1-Phenyl-2-propanone (P2P) Leuckart amination to amphetamine and methamphetamine. Smale scale.

[Hank Schrader]

I will share the table with you.

 

[OrgUnikum]

I will share the table with you.
View attachment 7998

Hank SchraderMaybe it is just fair to add that temperatures over 180 °C like the named 200 and 210 °C for sure completely destroy P2P and even the Formamide, the resulting vapors and gases are highly toxic. Vent everything coming from top of the condenser outsides! Seriously!
Keep it below 180, better below 175°C and calibrate the Infrared thermometer to the flask/setting you use or you will never exactly know how hot it is.

Good luck

 

[Throw-off]

I attach the article and you can look for yourself. I saw a post elsewhere where somebody claims good yields like 80% in a modified household microwave(hole for condenser) with temperatures not over 175°C to avoid Formamide decomposition. No further details were given on this.

OrgUnikumWait a second.. @OrgUnikum does that mean that after drying the methylene chloride you can potentially just start adding D-(-)-Tartaric acid (cas 147-71-7) and participating d-meth salt??

If so is there anymore literature on microwave irradiation? You guys are worth your weight in gold thank you.

 

[OrgUnikum]

Wait a second.. @OrgUnikum does that mean that after drying the methylene chloride you can potentially just start adding D-(-)-Tartaric acid (cas 147-71-7) and participating d-meth salt??

If so is there anymore literature on microwave irradiation? You guys are worth your weight in gold thank you.

Throw-offPlenty literature but be aware that the trick is less the Microwaves but that this is a pressure vessel in a micro and the pressure makes it happen. I realized this myself only lately: The key to a successful Leuckart reaction for Amphetamine is to use a pressure vessel for reaction and hydrolysis. Methamphetamine can be made by the Leuckart without pressure vessel, yields are not stellar though, Al/Hg or NaBH4 is far better for this.

And separation of the Stereoisomeres, of d- meth and l-meth is not as easy as adding D-(-)-Tartaric acid, sorry. But there is no need for the rare and expensive D-(-)-Tartaric acid, the normal tartaric acid, the natural derived one, can be used. The process involves the natural tartaric acid 1/4 mol, HCl 1/2 mol, d/l-meth 1 mol and involves salt formation and partial dissolution/reformation of the salt (ripening) until virtually complete separation is achieved. Not trivial. Very temperature and setup dependent AFAIK.

 

[Throw-off]

Plenty literature but be aware that the trick is less the Microwaves but that this is a pressure vessel in a micro and the pressure makes it happen. I realized this myself only lately: The key to a successful Leuckart reaction for Amphetamine is to use a pressure vessel for reaction and hydrolysis. Methamphetamine can be made by the Leuckart without pressure vessel, yields are not stellar though, Al/Hg or NaBH4 is far better for this.

And separation of the Stereoisomeres, of d- meth and l-meth is not as easy as adding D-(-)-Tartaric acid, sorry. But there is no need for the rare and expensive D-(-)-Tartaric acid, the normal tartaric acid, the natural derived one, can be used. The process involves the natural tartaric acid 1/4 mol, HCl 1/2 mol, d/l-meth 1 mol and involves salt formation and partial dissolution/reformation of the salt (ripening) until virtually complete separation is achieved. Not trivial. Very temperature and setup dependent AFAIK.

OrgUnikumWhen you say yields are not stellar what type of percentage are we talking? Is it not similar too the study above with the Methly derivative of formamide?

The reason for the use of D-(-)-Tartaric instead of the natural derived one is because I have it readily available and free. The solid mass is the D isomer and the solution is the L isomer correct?

 

[Throw-off]

When you say yields are not stellar what type of percentage are we talking? Is it not similar too the study above with the Methly derivative of formamide?

The reason for the use of D-(-)-Tartaric instead of the natural derived one is because I have it readily available and free. The solid mass is the D isomer and the solution is the L isomer correct?

Throw-offNever mind about the Tartaric question, I worked it out today. Thanks friend.

 

[Throw-off]

Maybe it is just fair to add that temperatures over 180 °C like the named 200 and 210 °C for sure completely destroy P2P and even the Formamide, the resulting vapors and gases are highly toxic. Vent everything coming from top of the condenser outsides! Seriously!
Keep it below 180, better below 175°C and calibrate the Infrared thermometer to the flask/setting you use or you will never exactly know how hot it is.

Good luck

OrgUnikumWith Hydrolysis of the formyl amide in these measurements.
NMF - 130ml
P2P - 100ml
Formic - 84ml
How much naoh solution do you need and how much HCI? Is 35% lab grade sufficient?

