Amphetamine => Methedrine via Al/Hg

hAzzBEEn · Mon May 16, 2005 10:39 pm

This curiosity stemmed from the discussion of P2NP => Amphetamine via the Al/Hg at this thread:
https://www.synthetikal.com/synthforum/about304.html
Does anyone have any information or experience with the conversion of amphetamine freebase to methedrine via Al/Hg with formaldehyde.

IndoleAmine · Dreamreader Deluxe

Route 1 is more efficient both yield- and workwise.

HCHO methylation of amphetamine is not very nice to do, especially when you have to isolate pure amph first and then put it back into another rxn.

Better keep the regents cheap until attemting the last step of your synthesis, else you will be frustrated when losses occur. Another reason to go via p2p instead amph as intermediate..

brain · Linguist Extraordinaire

hm, its easy like hell !! Smile

-extract the amine from first reduction(p2np+al/hg) with ethyl ether, add to ether exes of HCHO, reflux that! destill ether, reduce product on al/hg , extract with ether-make salt in ether... for small scale its easy and cheap Smile

IndoleAmine · Dreamreader Deluxe

Cheap? Not everyone is literally swimming in ether like you, brain! Very Happy

Also you need to do at least one a/b extraction somewhere in between, I would say after making amph is the best point, also purification after n-methylation is important too...

And you still have to make two Al/Hg reductions and two condensations - why not condense BzCHO to P2NP, reduce to P2P with Fe/HCl, condense with methylamine (from nitromethane) and reduce directly with Al/Hg or borohydride or sodium/EtOH or Pd-C/HCOOH or what you like...

Yields are better, reagents are cheaper, same amount of work.

hAzzBEEn · Wed May 18, 2005 9:28 pm

This was exactly the kind of knowledge that SWIM hoped to gain.

There were sevaral things that lead to the initial post.
After seeing the successful Al/Hg to amphetamine by other BEEs, SWIM was just curious if anyone had methylated the product. There was also some concern as to the difference in the evolved gas from the different routes. When doing Al/Hg with nitromethane, is the methylamine nicely dissolved into reaction mixture, or is lots escaping into the air (big stink)? Compared to Al/Hg of P2NP and Al/Hg of the obtained product with formaldehyde?

Is there any difference in the isomers produced by the two routes?

SWIM hopes to experiment with the various procedures eventually (several months from now) and was leaning toward the P2NP=>P2P=>SOMETHING from the beginning, but using Stannous Chloride Dyhydrate to reduce P2NP (because of horror stories about the Fe/HCl). Probably will start thread with regards to this, too.

Also... Is ether actually required (for the methylation reaction) or can other solvents be used, instead (toluene, xylene, etc)? Is there any particular reason that DCM is used for extraction? My first thought was their low Boiling Point. SWIM only has basic knowledge about solvents.

brain · Linguist Extraordinaire

its deam right ! Smile

but in small scale costs are "minimal" Smile

only more work Smile

IndoleAmine · Dreamreader Deluxe

If you calculate exactly how much you have to spend for reagents per gram amph.sulfate when doing Al/Hg on nitropropene, using ether and all the stuff Wink

, and then another reaction with this, more losses and more cost of reagents, then you arrive at a much bigger material cost for 1g of methedrine.HCl than if you would make p2p and reductively aminate (and this is without the work involved!!).

Also true for smaller scales, it just isn't of much concern but still more expensive.

You only realize the difference if doing rxns in the 0.5-1mol scale though, thats true... Wink

Methylamine stinks, yes. You can of course use a hose takeoff adapter on top of your condenser, and a hose leading to the fume cabinet/to the outside.... Idea

Al/Hg on nitropropenes just produces H2, no methylamine. HCHO methylation stinks too, but from the formaldehyde.. Very Happy

Both routes lead to racemic d,l- stuff, and SnCl2 makes really clean ketone provided you use anhydrous EtOAc as solvent to reduce to the oxime, then add lots of aequ. HCl to hydrolyze to the ketone, don't use toluene/H2O or acetone - toluene/H2O biphasic solvent makes lots of BzCHO and only 40-60% yield of ketone, compared to 5% BzCHO and >80% ketone when anhydr. ethylacetate is used..

Fe/HCl is messy, but can be scaled enormously and is cheap and otc. I even recall reading a patent where they stated that you could directly make p2np, add Fe powder and drip in HCl into same rxn vessel, then steam out the crude p2p directly, extract and fractionate. Then reductively aminate the so obtained ketone with a "MethylMan" Nitro Al/Hg, then isolate and purify.
Much less work and solvents, compared to making p2np, isolating, reducing to amph, isolating, methylating, isolating, purifying.... and yields are better too! Smile

I can search the mentioned patent if you're interested - but it was nothing special, just a direct one-pot combination of henry condensation between BzCHO/C2H5NO2 using n-BuNH2/PhMe, and then Nef rxn on the resulting nitro compound using Fe/FeCl3/aequ.HCl, followed by steam distillation, extraction with toluene and fractionation over a vigreux column under vacuum to obtain pure ketone....

