Author Topic: Synthesis of para-fluoro-(4-methylaminorex)  (Read 8600 times)

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Bandil

  • Guest
Synthesis of para-fluoro-(4-methylaminorex)
« on: October 14, 2003, 11:25:00 PM »
Para-fluoro-(4-methylaminorex) writeup

Theoretical route:
The synthesis of the title compound is intended to proceed from the precursor para-flurobenzaldehyde. Using the following

method

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenyl-2-nitropropanol.html), the nitroalcohol is to be formed. A 1:1,2:1 molar ratio of benzaldehyde : nitroethane : triethylamine will be used in a proper solvent. The product is to be reduced with Zn/formic acid to the aminoalcohol, which is to be reacted with sodiumcyanate, to make the carbamyl-intermediate. This may or may not be isolated and then further reacted with hydrochlorid acid, to form the oxazoline ring.

Practical experience:
Condensation:
10 grammes(0,0806 moles) of para-fluorobenzaldehyde(99%+ purity, 124,11 g/mole) was mixed with 15 mL’s of methanol in a 100 mL Erlenmeyer flask, and put in the fridge and refrigerated till the temperature was –10 degrees celcius. Fortunately the benzaldehyde was soluble at these low temperatures, which means that the reaction can be conducted as originally intended. In a separate beaker, 7,3 grammes(0,0967 moles) of nitroethane(75 g/mole) was mixed with 8,14 grammes(0,0806 moles) of triethylamine(99%+ purity, 101 g/mole). This was also cooled to –10 degrees. Once the mixture was cooled satisfyingly, the contents from the beaker with nitroethane/triethylamine was poured into the Erlenmeyer flask with the fluoro-benzaldehyde. This was swirled a few times, and put back in the freezer. Once every 30 min’s it was taken out and swirled. The color of the mixture went from totally clear to yellowish over the course of the 2½ hours, which the reaction was allowed to run. Once the reaction was complete(2½ hours), the amine was quenched with an 1,1 equimolar amount of GAA., while the reaction mixture was still cool. It is very important to quench the reaction while it is still very cold, as the isomers will reach an equilibrium once the temperature rises, if there still is active catalyst present. Most of the solvent was stripped under vacuum, and the remains where dissolved in DCM and washed two times with water and once with brine. The DCM was stripped, leaving behind about 15 grammes of the crude nitroalcohol.

Reduction:
The nitroalcohol was reduced in the usual manner, by Zn/formic acid.

This

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitro2amine.zn-formate.html) method was used, with the following amounts:

15 grammes crude nitroalcohol
100 mL methanol
18,6 grammes of Zinc
70 mL’s of formic acid

After filtering the reaction mixture, a slightly reddish liquid remained. Most of the solvent was stripped, and the remains where dissolved in 100 mL’s water and acidified with hydrochloric acid to pH 2(for some reason it was almost neutral, even though a huge excess of formic acid was used; maybe the zinc ate most of it?). The mixture was nearly pink at this point. This was washed twice with DCM to give a very pale red-tinted solution. Upon basification of this mixture, a lot of inorganic salts precipitated. This has probably been some Zinc salts of some sort.  The whole lot was extracted once with chloroform and twice with DCM. After the first chloroform extraction and addition of DCM, the whole lot was filtered to remove the inorganic salts. The combined organic phases where stripped of solvents and left 7,6 grammes of para-fluoro-norephedrine(42,5 mmole) freebase as a pale yellow liquid.

Reaction with cyanate:
The para-fluoro-norephedrine was poured into 70 mL’s of water and titrated with hydrochloric acid, until weakly acidic, where after the while lot dissolved. 3,5 grams (44 mmoles) of KOCN was added to this in one portion. The mixtures was refluxed in an oil bath for 2½ hour. After this time a clear oil was present at the top of the refluxing water. After completion of the reaction, the mixture was put in the freezer in order to isolate the carbamoyl intermediate. A slightly reddish oil precipitated on the bottom of the flask, but no crystals formed. It was decided, simply to do the reaction as a one pot synth.

Formation of the oxazoline ring:
The reaction mixture was mixed with a 3 times molar excess of hydrochloric acid and refluxed for 2½ hour. After this time, the flask was removed from the oil-bath and cooled. No oil was present anymore, so a reaction has definately occurred. At 40 degrees celcius, sodium carbonate as a 20% solution was added to part of the solution. The mixture turned opaque and white upon basification, but no real formation of crystals could be noted right away. This was late in the evening, so the mixture was allowed to stand a low temperatures and cool of (and hopefully provide some neat crystals.). The mixture smelled somewhat of ammonia after basification. Hopefully this is not due to breakdown of aminorex to the norephedrine and HOCN. 3,4-Dimethylaminorex is supposed to do this in contact with NaOH. Anyone have some ideas if this could be the case here?

