Experimental section. The synthesis of the Amphetamine sulphate using P2P with ammonium formate and reduction with Mg

[GhostChemist]

The reactions proceed according to Scheme 1.

Scheme 1

Starting reagents and materials​

• 5 g purified P2P (P2P obtained through the reduction of P2NP with sodium borohydride)
• 4.1 g Mg
• 30 г HCOONH4
• 10-15 ml H2O
• 50 ml EtOH 88%
• 30 ml HAc
• 100-150 ml DCM
• 5+5 ml Ethyl acetate
• 2-3 mL of concentrated sulfuric acid (83%)
• pH indicator paper
• 2 liters of technical-grade cold water
• 20-30 g of anhydrous sodium sulfate
• 50 mL of 25% NaOH (sodium hydroxide)
• 500 mL and 250 mL flasks
• Reflux condenser
• Separatory funnel
• Filter paper
• Funnels
• Beakers
• Heater

In Figure 1, the starting components are presented.

Figure 1​

P2P is placed into a 1 L flask along with ammonium formate and ethanol, and the mixture is well stirred. Figure 2

Figure 2​

Mg is added to the obtained mixture. The reaction starts almost immediately. Figure 3

Figure 3​

During the reaction, 5 mL of acetic acid (HAc) is added. Figure 4

Figure 4​

The reaction proceeds quite vigorously; the flask needs to be cooled by placing it in an ice bath. Figure 5

Figure 5​

The reaction is completely finished within 30-40 minutes. Figure 6

Figure 6​

After the reaction is complete, the mixture is filtered. Figure 7

Figure 7​

After filtering, the paper filter is rinsed with 15-25 mL of acetic acid. Figure 8

Figure 8​

50-70 mL of DCM is added to the filtrate for the extraction of the amine. Figure 9

Figure 9​

Next, a 25% aqueous solution of NaOH is added until the pH reaches 8-10. During this process, a white precipitate of magnesium hydroxide will form, accompanied by the release of the amphetamine as a free base, characterized by a distinctive pleasant odor. Figure 10

Figure 10​

The amphetamine free base from RM is further extracted with several portions of DCM. Figure 11

Figure 11​

The extract in DCM is dried with anhydrous sodium sulfate. Figure 12

Figure 12​

The DCM is distilled off. Figure 13

Figure 13​

After DCM distilled off, the flask contains the oil of the amphetamine free base. Figure 14

Figure 14​

The amine free base is transferred to a glass beaker, and the residues in the flask are washed with 5 mL of ethyl acetate. Figure 15

Figure 15​

Sulfuric acid is added to the amphetamine free base solution in ethyl acetate until the pH 7. A precipitate of amphetamine sulfate is forms. Figure 16

Figure 16​

The precipitate of amphetamine sulfate is filtered through a paper filter and washed with 5 mL of ethyl acetate. Figure 17

Figure 17​

The precipitate is air-dried. Figure 18

Figure 18​

The yield of amphetamine sulfate was 1.17 g or 17%. Figure 19

Figure 19



Conclusions and Recommendations​

• The method is relatively simple for synthesizing the amine from P2P and ammonium formate through magnesium metal reduction.
• The method is suitable for scaling up by adding magnesium metal in portions to the reaction mass.
• A drawback of the method is the product yield of 17%.

 

[btcboss2022]

Congratulations! If that method worked as you say could be posible to obtain meth replacing ammonium formate by Methylammonium Formate CAS 25596-28-5
I cant wait the moment to have free time to test it!
Could be very interesting and honestly chemically has all sense.
Thanks.

 

[GhostChemist]

Hi! Thanks!
Theoretically, everything should react similarly with methylamine formate.
However, it`s essential to consider that the fact acetates and formates of both ammonia and methylamine react differently under various conditions. Therefore, different co-products can be formed.

 

[btcboss2022]

Anyway I must try it no other way.
I will update once I test it and about yield I think I can give you some tips to improve it.

 

[花谢花开]

Looking forward to it. Maybe the methyl made will have surprises and different effects.

 

[OrgUnikum]

Using methylammonium formate will give much better yields but nothing what would compare to the known high yielding ways like Al/Hg or NaBH4.

The problem with amination by ammoniua or a salt of it is that the formed Amphetamine is much more reactive then the ammonia and it will grab all P2P and even kick ammonia off already formed Imine. This secondary Imine is then reduced to the Amine - Di-Alkylamphetamine. This is no fun, quite the opposite but it can be removed by steamdistilling the product.

As there was no steam or other distillation I can assure you the 17% product was mostly Di-Alkyl Amphetamine.

This problem does not exist with methylamine (or not so bad) as thats as strong a nukleophile as Amphetamine so if there is an excess MeNH2 its fine.

Mg is though a lousy reducing reagent for Imines. Use something else or get very unhappy. Seriously.

 

[btcboss2022]

Did you think in the possible option to use formic acid instead of acetic acid?
Thanks.

 

[btcboss2022]

Today I synthesized (or at least tried, hahaha) my own methylammonium formate. At first glance, it seems to have turned out as it should, but I won't be able to confirm it 100% until tomorrow.
Tomorrow, I'll also receive the magnesium, and if the formate is what it's supposed to be, I'll test your synthesis by substituting ammonium formate with methylammonium formate and acetic acid with formic acid, all following your molar equivalences. I've been studying the reaction equation, and theoretically, it should gives Methamphetamine freebase(racemic) but we'll see the reality later. As we know, in these things, any small detail can completely change the final result. I'll keep you posted ;-)

 

[btcboss2022]

I didnt obtained the proper product in the methylammonium formate synth
Seems an easy reaction I must check what I did wrong and try it again.

 

[btcboss2022]

I have been checking my methylammonium formate synth and I think I know what I did wrong. I hope have more news after new year eve.

 

[loadingST]

What problem you think you observerd, i dont know how much is the temperature for NMF reduction before producing toxic gases but who who need reacmic methamp when you can do a leuckard and obtain double active isomers even throw you can separete the levo-amphetamine from the dextro one, and trust me the dextro-amphetamine is stronger than reacemic meth and less toxic by the way with the same crystal properties,able to smoke etc

 

[OrgUnikum]

what is this supposed to be?

Magnesium is just not a good metal for reductive aminations. Magnesium is great for Grignards and making Sodium metal. The Indian article this is based on is one of the worst examples og bullshit in chemistry, the do not even get the basic principles right, dissolving metal reactions are not catalytic. Those Indian articles have a purpose though, they provide protection against lawsuits regarding violation of patented IP and enabling India to produce the cheap generics the worlds health depends on.
If you look for high yielding reductive amination systems which actually work I suggest to look into SmI2, samarium di-iodide, samarium metal is not so expensive from Russia and I2 + Sm = SmI2.
For really high-yielding Amphetamine from P2P elevated pressure (15 bar +) Nickel (Raney and others, forget about homemade Urushibura) works well but needs quite some knowledge and equipment. Without pressure amination with benzylamine for the Imine followed by in situ reduction of this Imine and de-benzylation using a palladium based catalyst. This can be done as CTH with an internal hydrogen source and then no hydrogen gas is needed.

It is not that there are not viable possibilities, so why zombies like the Mg reduction are re-surrected, crap known not to work forever, I have no idea. I the longer runit also damages the reputation of the board and on the internet its reputation what decides who you are. Never providing the sources the methods were lifted from is another thing. It makes you look like a ripoff and it violates one of the oldest and most basic rules of the Internet: All information is to be free but credit must be given.