Author Topic: Synthesis of amphetamines  (Read 25123 times)

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Rhodium

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Re: Synthesis of amphetamines
« Reply #40 on: November 30, 2001, 06:11:00 AM »
Try to use propanol if you don't like the idea of using ethanol or butanol. Isopropanol probably reacts too slow with Na.

Cyrax

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Re: Synthesis of amphetamines
« Reply #41 on: November 30, 2001, 02:52:00 PM »
I have to correct myself: it seems that very pure butanol has the approximately the same price as anhydrous denaturated EtOH.  But there can be some delivery restrictions, even with DENATURATED anhydrous EtOH.  The damned gouvernment thinks that every chemist is going to give a huge cocktail party.

I found another interesting article, and it seems that it is common lab practice to use 10 eq. Na.  Just like in the ref. you gave me, Rhodium.  Now I am convinced that it is the best. 

I found this in JOC (1964) vol 29 p 1419:
"To 1-oximo-2-phenylcyclohexane (52 g, 0.274 mol), dissolved in warm absolute EtOH (500 ml) was  added sodium (63 g, 2.74 mol) little by little and the solution was refluxed for 1 hour.  After cooling, the mixture was acidified with concentrated HCl, whan NaCl precipitated.  After separation of the salt and the solvent, the residue was treated with water and Et2O.  The aqueous solution was made alkaline to yield the crude base which was extracted with Et2O.  The base was then submitted to distillation and a fraction of bp 133 - 136 was collected and solidified on cooling.  On recrystallisation from petroleum ether, trans-1-amino-2-phenylcyclohexane was obtained (39 g, 0.223 mol, 81 %)

Xgoddess

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Re: Synthesis of amphetamines
« Reply #42 on: December 05, 2001, 01:28:00 PM »
why not just Zn HCL?? that seems much simpler.

Xgoddess

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Re: Synthesis of amphetamines
« Reply #43 on: December 05, 2001, 01:42:00 PM »
Rhod, or anyone, I was reading a novice's procedure for 1.Mescaline and 2. amphetamine.
For #1...3,4,5-TMB + NO2CH3 were mixed in MeOH with the an equimolar amount of NaOH in H2O and stirred at 25C for thirty minutes. Rxn flooded with H2O, and then poured into acidic solution to form crystals of beta nitro styrene.  This was then reduced with Zn/HCL to give 50% yield of mescaline.  The author did this for amphetamine the exact same way except started with benzaldehyde an NO2Et. Instead of the nitrostyrene, he got a yellow oil, then upon reductin he got nothing.  The author did not specify why this would not work!! And he did not say a way that would work. The author just kept on complaining about how he hated to waste NO2Et bc his grant could barely afford it. Please help ;D  :)  ;)

Rhodium

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Re: Synthesis of amphetamines
« Reply #44 on: December 05, 2001, 03:12:00 PM »
What is your reference for the NaOH catalyzed nitrostyrene condensation working with benzaldehyde/nitroethane? Different aldehydes wants different catalysts to work really good. In the case of benzaldehyde/nitroethane, butylamine is said to be the best, with ammonium acetate coming on second place.

A working procedure:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenyl-2-nitropropene.html

(in the first variation, you can use 10g anhydrous ammonium acetate instead of the amine).

sunlight

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Re: Synthesis of amphetamines
« Reply #45 on: December 05, 2001, 09:02:00 PM »
Could you detail the 3,4,5 nitrostyrene synthesis and the reduction to the amine ? Did he use Zn/Hg or just Zn/HCl ?

Xgoddess

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Re: Synthesis of amphetamines
« Reply #46 on: December 06, 2001, 11:44:00 AM »
Well Sunlight, since it was your procedure, I guess I can detail it...basically, just like you said w/out isopropyl (that part just made no sense to me). anyways, thanks for the great procedure. Will the Zn/HCl redn work for the nitrostyrene for benzaldehyde and NO2Et???? Rho, do you know??