The workup will be performed within a few days, and hopefully it will be positive news! It's probably a good idea to cool of the solution before basifying, to get the unreacted carbamoyl compound, originating from the wrong isomer, out of the solution first. After this the extraction of the compound it some 'clean'.

Keep your limbs crossed for a successfull extraction and bioassay  8)


Manichi

  • Guest
Good job!
« Reply #1 on: October 15, 2003, 01:05:00 AM »
Good luck! ;D

Megatherium

  • Guest
Great.
« Reply #2 on: October 15, 2003, 04:55:00 AM »
The mixture smelled somewhat of ammonia after basification. Hopefully this is not due to breakdown of aminorex to the norephedrine and HOCN. 3,4-Dimethylaminorex is supposed to do this in contact with NaOH. Anyone have some ideas if this could be the case here?

Do not worry.  This is good news.  Upon cyclization NH3 is liberated, which means the product is formed  ;) .

My sincere congratulations, this is some really excellent work  :)  :) .  I believe you just made my day  ;D  ;D  ;D .

Bandil

  • Guest
Liberation of ammonia
« Reply #3 on: October 15, 2003, 10:18:00 AM »
Don't see where that ammonia should have come from? Water is liberated upon cyclization, but no ammonia according to my reaction schemes...

Anyone have a good idea on how to check for the difference between the fluoromethylaminorex, and fluoro-norpephedrine(other than HPLC-MS and other expensive gadgets like that)?


Bandil

  • Guest
There should be about 30% of the (R,R),(S,S)...
« Reply #4 on: October 15, 2003, 12:36:00 PM »
There should be about 30% of the (R,R),(S,S) isomer which should form an amide when subjected to the synthesis. Couldn't the ammonia smell result in a hydrolysis of this compound caused by the basic environment?

Regards
Bandil


Megatherium

  • Guest
You 're right, sorry about the screwup.
« Reply #5 on: October 15, 2003, 02:04:00 PM »
You 're right, sorry about the screwup.  Well, it was early in the morning (this bee was partying all night & got over-excited when reading your post).

Upon second thought, I 'm pretty sure that the the ammonia smell is due to the hydrolysis of the residual isocyanic acid (--> NH3 + CO2). After all, the intermediate wasn't isolated.

Bandil

  • Guest
Megatherium> No problem ;-) ; after all...
« Reply #6 on: October 15, 2003, 02:21:00 PM »
Megatherium>
No problem  ;) ; after all life is more fun if you punish your body from time to time.

But i really can't understand where the isocyanic acid should have come from. All of the excess cyanate was destroyed upon addition of hydrochloric acid. Also the product did not smell like ammonia before being basified. Could it result from the amide some how?

Regards
Bandil


Bandil

  • Guest
Hydrolysis of oxazolines
« Reply #7 on: October 15, 2003, 02:33:00 PM »
According to

this

(https://www.thevespiary.org/rhodium/Rhodium/pdf/poos.aminorex-1.pdf) document, many of the oxazolines, will hydrolyse in the presence of mineral acids like hydrochloric acids or even plain water. How is this consistent with the nice yields obtained by relfluxing the carbamoyl compounds in a large excess of hydrochloric acid? The oxazoline ring should be torn to pieces almost immediately after being formed?

Regards
Bandil


Megatherium

  • Guest
But i really can't understand where the ...
« Reply #8 on: October 15, 2003, 03:46:00 PM »
But i really can't understand where the isocyanic acid should have come from. All of the excess cyanate was destroyed upon addition of hydrochloric acid. Also the product did not smell like ammonia before being basified.

42.5 mmol p-fluoro-norephedrine was reacted with 44 mmol in situ generated isocyanic acid.  Assuming that the yield of the N-carbamyl compound is 57.7 % (like in the J Chem Soc (1952) p 850 article), 1.5 + (42.3% x 42.5) mmol of unreacted isocyanic acid is still present in the solution.  Upon HCl acidification, the isocyanic acid is converted to ammonium chloride & upon basification the NH3 is liberated.  Hence the smell.

I still think the synthesis will be a bashing success.

For the workup, mabey a cold crystallization would work fine.  If the crude solid (after evaporation) dissolves in ether, I 'd add dropwise petroleum ether until the solution becomes turbid & put it in the fridge.

