Methamphetamine synthesis from 1- Phenyl -2 Propanone (P2P) by reductive amination with Sodium Triacetoxyborohydride (STAB)

[K-Cyanide]

Reagents:

• 134 gram 1-phenyl 2-propanone P2P (1 mol, 1.0 equiv)
• 46,58gram Methylamine (1.5 mol, 1.5 equiv) in 1000ml Tetrahydrofuran (THF)
• 120 gram Glacial acetic acid GAA (2 mol, 2.0 equiv)
• 318 gram Sodium Triacetoxyborohydride NaBH (AcO)3 (STAB ) (1.5 mol. 1.5 equiv)
• Tetrahydrofuran (THF) 2000ml​
• 2 N NaOH solution appr. 2000ml​
• Ethyl acetate EtAc​
• Magnesium Sulfate MgSO4​
• Brine​

​

Procedure

1. 134 g P2P are slowly dissolved in 1000ml absolute THF​

2. 46,58 g MeNH2 solution in 1000ml absolute THF is added over a 30 min period. (This solution prepared is by dropwise addition of 116 ml 40% aqueous solution of methylamine onto dry NaOH pellets (app. 250g) using a dropping funnel with constant pressure. The evolving MeNH2 gas is bubbled into cold THF placed on an ice bath.)

3. 120 g Glacial acetic acid is added slowly.

4. 318 g Sodium Triacetoxyborohydride is added in small portions of 10-15g.

5. RM is warming to appr. 40-50°C and foams a bit.

6. The pale whitish, light viscous RM is vigorously stirred (overhead) for 2 hours.

7. Solvent is removed by rotovap under reduced pressure.

8. Residue is carefully basified to pH 12 with 2 N NaOH solution.

9. Metamphetamine freebase is extracted with 2x300ml Ethyl acetate, the organic layer is washed twice with brine (appr. 50Ml each), dried over anhydrous MgSO4 and concentrated under reduced pressure.



Yield: 138 g pale brownisch/yellow Methamphetamine oil (92,6%)



Remarks:



Downside to this reaction is the high price of STAB. The good news, its quite easy to prepare from NaBH4, THF (or Toluene) and Glacial acetic acid in slight stoechiometric excess.​

 

[Acab1312]

Hello, does the reaction also have to be anhydrous?

 

[K-Cyanide]

Hi, unfortunately yes. Water would destroy the STAB prior to reduction. One idea would be to use Methylamine-HCl and Triethylamine as a stronger base to liberate the freebase of Methylamine.

 

[Acab1312]

Hi, unfortunately yes. Water would destroy the STAB prior to reduction. One idea would be to use Methylamine-HCl and Triethylamine as a stronger base to liberate the freebase of Methylamine.

K-CyanideToo bad, but thanks for the answer

 

[41Dxflatline]

Here's the thread instead of a second hand paraphrase of it:

Easy P2P reductive amination with NaBH(OAc)3 , Hive Novel Discourse

 

[Acab1312]

Here's the thread instead of a second hand paraphrase of it:

Easy P2P reductive amination with NaBH(OAc)3 , Hive Novel Discourse

41DxflatlineThanks for good link it is definitely worth a try

 

[K-Cyanide]

But even better than useless references to `second hand paraphrase`, are modified procedures that were actually carried out. And by the way, i never claimed to be the author of this synthesis procedure.

 

[w2x3f5]

But even better than useless references to `second hand paraphrase`, are modified procedures that were actually carried out. And by the way, i never claimed to be the author of this synthesis procedure.

K-Cyanidewhy not use dry acetate methylamine in acetic acid?

 

[Katty Korner]

Why couldn't one produce methylamine gas through whatever method, and run it through sodium or potassium hydroxide before into the solvent? Would methylamine absorb into thf or toluene like that, like it does methanol?

 

[UWe9o12jkied91d]

Why couldn't one produce methylamine gas through whatever method, and run it through sodium or potassium hydroxide before into the solvent? Would methylamine absorb into thf or toluene like that, like it does methanol?

Katty KornerIt's possible, it is soluble in most organic solvents.But you can just dissolve the HCl salt in methanol and add sodium hydroxide in stoechiometric amount under chilling, followed by drying agent.

 

[mithyl2]

is there any alternative to Tetrahydrofuran in this synthesis?

 

[K-Cyanide]

is there any alternative to Tetrahydrofuran in this synthesis?

mithyl2Well, crucial properties of a solvent in a reaction is the boiling point which must be above the expected reaction temperature and it must NOT participate in the reaction and should behave more or less inert. Taking this into account, there are only a few left that come into question.

I think toluene as well as ethyl acetate should work though I am not sure if EtOAc does not react with one of the reagents. I will conduct some testing with toluene and ethyl acetate in the near future. Furthermore I intend is to prepare the STAB in situ prior to reduction by dripping GAA into a cooled suspension of NaBH4 in ethyl acetate. The reason is the tedious preparation of STAB in a separate synthesis step.
I will post the results here.