Xgoddess

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Re: Synthesis of amphetamines
« Reply #47 on: December 06, 2001, 11:51:00 AM »
Rho, the experiemnter never saw a procedure using NaOH. But in this rxn, all that happens is that a base removes an alpha proton from the NO2 alkane to form the "enol-type" (without the OL) molecule. Once that is formed, why would it not attack the aldehyde and dehydrate to from the nitro-styrene. Also, the yellow oil that was got after the first rxn, what do you think that was? The author said it smelled a lot like benzaldehyde still. And finally, any problem with a Zn / HCL redn of the intermediate? Thanks for all your help!! ;D

sunlight

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Re: Synthesis of amphetamines
« Reply #48 on: December 06, 2001, 01:31:00 PM »
God, someone reduced 3,4,5 TMNS with Zn/HCl before me ? it was my next test...
Anyway if it is a very good new, do you confirm is has been done with success ?
I would like to know the recipe for the nitrostyrene synthesis, it seems much easier than the others with cyclohexylamine...
The alcohol is used to avoid foaming.

Rhodium

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Re: Synthesis of amphetamines
« Reply #49 on: December 06, 2001, 01:34:00 PM »
Yes, the reaction mechanism calls for just any base to do the job, but in reality both which catalyst to use, and the amount of catalyst used is VERY important to get a good yield (or any yield at all). Check the table in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/edda.html

for various yields with different benzaldehydes and exactly the same reaction conditions - the yields fluctuate wildly between 3% and 96%.

The oil you got after the reaction was probably just a mixture of unreacted benzaldehyde and nitroethane, the intermediate nitro-alcohol along with the product phenyl-2-nitropropene. Some nitropropenes are very hard to crystallize unless they are very pure. A reason why the intermediate nitro-alcohol would not dehydrate (if that would be the case) is an excess of water in the reaction mixture. If there is a lot of water around, the molecule is less prone to give off a water molecule itself, compared to an anhydrous reaction, where the water very readily would split off in comparison.

I don't know so much about the Zn/HCl reduction, I think Sunlight is the authority on that reduction method. But as a general rule, any reduction method that works for nitrostyrenes also work for phenylnitropropenes.

hest

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Re: Synthesis of amphetamines
« Reply #50 on: December 06, 2001, 02:04:00 PM »
My personal exp. with the synth of 3,4,5-TMNS is that the Shulgin way is the absolut best one. The use of edda was a disaster (<30%).
The red. of the dubble bond with NaBH4 goes smooth (and the nitro alkan is a nice solid).

Rhodium

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Re: Synthesis of amphetamines
« Reply #51 on: December 06, 2001, 02:09:00 PM »
What is the melting point of that nitroalkane?

Xgoddess

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Re: Synthesis of amphetamines
« Reply #52 on: December 06, 2001, 04:58:00 PM »
Sunny -D, the redn, according to the author, couldnt be any simpler...solution starts yellow...after much addition of Zn/HCl over a couple hours, almost all yellow is replaced by a transparent solution. temp kept cool, arount 15-20. workup was a slight bitch bc of all the precipitate when base is added. upon HCL gas, the author got 2.5 grams of pure white crystals.  No GC/MS, NMR, IR, or HPLC was run, but he did a biological assay at 250 mg. It was the real deal.  However, the author did run an IR of his nitro styrene before reduction...It showed perfect evidence (no carbonyl peak, strong alkene peak, etc).
  Like the author wrote, the NaOH works fine for this nitro styrene.
  Now I have a question for you...what is all the hype about 2 C H...PIKAL says its not even active???
  Finally, since your the pioneer of the Zn/HCl redn, go ahead and try it for the product of benzaldehyde and NO2Et and let me know how it works. Dont wait too long or I'll be writing up the authors results before you. :P

Xgoddess

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Re: Synthesis of amphetamines
« Reply #53 on: December 06, 2001, 05:02:00 PM »
Nope...the shulgin way is only the best way if you want to spend more time and use more exotic chemicals.  most researchers prefer to keep it as simple as possible when that gives the best yields (NaOH,H20, 25C, 30 min, stirring).  As for your two step redn, thats even worse. why not just do a one-pot, and not even deal w/ NaBH4??? ::)

