synthetic cocaine q

labgurl - 6-1-2005 at 02:16

What would be the simplest reactions to use here? Tropinone

to

2-Carbomethoxytropinone

to

Methylecgonine

to

Cocaine

runlabrun - 6-1-2005 at 02:39

like many natural plant alkaloids there is NO simple way to make them.... if any at all...

Although back at the hive there was a few threads about synthtic cocaine, dont have those on
disk though.... dont think they were very viable and were therefore abandoned....

-rlr

Ref. cocaine synthesis

solo - 6-1-2005 at 06:22

Of course rhodium had this pdf's on the subject.....let me know which one is of your
interest.....solo

cocaineanalogs.pdf
cocaine.piperidine-based.analogs.sar-2.pdf

cocaine.biosynthetic.pathway.pdf

cocaine.biosynth.n-methylputrescine.pdf

cocaine.analogs.clarke.pdf

cocaine.total.synthesis.html

cocaine.synthesis.txt

[Edited on 6-1-2005 by solo]

guaguanco - 6-1-2005 at 08:57

Quote:

Although back at the hive there was a few threads about synthtic cocaine, dont have those on
disk though.... dont think they were very viable and were therefore abandoned....

-rlr

I actually knew of someone who tried this synthesis. They synthesized the tropanone ring
structure (glutaraldehyde/methylamine/dimethyl acetonedicarboxylate) but abandoned the
project. I still have the small amount of the product, isolated as the picrate.

labgurl - 6-1-2005 at 09:53

Once again the question is which REACTIONS would be most feasable?

guaguanco - 6-1-2005 at 10:07

Quote:
Originally posted by labgurl

Once again the question is which REACTIONS would be most feasable?

The classic synthesis is reacting glutaraldehyde, methylamine and acetone dicarboxlic acid (I
misspoke in a previous post; the ester is not used)

You end up with 4 diastereoisomers that have to eventually seperated by chromatography (if
you want to end up with pure cocaine).

Then you esterify the acid (diazomethane would work well), reduce the ketone, react with
benzoyl chloride and trimethylamine in chloroform.

[Edited on 6-1-2005 by guaguanco]

JohnWW - 6-1-2005 at 13:03

Diazomethane, CH2N2, is very dangerous to work with for esterification of carboxylic acids to
methyl esters, being both highly toxic and explosive, like azide. The usual method of
esterification is reaction of alcohols with carboxylic acids with a trace of a strong mineral acid as
catalyst, heating under reflux (takes a few hours usually). This is an equilibrium reaction, the
yield of which can be increased by removing water as it is formed. Anhydrides react similarly
with alcohols in the absence of acid. Acyl chlorides similarly react with alcohols with evolution of
HCl. A more powerful methyl esterification reagent is sodium methoxide.

[Edited on 6-1-2005 by JohnWW]

guaguanco - 6-1-2005 at 13:15

Sure, I just picked that as an example. There are a variety of reagents that could be used,
although I would look for one that operated under mild conditions. I don't know what the
ruggedness of the tropanone moiety is.

labgurl - 6-1-2005 at 17:29

What role does dimethylcarbonate play in the sodium methoxide/tropinone/
toluene/dimethylcarbonate reflux?

Mendeleev - 6-1-2005 at 20:05

In my opinion it would be better to synthesize the methyl ester of tropinone in one huge step
instead of first tropinone and then 2-CMT. Reaction of succindialdehyde, methylamine, and the
anhydride of acetonedicarboxylic acid yields 2-CMT. Acetone dicarboxylic acid anhydride is
produced by reacting acetone dicarboxylic acid with acetic anhydride.

2-CMT is then reduced to methyl ecognine. This can be done by catalytic hydrogenation or
sodium amalgam, both methods kind of suck in my opinion. Hydrogenation = assloads of
equipment construction (welding together apressure vessel, hydrogen tanks and connections,
shaker, catalyst, eeeek!). Sodium amalgam=expensive + hard.