 

[w2x3f5]

Dichloromethane, dichloroethane work great, makes the job a lot easier, getting a stab from NaBH4 also works great. Additional acid can not be used for the stab, the reaction is slower due to the lack of additional acid, but in dichloroethane the reaction is faster than in THF. The yield is presumably above 90 percent, the exact yield will be published later, after a few checks.

 

[K-Cyanide]

Dichloromethane, dichloroethane work great, makes the job a lot easier, getting a stab from NaBH4 also works great. Additional acid can not be used for the stab, the reaction is slower due to the lack of additional acid, but in dichloroethane the reaction is faster than in THF. The yield is presumably above 90 percent, the exact yield will be published later, after a few checks.

w2x3f5Yes correct, DCE is the first choice, though harder to obtain and quite toxic, what should not be a concern. DCM I am not sure, the reaction warms up notably, guess using more solvent could do the trick.

 

[w2x3f5]

Yes correct, DCE is the first choice, though harder to obtain and quite toxic, what should not be a concern. DCM I am not sure, the reaction warms up notably, guess using more solvent could do the trick.

K-Cyanidein photo reaction in dcm solvent =)

 

[K-Cyanide]

in photo reaction in dcm solvent =)

w2x3f5Oh thatś cool . So the temperature is obviously no issue. What ratio solvent/ketone did you use ?

 

[w2x3f5]

Oh thatś cool . So the temperature is obviously no issue. What ratio solvent/ketone did you use ?

K-CyanideThe solvent was added during the synthesis, I can not say exactly the amount. Thick porridge stab that had to be diluted otherwise it is not possible to mix.

 

[Akashic]

@K-Cyanide would you happen to have any expirence using NaBH3CN to MA? theirs a decent workup on rhodium using cyano with ammonium to MDA, not much out there using methylamine aside from ch3nh2 hcl is called for, reaction completeness once ph stable, carried out under nitrogen atmosphere at room temperature. Given your write up with stab thought you may be the one to ask? Thx

 

[Win Win]

Reagents:

• 134 gram 1-phenyl 2-propanone P2P (1 mol, 1.0 equiv)
• 46,58gram Methylamine (1.5 mol, 1.5 equiv) in 1000ml Tetrahydrofuran (THF)
• 120 gram Glacial acetic acid GAA (2 mol, 2.0 equiv)
• 318 gram Sodium Triacetoxyborohydride NaBH (AcO)3 (STAB ) (1.5 mol. 1.5 equiv)
• Tetrahydrofuran (THF) 2000ml​
• 2 N NaOH solution appr. 2000ml​
• Ethyl acetate EtAc​
• Magnesium Sulfate MgSO4​
• Brine​

​

Procedure

1. 134 g P2P are slowly dissolved in 1000ml absolute THF​

2. 46,58 g MeNH2 solution in 1000ml absolute THF is added over a 30 min period. (This solution prepared is by dropwise addition of 116 ml 40% aqueous solution of methylamine onto dry NaOH pellets (app. 250g) using a dropping funnel with constant pressure. The evolving MeNH2 gas is bubbled into cold THF placed on an ice bath.)

3. 120 g Glacial acetic acid is added slowly.

4. 318 g Sodium Triacetoxyborohydride is added in small portions of 10-15g.

5. RM is warming to appr. 40-50°C and foams a bit.

6. The pale whitish, light viscous RM is vigorously stirred (overhead) for 2 hours.

7. Solvent is removed by rotovap under reduced pressure.

8. Residue is carefully basified to pH 12 with 2 N NaOH solution.

9. Metamphetamine freebase is extracted with 2x300ml Ethyl acetate, the organic layer is washed twice with brine (appr. 50Ml each), dried over anhydrous MgSO4 and concentrated under reduced pressure.



Yield: 138 g pale brownisch/yellow Methamphetamine oil (92,6%)



Remarks:



Downside to this reaction is the high price of STAB. The good news, its quite easy to prepare from NaBH4, THF (or Toluene) and Glacial acetic acid in slight stoechiometric excess.​

K-CyanideHi sir i am not understand item 2. And Sodium Triacetoxyborohydride can i replace to nabh4?

 

[ItsMee]

Does this work in the same manner with ammonia or ammonium acetate to form amphetamine?
Need an easy way to go to amphetamine from the ketone. Titanium(IV)isopropoxide is an option, but expensive.

 

[w2x3f5]

Does this work in the same manner with ammonia or ammonium acetate to form amphetamine?
Need an easy way to go to amphetamine from the ketone. Titanium(IV)isopropoxide is an option, but expensive.

ItsMeethis may work, need to check