Dextroamphetamine synthesis from P2P by (S)-(−)-α-Methylbenzylamine

[G.Patton]

Oh sry didn't know that, does the same apply to fenethyline?

cokemuffinI think yes, it is Nucleophilic substitution reaction, which gives racemic product.

Edit: stereoselective reductive alkylation into d-meth

 

[OrgUnikum]

I think yes, it is Nucleophilic substitution reaction, which gives racemic product.

G.PattonIt is a reductive amination also called reductive alkylation with the formaldehyde being the alkyl. There is no inversion or razemisation so Dextro-Amphetamine will yield Dextro-Methamphetamine when reductivly alkylated with formaldehyde.

 

[G.Patton]

It is a reductive amination also called reductive alkylation with the formaldehyde being the alkyl. There is no inversion or razemisation so Dextro-Amphetamine will yield Dextro-Methamphetamine when reductivly alkylated with formaldehyde.

OrgUnikumYou are right, thank you for your note.

 

[mygodson]


This reaction must not use Raney nickel, palladium carbon can be reduced to 5% to 10%, and chloroethyl chloroformate can also be used

 

[ossi]


This reaction must not use Raney nickel, palladium carbon can be reduced to 5% to 10%, and chloroethyl chloroformate can also be used

mygodsoncan you please explain for beginner?
don’t work with raney nickel? reduced 5% to 10% ?

 

[mygodson]

can you please explain for beginner?
don’t work with raney nickel? reduced 5% to 10% ?

ossiRaney nickel cannot be used for debenzylation reaction

 

[btcboss2022]

Raney nickel cannot be used for debenzylation reaction

mygodsonUntil I know Raney nickel could be used in debenzylation the important thing in that case is the solvent used, it can't be used with ethanol or methanol due the byproducts but with IPA it should works properly and for the amounts used in that synth around 300-400gr of Raney nickel 50% would be used. What is the base of that affirmation exactly?
Thanks.

 

[ossi]


This reaction must not use Raney nickel, palladium carbon can be reduced to 5% to 10%, and chloroethyl chloroformate can also be used

mygodsonand chloroethyl chloroformate can also be used
this instead of Pd/C ?

 

[mygodson]

and chloroethyl chloroformate can also be used
this instead of Pd/C ?

ossi
Yes, there are many methods for debenzylation

 

[OrgUnikum]

The reaction can be done in one step, the borohydride reduction is not necessary ecept one wants to isolate the intermediate for further enhancement of the optical purity by recrystallisation.

But there is no way around the Pd/C as most other more common methods of reduction cannot cope with de-benzylations. And even then it takes quite some time, 48 hours with 50 psig pressure of Hydrogen gas and 10% Pd/C. I guess a high loading of Pd/C is unavoidable to get this going and not taking forever when doing this CTH style.
Here is the Nichols article where it is described:

 

[ossi]

The reaction can be done in one step, the borohydride reduction is not necessary ecept one wants to isolate the intermediate for further enhancement of the optical purity by recrystallisation.

But there is no way around the Pd/C as most other more common methods of reduction cannot cope with de-benzylations. And even then it takes quite some time, 48 hours with 50 psig pressure of Hydrogen gas and 10% Pd/C. I guess a high loading of Pd/C is unavoidable to get this going and not taking forever when doing this CTH style.
Here is the Nichols article where it is described:

OrgUnikumdon’t understand. doesn’t work with raney nickel?

 

[mygodson]

don’t understand. doesn’t work with raney nickel?

ossiyes，don't work

 

[ossi]

how much should be used instead 475gr? @mygodson

 

[mygodson]

how much should be used instead 475gr? @mygodson

ossiAdd 5% to 10% by mass, because amino will weaken the catalyst activity, and the catalyst may be 10%

 

[ossi]

Add 5% to 10% by mass, because amino will weaken the catalyst activity, and the catalyst may be 10%

mygodsonthat means for 1000gr P2P max. 100gr Pd/C ?
and how often can i use Pd/C?

 

[OrgUnikum]

I would strongly suggest to do this in one step, methanol or ethanol as solvent and to use the formic acid salt of a-methylbenzylamine in the amination step for better yields the acid serving also as hydrogen donor in the Imine reduction. Although the ph in the debenzylation should be acidic I would use the bigger part of of the formic acid in form of the a salt too, if one uses IPA as solvent this could serve as hydrogen donor by itself (or secondary hydrogen donor).
Also the methylbenzylamine should be limiting reagent and the phenylacetone be used in excess what will avoid separation problems in the workup.

