Post 412547 (https://www.thevespiary.org/talk/index.php?topic=12738.msg41254700#msg41254700)
(pHarmacist: "Synthesis of LSD from Lysergic Acid", Tryptamine Chemistry), as it starts with (optically pure) lysergic acid too (pretty simple: defat/extract woodrose seeds, chromatograph and isolate optically active isomers via tartrate), and promises acceptable yields with using easy chemicals (DMF, diethylamine and CDI and obviously that gas cylinder of argon/helium/N2 or whatever) and affordable equipment. Only thing that could bee difficult is getting hold of some carbonyldiimidazole. Doesn't sound very common!? (any ideas for synthing your own?)Post 447646 (missing)
(Rhodium: "DEET -> Diethylamine", Newbee Forum)Post 458213 (https://www.thevespiary.org/talk/index.php?topic=12738.msg45821300#msg45821300)
(PapaSmerck: "flipper yield discrepancies", Tryptamine Chemistry)It is by far the weaker base. As long as there is excess diethylamine, the indolic NH2 won't react to any appreciable rate (or did I miss something?)
That's what I thought, just wasn't 100% sure. Thanks. Guess that takes care of that portion.
n00dle, that's excellent regarding the amide hydrolysis. With respect to the procedure involving tetrabutylammonium hydroxide - if it is indeed a far superior route, a preliminary SciFinder search seems to indicate that quarternary ammonium hydroxides can be made from their corresponding iodides using silver oxide in water. Around here, tetrabutylammonium iodide is extremely common.
As to the coupling agents, do you (n00dle) have any idea what this new coupler suited for dialkyl groups is? Would be worth looking into. These coupling reactions are nice and fast as well, in solid-phase peptide synthesis someone I once knew used HBTU as the coupling agent, allowing each amino acid to react with the HBTU (DMF as solvent) for 2 minutes prior to addition to the peptide resin, where it was allowed to run for 5 minutes before flushing the reactants away; this minimized racemization and gave high coupled yields in under 10 minutes, which is pretty cool if you think about it. Never used HBTU for solution-phase coupling however; both EDC for normal amide formation and 1-hydroxy-7-azabenzotriazole (HOAt) for dipeptide linkage have been personally observed by my previous friend to produce exceptionally high yields.
The inert gas setup is indeed a breeze; by bargain-hunting, someone put together a setup with a small tank and regulator for under $100, the argon fill was around $15. This is all in the name of welding.
I really think this seems like a worthwhile idea, even worth running two columns for purity's sake. :)
-SpicyBrown
Post 353379 (https://www.thevespiary.org/talk/index.php?topic=12853.msg35337900#msg35337900)
(Rhodium: "New LSD analogs from the Nichols Lab", Tryptamine Chemistry)?Post 355652 (https://www.thevespiary.org/talk/index.php?topic=12853.msg35565200#msg35565200)
(Cyrax: "Nice, they use the pyBOP coupling reagent, which ...", Tryptamine Chemistry)https://www.thevespiary.org/rhodium/Rhodium/pdf/azetidine-lsd.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/azetidine-lsd.pdf)
, the topic of the thread Moo linked too - so thank him for the insight, and maybe me for retyping...Post 488687 (https://www.thevespiary.org/talk/index.php?topic=11745.msg48868700#msg48868700)
(Organikum: "Mono and trimethylamine by electrolysis", Novel Discourse)Post 374511 (missing)
(terbium: "No gas is evolved.", Chemistry Discourse)Post 450362 (https://www.thevespiary.org/talk/index.php?topic=12648.msg45036200#msg45036200)
(Chimimanie: "Maybee", Tryptamine Chemistry)Post 400250 (https://www.thevespiary.org/talk/index.php?topic=13159.msg40025000#msg40025000)
(Vibrating_Lights: "Missing part", Tryptamine Chemistry)http://www.polycarboninds.com/html_pages/activ_for_pep_synth.html (http://www.polycarboninds.com/html_pages/activ_for_pep_synth.html)
