tr41414
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Naloxone & friends
Naloxone is drug used in opioid overdoses, helping with CNS & respiratory system depression.
More info: http://en.wikipedia.org/wiki/Naloxone
The synth of this drug is described in Pharmaceutical_Substances.pdf and uses oxycodone as starting point:
Oxycodone >demethylate w HBr> oxymorphone >AA, BrCN, HCl> 14-hydroxydihydronormorphinone (Noroxymorphone ?) >allyl bromide> Naloxone
My question is if it is possible to make this drug without the use of illegal / controlled substances... It is simple (or not) to extract codeine from
pills and syrup, but that just ain't my style...
Also are there drugs with similiar action which aren't based on that mostly illegalized morphine structure? Maybe something with fentanyl-like
structure?
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Nicodem
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Wow, miracles still exist! Someone actually wants to make an opiate antagonist from an opiate agonist. Junkies would vomit at such an idea. They are
afraid of naloxone as if it was the devil incarnate. But I like the idea. Just go for it!
Though these days naloxone is easily available as it is used for relapse prevention for all kind of addictions. The pharmaceutical corporations push
it not just for opiate addictions, but alcoholism, benzo's addiction, even gambling addiction. I think soon we'll all have to take it just for the
sake of general addiction prevention (and to increase profits to same shady pharm. corp.).
…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)
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tr41414
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It might look like a sin converting the useful oxycodone to "antidrug", but i think if these antidrugs would be more available to opioid abusers, many
deaths because of accidental overdoses could be omitted. But on the other hand that would make powerful drugs such as fentanyls safer and could result
in even more abusers...
Search revealed some similiar drugs (by structure and action): Naltrexone, Nalmefene, Nalorphine, Levallorphanol
And another one, Amiphenazole, which seems more interesting to me, because of its simpler structure (5-phenyl-2,4-thiazolediamine), which means
synthesis form more easily available chemicals. The ref from first post it is synthed from thiourea and a-halo-phenylacetonitrile (which can probably
be made by reacting benzalchloride with alkali cyanide).
Refs. (don't even have abstracts  )
Davis, W. et al.: J. Chem. Soc. (JSCOA9) 1955, 3491.
Chase, B.H. et al.: J. Chem. Soc. (JSCOA9) 1955,4443.
[Edited on 15-9-2006 by tr41414]
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Sandmeyer
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| Quote: | Originally posted by tr41414
Naloxone is drug used in opioid overdoses, helping with CNS & respiratory system depression.
More info: http://en.wikipedia.org/wiki/Naloxone
The synth of this drug is described in Pharmaceutical_Substances.pdf and uses oxycodone as starting point:
Oxycodone >demethylate w HBr> oxymorphone >AA, BrCN, HCl> 14-hydroxydihydronormorphinone (Noroxymorphone ?) >allyl bromide> Naloxone
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I meen you really don't have to work with cyanogen bromide, I'd prefer to do the key step analogous to the following using allyl bromide or iodide,
ultimately making naloxone the leaving group:
First Intermediate
To a stirred flask were added 12.8 g of 8,9-dihydroelymoclavine (Kawaken), 10.6 g of 1-iodopropane, 0.42 g of anhydrous sodium carbonate, and 25 ml of
molecular sieve-dried N-methylpyrrolidinone. A nitrogen atmosphere was maintained over the mixture while it was stirred and heated to 75 DEG .
The reaction was allowed to continue at constant temperature for about 18 hours, and was then analyzed by liquid chromatography on a Zorbax CN column,
eluting with 4:1 methanol:0.1 M ammonium acetate, using a 290 nm detector. (Zorbax CN is obtained from DuPont). No 8,9-dihydroelymoclavine was
detected in the reaction mixture, illustrating complete conversion to the first intermediate.
The reaction mixture, about 39 ml in volume, was divided into five equal aliquots for further experiments.
Second Intermediate
One of the aliquots of the first intermediate mixture obtained above was combined under dry nitrogen with 39 ml of molecular sieve-dried pyridine in a
100 ml flask equipped with a nitrogen inlet, ice bath, thermometer and stirrer. The solution was chilled to 0 DEG , and 2.86 g of methanesulfonyl
chloride was added dropwise, taking care that the temperature of the reaction mixture did not exceed 5 DEG . The addition time was about 8 minutes.
