Synthesis of LSD from Lysergic Acid

[flipper]

I don't understand this. If I look to this:

Svensk Farmaceutisk Tidskrift, Vol.75, 933-40 (1971).
A suspension of 1.34g (5mmol) anhydrous D-Lysergic Acid in 80ml DMF was mixed at 20°C with a solution of 0.89g (5.5mmol) N,N'-Carbonyldiimidazole in 25ml DMF and the reaction mixture was then stirred for 30 min at 20°C in the dark. The clear solution was then mixed with a solution of 0.40g (5.5mmol) Diethylamine in 5ml DMF, and the mixture allowed to stand for 2h at 20°C followed by 20h at 5°C. The resulting amber solution was freed from DMF by evaporation at 50-60°C under aspirator vacuum, the residue dissolved in 250mL 2% aqueous tartaric acid and the solution washed with diethyl ether. To the aqueous phase was added a small amount of Ostacol (activated carbon), the solution filtered with suction and basified to pH 8 with aqueous ammonium hydroxide. The liberated freebase was extracted with a 9:1 ether/ethanol mixture, and after separation and drying of the organic phase, the solvent was evaporated in vacuo to give 2.3g of crude product, which consisted of 57 weight% of the diethylamides of D-Lysergic acid (I) and D-Isolysergic acid (II) (81% yield calculated on the starting acid) and the rest being chiefly Imidazole. According to qualitative TLC analysis the crude product contained only the amides (I) and (II) as well as traces of D-Lysergic acid and a decomposition product.

The yields are It's 57% D-LSD and 24% D-isoLSD
But in this example of patent US2003013131

US2003013131
A mixture of 10.0 g (0.037 mol) of d-lysergic acid in 500 ml of dry dimethyl formamide (DMF), under argon, was treated with 9.0 g of carbonyl diimidazole and stirred at room temperature for 1 hour. The reaction was then treated with 38 ml of diethylamine and stirred at room temperature overnight. The reaction was concentrated under reduced pressure. The residue was taken up in 500 ml of methylene chloride and washed with 500 ml of water. Insoluble material was removed by filtration and the layers were separated. The organic portion was washed with 250 ml of saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on 800 g of silica gel using 3% methanol in methylene chloride to yield 9.0 g (75%) of d-lysergic acid diethylamide (LSD) as a light brown amorphous solid after evaporation of the solvents.

It only gives 75% of D-LSD. Where is the D-isoLSD?!?! What is done differently in this synth that it does not give much isoLSD?

[neohippy]

Looks like in the first synth they basified it.
May have given the epimerized iso LSD.

[bbell]

The iso-lsd will be the second band in the chromatographic column.(the slower band, blue florensent under black light)In the first synthesis Svensk Farm. Tidskrift by A.Hofmann you omited the chromatography on 50g. Al2O3 activity three-four.10mL benzene with 1% acetone, as elutant.
To many numbers in your U.S.patent number?

[Rhodium]

As mentioned in

Post 415643

(Lilienthal: "LSD is not that light sensitive as you might think", Tryptamine Chemistry)
Scans made available by FreakyDMT, thanks!

Stability study of LSD under various storage conditions
Li Z, McNally AJ, Wang H, Salamone SJ.

J. Anal. Toxicol. 22(6), 520-5 (1998)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/lsd.storage.stability.pdf)

[PapaSmerck]

flipper, some possibilities:

an excess of carbonyldiimidazole and DEA was used in the first reaction, and the resulting residue would hence contain LSD along with any remainders of the other two reagents. this residue was then dissolved in 250mL of 2% tartaric acid, enough water to be sure to react with residual carbonyldiimidazole, which decomposes to CO2 + imidazole. Under certain physical conditions, pockets of carbonic acid may drop in pH enough to influence yields. i also found a couple of papers that implied that imidazole group may bind with heavy metals, a la EDTA. the fact that imidazole accounted for the bulk of the 19% impurity in the raw  product indicates that virtually all of the catalyst was decomposed.

another possibility is that the activated charcoal in the first reaction contained trace amounts of heavy metals. a bit of both seems the most likely explanation for the large discrepancy, as the imidazole was still in solution when it was passed through the charcoal.

i notice that DMF is boiled off at 50-60degC under pressure in the first reaction. this seems an unusually high temperature to expose lsd to, so it may possibly explain the bizarre yield.

just a few educated guesses, please corrent me if i'm wrong  

[flipper]

Can you use DCM, THF, acetonitrile or Chloroform instead of DMF in this synthesis?
Why do they prefer DMF?
In those other peptide synthesises they just say "In a suitable solvent". Why Don't that aply to this synthesis with the Carbonyldiimdazole?

[Bubbleplate]

reasons. First, it is a good solvent for gasses and will tend to keep the diethylamine in solution. It also has a slow rate of evaporation. The reactants, lysergic acid, Carbonyldiimidazole also dissolve well in it. DMF also is alkaline, which I believe helps the reaction conditions.
DMF is known as a "universal solvent".
THF is an ether and would be hard to get/keep anhydrous.

[Lilienthal]

Wrong answer   . Polar solvents extremely enhance the reaction speed for nucleophilic substitutions.

Polar protic solvents promote the SN1 mechanism (by solvating and separating the ions) and polar aprotic solvents the SN2 mechanism (by stabilizing the transition state and by solvation of reactands and products).

You usually prefer solvents with a low boiling point (depending on the reaction temperature). DMF (which is not basic) could probably be substituted with acetonitrile which has a similarly high dielectricity constant.

(This should have been provided you with enough keywords...)

[Bubbleplate]

then, in the particular reaction he referred to?
Feel free to use molecular diagrams, etc.
TIA.

[moo]

http://www.google.com/search?q=sn1+mechanism