Author Topic: Chloramphenicol to amphetamine  (Read 586 times)

headstrong

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Re: Chloramphenicol to amphetamine
« Reply #20 on: October 26, 2010, 05:15:42 PM »
Actually i just worry if it was going to somewhat like emotional argumentation, and i tried to did something to redirecting to the right state ;D, but from what you said (glad hear that) i no need to worry, sorry and thank you :) 
I don't mind about positive argumentation and being wrong, feel free to prove me wrong.

Sure i'll gladly post it here soon i after find sulfite reference, i read it months ago so take time to find it. For R-X --> R-H low valence metal procedures i just read it days ago so i can find it easily;
Na, THF, t-BuOH   (alkyl , vinilic, aryl) 
ref;
OrgSyn 48 68 (1968)
JACS 108 1265 (1986), 114 5018 (1992)
JOC 53 5186 (1988), 59 661 (1994)

Mg, i-PrOH (alkyl, vinilic, aryl)
Proc Chem Soc 219 (1963)

Mg, TiCl3, THF (alkyl, aryl)
CC 781 (1985)

Zn, HOAc (alkyl, vinilic, aryl)
Org Syn Coll Vol 2 320 (1943)
JACS 91 1767 (1969)
TL 28 3225 (1987)

CrSO4, DMF, H2O (1*, 2* alkyl; allylic, benzylic)
JACS 85 2768 (1963)

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I wonder if there are any antibiotics analogues of C. without nitro group..
If you don't find it yet, there are 4 antibiotics in Amphenicol class; Chloramphenicol and  Azidamphenicol for human, Thiamphenicol and Florphenicol for veterinary. I think you will be more interent to Florphenicol, sometimes it's written Florfenicol, tradename nuflor and aquaflor, no nitro arene and even no primary alcohol 8)

I have no idea yet about the route Chloramphenicol-->amphetamine derivatives, i should do some experiments to get it.

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #21 on: October 26, 2010, 06:39:42 PM »
Wow, that is nice that such easy routes of reduction are available. Btw, you may also use thiol reduction with Ni raney (without hydrogen). It is known for thioacetals, but something similar should work with sulfides. The procedure for merkaptals is as simple as following:
"The reaction of hydrohenolysis is being carried out by refluxing thioacetal in 70% alcohol with Ni raney for 5 hours"
You can make sulfide from thiol and haloalkane, but then there is a side reaction of aziridine formation possible(i should inquire, not very positive). It is quite possible, that thiocyanate + 2-aminopropane-3-ol followed by HCl reflux yould yield thiazolidinone, that after hydrolysis(or without it?) can be reduced by Ni raney. Still not sure about thiazolidinone formation, besides benzylic OH would react faster, you neen to get rid of it wirst or also protect it
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #22 on: October 28, 2010, 01:55:05 PM »
Quote
i'm sure aziridine would form fasted then alcohol, because it is intramolecular reaction. Better to see experimental of Java's paper, they should have isolated this 2-iodoamine, maybe it is quite stable
I'm still confusing about this one, in acid condition (HI/P rxn) trace aziridine is formed. Maybe what you mean is in base condition aziridine will be formed fast. How fast and how easy organic iodides will be replaced by OH-...


I got an idea to do iodination-reduction in one pot, please tell me what you think :)

Basically iodination by HI in HOAc, follow by Zinc reduction without isolation, the problem that batch should contains many HI we should do something before addition Zinc dust.

And about HI in HOAc, i ever made instant HI by these ways;
1. Dissolve NaI in GAA, add powdered unhydrous Oxalic acid, heat to 60 c with stirring, Sodium Oxalate precipitated and HI is produced (as H+ and I-).
2. Dissolved KI in water (just enough to dissolve KI) pour to 100% H3PO4, many KH2PO4 will be precipitated, many HI is produced, gaseous solution. Propanediol can be dissolve in HOAc then mix with that HI solution.

But maybe Nitro group should be reduced first, it can oxidized HI isn't it? If not, will be more HI needed.