Once you have your methyl ecognine, it is reacting with either the chloride or the anhydride of
benzoic acid. This last step doesn't seem too difficult, just react benzoic anhydride with methyl
ecognine in benzene, nothing too fancy. I think the difficulty of this synthesis lies in the
resolution of racemic mixtures over and over.

[Edited on 7-1-2005 by Mendeleev]

labgurl - 6-1-2005 at 21:57

Darn, was hoping there was another reduction method besides those 2. Hmmm wonder how
one could obtain cocoa seeds within the u.s.? lol

JohnWW - 7-1-2005 at 17:17

You have confused cocoa (cacao) seeds with coca seeds. They are two quite different species,
the active principles in cocoa being theobromine and caffeine. It is coca, from elevated forest
areas in northwestern South America, that contains cocaine and some related alkaloid
compounds. Coca should grow well in subtropical and warm temperate areas that do not have
heavy frosts.

(Cocoa, however, is strictly tropical; most commercial cocoa plantations are within 10 of the
equator, e.g. west Africa, and almost all are within 20 of the equator. This has to do with why
cocoa butter is the vegetable oil with the highest melting point).

labgurl - 8-1-2005 at 01:26

Thanks for clearing that up, I shall retry my search.

jimwig - 8-1-2005 at 12:54

was looking into the same line of reactions and their viability OTC. it sounds something like this
(if I remember correctly)

lactose > mucic acid > pyromucic acid >

pyrrole > succinaldehyde > &

at which point i concluded my study

further along tropinone et al would have been realized but my masochistic/curious side got tired
and quit on me.

as has been said it seems cheaper down on the corner.

Nuke_Dukem - 12-1-2005 at 19:28

that shit is to involved. Go with the analog N-methyl,4-para-chloro-Phenyl, 3 -carboxy methyl

ester staring with Arecoline. or you could make tropacocaine by hydrolysis of atropine to
tropine and then esterfication with benzoic acid.

warfox - 17-1-2005 at 14:46

Quote:

Originally posted by solo

cocaine.piperidine-based.analogs.sar-2.pdf

Can you send me the file to warfox@gmx.de

Thanks

analog clareify

yogi - 17-1-2005 at 15:48

Quote:

Originally posted by Nuke_Dukem

that shit is to involved. Go with the analog N-methyl,4-para-chloro-Phenyl, 3 -carboxy methyl

ester staring with Arecoline.

Hi.

Ive looked into this compound and cant find it in the documents. Can u provide ref for this one?
Chemdraw wont draw its structure either.

Can u please clarify Nuke_Dukem?

[Edited on 17-1-2005 by yogi]

[Edited on 17-1-2005 by yogi]

Nuke_Dukem - 17-1-2005 at 17:39

hey sorry that name I gave is just the name of arecoline. Heres one write up from rhodium, the
authors calls the analog Coke-lite.
http://web.archive.org/web/20040210013016/www.rhodium.ws/che...

[Edited on 18-1-2005 by Nuke_Dukem]

Reference for Worfox

solo - 17-1-2005 at 18:05

Attachment: cocaine.piperidine-based.analogs.sar-2 copy.pdf (256kB)

This file has been downloaded 699 times

Ref: synthetic cocaine

solo - 18-1-2005 at 16:54

The work on Piperidine analogs of Phenyltropanes was done by Kozikowski...that should give
you a start for looking in chem abstracts or med line.....solo

labgurl - 19-1-2005 at 04:46

Can someone explain why benzocaine wouldn't be a viable starting material?

sparkgap - 19-1-2005 at 07:04

Maybe that's because benzocaine is a derivative of PABA, not any of them two-ring heterocyclics
that comprise cocaine. Same goes for most of the other "-caines" (check ChemFinder or the
Merck Index if you want to verify my claims). Cocaine is quite unique among them.
Stick with the route from atropine. It isn't too hard to obtain, especially if
nightshade/belladonna, bittersweet or henbane are common plants in your area.

