The simplest Methamphetamine synthesis from Amphetamine

G.Patton

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Introduction

There are many procedures out there for the production of N-methyl-amphetamines (methamphetamines) from various starting materials, such as phenyl-2-propanone (P2P), phenylacetaldehyde or ephedrine, but what if you already have an amphetamine and wanted to add a methyl group to amino group? If you used the first reaction that comes to mind for the conversion, to alkylate the amphetamine with methyl iodide or dimethylsulfate, you would be disappointed, as you would get a mixture of products, most important the N, N-dimethyl-amphetamine (of very low activity), as once the amphetamine has been methylated to methamphetamine, the molecule is much more susceptible to another alkylation, and thus the dimethyl- amphetamine is formed much faster than the remaining amphetamine is alkylated to methamphetamine. Actually, in the reaction mix you would find unreacted amphetamine, N-methylamphetamine, N, N-dimethyl- amphetamine and even some of a quaternary N, N, N-trimethylamphetammonium salt.

To avoid this happening, we must usually resort to indirect methods of introducing the methyl group. One way is to react the amphetamine with formaldehyde (either as an aqueous solution, or as paraformaldehyde) to get the amphetamine formaldehyde imine, which can then be reduced to N-methylamphetamine using a several different reducing agents, for example Al/Hg or Pt/H₂.

In this topic, I described the simplest synthesis of methamphetamine (4) from amphetamine salt via Imine (3) with help of Al/Hg reduction.

Equipment and glassware:
  • 5 L Round bottom flask;
  • Reflux condenser;
  • 1 L Separatory funnel;
  • Laboratory grade thermometer (0 °C to 100°C);
  • HCl gas apparatus;
  • Boiling chips;
  • Measuring cylinders 100 and 500 mL;
  • Vacuum source;
  • 2000 mL x1; 250 mL x3; 500 mL x3; 100 x2 Beakers;
  • Glass rod and spatula;
  • Laboratory scale (0.01-500 g is suitable);
  • Buchner flask (2 L) and funnel (or small Schott filter);
  • Retort stand and clamp for securing apparatus;
  • Ice water bath;
  • Glass rod;
  • Rotary evaporator (optional);
  • pH indicator paper;
  • 1 L Erlenmeyer flask.

Reagents:

  • 1 mole Amphetamine salt;
  • ~1 L 20% Sodium hydroxide (NaOH) water solution;
  • ~700 mL DCM or petrolium ether;
  • 1 mole (81 mL 37% or 75 mL 40%) Aqueous formaldehyde (CH2O);
  • 350 mL EtOH (ethanole 96-98%);
  • ~70 g of Al foil;
  • 1.62 g Mercury(II)nitrate (Hg(NO3)2);
  • ~500 mL 20 % Hydrochloric acid aq solution (HCl);
  • ~200 g Sodium or Magnesium sulphate (Na2SO4 or MgSO4) anhydrous.

Procedure

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  1. You have to get 1 mole amphetamine free (1) base by addition salt of your amphetamine salt (sulphate or phosphate) to 20% NaOH water solution to pH 12. Stirr it for 15 min and extract amphetamine free base by DCM or petrolium ether 3 x 75 mL.
  2. Prepare Al amalgam. You have to use approximately ~70 g of Al foil and 1.62 g mercury(II)nitrate (Hg(NO3)2) to make amalgam as described in following topic.
  3. A mixture of 1 mole amphetamine freebase (136 g) and 1 mole aqueous formaldehyde (2) (81 mL 37% or 75 mL 40%) in 350 mL EtOH (ethanole) is poured into a 5 L round bottom flask with reflux condenser and an excess of aluminum amalgam, which was prepared in advance.
  4. Imine (3) is reduced for approximately two hours, to keep reaction temperature below ~50-60 °C. Cooling have to be applied if the reaction becomes too violent.
  5. 1 L Of cooled distilled water is added to the reaction mass, aluminum hydroxide solids are filtered off.
  6. The whole reaction mass is treated with 20 % HCl to pH 3 and extracted by DCM or petrolium ether 3 x 75 mL. DCM extracts are combined. Resulting water layer from filtration is alkalinized by 20% NaOH aq to pH 12 and extracted with DCM or petrolium ether 3 x 75 mL. Organic layers with methamphetamine (4) are combined (from first and second extraction of alkilized water layer), dried over Na2SO4 or MgSO4 anhydrous and concentrated in vacuum.
  7. Preparation of methamphetamine hydrochloride is carried out by bubbling of dry HCl gas via organic (DCM with methamphetamine) layer. The methamphetamine hydrochloride precipitate is filtered off by suction filtration, dried. Also, you can grow Ice methamphetamine by following methods.
 