Xgoddess

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Re: Synthesis of amphetamines
« Reply #54 on: December 06, 2001, 05:10:00 PM »
Rho,in your opinion, what is the best phenethylamine...also, is there a phenethylamine that somewhat resembles MDA? 
Also, is 2CH active?
Can 2CB be prepared from the aldehyde that is already brominated(ie: from 2,5-dimethoxy-4bromo benzaldehyde) , or does bromination have to be done after the reduction?
Finally, in you opinion, what is the best phenyl -2-amino propane?? Sorry for all the questions, but you seem to really know you chemistry.  Thanks a lot.

sunlight

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Re: Synthesis of amphetamines
« Reply #55 on: December 06, 2001, 06:04:00 PM »
I'm very happy that a bee have tried with success the Zn/HCl rdxn, as he saw it's very simple, just first course of psychedelic chemistry, and probably we can make almost all PIHKAL.
About nitropropenes I tried in a small test a rdxn of 345TMPNP, the rdxn went perfect, with the tipical change of color of this reation, and when basifying I saw the oil floating and a clear amine smell, my impression is that it worked fine. Other test was made with 34MDPNP and it seemed to work, but I was not there in the workup and may be the other person fucked the essay (or may be not).
We have a lot of products to test, but now the question is if as we think the nitropropenes can be reduced as well with this procedure. I wan't try P2NP but I'll try others compounds, may be other can bee the job.
I'll try the NaOH for 345TMB.
I've tested the procedure for nitrostyrenes that is in a new entry of Rhodium's page, 19.5 gr of 3,4,5 TMB, 7.8 gr of am. acetate, 10 ml of nitromethane and 70 cc of acetic acid refluxed 2 h 15 minutes, then 50 gr of ice was added and the precipitate filtered and wash with cold IPA. It gave 14.8 gr of a crystalline product that was greenish instead of yellow, I made a TLC and showed one spot and the mp was 118-120, in a recent uemura reference the mp was reported as 120-121, so it was the nitrostyrene but probably with a small contamination that gave the greenish color.

Rhodium

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Re: Synthesis of amphetamines
« Reply #56 on: December 06, 2001, 10:09:00 PM »
2C-H is not active in itself, but as it is used as a precursor for 2C-B, it is widely discussed there. The bromination may be done in forehand on the benzaldehyde, but some reduction agents like LAH may hurt the bromine, something like diborane or alane could work.

Xgoddess

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Re: Synthesis of amphetamines
« Reply #57 on: December 07, 2001, 10:58:00 AM »
Rho, the researcher appreciated your advice for using ammonium acetate...unfortunately, he will never be able to get that. He has Na acetate. can you think of any reason why that would/ or would not work?
He also has propyl amine, di isopropyl amine,  1,2-phenylene diamine,ethylenediamine, and pyridine.  Would any of those work?
Sorry, no melting point was reported in the paper for 345 TMNS.

Rhodium

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Re: Synthesis of amphetamines
« Reply #58 on: December 07, 2001, 11:25:00 AM »
I don't think sodium acetate would work. Propylamine and isopropylamine are probably good butylamine substitutes. However, I really advise you to use that ethylenediamine and make the acetate salt of it with acetic acid and use that for your condensation reactions, see

https://www.thevespiary.org/rhodium/Rhodium/chemistry/edda.html

for the preparation and use.

Someone said that it is not good for 3,4,5-trimethoxybenzaldehyde though, I believe your propylamine would be much better there.

What is the paper/article you are referring to?

Osmium

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Re: Synthesis of amphetamines
« Reply #59 on: December 07, 2001, 11:27:00 AM »
Ethylene diamine diacetate will work in about 60% yield.

https://www.thevespiary.org/rhodium/Rhodium/chemistry/edda.html



I'm sure at least one or two of the others will work too, maybe even with better yields. UTFSE. All the info is here, and all you have to do is digging it up.

And what did you try to say when you mentioned

> ammonium acetate...unfortunately, he will never be able
> to get that.

If you really can't buy it (very unlikely), then simply prepare your own! That's not exactly rocket science...