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tr41414
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Playing with tyrosine
I just happen to have 100g of quite pure tyrosine (USP, label says 100% !?)... It's one of most easily available aminoacids - can get it in almost any
body building store...
There are a few reactions i have in mind:
1-decarboxylation to 4-ho-phenethylamine (ala Trp -> T)
2-methylation to 4-meo-phenylalanine (methylnitrate)
3-oxidation to 4-ho-phenylacetonitrile (wtih TCICA)
4-iodination to 3,5-diiodo-4-ho-phenylacetonitrile (basic iodine)
The only reaction i think will work without any modifications is 1... In rxn 2 Tyr will probably have to be N and COOH protected? Rxn 3&4 are more
speculations than anything else, as #3 will probably also result in a ring halogenated product... dunno if product of 4 is right...
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smuv
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You could start from N-acetyl tyrosine. I think (although am not sure) the acetyl group will block N-methylation...if this is so...
1-methylate
2-remove protecting group (amide hydrolysis)
3-decarboxylate
4-halogenate 3,5 positions
5-methoxylate 3,5 (assuming you want to make mescaline)
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tr41414
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If you look closer, you would see that the reactions i posted are different, all starting from tyrosine... Mescaline is not my ultimate product, but
the procedure should be as follows:
- decarboxylation to tyramine
- iodination (halogenation) to 3,5-diiodo-4-oh-phenethylamine
- methylation (also many other analogs can be made by substituting other alochol - IP, P, E, AL) to 3,5-diiodo-4-meo-phenethylamine (don't think it
has been tested, but is probably neurotoxic)
- removing the halogen groups (alkoxide + CuI + ultrasound/MW?) if possible directly exchanging them for methoxy
The last two steps could be exchanged to maybe give better yields, but then exclusion of water (when ripping of those Is) would probably be a
problem...
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SecretSquirrel
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| Quote: | | Mescaline is not my ultimate product, but the procedure should be as follows: |
If you perform the reaction in your last step, you'll end up with mescaline as your product.
[Edited on 28-6-2007 by SecretSquirrel]
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smuv
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I think we all would be able to help you better if we knew what you wanted to make.
@SecretSquirrel if you look a bit more closely Trxxxx never said he was making mescaline...I just assumed he was
P.S. N-acetyl tyrosine is just as OTC as tyrosine...but now that I have thought about it...I doubt an acetyl group would block the methylation of the
amine.
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tr41414
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@SecretSquirrel: 3,5-diiodo-4-meo-phenethylamine would certainly yield mescaline... but other 4 substitutes should make other phenethylamines... or
would there be problems with transetrification (if such thing does exist)?
That acetyl group may do something wierd in the course of decarboxylation or iodination... It may easily be attached on later... I think that
methylation of phenol procedes faster in basic environment (and as i said that step is already documented)... the only step into unknown (at least on
this substrate) would be exchange of halogen...
would o-methyl or o-alkyl group on tyrosine protect it from getting ring halogenated and would yield p-alkyl-phenylacetonitrile on oxidation using
tcica?
PS: will find the references soon...
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PainKilla
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http://www.sciencemadness.org/talk/viewthread.php?tid=3846&a...
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smuv
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| Quote: | Originally posted by tr41414
@SecretSquirrel: 3,5-diiodo-4-meo-phenethylamine would certainly yield mescaline... but other 4 substitutes should make other phenethylamines...
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This is true...but in you original writeup you metylated the 4 position...Anyhow...I will just assume that you want to make a 3,4,5
alkoxyphenylethylamine.
| Quote: | | Originally posted by tr41414 I think that methylation of phenol procedes faster in basic environment (and as i said that step is already
documented)... |
I admittadly know little about methyl nitrate, but for common methylation agents such as DMS and methyl halides, the amine must be protected.
I think you are taking an indirect route to these compounds.