 

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #23 on: October 30, 2010, 09:01:30 AM »
Headstrong, please look the article below, it may be of your interest, as it deals with reactions of 1-phenyl-2-amino-1,3-dihydroxypropane and production of 3-amino-2-phenylthietane which is one step converted to amphetamine(Ni raney/ethanol, without H2). Specially, ctrl+F for words "Dissolving the cyanothiamine", look pages 32, 29. It seems you may avoid using HI, P and reduction of terminal I, and stick with thiourea or alkali metal thiocyanate and base followed by Ni raney. And it seemed from the article for me that you may not even need to use HCl, just diol and thiourea or thiocyanate , but here i may be wrong(lost the page where i probably seen it) and you should first convert benzylic position to Cl and then treat with thiocyanate. Anyway, it is much easier then HI route. Also google for 3-amino-2-phenylthietane, there are many refferences of their synthesis as they are mao inhibitors
https://circle.ubc.ca/bitstream/handle/2429/20317/UBC_1977_A6_7%20K35.pdf?sequence=1
(the pdf is 6mb, better use right button and save as)
« Last Edit: October 30, 2010, 09:50:46 AM by zzhuchila_clocker »
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #24 on: October 30, 2010, 04:11:00 PM »
Quote
Btw, you may also use thiol reduction with Ni raney (without hydrogen). It is known for thioacetals, but something similar should work with sulfides. The procedure for merkaptals is as simple as following:
"The reaction of hydrohenolysis is being carried out by refluxing thioacetal in 70% alcohol with Ni raney for 5 hours"
I try to find commercially available Thiol, but not sure it available in my place. Anyhow i still interest in the mechanism, usually raney nickel in EtOH or i-PrOH as solvent and hydrogen source, what the function of thiol in this rxn?

Quote
Headstrong, please look the article below, it may be of your interest, as it deals with reactions of 1-phenyl-2-amino-1,3-dihydroxypropane and production of 3-amino-2-phenylthietane which is one step converted to amphetamine(Ni raney/ethanol, without H2).

I'm interest in almost any procedure, but my problem is chemichals, they are far from me. To find simple things like Zinc dust, NiCl2 i have to go to a city 300 km from my place, hexamine only as veterinary drug. What i want to say, if i doesn't give a proper and fast response to any method you posted it was not because i'm not interest (please don't get me wrong :)). But i have to check the availability of chemicals, and a little time scratching my head ;D
Still very enjoyable for me to learn new procedures and doing chemistry with limited chemicals, the latter you posted is the most interesting.

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #25 on: October 30, 2010, 07:08:42 PM »
You always respond almost immediately! this article is just for information, that such method exist. it does not need immediate respond as it is big and you can't read it immediately :) so, feel free to respond or not respond any time you like.
Function of thiol is that it forms thioacetal with aldehyde R'CH(SR)2 that is further reduced. i dont know the exact mechanism of Ni raney desulfurization(you can google it) but it is seemingly radical. but instead of thioacetal you need sulfide made from thiol or H2S and haloalkane. I recognized the method that avoids using chloroalkane, it is this one http://pubs.acs.org/doi/abs/10.1021/jo00832a032 but making cyclic carbonate from OTC reagents is a problem, unless you have CCl4 available in some glues, or if it can be done with urea the same way it reacts with propylene glycol to yield propylene carbonate. Both reactions may not work, also because of nitrogen between 2 OHs. Or there is a slight possibility that oxazolidinone, if it would form instead of cyclic carbonate in either of routes, especially the product of esterification of benzylic oxygen, can be opened by same nucleophilic attack with thiocyanate, and then it would form thietane as on scheme.
I understand your point about chemicals. But if the only source of sulfur in your area is thiosulfate, no thiocyanate, then this route would be harder(using KCN). Other routes for making thietane are also not very kitchen friendly, you would need 2 times chlorinate alcohols with HCl if you want to use thiosulfate(first benzylic OH to Cl, then thisulfate treatment, then primary OH to Cl, then cyclization with base). For reducing only primary OH, you need any thiol and primary alkylhalogenide that you would make using HI. And then Ni raney. If there is no possibility to find Ni raney as well - better to give up this route with sulfur reagents, because you found quite convenient one using metal reduction of terminal Hal and there should be no problems with matches for P and pharmacy stores for I2. Or, try to find the most convenient route, write out all not available chemicals in your area and travel those 300 km and buy many things that you want to experiment with.. i don't see other options, as number of syntheses from only OTC reagents is limited
« Last Edit: October 30, 2010, 07:28:56 PM by zzhuchila_clocker »
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #26 on: October 31, 2010, 08:12:38 AM »
Many thanks  :)
Raney nickel should be available worldwide, but in a country like mine it's probably sold as spareparts for certain machine in certain factory, just matter of time....I already have homemade Urushibara nickel that should work well for that procedure (intuition only ;D)