http://www.merckbiosciences.co.uk/product/01-62-0016 (http://www.merckbiosciences.co.uk/product/01-62-0016)
)http://www.erowid.org/plants/morning_glory/morning_glory_extraction2.shtml (http://www.erowid.org/plants/morning_glory/morning_glory_extraction2.shtml)
Post 505109 (https://www.thevespiary.org/talk/index.php?topic=5399.msg50510900#msg50510900)
(doktor_alternate: "practicality of large scale column chromatography", Chemicals & Equipment)Post 488767 (https://www.thevespiary.org/talk/index.php?topic=12897.msg48876700#msg48876700)
(Freemings: "LSD chromatographia", Tryptamine Chemistry)Post 482624 (https://www.thevespiary.org/talk/index.php?topic=12948.msg48262400#msg48262400)
(Sleen: "LSD - CDI Method?", Tryptamine Chemistry) (this one answers the chromatography question quite well)Post 436693 (https://www.thevespiary.org/talk/index.php?topic=12977.msg43669300#msg43669300)
(chemotype: "hmmm... 250 mg of ergotamine tartrate", Tryptamine Chemistry) (this is even better :) )Post 350684 (missing)
(Rhodium: "Half-a-Pint - RIP", General Discourse)N-( (R )-l-Methylpropyl)-9,lO-didehydro-6-methylergoline-
B&carboxamide (2). (+)-Lysergic acid monohydrate
(150 mg, 0.52 mmol) and 25 mL of dry, ethanol-free CHCl, were
placed in a flamedried 50 d, three-necked, round-bottom flask
equipped with a condenser, N2 line, and septa inlets. The stirred
slurry was brought to reflux in a preheated 90 "C oil bath after
which 384 mg (5.2 mmol) of (R)-(-)-2-butylamine (Aldrich) in 1.0
simultaneously, via syringe, over 3 min. The mixture was allowed
to stir at reflux for an additional 5 min and was then cooled to
room temperature. The clear amber CHC13 solution was then
washed with 1 M NHdOH (3 x 30 mL) and brine (1 X 10 mL)
and dried (Na,SO,). The drying agent was removed by fitration,
and the solution was concentrated in the dark by rotary evaporation
at 30 "C.
The residue was purXed and fractionated by radial centrifugal
chromatography (Chromatotron, Harrison Research) using a silica
gel rotor and eluting with ethyl acetate in an N2-ammonia atmosphere.
TLC (silica gel, EtOAeNH3) showed a large blue
fluorescent product spot at R, 0.21 corresponding to the (R)-2-
butyllprgamide and a much smaller spot at Rf 0.15 corresponding
to the S isomer. The faster moving component was collected and
concentrated by rotary evaporation. The residue was taken up
into CH2ClZ, washed with HzO, and dried (MgSOJ, and the
CHzClz was removed by rotary evaporation followed by pumping
under high vacuum. The free base (158 mg, 94% yield) was taken
up into 2 mL of methanol, and 57 mg of maleic acid in 0.75 mL
of methanol was added. The maleate salt (1:l stoichiometry)
spontaneously crystallized as a white crystalline solid mp 210
"C dec; lH NMR (free base, CDClJ S 0.91 (t, J = 7.5 Hz, 3 H),
1.13 (d, J = 6.7 Hz, 3 H), 1.36-1.56 (m, 2 H), 2.60 (s,3 H), 2.68-2.82
(m, 2 H), 3.05-3.13 (m, 1 H), 3.31-3.56 (m, 3 H), 3.89-3.98 (m,
(m, 3 H), 8.15 (br 8, 1 H); [(Y]D = +48" (c = 0.1, HZO); IR (free
base, neat) 1650 cm-l (C=O). Anal. (CzrH&I3O5) C, H, N.
N - (( S ) - 1 -Met hylpropyl)-g, 1 0-didehydro-6-met hylergolina88-
carboxamide (3). An exact replication of the above
procedure using 150 mg of (+)-lysergic acid monohydrate and 384
mg of (S)-(+)-2-butylamine (Aldrich) gave 154 mg (91.7% yield)
of the free base. The free base in methanol was combined with
55 mg of maleic acid in methanol to again yield a white aytalline
solid with 1:l stoichiometry: mp 213 "C dec; 'H NMR (free base,
CDC13) 6 0.93 (t, J = 7.5 Hz, 3 H), 1.13 (d, J = 6.7 Hz, 3 H),
1.37-1.58 (m, 2 H), 2.60 (a, 3 H), 2.66-2.82 (m, 2 H), 3.05-3.13
(m, 1 H), 3.31-3.56 (m, 3 H), 3.89-3.98 (m, 1 H), 6.45 (e, 1 H),
6.60 (d, J = 8.0 Hz, 1 H), 6.92 (8, 1 H), 7.12-7.23 (m, 3 H), 8.02
(br 8, 1 H); [(Y]D = +59" (c = 0.1, HzO); IR (free base, neat) 1650
cm-l ( C 4 ) . Anal. (CurH~N305) C, H, N.