Arecoline? Are areca/betel common plants there?

cyclohexane - 19-7-2009 at 20:48

benzylmethylecgonine can be achived via a nitrone synthesis.

look on rhodium....its a picture.

in littile letters is refrences.

get those. yeild is lower slightly.......but seems less involved...more like a short series of brutal
grignards lol :)

but what about benzoylecgonine.....can this be selectivly remethylated?

setback - 19-7-2009 at 21:54

If it was practical to do this the Colombian drug lords wouldn't still be doing it the old fashion
way.

cyclohexane - 19-7-2009 at 23:11

its not as profitable to do it if you happen to live where there is millions of coca plants

and can make peons pick em in order to not get shot........

but this is about chemistry, not profit.

any fool can make tweek,

make ecgonine takes real skill.

and the nitrone route benafits from uncommon reagents.....

not hard to get anhydride,methylamine, sodium metal, ect.

Sandmeyer - 20-7-2009 at 03:24

I don't know about the pharmacology of conformationally restricted analogues, but going from 1
to 2 gives 2 regioselectivly in 36% yield. Compund 2 can be elaborated further with conventional
chemistry to potentially strong analogues.

EDIT: I forgot to put methyl group on para pos. of phenyl ring in structure 1. :D

[Edited on 20-7-2009 by Sandmeyer]

Nicodem - 20-7-2009 at 04:07

That is a very ingenuous polar cycloaddition. What is the reference? A dipolar addition with a
plain alkene as dipolarophile is a bit unusual. I could only find two papers on 2-like structures
(attached), both using this same synthetic strategy. In the attached papers they used vinyl
sulfones as dienophiles, but the pericyclic reactions were intermolecular.

I don't think LiClO4 or any other Lewis acid would catalyse the reaction. LiClO4 helps to activate
either the dienophile or diene in the Diels-Alder reactions, but I doubt it could find any role in a
dipolar reaction of this type. The Li(+) might just sit on the -O(-) group and thus reduce the
speed of resonance interchange between the carbaoanion (required for the addition) and
oxyanion.
Attachment: Tuning the Selectivity of Monoamine Transporter Inhibitors by the Stereochemistry
of the Nitrogen Lone Pair.pdf (68kB)

This file has been downloaded 151 times

Attachment: The synthesis of tricyclic cocaine analogs via the 1,3-dipolar cycloaddition of
oxidopyridinium betaines.pdf (249kB)

This file has been downloaded 176 times

Sandmeyer - 20-7-2009 at 04:18

Quote: Originally posted by Nicodem

I don't think LiClO4 or any other Lewis acid would catalyse the reaction. LiClO4 helps to activate
either the dienophile or diene in the Diels-Alder reactions, but I doubt it could find any role in a
dipolar reaction of this type. The Li(+) might just sit on the -O(-) group and thus reduce the
speed of resonance interchange between the carbaoanion (required for the addition) and
oxyanion.

I realised that too on a closer look...

Sandmeyer - 20-7-2009 at 04:30

Quote: Originally posted by Nicodem

That is a very ingenuous polar cycloaddition. What is the reference? A dipolar addition with a
plain alkene as dipolarophile is a bit unusual. I could only find two papers on 2-like structures
(attached), both using this same synthetic strategy. In the attached papers they used vinyl
sulfones as dienophiles, but the pericyclic reactions were intermolecular.
The reference is in your own post, scroll down in the Kozikowski's tet. lett. paper and you'll see
the intramolecuar cycloaddition...

[Edited on 20-7-2009 by Sandmeyer]

Nicodem - 20-7-2009 at 05:58

Quote: Originally posted by Sandmeyer

The reference is in your own post, scroll down in the Kozikowski's tet. lett. paper and you'll see
the intramolecuar cycloaddition...

Don't know how I managed to miss that page on an only 4 page paper. :o

They point to J. Chem. Soc., Chem. Commun., 1976, 367-368 as their reference, but at the
moment I can't access the digital version. Sounds like a nice cyclisation reaction for building
complex polycyclic systems - I never considered N-alkylated 3-hydroxypyridines as potential 1,3-
dipoles. It is interesting that the reacting 1,3-dipole is the resonance structure that one would
least likely draw: cationic and anionic charges on carbons. Kind of logical and simple, but only
after you see the reaction scheme. Otherwise, I would not have thought of it in a hundred years.