Time for me to learn and do research on precursors including homemade precursors (you have give some hints).

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #27 on: October 31, 2010, 04:58:39 PM »
Concerning thiocyanate, it seems it can be done OTC as well. It forms while prolonged heating of thiourea http://pubs.rsc.org/en/Content/ArticleLanding/1974/P2/p29740000896
and thiourea can be made from hydrogen sulfide and cyanamide(can be made from urea and CaO http://www.sciencemadness.org/talk/viewthread.php?tid=14267). Hopefully in thiourea synthesis hydrogen sulfide can be changed to alkali metal sulfide, but i'm not sure. Hydrogen sulfide is toxic, but can be made by several routes OTC.
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #28 on: November 04, 2010, 09:37:58 AM »
Hello ZC, i've read the paper, i got the point that is reduction of propanediol into propane via organic sulfur intermediate, specifically via thiatane. Via thiatane intermediate is not yet simplified, takes a little more time for me to simplify from the precursor preparation to thiatane reduction cleavage.
I.e, for thiocyanate preparation can be done by heating Sulfur and KCN, S + KCN --> KSCN (hanbook of inorganic chemistry pages 776). And IMO it heating KOCN and excess of Sulfur will result KSCN as well, KOCN can be easily made by heating urea and KOH. Kitchen friendly :)

And also the possibility other kind of organic sulfur intermediate like sulfonic acid is very interesting. 

For now I propose 2 simple methods to you,   
1. via organic iodide intermediate, i'll re explain this topic because i think you were misunderstood (my english is much worse than you ;D) that made you think this route is difficult.
- iodination
reagents; KI, H3PO4, HOAc, this step is only iodination (without reduction), so heating in few hours is sufficient enough.
- reduction
directly without isolation of that di iodo compound, reagent; zinc dust, HOAc

2. via carbonyl compound intermediate,
- oxidation by NaOCl-HOAc, secondary benzylic alcohol to ketone and the primary one to aldehyde
- isolation
- reduction by clemmensen aqueous HCl + zinc dust, under reflux

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #29 on: November 06, 2010, 04:39:11 PM »
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And IMO it heating KOCN and excess of Sulfur will result KSCN as well, KOCN can be easily made by heating urea and KOH. Kitchen friendly
it would be a nice reaction if it really works, sulfur melts easily so the surface contact with oxidizer and reductant is substantial, but it evaporates at about 400, and that is not that good, loo low temperature for reaction i suppose, but maybe it is sufficient or some special catalytsts should be used. i failed to find anything in google but it does not mean such reaction is impossible

As for diiodo route, i think it is possible then, and should be the easiest one.
But the clemmensen route on this substrate may give many by product, because those two carbonyl groups would be present as conjugated system (one CO is in a form of enol and its double bond conjugated to second carbonyl). Such conjugated systems, i suppose, would react not normally, and even if they do(maybe there is osmething in literature) - aminogroup can as well become a ketone instead of terminal OH and split off, so you can get a mixture of 3-phenylpropanol, 1-phenylpropanol and 2-phenylpropanol along with amphetamine. Amine can be easily separated by acid-base extraction but its yield may be not high also. This is a proposal, but if there are examples in literature then it is ok.
« Last Edit: November 06, 2010, 04:41:45 PM by zzhuchila_clocker »
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #30 on: November 08, 2010, 09:14:41 PM »
Quote
it would be a nice reaction if it really works, sulfur melts easily so the surface contact with oxidizer and reductant is substantial, but it evaporates at about 400, and that is not that good, loo low temperature for reaction i suppose, but maybe it is sufficient or some special catalytsts should be used.
Points taken, i'll try to find the data.

