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

[Hank Schrader]

I will share the table with you.

 

[OrgUnikum]

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

 

[Throw-off]

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.

 

[OrgUnikum]

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.

 

[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-off]

Never mind about the Tartaric question, I worked it out today. Thanks friend.

 

[Throw-off]

With 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]

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

 

[Throw-off]

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

 

[Throw-off]

87ml **

 

[OrgUnikum]

You 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]

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.

 

[rothschild33]

What is the function of the NaOH in steam distillation?

 

[gus.fring]

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.

 

[TheNut22]

Yeah. In Leuckart, you have to make sure there is no water at all.

 

[loadingST]

Im quite intrested in tring this reaction (yeah i still havent tried leuckard), i have some questions :
1. Is the reaction yield the same for primary amines and secondary amines ?
2. Perfect temperature : 175C or lower ?
3. Maybe using dean stark apartatures to keep reaction dry will boost the yield ?
4. HCL hydrolisis of reaction mixture, then adding a little bit of methanol and KOH or NAOH to hydrolise the remaining formil derivate and preparing destilation aparatures to directly distil freebase in vacum is the best work-up that comes to my mind ?

 

[TheNut22]

1. No, it is not. For heating I think it is, but the rest of the work-up is not.

2. I'm keeping temperature ~ 155 C for 24-27 hours. Many people have said 180 C or even 175 C is way too hot. Uncle Fester said in his books to keep the lowest temperature that the reaction goes (bubbles keep appearing). Low heat and long reaction time. Opposite to too much heat and too little time.

 

[TheNut22]

Now, when I'm done with the heating (amphetamine), I'm doing the formyl hydrogenation with a base, so do I still put H2O2 (30%) first in the last reaction steps? What is the role of H2O2 in here?

 

[TheNut22]

Well, I searched the info myself. The role of H2O2 is pretty important, considering the yields.. H2O2 is an oxidizer, but regarding to it's molecular form, I've always thought it can easily act also as reducing agent. Pretty facinating compound!

 

[loadingST]

Why you need oxidizer when in all patents i have studied there isnt no one using h2o2 ??? Can you tell the mechanism of action ?

 

[TheNut22]

I just told about the half of the mechanism. I was little bit skeptic myself, because I didn't find anything about it also. The H2O2 behaves like a reducing agent.
Hydrogen peroxide reduces P2P formamide to ---> N-formylbenzedrine, so the formyl group is now a better leaving group, and when you do hydrogenation, the amine will be intact to benzedrine molecule, and the formyl group leaves, producing benzedrine in better yield, I think. The point is that the formyl group leaves the molecule easier.

 

[TheNut22]

But I am also still skeptic myself, because I got this info on H2O2 use from AI-robot chemistry assistant, and that is the worst place to get any info regarding chemistry. I have also noticed that no one is using H2O2 at nowhere in these types of syntheses. So, when I'm now in the same place in this synthesis, I think I'll use just pure water, if someone with some knowledge could enlighten me with this. So, should I make 30% H2O2 or use just pure water at this stage?

 

[edy's]

Can i just double the amount of h2o2 if my peroxide is just over 15 +%,its a bitch finding stronger in my place,ore maby some other compound to substitute?

 

[TheNut22]

One time I made around 25% H2O2 from my 12% H2O2 (wrong calculations), and it still worked for my peracetic acid!

 

[TheNut22]

edy's: You can calculate how much you have to evaporate from that 15% H2O2 to make 35%, and then you can make good peracid. This was the first time I got from 40 g of MPB ---> 35,60 g of acetoxyphenylpropene. So, wow. And I made 30% H2O2 from 12% H2O2 to calculate how much water I have to remove with careful evaporation, and the peracid worked this well! But to be exact, I will put the peracid in side to 3 to 4 days with H2SO4 catalyst to make it work.