Lsd

[fafalone]

I have readded the pharmacology forum, and based on my interest in psychopharmacology, I'll be posting a series of threads regarding roads to synthesis of psychoactive drugs. The purpose of these threads will to comment on the syntheses and the mechanism of action of the product. Do not discuss your personal use of anything, or where to get it, or if you're actually performing one of these syntheses without a license. Talking about these procedures is legal, actually performing them is not. Enjoy:-)

 

NOTICE: The following directions and instructions are in violation of United States Federal, State, and Local laws if carried out in part or in whole. As such, neither ScienceForums.net staff, members, administrators, owners, nor anyone affiliated either directly or indirectly with the website (http://www.scienceforums.net) condone or encourage its production. Any indication that a serious attempt is being made at synthesizing the compound will be immediately reported to proper authorities. This information is for educational use only, and can readily be found in scientific journals, and various books written on the subject.

 

 

Part I: LSD from ergotamine tartrate (a Schedule III (US) chemical)(from TiHKAL (Tryptamines I have known and Loved, by Alexander and Ann Shulgin)

 

ACID; LYSERGIDE; D-LYSERGIC ACID DIETHYLAMIDE; METH-LAD; D-LYSERGAMIDE, N,N-DIETHYL; N,N-DIETHYL-D-LYSERGAMIDE; 9,10-DIDEHYDRO-N,N-DIETHYL-6-METHYLERGOLINE-8b-CARBOXAMIDE

 

 

SYNTHESIS : A solution of 6.7 g KOH in 100 mL H2O, under an inert atmosphere and magnetically stirred, was brought to 75 °C, and 10 g ergotamine tartrate (ET) added. The reaction mixture turned yellow as the ergotamine went into solution over the course of 1 h. The stirring was continued for an additional 3 h. The reaction mixture was cooled to about 10 °C with an external ice bath, and acidified to a pH of about 3.0 by the dropwise addition of 2.5 N H2SO4. White solids started to appear early in the neutralization; approximately 60 mL of sulfuric acid was required. The reaction mixture was cooled overnight, the solids removed by filtration, and the filter cake washed with 10 mL Et2O. The dry solids were transferred to a beaker, suspended in 50 mL 15 % ammonia in anhydrous ethanol, stirred for 1 h, and separated by decantation. This extraction was repeated, and the original decantation and the second extract combined and filtered to remove a few hundred milligrams of unwanted solids. The clear filtrate was stripped of solvent under vacuum, the residual solids dissolved in 50 mL of 1% aqueous ammonia, and this solution was acidified as before with 2.5 N H2SO4. The precipitated solids were removed by filtration and washed with Et2O until free of color. After drying under vacuum to a constant weight, there was obtained 3.5 g of d-lysergic acid hydrate, which should be stored in a dark, sealed container.

A suspension of 3.15 g d-lysergic acid hydrate and 7.1 g of diethylamine in 150 mL CHCl3 was brought to reflux with stirring. With the external heating removed, there was added 3.4 g POCl3 over the course of 2 min, at a rate sufficient to maintain refluxing conditions. The mixture was held at reflux for an additional 5 min, at which point everything had gone into solution. After returning to room temperature, the solution was added to 200 mL of 1 N NH4OH. The phases were separated, the organic phase dried over anhydrous MgSO4, filtered, and the solvent removed under vacuum. The residue was chromatographed over alumina with elution employing a 3:1 C6H6/CHCl3 mixture, and the collected fraction stripped of solvent under hard vacuum to a constant weight. This free-base solid can be recrystallized from benzene to give white crystals with a melting point of 87-92 °C. IR (in cm-1): 750, 776, 850, 937 and 996, with the carbonyl at 1631. The mass spectrum of the free base has a strong parent peak at mass 323, with sizable fragments at masses of 181, 196, 207 and 221.

 

This base was dissolved in warm, dry MeOH, using 4 mL per g of product. There was then added dry d-tartaric acid (0.232 g per g of LSD base), and the clear warm solution treated with Et2O dropwise until the cloudiness did not dispel on continued stirring. This opaqueness set to a fine crystalline suspension (this is achieved more quickly with seeding) and the solution allowed to crystallize overnight in the refrigerator. Ambient light should be severely restricted during these procedures. The product was removed by filtration, washed sparingly with cold methanol, with a cold 1:1 MeOH/Et2O mixture, and then dried to constant weight. The white crystalline product was lysergic acid diethylamide tartrate with two molecules of methanol of crystallization, with a mp of about 200 °C with decomposition, and weighed 3.11 g (66%). Repeated recrystallizations from methanol produced a product that became progressively less soluble, and eventually virtually insoluble, as the purity increased. A totally pure salt, when dry and when shaken in the dark, will emit small flashes of white light.