Bandil

  • Guest
Ahhhh, yes of course 8-) I could kiss you...
« Reply #9 on: October 15, 2003, 03:53:00 PM »
Ahhhh, yes of course  8)  I could kiss you Megatherium; you really made my day!

I'll do the workup saturday and let you all know of the outcome!


SPISSHAK

  • Guest
another explanation
« Reply #10 on: October 16, 2003, 06:23:00 AM »
not contradicting what Megatherium said, if your starting material is racemic (erythro, and threo isomers) when the oxazolidone by-product is formed NH3 is a reaction product of that cyclization, and yes the cyanic acid decomposition will happen too.
See the stereochemcal course of conversion of carbamates to amino oxazines document on Rhodium's page.
Curious, what is the Fluoro analog Like???

Megatherium

  • Guest
Curious, what is the Fluoro analog Like???
« Reply #11 on: October 16, 2003, 07:49:00 AM »
Curious, what is the Fluoro analog Like???

It should be rather potent  - but we 're going to know it for sure within a few days  ;) .

Bandil

  • Guest
Continuation of the saga...
« Reply #12 on: October 18, 2003, 09:55:00 PM »
Continued from the first post.

Post reaction workup


The post reaction mixture was washed twice with 30 mL's of DCM to remove any amide present. After discarding the DCM the water phase was acidified with sodium carbonate and a little sodium hydroxide. The solution turned nice and cloudy  :) . This was extracted with 3 times 30 mL's of DCM. The DCM was evaporated under reduced pressure and 2,6 grammes of slighly yellow oil remained. The oil was negative on marquis test.

The overall yield from the fluorobenzaldehyde was 19%, the yield of the first step was 53% and the last was 35%. It's somewhat on the low side, but if this compound turns out to be mega potent it's not to bad. The synthesis is very easy and it's obtainable chemicals that are used.

Bioassay will be conducted during the forthcoming week  8)

The first dosage will probably be 200 mcg's of the freebase to check for toxcity!

So all in all, this has been yet another cool success  8)

Regards
Bandil


Vitus_Verdegast

  • Guest
Great!!!
« Reply #13 on: October 19, 2003, 12:22:00 AM »
__>  8)  <__

Very promising! Looking forward for bioassay details  :)



After discarding the DCM the water phase was acidified with sodium carbonate and a little sodium hydroxide  --> typo, probably the excitement  ;)


Bandil

  • Guest
Re: After discarding the DCM the water phase...
« Reply #14 on: October 19, 2003, 03:43:00 AM »

After discarding the DCM the water phase was acidified with sodium carbonate and a little sodium hydroxide  --> typo, probably the excitement



typo, probably the LSD  8)




Prometheuz

  • Guest
First series of bioassays
« Reply #15 on: October 21, 2003, 12:04:00 PM »
A solution of the aforementioned freebaseoil was made. 700 mg dissolved in 350 ml 40% alcohol. (2mg/ml)
200 µg was tried first, and no effect, positive or negative was felt. The same day, a total of 2,5 mg was ingested, in small amounts over the entire day. No definate effect was felt. The solution had a definate taste of benzaldehyde...?
Today, a dose of 5 mg was ingested 2 hours earlier. Some degree of stimulation is felt, but definately not more than 12 mg of 4-MAR would give.
First conclusion: Either the compound is impure, or it is not very potent.
More to come....


SPISSHAK

  • Guest
I think the halo derivatives
« Reply #16 on: October 24, 2003, 12:04:00 AM »
have a greater affinity for 5HT which explains the weaker stimulant properties.

SPISSHAK

  • Guest
Bioassay???
« Reply #17 on: November 20, 2003, 04:52:00 PM »
So Bandil remember me back when we used to pm about this and that.
You never gave a full bioassay report we here at the hive would like to hear more
Certiorari??? (latin: we wish to be informed!)
P.S. I'd like to hear more about the qualitative aspects of this hypothetical expierience as compared to regular 4-MAR

Bandil

  • Guest
Bioassay
« Reply #18 on: November 20, 2003, 06:18:00 PM »
Well that's because i havn't tried the stuff yet :)

I really busy at the moment and i only just now got mentally fit to test new compounds...

But i will of course report back as soon as i junk it into my groin, which hopefully will be soon!

Regards
Bandil


suttleila

  • Guest
4-methylaminorex
« Reply #19 on: November 28, 2003, 10:23:00 AM »
swim has been playing around with chemistry for a couple of years and has mastered methamphetamine now swim wants to move on to 4-methylaminorex is there an easy method with easy to find precursors swim wants the best of the best and is sick of playing with hi or nh3 please advise it would make my day to finally have ice!!!!!!!!!!!!