CS209152B1 - Method of lysergic acid preparation from its sulphate - Google Patents

Description

(54) A method for preparing lysergic acid from its sulfate

The invention relates to a novel process for the preparation of D-lysergic acid from its sulphate. D-lysergic acid is an important starting material for the partial synthesis of therapeutically important analogues of natural ergot alkaloids, such as methylergobasin, as well as for the partial synthesis of natural alkaloids, such as ergobasin.

For practical purposes, D-lysergic acid is obtained by alkaline hydrolysis of the ergot peptide-type alkaloids or mixtures of D-lysergic and D-isolysergic amides isolated from saprophytic cultures of various Claviceps species (see, e.g., Jacobs WA, Craig LC: J. Biol. Chem. 104, 547 (1934) and Rutschmann, J. and Kobel H., Franc, U.S. Pat. D-lysergic acid is usually isolated from the hydrolyzate in the form of sulphate, which, depending on the quality of the starting material and the method of its treatment, is more or less contaminated with non-alkaloid concomitants, alkaloid degradation products formed during hydrolysis and inorganic salts. The liberation of D-lysergic acid from its sulphate is carried out by treatment with a solution of ammonia in methanol or ethanol, and the resulting acid solution is then evaporated to dryness. Thus, the release of D-lysergic acid from its sulfate is not associated with a cleaning effect since all the ballast substances remain in the obtained evaporator. This is followed by purification operations, which may vary in detail, but in principle it is always either the crystallization of the crude D-lysergic acid from water or its previous digestion with methanol to remove some of the colored impurities (see eg Jacobs WA, Craig LC, loc. Cit.), Or decolorizing the crude acid solution with activated carbon and precipitating it from the salt solution (e.g., Rutschmann J., Kobel H., loc. Cit.). All of these cleaning operations are associated with considerable losses if a product of satisfactory quality is to be obtained. The only known procedure in which i-D-lysergic acid is not isolated from the alkali hydrolyzate as the sulfate is the process of U.S. Pat. In this case, D-lysergic acid is removed from the alkaline hydrolyzate into a mixture of ether and ethanol. Further purification is carried out using ion exchange resins, removing most of the impurities. This process achieves relatively good yields for a mixture of D-lysergic acid and D-isolysergic acid (in a ratio of about 6.5: 3.5), but the process requires the processing of large volumes of ether-ethanolic acid solutions and is therefore labor intensive on an industrial scale. , in terms of time and work safety. The product obtained according to U.S. Pat. patentu event. further purifies, in order to reduce the content of D-lysergic acid, primarily in D-lysergic sulfate.

According to the invention, the crude D-lyser209152 gic acid sulphate obtained by some of the processes described above, or by modification of these processes, is converted to D-lysergic acid by converting it in an aqueous suspension by reacting with excess calcium hydroxide into a calcium salt of D- lysergic, the aqueous calcium salt solution is basified with ammonia, then saturated with carbon dioxide, and after separation of the precipitated calcium carbonate, the filtrate is treated to D-lysergic acid, e.g. by concentration and separation of the crystallized acid.

The process of our invention has several advantages over the prior art processes. Firstly, it is a combination of the purification operation with the release of D-lysergic acid from the sulfate.

A further, essential advantage of the process of the invention is that it makes it possible to obtain D-lysergic acid very pure and almost free of D-isolysergic acid. The crystalline solvent-free D-lysergic acid thus prepared is 98 to 99% (determined spectrophotometrically) and contains only about 1 to 5% D-isolysergic acid, as determined from the determined [a] p ° value, e.g. +32.5 (C 0.2, pyridine). According to our invention, the D-lysergic acid obtained is a suitable starting product for the synthesis of the above-mentioned pharmaceutical preparations and other D-lysergic acid derivatives, respectively. D-dihydrolyserges.

It is also important that the successful application of the process according to the invention does not interfere with the presence of large quantities of inorganic salts in the crude D-lysergic acid to be treated. Otherwise, removal of said inorganic salts from D-lysergic acid sulfate is associated with considerable losses to the desired acid. The process according to the invention is material-intensive, fast and easy to implement on an industrial scale.

The details of the process according to the invention follow from the example below.

A mixture of 5.8 g of crude ergotamine containing 84.8% alkaloids (calculated on ergotamine) with 151 ml

2 N aqueous methanolic (1: 1) potassium hydroxide and 151 ml of ethanol were immersed in a pre-heated to 90-95 ° C bath under gentle reflux in a flask equipped with a KOH stopper and boiled gently for 4 h. of a volume of about 80 ml, the mixture was acidified, under external cooling, with 20 ml of dilute sulfuric acid (1: 1, v / v) and after standing at about 5 ° C for 1 h, D-lysergic sulphate dried in desiccator over KOH. 22.3 g of crude product were obtained, which, according to a photo-colorimetric determination, contained 9.5% of D-lysergic sulfate.

The crude D-lysergic sulphate (22.3 g) was 1: 1. mixed with 22.3 g techn. calcium hydroxide; and the mixture was triturated with 44.6 ml of water to fine! paste. After 10 min of spreading, the paste is quantitative! transferred, using a total of 280 ml of water to the flask; The mixture was heated to 50 [deg.] C., stirred for 30 min and suction filtered while still warm. The filtrate was made alkaline with concentrated aqueous ammonia and saturated with carbon dioxide until no more calcium carbonate was precipitated (about 30 min). At the end of the introduction of carbon dioxide, the atmosphere j above the solution must be ammoniacal. The precipitated calcium carbonate was aspirated, the filtrate was concentrated to a small volume and stored in a refrigerator at 5 ° C. After crystallization was complete, the precipitated crystallisate was stirred with a small amount of warm water at 35 ° C and D-lysergic acid was aspirated while still warm, washed with a small amount of chilled water. 1.24 g of D-lysergic acid with a content of 98.8% in a solvent-free substance were obtained. From the mother liquor after the first crop of acid, 0.094 g of the same product was obtained. The total yield of D-lysergic acid, based on the content of alkaloids (expressed as ergotamine) in the starting summary is 50%, calculated on the content of D-lysergic acid in the crude sulfate, 64%.

Claims (1)

SUBJECT A process for the preparation of D-lysergic acid from its sulphate, characterized in that the crude D-lysergic sulphate is processed to D-lysergic acid by reaction with excess calcium hydroxide into the calcium salt of D-lysergic acid. BACKGROUND OF THE INVENTION The aqueous calcium salt solution is basified with ammonia, saturated with carbon dioxide and after separation of the precipitated calcium carbonate, the filtrate is treated to D-lysergic acid.