 

 

Part II: LSD (original synthesis route by Albert Hoffman, inventor of LSD)

U.S. Patent 2,438,259; Patented Mar. 23, 1948.

 

d-LYSERGIC ACID DIETHYLAMIDE

 

Arthur Stoll and Albert Hofmann, Basel, Switzerland, assignors Sandoz Ltd., Fribourg, Switzerland, a Swiss firm.

 

No Drawing. Application April 28, 1944, Serial No. 533,264. In Switzerland April 30, 1943

 

1 Claim. (CI. 260--236)

The present invention relates to new d-lysergic acid dialkylamides which are valuable therapeutic products and to a process for their preparation.

 

It has been found that by condensing azides of d- or d,l-lysergic acid respectively or of d- or d,l-isolysergic acid respectively or mixtures of these compounds with diakylamines, d-lysergic acid dialkylamides are obtained, which products have not yet become known hitherto. The alkyl groups present in the dialkylamines used according to the present invention can either be identical or different and may be of saturated or unsaturated character. Such amines are for instance dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, methyl-ethylamine, ethyl-allylamine, butyl-amylamine, etc.

 

The new d-lysergic acid amides are distinguished from the known natural and synthetic ergot alkaloids and from the d-lysergic acid amides described in our U. S. Patent No. 2,090,430 by their powerful specific action on the central nervous system.

 

The condensation of the d-lysergic acid- or d-isolysergic acid azides with the dialkylamines is carried out in the presence of an inert organic solvent and preferably at room temperature. During the reaction taking place between the azides and the dialkylamine generally mixtures of different dialkylamides will be obtained. This can, for instance, be seen in the following illustrative example showing the reaction of d-lysergic acid azide with diethylamine. During the interaction of these compounds a mixture will be obtained consisting of d-lysergic acid diethylamide and of d-isolysergic acid diethylamide, from which mixture the d-lysergic acid derivative will be separated. By using as a starting product d-isolysergic acid azide and diethylamine a mixture of d-lysergic acid diethylamide and of d-isolysergic acid diethylamide will be obtained, this mixture being subsequently separated into its constituents. Finally by starting from racemic lysergic acid azide or racemic isolysergic acid azide, mixtures consisting of d,l-lysergic acid diethylamide and d,l-isolysergic acid diethylamide will be obtained, from which the d-lysergic acid diethyl amide can be separated in a suitable manner, e.g., in form of its tartaric acid salt.

 

The following examples, without being limitative, illustrate the present invention, the parts being by weight.

 

Example 1

3 parts of d-isolysergic acid hydrazide are transformed in the usual way in a hydrochloric acid solution by a treatment with sodium nitrite at 0 degrees C. into the azide, and, after neutralization of the acid solution with sodium bicarbonate, the azide thus formed is shaken out by means of 300 parts ethyl ether. The ethereal solution is then dried with freshly calcinated potassium carbonate and treated with 3 parts of diethylamine. The solution is allowed to stand, preferably in the dark and at room temperature, for 24 hours with repeated shaking. The ether is then evaporated in vacuo, the residue triturated with 30 parts of water and filtered by suction. The dark amorphous product thus obtained possesses a specific rotation of [alpha]20/D=about+100 degrees (in pyridine) and consists essentially of a mixture of nearly equal parts of d-lysergic acid diethylamide and d-isolysergic acid diethylamide.

 

The separation of both isomers can be carried out for instance by the so-called chromatographic adsorption method. For this purpose the mixture is dissolved in chloroform containing about 0.5% of ethanol and is passed through a column of aluminium oxide of 60 cm. length and 4 cm. radius and the chromatogram developed with the same solvent. The dark impurities pass rapidly into the filtrate. Then follows a bright zone, which has a blue appearance in ultra-violet light and which contains the d-lysergic acid diethylamide. From this fraction 1.0 to 1.3 parts of this product will be obtained.

