Novel Condensation of d-LA into d-LSD via PyBOP

Casey William 'Freeblood' Hardison

Abstract: A new method facilitating Experimental: 2.80 g lysergic acid was added
condensation of d-lysergic acid into to 100 ml of magnetically stirring CH2Cl2. To
d-lysergic acid diethylamide under mild this was added 1.81 g N,N-
conditions, in high yield, using PyBOP1, a diethylmethylamine and the solution was
peptide coupling reagent. allowed to stir for 5 minutes. Then 5.70 g
PyBOP was added and the solution allowed to
Discussion: A recent publication by Dr stir for an additional 5 minutes. Then 0.84 g
Nichols et al.2 on the isomeric diethylamine was added and the reaction was
lysergamides of dimethylazetidine allowed to stir at RT for 60 minutes.
catalyzed a revolution in the realm of
clandestine LSD synthesis. The reaction mixture was quenched with
100 ml of 7.5 M concentrated NH4OH, the
I do not know if Dr Nichols is to be layers were separated and the aqueous phase
credited with the first use of PyBOP for was then thrice extracted with 30 ml CH2Cl2,
lysergamide condensation as theoretical the organic layers were combined and rotary
discussions on the use of a variety of evaporated at 35 °C under high vacuum.
peptide coupling reagents have been
occurring on The Hive and Rhodium The residue was dissolved in 40 ml of cold
websites since 2001.3 saturated NaHCO3 and extracted thrice with
20 ml EtOAc, the organic layers were
In early 2004, I engaged Dr Nichols in a combined and washed with deionized H2O,
theoretical discussion as to his expected brine, and then dried over MgSO4, filtered and
limits on scalability and it was clear that rotary evaporated at 40 °C under high vacuum
he did not know as he is limited to NIDA to a constant weight. Yield 3.13 g before
quantities of lysergic acid, i.e. < 250 mg. chromatography, 93%.

After studying Dr Nichols' papers, the
Internet, and doing further bookwork on
peptide synthesis, I conducted a series of
experiments to determine the limits and
parameters of the reaction, i.e., the best
solvent, the best tertiary scavenger amine,
the best sequence of introducing the
reagents, and the most effective reaction
time.
I worked with several solvents, but I found
CH2Cl2 to be most suitable as it evaporates
easily and keeps the reaction temperature
low.
I worked with several tertiary amines but
Another run of 5.12 g LA with the same
amines, equivalents and times yielded 5.55 g
after chromatography, 90%.
References:
1
Coste, J.; LeNguyen, D.; Castro, B. PyBOP: A new
peptide coupling reagent devoid of toxic byproduct.
Tetrahedron Lett. 1990, 31, 205-208.
2
Nichols, D.E.; Frescas, S.; Marona-Lewicka, D,;
Kurrasch-Orbaugh, D. Lysergamides of Isomeric 2,4-
Dimethylazetidines Map the Binding Orientation of the
Diethylamide Moiety in the Potent Hallucinogenic Agent
N,N-Diethyllysergamide (LSD). J. Med. Chem., 2002, 45,
4344-4349.
3
https://www.rhodium.ws/chemistry/et2lsd.txt
https://www.the-hive.ws

N,N-diethylmethylamine added slowly

Correspondence:
after the dry lysergic acid gave the most Casey Hardison POWD A6078AJ
effective results and work-up. Her Majesty’s Prison Wellingborough
Millers Park
I varied the reaction time between 30 to Doddington Road
120 minutes; however, I am of the opinion Wellingborough
that the reaction completes in less than 1 NN8 2NH
hour. England

It is unfortunate that as I was perfecting this reaction I was

All reactions were conducted under a 15W
under police surveillance. I had been brought to the
red light, an argon atmosphere, and with attention of the London DEA by an informant in the
dried Sigma-Aldrich solvents and reagents. United States.

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