A lot depends on the quality and activity of the Pd/C you got.

Catalyst should be re-usable up to 5 times, using all amines as salts prevents most of the deactivation. Nevertheless one should add 10 to 20% of fresh catalyst every time.

As heterogeneous reaction this needs good agitation to keep the catalyst suspended but be aware that strong stirring atomizes the Pd/C and filtration of this post-reaction is a major pain in the ass anyways. No chance without Celite or similar filtration aids, also the catalyst when allowed to dry out might catch fire. Keep it moist.

@mygodson What other ways for debenzylation would you have in mind? Chloroethyl chloroformate and its derivates are quite nasty, I know only of one other way where the needed reagents are actually available and not highly toxic. And thats Sodium metal on Silicagel.

 

[ossi]

I would strongly suggest to do this in one step, methanol or ethanol as solvent and to use the formic acid salt of a-methylbenzylamine in the amination step for better yields the acid serving also as hydrogen donor in the Imine reduction. Although the ph in the debenzylation should be acidic I would use the bigger part of of the formic acid in form of the a salt too, if one uses IPA as solvent this could serve as hydrogen donor by itself (or secondary hydrogen donor).
Also the methylbenzylamine should be limiting reagent and the phenylacetone be used in excess what will avoid separation problems in the workup.

A lot depends on the quality and activity of the Pd/C you got.

Catalyst should be re-usable up to 5 times, using all amines as salts prevents most of the deactivation. Nevertheless one should add 10 to 20% of fresh catalyst every time.

As heterogeneous reaction this needs good agitation to keep the catalyst suspended but be aware that strong stirring atomizes the Pd/C and filtration of this post-reaction is a major pain in the ass anyways. No chance without Celite or similar filtration aids, also the catalyst when allowed to dry out might catch fire. Keep it moist.

@mygodson What other ways for debenzylation would you have in mind? Chloroethyl chloroformate and its derivates are quite nasty, I know only of one other way where the needed reagents are actually available and not highly toxic. And thats Sodium metal on Silicagel.

OrgUnikumI would strongly suggest to do this in one step, methanol or ethanol as solvent and to use the formic acid salt of a-methylbenzylamine in the amination step for better yields the acid serving also as hydrogen donor in the Imine reduction. Although the ph in the debenzylation should be acidic I would use the bigger part of of the formic acid in form of the a salt too, if one uses IPA as solvent this could serve as hydrogen donor by itself (or secondary hydrogen donor).
Also the methylbenzylamine should be limiting reagent and the phenylacetone be used in excess what will avoid separation problems in the workup.

Hi, thank you very much for your reply. I more or less understood the lower part of your text. but I read the first part a hundred times and didn't understand how to do it. can you perhaps write in more detail for an amateur and non-chemist, as the author wrote it? that would be great

 

[mygodson]

Then use the method of palladium carbon debenzylation. The post-treatment is simple, and the by-product is also easy to treat. The post-treatment is suction filtration and vacuum concentration. The by-product is toluene.

 

[OrgUnikum]

Actually there are two possibilities to get dextro-Meth in one pot by one or one-and-a-half steps. First option would be to use (S)-N-Methyl-1- phenylethylamine; (CAS:19131-99-8) whats a naturally occurring compound and as such should be available. It is a secondary Amine and the Imine formation might need some catalyst like triflic acid. Otherwise same same, reduction of the amine and debenzylation to d-Methamphetamine.
Second option is reductive amination with (S)-alpha-Methylbenzylamine with one pot hydrogenation to (S)-Amphetamine followed by addition of the required amount of paraformaldehyde and alkylation to d-Meth.

The attached article proves the second option is well possible, it covers amination of P2P (95% yield) and of formaldehyde (85% yield), there is no doubt this can be done consecutively in one pot. Author is Repke who like Nichols belongs to the big "no bullshit" ones.

@ossi You will get this as step by step procedure as soon I have figured out how to do it as CTH, say without the need for a hydrogen bottle but an internal chemical hydrogen source and with the salts of the amines to minimize catalyst poisoning make the catalyst re-usable.

 

[ossi]

Actually there are two possibilities to get dextro-Meth in one pot by one or one-and-a-half steps. First option would be to use (S)-N-Methyl-1- phenylethylamine; (CAS:19131-99-8) whats a naturally occurring compound and as such should be available. It is a secondary Amine and the Imine formation might need some catalyst like triflic acid. Otherwise same same, reduction of the amine and debenzylation to d-Methamphetamine.
Second option is reductive amination with (S)-alpha-Methylbenzylamine with one pot hydrogenation to (S)-Amphetamine followed by addition of the required amount of paraformaldehyde and alkylation to d-Meth.