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diogenes

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Hi Patton, are you planning to add some pictures of this synthesis? What is the usual yield?
 

diogenes

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Also is it stereosopecific? Is D-methamphetamine obtained if starting from D-amphetamine?
 

MadHatter

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In the original Rhodium article it's described as stereospecific:
"70g d-amphetamine in alcohol with aluminum and 1 mole formaldehyde gave d-methamphetamine, which was converted to the phosphate salt. 1-Phenyl-2-aminopropanol similarly yielded ephedrine."
 

G.Patton

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Hi Patton, are you planning to add some pictures of this synthesis? What is the usual yield?
diogenesHello. No, I'm not planing to do it now. I can't say exactly.
 

BongMan

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i don't know what gone wrong but i lost almost 20 gm of pure amphetamine , i tried to neutralist it with NaOH, and extract with petroleum ether nothing was left on evaporation , tried again with DCM again nothing left on evaporation , guys anybody tried this method , if anyone going to try use small quantity ..
 

metux

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i don't know what gone wrong but i lost almost 20 gm of pure amphetamine , i tried to neutralist it with NaOH, and extract with petroleum ether nothing was left on evaporation , tried again with DCM again nothing left on evaporation , guys anybody tried this method , if anyone going to try use small quantity ..
BongMan20gram is alot,i think you need more practise,but doint lose another 20gram mate,you can start 1gram scale
 

redsm

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i don't know what gone wrong but i lost almost 20 gm of pure amphetamine , i tried to neutralist it with NaOH, and extract with petroleum ether nothing was left on evaporation , tried again with DCM again nothing left on evaporation , guys anybody tried this method , if anyone going to try use small quantity ..
BongManare you referring to the first step of the synthesis?

if you are failing with conversion of amphetamine salt to freebase you need to learn basic chemistry skills. try an organic chemistry textbook as well as a practical/experimental organic chemistry guidebook.
 

G.Patton

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i don't know what gone wrong but i lost almost 20 gm of pure amphetamine , i tried to neutralist it with NaOH, and extract with petroleum ether nothing was left on evaporation , tried again with DCM again nothing left on evaporation , guys anybody tried this method , if anyone going to try use small quantity ..
BongManHave you used deep vacuum? Are you sure that it was amphetamine salt? What exactly did you do, can you describe your procedure?
 

diogenes

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Hi Patton, what do you do with the solvent (petroleum ether) after extracting the free base? Do you evaporate it until it is very small amount and then add EtOH? Can IPA be used as well? (Just because EtOH can be difficult to dry - or is dryness not a requirement at that stage?)

When the organic layer containing Methamphetamine are combined and then concentrated in vacuum - is the solvent heated as well or just add vacuum. What is the advantage of this vs gentle evaporation by heating of the organic layer?

Sorry for so many questions, but this is a really great route and I would like to try it as soon as I get the time, so it would be great to clarify all the details so that it will go relatively smoothly. Thank you ever so much for sharing this.

i don't know what gone wrong but i lost almost 20 gm of pure amphetamine , i tried to neutralist it with NaOH, and extract with petroleum ether nothing was left on evaporation , tried again with DCM again nothing left on evaporation , guys anybody tried this method , if anyone going to try use small quantity ..
BongManIf I get it right what you wrote BongMan, you neutralised the amphetamine aquous solution with NaOH. You actually have to raise the Ph up to about 12-13, and when the right Ph is reached there will be a layer of freebase on top of your aqueous solution. When this disctinct layer appears you are ready for the extraction.
 