(you see, I'm trying really hard to avoid having anyone request it! Don#T want to search. Damn lazyness.. Very Happy

)

i_a

icecool · Insistent Chemist

What would be a better method?
Adding formic acid to amphetamine freebase with toluene and put a dean&stark trap on it, and then reduce it via Al/Hg.
Or amphetamine freebase with formaldehyde and then reduce that via Al/Hg at once.
So in one big RBF Al+Hg+freebase+formaldehyde...

And what about the method of using freebase+benzaldehyde+toluene, remove the water with dean&stark trap, then add MeSO4 and reflux it, heat it longer, add water heat longer, wash with Et2O to remove benzaldehyde which did not react, then make alkaline and extract the amine, vacuum distill off the Et2O and be left with a crude oil which then needs to be hydrolised in EtOH+Et2O mixture with HCl.
Then one has methedrine.HCl after cooling.

bio · Working Bee

The HCHO reaction is cleaner than the formic producing less byproducts and no wasted benzaldehyde as in the last.

Even though the last method mentioned would recover PhCHO there is always some loss associated with manipulation.

icecool · Insistent Chemist

That's true but if you have unlimited acces to benzaldehyde, and besides it is a huge advantage that you don't have to do an Al/Hg reduction anymore or LiAlH4.
Just one pot thing everything directly from amph to methamph.

And in the synthesis of diethyl sulfate.
I suppose the ethanol can also be substituted by methanol to yield dimethyl sulfate right?
And why does the synthesis say to make it vacuum and add the mixture of ethanol and sulfuric acid via the capillairy can't one just mix H2SO4 and EtOH and Na2SO4 to get diethylsulfate and then distill it.
I suppose the Na2SO4 is there to have enough SO4 present to drive the reaction forward in the equilibrium and also to suck up water...
But why under vacuum.

SWIM tried to make methyliodide yesterday, and well first off all the whole fumehood is full of iodine stains now.
SWIM added 43g of red phosphorous to a 500ml round bottom flask, and put a seperatory funnel on top of it which contained 83g of iodine crystals and 120ml methanol.
As in the synthesis, well no way that much iodine is going to be dissolved in 120ml methanol.
A whole layer of iodine remained on the bottom of ther erlenmeyer flask.
Anyway the liquid layer was put in the seperatory funnel and added dropwise to the red phosphorous it got a little bit warmer, then it was stirred and tried mixing it with a glas stir rod, one big mess, more MeOH+I2 was added and when everything was a liquid heat was added by the means of a waterbath at 50*C, it started to warm up a bit more, but no vigorous reaction or anything.
Then a yellow liquid started to distill over at 43*C that is the methyliodide but well then it raised to 60*C and nothing more came over only a few ml had come over as the product should be around 40-50ml.
What has SWIM done wrong?
SWIM will heat the mixture again today, and add more MeOH with I2 in it which didn't dissolve yesterday.
Or should one heat the RP when only a few drops have been added...

bio · Working Bee

.......And why does the synthesis say to make it vacuum and add the mixture of ethanol and sulfuric acid via the capillairy can't one just mix H2SO4 and EtOH and Na2SO4 to get diethylsulfate and then distill it. ..............

Take a look at the patent I posted in the dimethyl sulfate thread the other day.
That method is much better for the reasons described in the patent.

Problem with the way you described is that it decomposes so fast that even under vacuum the yield is shitty. The vacuum keeps the temp down and slows decomposition.

I only tried it a couple of times and very dissapointing. I think the key here is that the distillation must go as fast as possible because otherwise you end up with what you started with.

The diethyl sulfate in the dupont patent mentioned uses NaHSO4 which forms the dehydrating agent insitu and doesn't require H2SO4. Seemsa it should work with MeOH as well but it's puzzling that other alcohols weren't mentioned.

Most anyone has unlimited access to PhCHO by the way but last I checked they weren't giving it away yet.

icecool · Insistent Chemist

I'dd reather go for methyliodide then.
It is easier to make out of HI 57% and methanol.
Or red phosphorous and iodine and methanol.
Anyway once you get the reaction right.
Rather easier is via HI and methanol, since I2 doesn't all dissolve very well in methanol and well just fucked up...
You need a lot of I2 and a bit of methanol and I don't know if all the I2 actually needs to go in the reaction or not, and besides it very quikcly roses to 60*C insted of staying at 43*C like it is supposed to...

loki · guinea pig

the trick with making methyliodide is to form the phosphorus iodides first. it might be easier to use PCl3 and then iodinate it with HI (i think KI even works for this)

the question is tho, how good is the yield using it to methylate. one has to undershoot on MeI to get adequate monomethylation. too much and it goes all the way to quaternary iodide.

icecool · Insistent Chemist

What do you mean?
Concerning methylating amphetamine or forming CH3I.
And besides it is also possible to make CH3I from HI 57% and red P.

bio · Working Bee

.........'dd reather go for methyliodide then. .......l. Or red phosphorous and iodine and methanol. ..........

Or Al, I2 and MeOH with no preforming the AlI3.

I have a CA abstract that uses Al or Mg with alcohols.