I beleive a more direct route would be:
1. Bromate 3,5 positions (Br2 in AcOH)
2. Hydroxylate (is that a word) I beleive Cu dust in NaOH does this. This would form 3,5 hydroxytyrosine
3. Oxidize to nitrile
4. Alkylate 3,4,5 positions while making sure conditions are not harsh enough to hydrolize nitrile.
5. Reduce Nitrile to Amine
[Edited on 28-6-2007 by smuv]
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SecretSquirrel
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| Quote: | Originally posted by smuv
@SecretSquirrel if you look a bit more closely Trxxxx never said he was making mescaline...I just assumed he was |
I know that. He said he does not want to make mescaline, but then he said:
| Quote: | | removing the halogen groups (alkoxide + CuI + ultrasound/MW?) if possible directly exchanging them for methoxy
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And that would most certainly yield mescaline.
[Edited on 29-6-2007 by SecretSquirrel]
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smuv
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Good call...I guess I didn't read his post very closely.
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tr41414
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Depending on that 4-alkyl group (it's made in step 3; the substrate must be acetyl protected  ) the product could be just about anything  Would transetrification
(if that does exist) be an issue?
I would suggest not to put out mescaline... After all we are doing mostly chemistry and not drugs
PS: The oxidation of Tyr to Dopa using persulfate is also interesting, although yields are a bit low (20%)
[Edited on 29-6-2007 by tr41414]
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smuv
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| Quote: | Originally posted by tr41414
I would suggest not to put out mescaline... After all we are doing mostly chemistry and not drugs |
You are the one mentioning neuro-toxicity. Mescaline analogues (which you are making) are still drugs.
| Quote: | | Would transetrification (if that does exist) be an issue? |
I dont really understand what you mean by this, could you be a little clearer when exactly this would occur. I see no carboxylic acid involved to
form an ester with.
| Quote: |
PS: The oxidation of Tyr to Dopa using persulfate is also interesting, although yields are a bit low (20%) |
Dopa can also be produced electrochemically. Which may be of interest.
Oh I now think an acetyl group is not sufficiently bulky to block alkylation of the amine. You would need to use a more stericly hindering group.
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tr41414
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Banana peels can also be used as drugs  So, dont even dare to talk about growing
bananas 
If you read properly i said transETRIFICATION (without s), but now i don't think such thing does exist... I'm still searching for proper ketone (MEK
and acetone in turpentine just seem to boil) for that decarbox... will be buying some spearmint oil soon maybe also phorone would work? (hmm... but on the second tought it will probably form the piperidone ring around our
amine)
PS: can one not just oxidise some pinene to get the ketone? but i only found refs. on pb acetate oxidation kmno4 seems to do some unwanted cleaveing...
[Edited on 30-6-2007 by tr41414]
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smuv
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Transeterfication? Transtherfication? At any rate, i've never heard of it but could see it occuring under certain conditions.
Why are you considering decarboxylating already...how are you going to protect your amine? Why are you even decarboxylating the amine. You can
convert Directly from the amino acid to nitrile without decarboxylation. Also your step, where you Halogenate p-methoxy phenylacetylnitrile will
proceed with shitty yeilds as I would expect the nitrile to hydrolize under these conditions (forming either an amide or carboxylic acid).
To do things the way you want to do them you should change your order:
1. Bromate 3,5 positions (Br2 in AcOH)
2. Williamson ether synthesis to alkylate 3,5 positions
3. Convert to nitrile w/ tcca and NaOH in water
4. Alkylate 4 position of nitrile
5. reduce nitrile to amine
The only step I am not sure about is the 4th, common reagents for alkylation might play with the nitrile...but I I'm not sure.
Maybe someone else could check up on my (so, so) chemistry.
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tr41414
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it is much simpler to decarboxylate and not go the nitrile / reduction way (that would be more useful - worth the effort - if one would be interested
in amphetamine analogs: nitrile -> p2p)... tcica would probably halogenate and decarboxylate/oxidise the tyr to nitrile in one step...
halogens on the phenyl ring are not as good leaving groups, so conditions will have to be pretty harsh...
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smuv
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The only reason to create the nitrile is to avoid protecting the amine. Plus decarboxylations are a bitch and usually require fairly harsh
conditions.
| Quote: | | tcica would probably halogenate and decarboxylate/oxidise the tyr to nitrile in one step... |
No
| Quote: | | halogens on the phenyl ring are not as good leaving groups, so conditions will have to be pretty harsh. |
Yes (I think i have seen a Cu(I) catalyzed reaction with sodium methoxide in dmf or something like that) but its possible...anyhow I am just
correcting your original proposed synthesis...by creating something that has a higher chance of working out while still sticking to your original
outline.