The reaction mixture was monitored by liquid chromatography as explained in the step above, and it was found after one hour of stirring at about 0 DEG
that the mixture contained 5.9% of the first intermediate. After two and a half hours, the content of the first intermediate was down to about 4%, and
the reaction mixture was advanced to the next step of the process.
Sodium Thiomethoxide
Thirty ml of molecular sieve-dried N-methylpyrrolidinone was added under a nitrogen blanket to a flask, and was chilled to -5 DEG . Then 6.2 ml of
methanethiol and 4.0 g of powdered sodium hydroxide were added. The temperature of the mixture immediately rose to 5 DEG , and the mixture was cooled
and stirred for one hour, maintaining the temperature at about -2 DEG .
Pergolide
To the above mixture was added the second intermediate mixture, allowing the temperature to rise exothermically to 21 DEG . The mixture was stirred at
ambient temperature for 15 minutes and was then heated to 80 DEG and stirred at that temperature for 2 hours. The reaction was then quenched by the
addition of 60 ml of water, and the aqueous mixture was cooled to 5 DEG and filtered. The solid was washed with 60 ml of water, and dried in a vacuum
oven at 50 DEG overnight. Analysis of the dried solid showed that it was 94.1% pure pergolide. The yield was 2.86 g, equivalent to 90.8% yield, based
on the starting 8,9-dihydroelymoclavine.
[Edited on 15-9-2006 by Sandmeyer]
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tr41414
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That's a nice thing we can use quart. ammonium salts, much nicer than the use of BrCN or chloroformates (ahh, the lovely smell of phosgene, which by
the way isn't very hard to make, but isn't very good for your health either...). It also seems that the use of AA for protecting OH groups can be
omitted. Tihkal #6 - DMT has a procedure described for n-demethylation of quart. ammonium salts by simple pyrolysis, but that might damage our
compound, and also the yields are much lower...
The cleveage of methyl ether can also be done using methanesulfonic acid and methionine (Conversion of Oxycodone to Oxymorphone by Epikur, Rhodium) or
by the use of boron trihalide (WO 8000841, Rhodium). I have seen a fairly simple & OTC synth of BCl3 (borax >acid> boric acid >heat?>
b2o3>?NaCl???> BCl3) somewhere in TheHive files (with writeup of the synth and codeine>morphine procedure), but can't seem to find it.
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Nicodem
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Actually, I just realized I confused naloxone with naltrexone. It is naltrexone that is widely available and prescribed for whatever addiction. So, if
your goal is just to get an opiate antagonist, naltrexone would probably do. Just ask a friend that is an alcoholic or an ex junky to ask the doctor
for a prescription. Where I live, the addicts get these pills for free if they join the program. (Needless to say that if they were chemists they
would realize that naltrexone can be transformed from an antagonist to an agonist and that would be a very wicked trick to play on the pharmaceutical
industry. But obviously the synthesis is not very easy and opiate users know shit about chemistry or else they would be using better drugs.)
PS. Simple preparation of BCl3 from boric acid? Obviously you never worked with that stuff. Well, neither did I and I hope it stays like this. In no
case would I want to deal with any boron halide outside of a well equipped lab.
Edit: I think you confused BCl3 with BF3 which can be prepared from B2O3 and ammonium bifluoride. BCl3 can not be prepared by similar reaction with
chlorides, as far as I know. BF3 is even much worse unless in ether solution (and even that is something you don't want to deal with!).
[Edited on 16-9-2006 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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tr41414
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I just found the post i was reffering to. Here is just a part on BCl3 production.
| Quote: | TheHive>novel>OTC Di-acetyl Morphine (post by "hoffman")
Boron Halides
Swim prefers Bcl3, as it is a gas at room temperature, you will find out why in a second.
It took swim about a week to get this into a reliable working proceedure, as All he had to follow were old patents,.
This is where it gets really interesting.....,ready?
We need a source of boron obviuosly, so if we look around we find out that borax, is the easist to obtain, then boric acid,.Boric acid is a welding
flux commonly sold at hardware stores, but sometimnes it is mixed with impurities, so it is probably easier to just start from borax,.
Borax is fucking cheap, non suspiciuos and common, so..
46 g borax is dissolved in the smallest amount possible of water, 20.3 mls of Conc. HCL is added
The mixture is then cooled down, and filtered,
Hey you've just made boric acid, well done!
To purify it just dissolve again in the smallest amount possible of hot water, cool again in ice bath, filter.
Then another wash with etoh, will give you pure boric acid.