The attached article proves the second option is well possible, it covers amination of P2P (95% yield) and of formaldehyde (85% yield), there is no doubt this can be done consecutively in one pot. Author is Repke who like Nichols belongs to the big "no bullshit" ones.

@ossi You will get this as step by step procedure as soon I have figured out how to do it as CTH, say without the need for a hydrogen bottle but an internal chemical hydrogen source and with the salts of the amines to minimize catalyst poisoning make the catalyst re-usable.

OrgUnikum@OrgUnikum great thank you very much

 

[Caleb_Crawford338]

How do you make Dextroamphetamine as it is in Dexedrine? How do you make Dextroamphetamine XR

 

[the money]

Palladium on carbon

William DampierIs there an alternative

 

[OrgUnikum]

The method for Crystal Meth:

An equimolar mixture* of P2P and (S)-(-)-alpha-methylbenzylamine, CAS Number: 2627-86-3, and 20% by weight of 10% Pd/C in anhydrous ethanol (IPA) was shaken under 50p.s.i. hydrogen (3,5 atm or bar over normal pressure) for 16 hours. The mixture was acidified with concentrated hydrochloric acid (30% or better), filtered (Celite), and the filtrate concentrated under reduced pressure, a part of the alcohol is distilled off. The residue was dissolved in water, basefied with 30% sodium hydroxide solution, and the amine extracted with ether (Toluene). The organic solution was dried over MgSO4, filtered,and the filtrate acidified using HCl in ether or HCl in IPA. The precipitate (Crystals) was collected and recrystallized from ethanol/ether (IPA boiling hot 5 ml per gram Meth.HCl, later add acetone, filter, wash crystals with ICE-COLD acetone).

* 1 mol P2P = 134 gram, 1 mol (S)-(-)-alpha-methylbenzylamine = 121 gram (CAS Number: 2627-86-3, better known as 1-phenylethylamine btw.).
Say, per 100 g P2P 90 g of the phenylethylamine are needed.

Whats going on? It is a reductive Amination (or Alkylation to be more precise) but instead of Methylamine a chiral Amine is used which forces the formed molecule into the dextro orientation. So Amine and Ketone condense, splitting off water and the formed Imine is reduced to the Amine.
The Amine formed has some stuff attached which we do not want, and thats a Benzyl, Toluene basically. De-Benzylation is whats needed, and thats the heavy lifting the Pd/C has to do here. Splitting off the Benzyl-thing gives some Toluene and the oh so much desired d-Meth.

This must be tried on a not more then 10 g scale (P2P) first until it works, too many variables in play, same for catalyst re-usability: Theoretically yes, up to five times, but do not blame me if not.

80% or better yield. Improvements are possible, of course this is a working easy method though.
Improvement one: Do a CTH hydrogenation replacing most of the Hydrogen with an in-situ hydrogen donor like formic acid, formic acid salts, Limonene, Tetraline or mixtures thereof. Reaction must still be purged with hydrogen at the beginning, pump hydrogen through. pre-reduce the catalyst and attach an balloon filled with hydrogen. No pressure needed. Modern catalysts are more active, the 10% can be replaced by 5% Pd/C, the amount reduced to 15% of the P2P weight.Probably less, but thats still on the safe side. 2 mol of formic acid or its salts are needed per mol of P2P - simple, make the formate salt of the phenylethylamine and you have one mol covered, then add half a mol Limonene or a third or less of Tetraline (they donate more then one hydrogen) and its ok. Even NaBH4 can be used as hydrogen donor, donating four Hydrogens per mol. Running the reaction at about ph 4 protects the catalyst and speeds things considerably up. Hydrogenations are exothermic! You won't notice with small runs but it quickly gets interesting on bigger batches.
After the reaction let it sit under a blanket of hydrogen with mild shaking overnight - 5 to 10% better yields.

And this is a heterogeneous reaction to get the catalyst in contact the whole thing must be shaken. Not like mad but in a way that the catalyst is in even suspension and not near the bottom only. Stirring works but it atomizes the catalyst and it cannot be recovered by Celite filtration and the meth base must be vacuum distilled as the catalyst is not to remove by other ways. A PITA. Do not stir, shaking is easy. Look for "hydrogenation duck" on Google. Really. No joke.