[Edited on 30-6-2007 by smuv]
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tr41414
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According to Chem Pharm Bull 23, 2179 (1975): Tyrosine >-Cl2-> 3,5-Dichloro-4-hydroxyphenylacetonitrile
For decarboxylation diphenyl ether, aniline, p2p, acetophenone and probably also most other not-to-reactive ketones can be used... User urushibara has
attempted pressurized acetone decarboxylation @200-250C which seemed to work 
So i will probably do some nanoscale experiments with empty CO2 bombs... till i get my spearmint oil...
Oxidation to nitrile followed by a NaBH4 reduction is alternative to thermal decarboxylation...
| Quote: | Ref. found by Foxy2
Synthesis of 3,5-diiodo-4-methoxyphenethylamine
Jatzkewitz, Horst; Noeske, Hans Dietrich
(Hoppe-Seyler's Zeitschrift für physiologische Chemie) Hoppe-Seyler's Z. physiol. Chem. 287, 43-6 (1951)
Journal written in Unavailable. CAN 49:4568 AN 1955:4568
Abstract
The synthesis of 3,5-diiodo-4-methoxyphenethylamine (I) is described.
I is used to study the effect of biogenic amines on the action of mescaline. To 14 g. tyramine-HCl in 23 cc. H2O and 46 cc. N NaOH, 11.8 g. iodine in
alk. KI soln. (contg. 20 g. KI, 160 cc. H2O, and 46 cc. N NaOH) is added dropwise with stirring, maintaining constant alky. The soln. is filtered and
acidified with excess H2SO3, giving 12 g. crude 3,5-diiodotyramine-HI (II), yellow leaves (from H2O) m. 232-4°C (decompn.).
II (12 g.) treated with the calcd. amt. of hot Na2CO3 soln. gives 6 g. free base (III), pale yellow, m. 188-90°C.
III (2 g.) boiled 10 sec. with 5 cc. Ac2O and dild. with H2O gives 1.75 g. N-acetyl-3,5-diiodotyramine (IV), colorless plates, m. 139-40°C.
IV (6 g.) (crude) in tetrahydrofuran is methylated with 60 cc. ethereal CH2N2 dild. with 40 cc. CHCl3, washed twice with 5% NaOH and H2O, dried and
the solvent removed, giving 5.2 g. N-acetyl-3,5-diiodo-4-methoxyphenethylamine (V), needles, m. 138-40°C.
V 3.8 g. is refluxed 5 hrs. with 19 cc. HCO2H, 14 cc. HCl, and 14 cc. H2O., evapd. in vacuo and dried with EtOH and C6H6, the residue extd. with three
15 cc.-portions of abs. C6H6 gives on evapn. of the solvent 3.4 g. crude I.HCl. The pure compd. m. 213-15°C. The salt dried in Et2O over anhyd.
K2CO3, on removal of solvent and crystn. from petr. ether gives I, colorless leaflets, loses its crystal structure at 41-3°C, and m. 55-7°C.
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PS: could anyone fetch the articles and attach them please?
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smuv
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See Synlett 2004, (12) 2180-2184. I am not saying your ref is crap...the conditions just are different
using a pressure vessel to decarboxylate defies Le Chatelier's principle.
This is interesting though...according to that ref the acetyl group protects just fine...thats good to know
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dr. nick
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| Quote: | | ... I'm still searching for proper ketone (MEK and acetone in turpentine just seem to boil) for that decarbox... will be buying some spearmint oil
soon maybe also phorone would work? (hmm... but on the second tought it will probably form the piperidone ring around our amine)
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Hoping not to bother you too much with my inadequate knowledge, but as i'm interested in anything from amino acids, too, i wonder if it shouldn't work
like the decarboxylation of phenylalanine - with Cyclohexanol and Cyclohexanon and so on ... ?
also, even if that's "drugs" again first things that comes to mind for me from tyrosine are opiat/opioides (->biochemistry poppies). but probably
that's too far out.
