LSD synthesis from lysergic acid via PyBOP

[WillD]

Reagents:

​

• Lysergic acid (cas 82-58-6)2.80 g;​
• Methylene chloride (DCM; CH2Cl2) 190 ml;​
• N,N-Diethylmethylamine (cas cas 616-39-7) 1.81 g;​
• PyBOP (cas 128625-52-5) 5.70 g;​
• Diethylamine (cas 109-89-7) 0.84 g;​
• Ammonium hydroxide (NH4OH) 100 ml 7.5 M;​
• Sodium bicarbonate (cold saturated aq solution) NaHCO3 40 ml;​
• Ethyl acetate (EtOAc) 60 ml;​
• Sodium sulphate (MgSO4) ~50 g;
• Deionized H2O ~200 ml;

Equipment and glassware:​

• Round bottom flask 250 mL;
• Retort stand and clamp for securing apparatus;
• Magnetic stirrer;
• Separatory funnel 500 mL (optional);
• Glass rod and spatula;
• Laboratory scale (0.1-100 g is suitable);
• Measuring cylinder 100 mL;
• Funnel;
• Filter paper;
• Rotovap machine (optional);
• Vacuum source;
• Buchner flask and funnel;
• Beakers 100 ml x2 and 250 ml x2;

Lysergic acid 2.80 g is added to a methylene chloride (DCM; CH2Cl2) 100 ml with a constant stirring. N,N-Diethylmethylamine 1.81 g is added to the reaction mixture and the solution is stirred for 5 min. Then PyBOP 5.70 g is added, and the solution is stirred for an additional 5 min. Then, diethylamine 0.84 g is added and the reaction is stirred at room temperature for 60 min.

The reaction mixture is quenched with concentrated ammonium hydroxide (NH4OH) 100 ml 7.5 M. Layers are separated, the aqueous phase is extracted with 3x30 ml DCM. Organic layers are combined and evaporated in a rotovap machine at 35 °C under high vacuum.

The residue is dissolved in sodium bicarbonate (cold saturated aq solution) NaHCO3 40 ml and extracted with 3x20 ml EtOAc. Organic layers are combined and washed with deionized H2O, brine, and dried over MgSO4. Solution is filtered and evaporated in a rotovap machine at 40 °C under vacuum to a constant weight. A yield is 3.13 g before chromatography purification (optional), 93% purity.​

 

[MrChan]

What is meant by washing with deionized water and brine? Just a super concentrated solution of sodium chloride and water? What is purpose of the brine?

 

[G.Patton]

You can use distilled water to wash it in separatory funnel, then use concentrated NaCl solution to wash and, finally, divide layers and dry organic layer over MgSO4.
It has higher density and can be easily separated from organic layer than distilled water.

 

[Gale]

This seems to easy lol..but I'm already dealing with too many projects don't temp me lol

 

[HerrHaber]

this looks fenomenal and makes perfect sense... there is nothing more I could look forward to than this prep... sourcing the hard to get thing is the main drawback but as soon as I do I will include it in a book called "Lord of the fantastic molecules and how to make them" by J.K. Rowlkien that I will write (more like an editor than an author)

 

[Nicoino]

Will the hydrated form of LA work the same or it has to be dried?

 

[psy]

It has to be dried. Drying LA is pretty easy though. Just heat and a strong vacuum.

 

[Nicoino]

I report anhydrous condition aren't needed

 

[CH3Tryptamental]

Does this synth result in any amount of ISO-LSD?

 

[psy]

Yes it would, but all the iso can be converted with KOH.

 

[HerrHaber]

True but it’s chiraly pure coupling so if done correctly it should only be in small amounts thus column elution is recommended. ISO can be racemized and the remaining iso again and so on but this is more true about the older methods.

 

[psy]

Depends on your lysergic acid. If you use pure d-lysergic acid, I don't believe any iso-lsd will form.

 

[HerbalHerb]

Does anyone made those way ? Does it works ?

 

[psy]

It does work. This is the work of Casey Hardison who got convicted of LSD production using this method.

 

[HerrHaber]

Thanks, I will research about the guy.

 

[mycelium]

This was first published in ER after his arrest, he is a hero!
The diethylmethylamine, according to the article, grabs all the excess diethylamine, called a scavenger amine...I'm not a chemist so this part is pretty interesting

 

[eu.lab]

Did anyone made a video of this method? Would help me alot.

 

[HerrHaber]

It would help everyone so I do plan to perform the synthesis and make a video depending on the result. I don’t have any content posted yet so if I happen to be the first may be an achievement. If not the experiment itself will be regardless of the result. Negative data is science too.

 

[Molecula25]

Hi guys, does anyone know about hydrolysis of ergotamine with sodium dithionite and KOH?

 

[psy]

Why would you use dithionite? You are trying to hydrolyze it, not reduce it. You have 2 double bonds that could certainly get reduced, and how are you suppose to get a pH of 5 with KOH?

 

[Nicoino]

Few mg of dithionite are used in some patents as antioxidant.

 

[The Alchemist]

This topic seems majorly underrated. It seems downright revolutionary compared to how I learned to make it.

I read an exchange where someone suggested the methyl ester could racemize during hydrolysis. Is this a concern with the entiopure d isomer? I notice TLC is not included in the work up.

Is a rotovap really optional? This method to be approaching bathtub synthesis without it. No heat? This sounds simpler than mdma or amphetamine.

What am I missing here? Do we work under yellow or red light? What are the major complications? Does the final product yeild isolsd at all?

 

[HerrHaber]

Light should be avoided or red. Rotavap I prefer to have beforehand (have a kit of its glassware but the machine is lost). I highly recommend column chromatography as a final step as well as TLC during the reaction.

 

[Nicoino]

Get reasonably pure LA is a pain in the ass, nearly all the hydrolysis lead to brown/black product which as to be purified.
Even with good quality LA the coupling reaction mixture gets brown black and the work up is not as simple as it is stated (maybe if you start with 100% pure precursors, solvents degassed and professional equipment you have a small change of not happening, but for the home chemist dark solution has to be expected).
Purification of the product is no joke if you don't have access to column chromatography or if you don't want to remove liters of solvent under vacuum.

 

[PlanckB1]

This has been my experience as well, repeated recrystallisations of the lysergic acid from hydrolysis resulting in a powder which becomes lighter brown each time but still not as light/pure as you would expect. Do you recommend column chromatography of the LA or just column chromatography of the final freebase LSD?

 

[Nicoino]

I don't think it's worth on the LA, probably with a good workup and enough experimentation it's not even need on the final product.
Big acid chemist like pichard used to synth kilos every month, and I really doubt they were able to chromatograph that amount of product, nearly impossible with a factory.