44% (13.2g)
Na2[B4O5(OH)4].8H2O + 2Hcl---- 4H3BO3 +2NaCl + 5H2O
(sweet)
And have a guess what happens when you heat this baby, well,,its..Its,......Boric Oxide( aka Boric anhydride)B2o3
So in RBF dump 25 g Boric Acid, heat at 300c for one hour
to leave 14.7 g of Boric oxide,.
So i hear you all say, why all this for Boric Oxide,
Well my friends, it's all inside patent 832,096 LONDON.
Which tells of the improvements made in the prep, of boron halides, Whoooh!.
Now for all intensive purposes, swim wants a gas to be the final product, so swim chose BCl3,.
Now there is a bit of a twist here, we are going to store the resulting gas inside Chloroform, at a certain molar ratio to de-methylate codeine,.
In a porcelin vessel, with a hole at the top, is placed Sodium chloride(salt) and Boric oxide, on a 1:3 ratio.
The hole at the top of the otherwise sealed ceramic vessel, is where you connect a thick pyrex tube, which leads out into chloroform, the tube is
made long enough to considerably cool the gas before it comes into contact with chloroform,.
Initially you weigh your chloroform, and calculate a target weight, to give you the molar strength to de-methylate codeine,.
Swim used Mapp gas(acetylene/propane) to heat the mixture to the point where Nacl melted, About 800c.,.
Boric ocide melts at ~450c, so the trick to this to continuosly agitate the two molten liquid,.
Boron trichloride begins to emerge at around 800C, and this is carried, cooled, and bubbled through chloroform,.
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Porcelain vessel? I think using quartz tube might be better, but it would probably shatter upon cooling down (because of salt xtalyzing). Sadly BX3
are incompatible with metals...
I agree that boric trihalides are nasty stuff... And as for me experimenting with this kinda stuff, i mostly do only theoretical chemistry 
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Chris The Great
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BX3 are only incompatible with metals because they hydrolyse to form the corresponding acids when any moisture comes into contact with them. If you
have no water in the reaction vessel, which you won't, metal will work.
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Sandmeyer
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| Quote: | Originally posted by Sandmeyer
...I'd prefer to do the key step analogous to the following using allyl bromide or iodide, ultimately making naloxone the leaving group
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Ooops, to correct myself:
I didn't take into consideration that Naloxone is a phenol, the ether cleavage should be done as last step or phenol group will be allylated as well.
If you're serious about this, it would be nice if you could try to bothe remove the methyl attached to nitrogen as well as oxygen in one step, like
above and this:
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0859
Except maybe stick to NMP instead of DMF
I suppose any soft nucleophile would do the job, instead of these stinking thiols giving even worse thioethers might be a better idea, but I don't
have reference for this claim! But the pyridine*HCl method of demethylating codeine seems to work according to some junkies who have tried it. I think
the chloride ion attacks the methyl group taking it away as MeCl, and there are much better and softer nucleophiles than Cl-. If these concepts worked
in lab it would be a quite an elegant synth of naloxone.
[Edited on 24-9-2006 by Sandmeyer]
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MagicJigPipe
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A few major cities have started selling naloxone HCl "kits" (syringe w/needle, IM/IV naloxone HCl solution, alcohol swabs, turnicate etc...) in order
to reduce the number of opiate overdose deaths. One I know of for sure is Chicago (they have a whole website and video explaining the program).
Naltrexone is a schedule III (I think) drug (actually, that's too high in my opinion and should be CV if scheduled at all), therefore it can be
purchased from an "online doctor". Just tell the online doctor that you are a recovering opiate addict and would like to take it daily so you can't
feel the effects of opioids. It has zero potential for abuse and is non-addictive so obtaining it usually isn't a problem.
Just remember, it can induce "whole body pain" even in someone who is not opioid dependent. This makes sense as it "blocks" endorphins as well as
(semi-)synthetic opioids.
EDIT
I found the site/video and a .PDF on the program.
Site & Video:
http://www.anypositivechange.org/NALOXONE/
[Edited on 25-2-2008 by MagicJigPipe]
Attachment: OD1202.pdf (19kB)
This file has been downloaded 649 times
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free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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chemrox
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Seems to me anyone working on any of the super opioids might want to have a supply of antagonists available. Anyway, see Casey & Parfitt,
Opiods,Chemistry and Receptors. Details of many of the syntheses there and refs for nearly all.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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