Quote
As for diiodo route, i think it is possible then, and should be the easiest one.
I'll do some research then propose overall procedure.

3nd experiment,
Chloramphenicol in 15% HCl, 90 c for 6 hours, solution color become clear-pink, then that solution temperature is increased to 100 c for 8 hours more. Solution color becomes clear-red, few black powder is precipitated (i guess the inactives something like cellulose maybe). Although the solution color is almost the same with experiment 2nd, but they are different, put in simply A/B is possible to perform to solution of 3rd experiment.
Unfortunately (After A/B )accident happens, too long on the hotplate (when evaporating water).

Quote
But the clemmensen route on this substrate may give many by product, because those two carbonyl groups would be present as conjugated system (one CO is in a form of enol and its double bond conjugated to second carbonyl). Such conjugated systems, i suppose, would react not normally, and even if they do(maybe there is osmething in literature) - aminogroup can as well become a ketone instead of terminal OH and split off, so you can get a mixture of 3-phenylpropanol, 1-phenylpropanol and 2-phenylpropanol along with amphetamine. Amine can be easily separated by acid-base extraction but its yield may be not high also. This is a proposal, but if there are examples in literature then it is ok.
Proposal only.....
O my my...that's why people say organic chemistry has billions possibilities, thanks.

zzhuchila_clocker

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Re: Chloramphenicol to amphetamine
« Reply #31 on: November 11, 2010, 08:29:15 AM »
why don't you try to reproduce procedure in reply #11 in this thread, it seems 0.5h is sufficient
« Last Edit: November 11, 2010, 08:30:57 AM by zzhuchila_clocker »
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headstrong

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Re: Chloramphenicol to amphetamine
« Reply #32 on: November 15, 2010, 08:24:37 PM »
Damn, lost from my attention, THANKS, and sorry for delaying and I'll back as soon as possible by more experiments result.

Balkan Bonehead

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Re: Chloramphenicol to amphetamine
« Reply #33 on: December 01, 2010, 12:59:08 PM »
Ho hum...I just looked at the structure of chloramphenicol, and hey, a hoffman degredation of the acetamide group through its intermediate isocyanate in aqueous medium, protection of the resulting N-methyl amine followed reduction of the nitro to an amine, then deamination of the aryl amine group with HNO2 in situ from NaNO2 and dilute H2SO4, deprotection then reduction of the two remaining hydroxyl groups on the sidechain with the classical hydriodic acid route of choice in 2x molar amount, and what do you get? damned near OTC amphetamine.  

wat

Start from phenylalanine instead; you'll have to perform an extra reduction, but you'll save two reductions and a hydrolysis.

headstrong

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Re: Chloramphenicol to amphetamine
« Reply #34 on: March 29, 2011, 10:46:04 AM »
I'm sorry for long delaying, maybe this topic have been out of date, my mistake..
I found some important reactions related to Chloramphenicol;
1. HI - H3PO3/H3PO2 rxn can reduce primary alkyl halide.

2. Reductive dehalogenation by zinc is not selective, it's also break down the amino group.

3. HNO2 can't be used for conversion of aromatic amine to fluorine, because clhoramphenicol is an amide from primary amine, that will react with HNO2.

I post the paper in attachment below including the pharmacology reference of p-nitro methamphetamine (that is awesome).


From my experiments;
1. Chloramphenicol Hydrolylis dilute HCl is fast like the paper, with total time about 3 hours (as like in the paper; 1 hour reflux + additional evaporating time about 2 hours).

2. Reduction nitroarene group to amino by Fe-HCl, yielding alot of tar, its was happened to chloramphenicol and p-nitrophenyl-2-amino-1,3-propanediol. But probably because of my reagent, i use steel wool that is not smooth enough (resulting many FeCl3 in the solution).
I'll try using other procedures like single  electron transfer FeSO4, Ni in Acetic Acid,...
Then after i get the para amino species i'll run it in I2-H3PO3 rxn to get para amino amphetamine, the most reasonable target synthesis.