G.Patton

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Hi, Diogenes =)
Do you evaporate it until it is very small amount and then add EtOH?
diogenesYou have to obtain free base oil of amphetamine. It has different appearance.
Can IPA be used as well?
maybe
Just because EtOH can be difficult to dry - or is dryness not a requirement at that stage?
You add aqueous formaldehyde, you don't need absolute EtOH for addition to aqueous solution, it's obvious.
and 1 mole aqueous formaldehyde (2) (81 mL 37% or 75 mL 40%) in 350 mL EtOH (ethanole)

When the organic layer containing Methamphetamine are combined and then concentrated in vacuum - is the solvent heated as well or just add vacuum. What is the advantage of this vs gentle evaporation by heating of the organic layer?
Free base of meth may partially be oxidized by air oxigen under heating, and you'll loose yield. The gold standard is vacuum distilling off.
Sorry for so many questions, but this is a really great route and I would like to try it as soon as I get the time, so it would be great to clarify all the details so that it will go relatively smoothly. Thank you ever so much for sharing this.
You are welcome! Share with us your results, please. Good luck!;)
 
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BongMan

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Have you used deep vacuum? Are you sure that it was amphetamine salt? What exactly did you do, can you describe your procedure?
G.Patton i dissolve amphetamine sulfate in 20 % NaOH and stir 15 minute , extract with MDC X 3 times , put solution on evaporation, that exactly i did. and yes i did marquis test for conformation of Amphetamine and it was 100 % amphi.
 

BongMan

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Hi Patton, what do you do with the solvent (petroleum ether) after extracting the free base? Do you evaporate it until it is very small amount and then add EtOH? Can IPA be used as well? (Just because EtOH can be difficult to dry - or is dryness not a requirement at that stage?)

When the organic layer containing Methamphetamine are combined and then concentrated in vacuum - is the solvent heated as well or just add vacuum. What is the advantage of this vs gentle evaporation by heating of the organic layer?

Sorry for so many questions, but this is a really great route and I would like to try it as soon as I get the time, so it would be great to clarify all the details so that it will go relatively smoothly. Thank you ever so much for sharing this.


If I get it right what you wrote BongMan, you neutralised the amphetamine aquous solution with NaOH. You actually have to raise the Ph up to about 12-13, and when the right Ph is reached there will be a layer of freebase on top of your aqueous solution. When this disctinct layer appears you are ready for the extraction.
diogenes.... oops i didn't check pH i thought i was around 12-13 already as usually NaOH pH and didn't wait for layer separation..........please share your results if you going to try .
 

G.Patton

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can we do this amphi to meth process before converting it into sulfate during amphetamine synthesis ....?
BongManYes, you can carry out this reaction with amph free base (stages 3-7).
i dissolve amphetamine sulfate in 20 % NaOH and stir 15 minute
You have to add 20% NaOH solution to amph sulphate water solution to 12-13 pH. Then, mix this and extract 3 times by DCM (not MDC).
put solution on evaporation,
How did you evaporate this?
 
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BongMan

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in hot air ..
 

primitiveintelectual

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to this reaction would be enough 4L Round bottom flask ?
 

ASheSChem

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hi guys;
@G.Patton , @Dragovich , & co

i don't understand this step..

organic layers with methamphetamine (4) are combined, concentrated in vacuum and dried over Na2SO4 or MgSO4 anhydrous.

it's a vacuum filtration or a vacuum distillation (if this, how many temp C°?)
no videos for this step?

and.. this result is ... ? pale yellow methamphetamine (liquid? powder?) the one you use for ice?

sory for noob time
 

UWe9o12jkied91d

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hi guys;
@G.Patton , @Dragovich , & co

i don't understand this step..



it's a vacuum filtration or a vacuum distillation (if this, how many temp C°?)
no videos for this step?

and.. this result is ... ? pale yellow methamphetamine (liquid? powder?) the one you use for ice?

sory for noob time
ASheSChemI attached a general scheme for vaccum distillation, or if you want an all-in-one fix you can get a short path head like one attached.You're also gonna need a vaccum pump, the mini ones off aliexpress do the job or you can treat yourself with a proper one ORR get a water jet pump and really strong aquarium pump to plug it into.You're also gonna need a cold trap probably, i think patton has a thread on this.
Or rotovap, its the most convenient.
 

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ASheSChem

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sorry but i never done this before so... i'm a little lost

can I use this assembly for example?
TKmwOq7GlR


so... i put the "organic layers with methamphetamine (4) combined" (and my MgSO4? or in the 500ml one...?) in the 2000ml balloon ... and.. i put how many temp ? all the distillate is retained?
 
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