 

[OrgUnikum]

I will share the table with you.
View attachment 7998

Hank SchraderAnd as a free service from yours truly, the ratios for P2P:

Formamide 50 ml 1,5 mol
formic acid 56 ml 1,5 mol
P2P 66 ml 0,5 mol

 

[Throw-off]

And as a free service from yours truly, the ratios for P2P:

Formamide 50 ml 1,5 mol
formic acid 56 ml 1,5 mol
P2P 66 ml 0,5 mol

OrgUnikumWhen using N-Methylformamide is 89.5ml 1.5 mol in your ratio @OrgUnikum

 

[Throw-off]

When using N-Methylformamide is 89.5ml 1.5 mol in your ratio @OrgUnikum

Throw-off87ml **

 

[OrgUnikum]

When using N-Methylformamide is 89.5ml 1.5 mol in your ratio @OrgUnikum

Throw-offYou look up the molekular weight of N-Methylformamide - mol/g - on Wikipedia and multiply by 1,5 as seen in the post of mine you refer to. I am not going to do this for you.

 

[BamBam]

7. Crude methamphetamine free base is distilled under vacuum (2 mbar, 60-100 °C) with help of Kugelrohr distillation apparatus (optional) to yield methamphetamine as a clear to pale yellow oil (2.5 g, 42%).

What’s other option? Simple, fractional or steam distillation? If don’t have Kugelrohr distillation apparatus?

 

[UWe9o12jkied91d]

7. Crude methamphetamine free base is distilled under vacuum (2 mbar, 60-100 °C) with help of Kugelrohr distillation apparatus (optional) to yield methamphetamine as a clear to pale yellow oil (2.5 g, 42%).

What’s other option? Simple, fractional or steam distillation? If don’t have Kugelrohr distillation apparatus?

BamBamYour mixture has easily separable components with very large range of bp's, so fractional is out.
Your product degrades before reaching bp, even more so than the primary amine derivative, so normal distill out too.
Steam is the way to go, preferably from an alkaline solution of 35% NaOH at most to prevent alkaline hydrolysis.

If by any means you prefer this you can also just perform a solvent extraction from basic sol. using something like toluene, strip off the organic layer and acidfiy to ph 2-3 followed by water. Next this added water is separated and organic fraction is discarded.Kept aq layer basified and rextracted with clean solvent.

 

[rothschild33]

Your mixture has easily separable components with very large range of bp's, so fractional is out.
Your product degrades before reaching bp, even more so than the primary amine derivative, so normal distill out too.
Steam is the way to go, preferably from an alkaline solution of 35% NaOH at most to prevent alkaline hydrolysis.

If by any means you prefer this you can also just perform a solvent extraction from basic sol. using something like toluene, strip off the organic layer and acidfiy to ph 2-3 followed by water. Next this added water is separated and organic fraction is discarded.Kept aq layer basified and rextracted with clean solvent.

UWe9o12jkied91dWhat is the function of the NaOH in steam distillation?

 

[gus.fring]

Amphetamine​

Reagents:

• 1-Phenyl-2-propanone (P2P) 0.827 g, 6.2 mmol;​
• Formamide 3.5 ml;​
• Hydrogen peroxide (H2O2) 5 ml 30%;​
• Benzene 50 ml;​
• Magnesium sulphate (MgSO4);​
• Methanol 5 ml (MeOH);​
• Hydrochloric acid (15 % aq HCl) 5 ml;​
• Distilled water 25 ml;​
• Dichloromethane (DCM) 90 ml;​
• Sodium hydroxide (NaOH) pellets;​
• Sulfuric acid;​
• Acetone;​

Equipment and glassware:

• Pear shaped flask 10 ml;​
• Retort stand and clamp for securing apparatus (optional);​
• Reflux condenser;​
• Heating plate;​
• Boiling chips;​
• Funnel;​
• Rotary evaporator (optional);​
• Syringe or Pasteur pipette;​
• pH indicator papers;​
• Beakers (50 mL x2, 100 mL x2);​
• Vacuum source;​
• Separatory funnel 100 ml;​
• Laboratory scale (0.1-200 g is suitable);​
• Measuring cylinders 10 mL and 100 mL;​
• Glass rod and spatula;​
• Laboratory grade thermometer; ​
• Buchner flask and funnel; ​
• Filter paper;​