Kozikovski et al also have a patent on his work from the above papers: WO0007994

Polverone - 20-7-2009 at 09:02

Quote: Originally posted by Nicodem

Quote: Originally posted by Sandmeyer

The reference is in your own post, scroll down in the Kozikowski's tet. lett. paper and you'll see
the intramolecuar cycloaddition...
Don't know how I managed to miss that page on an only 4 page paper. :o

They point to J. Chem. Soc., Chem. Commun., 1976, 367-368 as their reference, but at the
moment I can't access the digital version.

http://www.sciencemadness.org/scipics/c39760000367.pdf

Sandmeyer - 20-7-2009 at 15:04

Quote: Originally posted by Nicodem

Kind of logical and simple, but only after you see the reaction scheme. Otherwise, I would not
have thought of it in a hundred years.

Yes, that reaction is very nice. Anyhow, solution I find truly amazing is the following one step
reaction by Boger and his co-workers:

note how five contiguous stereocenters (not to mention all the rings) are neatly installed in
agreement with the natural prod vindoline. Now that's a hell of a reaction, imagine running the
NMR after it - pure euphoria. :D Such reactions should be made illegal, they release more
monoamines than MDxA.

...and also the first link in my signature is not to forget :D

sorry for driving the thread off topic... ;)

[Edited on 20-7-2009 by Sandmeyer]

setback - 20-7-2009 at 15:23

That's a synth for a chemotherapy drug, right?

benzylchloride1 - 21-7-2009 at 12:37

Make atropine, not cocaine. Same reactions, no illegal drug. Use acetone dicarboxylic acid
instead of the monomethyl ester for the reaction to form tropinone.

JohnWW - 21-7-2009 at 14:19

Atropine, the principal active substance in deadly nightshade, is used in small quantities as a
muscle relaxant drug, but has no hallucinogenic or euphoric effects. For this purpose, it is used
as an anti-diarrhetic, and may be use as an antidote for poisoning with other alkaloids which
cause muscle spasms, such as strychnine/brucine.

donlaszlow - 3-8-2009 at 12:30

If you are a Chemist you are faithful to your oath, you use your knowledge to help others. :D

Cocaine is illegal for a reason. :(

JohnWW - 3-8-2009 at 13:44

Quote: Originally posted by donlaszlow

Cocaine is illegal for a reason.

For largely political and business reasons, pushed by the pharmaceuticals, alcohol, and tobacco
lobbies, and religious reasons pushed by the so-called "temperance lobby", I am sorry to have to
say; - and propagandized in the phoney "War/Whore On Drugs". For many years, the stuff was a
principal active ingredient of Coca-Cola; and until about the 1920s, one could buy any amount of
it over-the-counter at any good drugstore, without a prescription and no questions asked.

S.C. Wack - 3-8-2009 at 17:15

It is always unwise to take a thread in a chemistry forum and turn it away from chemistry.

Quote: Originally posted by JohnWW

For largely political and business reasons, pushed by the pharmaceuticals, alcohol, and tobacco
lobbies, and religious reasons pushed by the so-called "temperance lobby"

You seem not much of an authority on cocaine. The early critics of cocaine were doctors who
already knew of its morphine-deep addictiveness starting at least as early as 1886 in both the US
and Germany, and in Britain in 1889, immediately after becoming widely used and available.
And its proponents were drug companies such as Merck and Parke, Davis & Co. Many early
addicts were members of the temperance lobby, who drank alcoholic preparations and became
both alcoholics and coke addicts.

Anyone who doubts the addictiveness of cocaine and the problems that that causes is ignorant
beyond belief.

The_Davster - 3-8-2009 at 17:35

Beginning of thread was cookery, and got worse inserting a drug debate. closed.

Unfortunate as the organic chemistry in the middle was valid.

[Edited on 4-8-09 by The_Davster]