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[*] posted on 5-3-2023 at 04:03


I repeat my question.

If you acid reflux CBD to get Delta-8, how do you work up your product to reasonable purity? The papers are paywalled, so I can't read them.




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[*] posted on 5-3-2023 at 05:42


Quote: Originally posted by blogfast25  
I repeat my question.

If you acid reflux CBD to get Delta-8, how do you work up your product to reasonable purity? The papers are paywalled, so I can't read them.


CBD or ethanol extract is dissolved in ethanol, concentrated, acidified, refluxed
then neutralize with excess aqueous bicarbonate solution then extract with
toluene,seperate and evaporate
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[*] posted on 5-3-2023 at 07:10


Quote: Originally posted by draculic acid69  


CBD or ethanol extract is dissolved in ethanol, concentrated, acidified, refluxed
then neutralize with excess aqueous bicarbonate solution then extract with
toluene,seperate and evaporate


Ok, thanks. And what acid is proposed: higher up p-toluenesulfonic acid was mentioned?




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[*] posted on 5-3-2023 at 16:38


If you just want to make some cheap THC, then *any* acid will work fine. A standard thing people do as kitchen chemistry is to microwave a solution of citric acid and CBD in water.
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