 

A further slowly passing portion of the solution contains the d-isolysergic acid diethylamide. By evaporating this chloroform fraction and crystallizing the residue from acetone, 0.8 to 1.2 parts of a compound crystallizing in beautiful prisms of melting point 182 degrees C. (corr.) under decomposition is obtained, this compound being the pure d-isolysergic acid diethylamide. Its specific rotation is [alpha]20/D=+217 degrees (c=0.4 in pyridine). Elementary analysis has given the following values: C 74.41; H 7.48; N 13.27%. The calculated values for d-isolysergic acid diethylamide, i.e., C20H25ON3 are C 74.25; H 7.79; N 13.00%.

 

The d-isolysergic acid diethylamide can be transformed into d-lysergic acid diethylamide by using the methods known for the ergot alkaloids. By allowing the solution of the iso- compound to stand in dilute alcoholic potassium hydroxide, a mixture of about equal parts lysergic acid and isolysergic acid compounds will be produced after a short time. The d-lysergic acid diethylamide can then be separated from the mixture in the manner described above.

 

The amorphous d-lysergic acid diethylamide, which can be separated by the chromatographic method, crystallizes, by dissolving it in a small amount of acetone and diluting this solution with ethyl ether, in bundles of needles. From benzene pointed prisms will be obtained, that melt under decomposition at 80-85 degrees C. (corr.). The new compound is difficulty soluble in water, but very soluble in methanol and ethanol. It possesses the specific rotation of [alpha]20/D=+30 degrees (c=0.4 in pyridine). Elementary analysis gives the following values: C 73.50; H 7.81; N 12.92%. For d-lysergic acid diethyl amide, C20H25ON3, the calculated values are C 74.25; H 7.79; N 13.00%.

 

By dissolving one equivalent of the base with one equivalent of d-tartaric acid in a small quantity of methanol the neutral tartrate of d-lysergic acid diethylamide crystallizes out in form of bundles of needles. The salt is very easily soluble in water and melts indistinctly and under decomposition at 200 degrees C. (corr.).

 

Example 2

An ethereal solution of d-lysergic acid azide, prepared in the usual manner from 3 parts of d-lysergic acid hydrazide, is treated with 3 parts of diethylamine and allowed to stand for 24 hours in the dark and at room temperature with occasional shaking. The isolation of the compound thus produced is carried out in the manner described in the Example 1. The first separation by means of the chromatographic adsorption yields 1.3 to 1.7 parts of d-lysergic acid diethylamide and about 0.5 to 0.8 part of d-isolysergic acid diethylamide.

 

Example 3

3 parts of racemic isolysergic acid hydrazide are transformed in the usual manner into the respective azide and the formed compound is precipitated by means of an excess of a sodium bicarbonate solution in the form of voluminous yellowish flocks, which are separated by suction and immediately introduced at -5 degrees C. into a solution of 3 parts of diethyl amine in 30 parts of ethanol. The azide readily dissolves in the solution which becomes brown and is then heated slowly to 30 degrees C. The solution is maintained at this temperature for 1 hour, whereupon the solvent is evaporated in vacuo. The sticky residue is triturated with 30 parts of water and filtered. The raw condensation product amounting to about 2.8 parts consists of racemic isolysergic acid diethylamide and of racemic lysergic acid diethylamide and is separated by the chromatographic method in the manner described in Example 1. During the chromatographic separation two zones are obtained which are colored, in ultra-violet light, in brilliant blue shades. The more rapidly passing zone contains the racemic lysergic acid diethylamide, whereas the slower passing zone consists of racemic isolysergic acid diethylamide.

 

From the racemic lysergic acid diethylamide the d-lysergic acid diethylamide can be separated by transforming the same for instance into its neutral tartaric acid salt. For this purpose 3.2 parts of racemic lysergic acid diethylamide (1/100 mol.) are dissolved in 6 parts of methanol and added to a solution of 0.75 part of d-tartaric acid (1/200 mol.) in 2 parts of methanol.

 

On inoculation with d-lysergic acid diethylamide tartrate this compound crystallizes out in nearly colorless bundles of needles. Yield 1.0 to 1.2 parts. The properties of the compound thus obtained are identical with those described in Example 1 for the neutral d-tartaric acid salt of d-lysergic acid diethylamide.

 

What we claim is:

 

The crystalline d-lysergic acid diethylamide which crystallizes from benzene in prisms melting with decomposition at 80-85 degrees C., which is difficulty soluble in water but easily soluble in methanol and in ethanol, which possesses the specific rotation [alpha]20/D=+30 degrees (c=0.4 in pyridine) and which corresponds to the formula C20H25ON3.

 

ARTHUR STOLL

 

ALBERT HOFMANN