This is amides of lysergacid made by the old synthesis by Nichols. look at the yeald's >90% on a sub g. scale.
Read also J.Med.Chem 1995,38,958-966 here Nicholas et.al produse amides from racemic amines and then purify them on their rotochrome (just a fancy prep. TLC plate). Yeald in the 90's (high 40's of each isomer)
EXTENSIONS AND COMMENTARY : LSD is an unusually fragile molecule and some comments are in order as to its stability and storage. As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely. There are two sensitive aspects of its structure. The position of the carboxamide attachment, the 8-position, is affected by basic, or high pH, conditions. Through a process called epimerization, this position can scramble, producing isolysergic acid diethylamide, or iso-LSD. This product is biologically inactive, and represents a loss of a proportionate amount of active product. A second and separate point of instability is the double bond that lies between this 8-position and the aromatic ring. Water or alcohol can add to this site, especially in the presence of light (sunlight with its ultraviolet energy is notoriously bad) to form a product that has been called lumi-LSD, which is totally inactive in man. Oh yes, and often overlooked, there may be only an infinitesimal amount of chlorine in treated tap water, but then there is only an infinitesimal amount of LSD in a typical LSD solution. And since chlorine will destroy LSD on contact, the dissolving of LSD in tap water is not appropriate.
I Think that Shulgin has a good point here. The big LSD-killer is not light but chlorine ions.
And for the reaction 1: use DCM or DMF as solvent. 2: Don't use the Hydrochloride of DEA use the freebase.
3 seperate on an prep.TLC plate, up to 1g can bee splited at once, an you don't have to learn collumchrom first.
And n00dle could you give me the ref for the tetrabutylammonium hydroxide hydrolysation, I would love to read it
../rhodium/chemistry
/paspalic.lysergic.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry
/paspalic.lysergic.html)
Post 415643 (https://www.thevespiary.org/talk/index.php?topic=12738.msg41564300#msg41564300)
(Lilienthal: "LSD is not that light sensitive as you might think", Tryptamine Chemistry)So maybe it would be better to first mix lysergic acid with pyBOP and tetiary amine buffer, let stir for x minutes to form the acyloxy salt, and then add diethylamine to be coupled with and stir for 2-3h.
Yes that is eksatly how you perform an usual peptide couling.
../rhodium/chemistry
/lsdpatent.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry
/lsdpatent.html)
Post 519261 (https://www.thevespiary.org/talk/index.php?topic=13024.msg51926100#msg51926100)
(Bubbleplate: "Process for Isolation of Indole Alkaloids", Tryptamine Chemistry) threadPost 511856 (https://www.thevespiary.org/talk/index.php?topic=7748.msg51185600#msg51185600)
(Rhodium: "the freebase should be used", Stimulants)Post 506241 (https://www.thevespiary.org/talk/index.php?topic=13322.msg50624100#msg50624100)
(Rhodium: "chirality of otc tartrate salts", Tryptamine Chemistry)Post 474569 (https://www.thevespiary.org/talk/index.php?topic=12689.msg47456900#msg47456900)
(bbell: "Hawian baby woodrose", Tryptamine Chemistry)Post 417270 (https://www.thevespiary.org/talk/index.php?topic=12757.msg41727000#msg41727000)
(pHarmacist: "Sandoz Ltd. LSD synthesis (1946)", Tryptamine Chemistry)Post 275468 (https://www.thevespiary.org/talk/index.php?topic=12767.msg27546800#msg27546800)
(El_Zorro: "Re: trouble getting yields for LSD", Tryptamine Chemistry)Post 477135 (https://www.thevespiary.org/talk/index.php?topic=13011.msg47713500#msg47713500)
(Mr_Rodgers: "sensitivity of ergolines", Tryptamine Chemistry)Post 481216 (https://www.thevespiary.org/talk/index.php?topic=12739.msg48121600#msg48121600)
(Rhodium: "An Interview With an LSD Clandestine Chemist", Tryptamine Chemistry)../rhodium/chemistry
/14c-lsd.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry
/14c-lsd.html)