Anyway, very informative thread, thanks!
of course you can well i couldn\'t before
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tr41414
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I think that decaboxylation should go well with cyclohexanon, but it is said that cycloxexEnone works much, much better... for the price i will pay
for 50ml of essential oil here, 1l could be had from india  is there really no
easy way to oxidise pinene to the ketone?
Decarbox. is one-way-only-reaction, so there is no equilibrium, but i agree with you that the last few CO2-s will be less happy to fly of... The
problem might be sideproducts (acetone selfcondensation, or even something with our amine) and some unreacted aminoacid...
Opiates? You mean fentanyl analogs? These would probably be legal and probably quite powerful (i don't think 4-oh would be active, but 4-meo almost
surely)... the phenethyl group can be exchanged, also aniline can be exchanged for another amine to lower / change the potency... You should take a
look at phenylethanolamine and PPA... ala drone's OTC fentanyl
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dr. nick
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| Quote: | | Opiates? You mean fentanyl analogs? |
ah, i see - pretty interesting! and no, i didn't have anything special in mind, it was just that i believe to remember the biosynth of morphin was
somehow outgoing from thyrosine ...
so you think there might be a way to something like that from thyrosine??
ohoho! pretty interesting indeed 
wonder if i might find something on it somewhere!
thanks!
of course you can well i couldn\'t before
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tr41414
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the fentanyl was just a guess, as it is an opiate and is not too hard to synth... synthesis of morphine - derivates are very complicated...
yes... the biosynth http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/alkaloid/mo... essentialy starts from tyrosine, but it is a looooong way there (involving around
20 enzymes, some have not even been determined yet)... but one could try doping the poppies... even more viable way would probably be to make poppy
cell culture, add some more advanced precursors and somehow try to extract the product from live culture, to have it produce more  it also seems many animals (also humans) are able to produce morphine from
tyrosine, but reports are somewhat confusing ...
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dr. nick
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yes, i'm reading this and that on cell culture the last time - interesting field, for lots and lots of interesting compounds (not only drugs ), also the idea of doping poppies is good. gonna try to get the stuff one needs for
analgetics tlc first, but it's complicated for someone new to this (at least to me) and not really cheap ...
as talking on stuff like that now anyway i hope i didn't make this thread go totally ot, but one thing i want to mention before i stop - there where
some hints on an corey-fuchs synth to morphin from phenylalanine in 10% yeild, if it's true. ok, not tyrosine, but hey ...
couldn't find much on it, and of course it's way beyond everything possible to me even if i wanted to do something like that.
of course you can well i couldn\'t before
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tr41414
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10% yield ??? that's a whole lot... couldn't find anything on your procedure... but as said before it won't go without more than 20 step procedures
and exotic reagents (probably hard to find but obivously not watched, as nobody uses them )
And for "doping" cacti would probably be much better subjects than poppies, I also think cultivating cactus cells would be simpler (a bit less
differentiated)... But you won't get any opiates from cacti
we should not get too off-topic here, so back to tyrosine & friends hehe... i really like these aminoacids as they can be made (as we found out not so
easily) into so many interesting things... hmm... not that happy anymore about that high pressure acetone decarboxylation (any leak might result in a
big boom)... what about decarboxylation in glycerol (higher BP, seen it done somewhere)? or maybe using camphor as a catalyst?
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dr. nick
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yes, amino acids are really cool - i always find new uses every time i start to chase again
my only practical experience with it was the phenylalanin decarboxylation a la rhodium and it worked. pretty frustrating i did never find anything to
do with the yeilded ß-pea
also tried it with turpentine and paraffin and some other strange stuff, forgot, but as i managed to do it the reported way i forgot it for a while.
maybe time to start again. it's really fascinating, somehow. never tried with acetone and so on since i can't prevent it from evaporating - the
proceedure seems to take some more time as mentioned at rhodium, but maybe just because i have only inferior material available (cyclohexanone from
some special thinner, and so on)
got some l-arginine and want to try to decarboxylate it the same way as the phe (right abbrev?) since i found something really interesting on fatty
acid amides ... if i ever proceed i'll report!
of course you can well i couldn\'t before
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