I checked and CAS Number: 2627-86-3 is available no issues, costs about the same as BMK, so the costs are fine IMHO, real Crystal Meth is so rare nowadays that selling it as anything but a high-price, high quality, low supply item would be stupid. Nobody wants real Crystal for cheap back on the streets, the madness!, the trouble! but push it for 200 €+ per g to the poofters and your children won't go hungry any time soon.

 

[OrgUnikum]

The method for Crystal Meth:

* 1 mol P2P = 134 gram, 1 mol (S)-(-)-alpha-methylbenzylamine = 121 gram (CAS Number: 2627-86-3, better known as 1-phenylethylamine btw.).
Say, per 100 g P2P 90 g of the phenylethylamine are needed.

Whats going on? It is a reductive Amination (or Alkylation to be more precise) but instead of Methylamine a chiral Amine is used which forces the formed molecule into the dextro orientation. So Amine and Ketone condense, splitting off water and the formed Imine is reduced to the Amine.
The Amine formed has some stuff attached which we do not want, and thats a Benzyl, Toluene basically. De-Benzylation is whats needed, and thats the heavy lifting the Pd/C has to do here. Splitting off the Benzyl-thing gives some Toluene and the oh so much desired d-Meth.

This must be tried on a not more then 10 g scale (P2P) first until it works, too many variables in play, same for catalyst re-usability: Theoretically yes, up to five times, but do not blame me if not.

80% or better yield. Improvements are possible, of course this is a working easy method though.
Improvement one: Do a CTH hydrogenation replacing most of the Hydrogen with an in-situ hydrogen donor like formic acid, formic acid salts, Limonene, Tetraline or mixtures thereof. Reaction must still be purged with hydrogen at the beginning, pump hydrogen through. pre-reduce the catalyst and attach an balloon filled with hydrogen. No pressure needed. Modern catalysts are more active, the 10% can be replaced by 5% Pd/C, the amount reduced to 15% of the P2P weight.Probably less, but thats still on the safe side. 2 mol of formic acid or its salts are needed per mol of P2P - simple, make the formate salt of the phenylethylamine and you have one mol covered, then add half a mol Limonene or a third or less of Tetraline (they donate more then one hydrogen) and its ok. Even NaBH4 can be used as hydrogen donor, donating four Hydrogens per mol. Running the reaction at about ph 4 protects the catalyst and speeds things considerably up. Hydrogenations are exothermic! You won't notice with small runs but it quickly gets interesting on bigger batches.
After the reaction let it sit under a blanket of hydrogen with mild shaking overnight - 5 to 10% better yields.

And this is a heterogeneous reaction to get the catalyst in contact the whole thing must be shaken. Not like mad but in a way that the catalyst is in even suspension and not near the bottom only. Stirring works but it atomizes the catalyst and it cannot be recovered by Celite filtration and the meth base must be vacuum distilled as the catalyst is not to remove by other ways. A PITA. Do not stir, shaking is easy. Look for "hydrogenation duck" on Google. Really. No joke.

I checked and CAS Number: 2627-86-3 is available no issues, costs about the same as BMK, so the costs are fine IMHO, real Crystal Meth is so rare nowadays that selling it as anything but a high-price, high quality, low supply item would be stupid. Nobody wants real Crystal for cheap back on the streets, the madness!, the trouble! but push it for 200 €+ per g to the poofters and your children won't go hungry any time soon.

OrgUnikumAttention! Correction!
I by accident I wrote CAS:2627-86-3, (S)-(-)-alpha-methylbenzylamine, 1-phenylethylaminewhere but thats for dextro-Amphetamine
the correct one for d-Meth is CAS:19131-99-8, (S)-N-Methyl-1- phenylethylamine, and there might be problems that it won't work for getting to crowded.
But the one pot -> d-Amph + formaldehyde -> d-meth works for sure.

 

[btcboss2022]

Attention! Correction!
I by accident I wrote CAS:2627-86-3, (S)-(-)-alpha-methylbenzylamine, 1-phenylethylaminewhere but thats for dextro-Amphetamine
the correct one for d-Meth is CAS:19131-99-8, (S)-N-Methyl-1- phenylethylamine, and there might be problems that it won't work for getting to crowded.
But the one pot -> d-Amph + formaldehyde -> d-meth works for sure.

OrgUnikumThere is a big problem with CAS 19131-99-8, its extremely expensive around 3k usd/kg!

 

[OrgUnikum]

There is a big problem with CAS 19131-99-8, its extremely expensive around 3k usd/kg!

btcboss2022You still have the option with CAS:2627-86-3,, thats not so expensive and formaldehyde/paraformaldehyde is very cheap (if you get at all).