Lysergic acids hydrazides

In order to prepare lysergic acid hydrazide, the suitable lysergic acid derivatives are heated with hydrazine hydrate preferably to 80-118° C. under reflux condenser, whereby it is sometimes also advantageous to work in closed vessels under pressure at a temperature of 80-160° C., or in a suitable solvent like propylalcohol, butylalcohol, pyridine, etc., or in an inert atmosphere like in nitrogen gas. 

The degradation of alkaloids of ergot with hydrazine to lysergic acid hydrazide is, especially with respect to the obtained 5neld, much... 

The lysergic acid hydrazide is very difficultly soluble in water, ether, benzene, chloroform, rather difficultly soluble in pyridine and in hot absolute ethanol. From this last solvent it crystallizes in form of beautiful, compact, clear, on six sides cut crystal plates, that melt under decomposition at 235-240° C. (corr). The hydrazide is easily soluble in acids yielding good crystallizing salts. 

One part of ergotamine is suspended in 10 parts of hydrazine hydrate and heated in a nitrogen atmosphere at 100° C. The substance becomes dissolved very rapidly, but as soon as complete dissolution has occurred, precipitation of a solid, nearly colourless compound takes place. The analysis of a test taken out shows that under the action of hydrazine, ergotamine has been transformed into the difficultly soluble ergotaminine. The suspension is then heated further and after about 20 hours it can be observed that complete dissolution has taken place. The brownish solution is then concentrated in vacuo to about 5 parts, whereby the lysergic acid hydrazide begins to separate out in the form of a crystalline greyish powder. In order to complete the precipitation, the reaction mass is left to stand for 1 to 2 days in a cool place in order to complete the crystallization. After this time the crystals are filtered and washed with some absolute alcohol. Yield 0.26 parts, which corresponds to 68 per cent, of the theoretical. 

Lysergic Acid Azides and Amides from Lysergic Acid Hydrazides... 

Thus, the new process, for example in preparing the hitherto unknown l-methyl-c/-lysergic acid hydrazide, is an important technical advance. 

The resulting c/-iso-lysergic acid hydrazide is washed into the filtrate with chloroform containing 0.5% of ethanol. Prisms from methanol/ether. Melting point 202°. [a]D20°=+445° (c.=0.5 in pyridine). 

A solution of 1.6 g. of 1-methyl-ergotamine hydrochloride in 6.4 cc. of anhydrous hydrazine are heated for 1 hour at 90°, the mixture diluted with 50 cc. of water, the water and the hydrazine hydrate are distilled off and after the addition of a further 6.4 cc. of anhydrous hydrazine the remaining procedure is repeated. The residue is then shaken between a diluted tartaric acid solution and chloroform. The bases liberated after the tartaric acid solution has been made alkaline are shaken with chloroform and the crude product remaining after evaporation of the chloroform is chromatographed on a column of 25 g. of aluminium oxide. l-methyl-c -iso-lysergic acid hydrazide is washed into the filtrate with chloroform containing 0.5% of ethanol. The compound crystallizes from ethanol in the form of nice leaflets. Melting point 201-204°. [a]D20=+400° (c.=0.5 in pyridine). Keller s colour reaction blue. 

A solution of 1 g. of ergotamine is heated with 5 cc. of anhydrous hydrazine and 1 cc. of glacial acetic acid to 120° for 30 minutes. The mixture is worked up as described in Example 1, the product being essentially d-iso-lysergic acid hydrazide with the properties mentioned. Source Hofmann 1966a... 

Hofmann, A. Rutschmann, J. Stadler, P., Troxler, R Process for Lysergic Acid Hydrazides 1966a US 3,239,530... 

Sandoz The Preparation of Lysergic Acid Hydrazide 1937 GB 463,936 Sandoz The Preparation of Synthetic Derivatives of Lysergic Acid 1938 GB 480,822... 

Starting Molecule d-iso-Lysergic acid hydrazide Reagents Acetylacetone d-2-AminobutanoM... 

The mixture is then diluted with water (approx. 20 mL per ynini of alkaloid). The water and hydrazine hydrate are distilled iilf Minder vacuum or reduced pressure. The residue is mixed Wiili ether and tartaric acid. The aqueous layer is separated, MKiile alkaline and extracted with chloroform. The chloroform iiiluhon is evaporated to leave the d-iso-lysergic acid hydrazide. 

Conversion of Ergot Amides To iso-Lysergic Acid Hydrazide... 

There are three main precautions to be followed while executing this procedure. Water must be rigorously excluded from the reaction mixture, as hydrazine hydrate will react with the amides to form racemic lysergic acid hydrazide rather than our desired product. To ensure the exclusion of water from the reaction, the glassware should be baked in an electric oven prior to use, and be allowed to cool off in a dessicator. A drying tube should be attached to the top of the condenser used, to prevent humidity in the air from getting in the mix. 

Pour the contents of the flask into a 500 ml sep funnel, and drain the lower layer (water solution of iso-lysergic acid hydrazide tartarate) into an Erlenmeyer flask wrapped in foil. To the ether layer still in the sep funnel, add 50 ml fresh decimolar tartaric-acid solution, and shake. Examine the water layer for the presence of iso-lysergic acid hydrazide with a black light. If there is a significant amount, add this also to the Erlenmeyer flask. 

Place the magnetic stirring bar in the Erlenmeyer flask, and stir it moderately. Monitor the pH of the solution with a properly calibrated pH meter, and slowly add. 5M (42 grams per liter) sodium bicarbonate solution until the pH has risen to the range of 8-8.5. Higher pH will cause racemization. The freebase is then extracted from the water solution with chloroform. Two extractions with 100 ml of chloroform should complete the extraction, but check a third extraction with the black light to ensure that most all of the product iso-lysergic acid hydrazide has been extracted. 

The chloroform extracts should be evaporated under a vacuum in a 500 ml flask to yield the product. This is best done by rigging the 500 ml flask for simple distillation, and applying an aspirator vacuum to remove the chloroform. Assume that the yield from this procedure will be about 5 grams of lysergic acid hydrazide if ergot... 

Both of these choices are really very poor, because lysergic acid hydrazide, unlike most other lysergic compounds, crystallizes very well with negligible loss of product. At the hydrazide stage of LSD manufacture, one has a perfect opportunity to get an exceedingly pure product, freed from clavine alkaloids and other garbage eompounds carried in from the extraction of the complex plant material. 

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