View attachment 1474 ​

1. A mixture of 1-phenyl-2-propanone (P2P) 0.827 g, 6.2 mmol and formamide 3.5 ml is heated at 160-170 ℃ for 16 h in a 10 ml pear shaped flask with a reflux condenser.
2. The mixture is cooled to room temperature, hydrogen peroxide 5 ml 30% (H2O2) is added. The mixture is stirred for 15 min.
3. The reaction mixture is extracted with benzene (2x25 ml) is separatory funnel. Extract is dried over magnesium sulphate (MgSO4) and filtered. A dark oil is obtained after benzene evaporation from combined extract.
4. The dark oil is dissolved in a mixture of methanol 5 ml (MeOH) and hydrochloric acid (15% HCl) 5 ml and refluxed with a constant stirring for 2 h.
5. The reaction mixture is evaporated under reduced pressure. Next, the remaining product is dissolved in distilled water 25 ml and extracted with dichloromethane (DCM) CH2Cl2 (2x20 ml).
6. The aqueous solution is alkalized to pH 10 by addition sodium hydroxide (NaOH) pellets and extracted with DCM (2x25 ml).
7. The combined DCM extracts are evaporated. The amphetamine free base is obtained as a yellow oil.
8. Amphetamine sulphate is prepared by addition of sulfuric acid in dry acetone in a volume ratio of 1:10 to pH 6. Product is filtered on Buchner flask and funnel, washed with a small amount of dry cold acetone and air dried (better to use vacuum desiccator to increase drying speed).​

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Methamphetamine

Download Video

Methamphetamine hydrochloride synthesis via Leuckart amination

• G.Patton
• Feb 13, 2023
• 5
• cas 51-57-0 cas 537-46-2 ice leuckart amination meth methamph methamphetamine methamphetamine hydrochloride methamphetamine video synthesis video

Methamphetamine hydrochloride total synthesis video from P2P and N-methylformamide via Leuckart...

​

Reagents:​

• 1-Phenyl-2-propanone (P2P) 5.4 mL, 40.2 mmol;​
• N-methylformamide 13.4 mL, 229 mmol;​
• Magnesium sulphate (MgSO4);​
• Hydrochloric acid (36-37% aq HCl) 10.7 mL, 0.004 mmol;​
• Toluene 60 ml;​
• Sodium hydroxide (NaOH);​
• Distilled water;​
• Acetone;​
• Hydrogen chloride gas (HCl);​

Equipment and glassware:​

• Pear shaped flask 50 ml;​
• Retort stand and clamp for securing apparatus (optional);​
• Reflux condenser;​
• Heating plate;​
• Boiling chips;​
• Funnel;​
• Rotary evaporator (optional);​
• Syringe or Pasteur pipette;​
• pH indicator papers;​
• Beakers (50 mL x2, 100 mL x2);​
• Vacuum source;​
• Separatory funnel 100 ml;​
• Laboratory scale (0.1-200 g is suitable);​
• Measuring cylinders 10 mL and 100 mL;​
• Glass rod and spatula;​
• Laboratory grade thermometer; ​
• Buchner flask and funnel; ​
• Filter paper;​
• HCl gas apparatus;​

View attachment 1475​

1. N-methylformamide 13.4 mL, 229 mmol, 5.7 equiv is added to 1-phenyl-2-propanone (P2P) 5.4 mL, 40.2 mmol with a constant stirring in 50 ml pear shaped flask with a reflux condenser.
2. Reaction temperature is gradually increased to 165-170 °C and maintained for 24-36 h.
3. The reaction mixture is cooled to room temperature. Sodium hydroxide (10 M NaOH aq) solution 24 mL, 0.24 mmol is added and the reaction mixture is refluxed for 2 h.
4. The reaction mixture is cooled to room temperature and separated to different layers. An aqueous layer is discarded. Hydrochloric acid (36-37% aq HCl) 10.7 mL, 0.004 mmol is added to a red organic layer.
5. The organic mixture is refluxed for 2 h. Then, the solution is cooled to room temperature. Sodium hydroxide (8.3 M aq NaOH) solution 16.0mL, 0.13 mmol is slowly added. The crude methamphetamine free base is extracted with toluene (3 × 20 mL).
6. Combined organic layers are dried over MgSO4 and solvent is evaporated in vacuum. Crude methamphetamine free base is obtained as a brown oil.
7. Crude methamphetamine free base is distilled under vacuum (2 mbar, 60-100 °C) with help of Kugelrohr distillation apparatus (optional) to yield methamphetamine as a clear to pale yellow oil (2.5 g, 42%).​

---

Methamphetamine hydrochloride crystallization

1. Free base is dissolved in toluene 50 mL and anhydrous hydrogen chloride gas (HCl) is bubbled through the solution until a white precipitate formation is over (pH 6).
2. The resulting white precipitate is filtered with help of Buchner flask and funnel, washed with small amount of toluene and dried under vacuum to produce methamphetamine hydrochloride as a white salt 2.0 g, 27%. ​

William D.I have question please can i use this reciepe ffor larger scale? Or just for small scale?

 

[Throw-off]

The leuckart is great for scalability if you've got a reactor, you can scale it too size.

 

[WillD]

The use of an additional amount of water in Leuckart reaction can increase yield. Who did it, can write about it here.