CS231802B1 - A method of purifying crude lysergic acid - Google Patents

Abstract

The invention relates to a new method for purifying crude D-lysergic acid obtained from a natural source. The crude D-lysergic acid is dissolved in a dilute aqueous ammonia solution and the solution thus obtained is passed through an alumina column, after which the filtrate is treated by evaporation to pure D-lysergic acid.

Description

The invention relates to a novel process for purifying crude S-lysergic acid obtained from a natural material. D-lysergic acid is an important starting material for the partial synthesis of therapeutically important analogues of natural ergot alkaloids, such as methylergobaaln, as well as for the partial aynthase of natural alkaloids, such as ergobaaln, ergotamine and others.

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For practical purposes, D-lysergic acid is obtained by alkaline hydrolysis of the ergot alkaloids of the peptide type, or ameles of simpler D-lysergic and D-isolysergic amides isolated from saprophytic cultures of various Clavicepe species (see e.g.

Jacobs W. A., Craig L. C., J. Biol. Chem. 104. 547/1934 and fiutechmann J. and Kobal H .:

Franc. U.S. Pat. 1,368,420). From the hydrolyzate, D-lyaergic acid is mostly isolated in the form of sulphate which, depending on the quality of the starting material and the method of its treatment, is or is less contaminated with non-alkaloid concomitant substances, decomposition products of alkaloids formed by Beth hydrolye 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 acid solution obtained is then evaporated. to dryness. Following purification operations, which may vary in detail, in principle always involve either crystallization of the crude D-lysergic acid from water, possibly after its previous digestion and methanol to remove some of the colored impurities (see, for example, Jacob WA, Craig LC, loc. cit.) or by decolourizing the crude acid solution with activated carbon and precipitating it from the salt solution (e.g.

Rutschmann J., Kobal H., loc. feeling.). All of these cleaning operations are associated with considerable losses in order to arrive at a product of the highest quality. The only known poetup in which D-lyaergic acid is not isolated from the alkaline hydrolysate as sulfate is the poetup according to the headings. U.S. Pat. 123689: from an ether-ethanolic extract of an alkaline hydrolysate, D-lysergic acid, after being transferred to an acidic medium, is purified using ion exchangers. In an unconventional manner, D-lyaergic acid is prepared by reacting crude D-lysergic sulfate in aqueous auspension with excess calcium hydroxide rather than calcium D-lyaergic acid, an aqueous calcium salt solution and alkalizing with ammonia, saturated with carbon dioxide, and separated after separation. The calcium carbonate is treated with D-lyaergic acid. This process is directed to the preparation of a practically uniform D-lysergic acid containing 2-Lysergic acid. only very small amounts of D-isolysergic acid <1 to 5%) ·

According to the invention, the crude D-lysergic acid contaminated with organic and inorganic substances obtained, for example, by liberation from the crude salt of D-lysergic acid, e.g. its sulphate, or obtained by another isolation process, is processed to D-lysergic acid such that the crude The D-lysergic acid is dissolved in a dilute ammonia solution and the solution thus obtained is passed through an alumina column, and the filtrate is treated with D-lyaergic acid, for example by concentration and separation of the crystallized acid.

The use of alumina and an aqueous system for purifying ergot alkaloids and crude D-lyaergic acid is quite original. Alumina ae acts as an ion exchanger in an aqueous medium, and is used in this amyal in inorganic analytical chemistry to make metal cations. In our case, we use the ability of alumina to capture from the solution of raw D-lysergic acid in dilute ammonia most of the dissolved colored balate compounds and fission products formed during the alkaline hydrolysis of the starting amides of D-lysergic acid or balate substances insoluble in the environment.

The colored and non-attached impurities remain in the filtrate after concentration of the purified solution and separation of the crystallized D-lysergic acid. Aluminum oxide, resp. aluminum hydroxide, is indifferent to the medium, insoluble in ammonia.

The crystalline solvent-free D-lysergic acid thus prepared is 95 to 96% (determined spectrophotometrically and photo-colorimetry) and contains 5 to 10 $ of D-iaolyaergic acid as determined from + 56.1 ° (c 0). (3, pyridine).

The presence of said amount of D-isolysergic acid is in no way detrimental to its use for partial aynthase of the above-mentioned pharmaceutical preparations.

The process using crude alumina to purify crude D-lysergic acid is clearly simpler, less expensive to operate and less time-consuming, compared to other similarly targeted processes.

The details of the process according to the invention are given in the example below.

Exemplary embodiment

The crude D-lysergic sulphate (10 g), which, according to photo-colorimetric analysis, contained 38% of D-lysergic acid, was dissolved in 30 ml of methanol containing 2.3 wt. ammonia and the solution filtered through a sintered glass frit. The captured undissolved balaetics and inorganic impurities from the starting sulfate were washed with 5 mL of methanol and the combined filtrates were evaporated to dryness in a water pump vacuum. The crude D-lysergic acid residue was dissolved in 180 ml of a 0.7% aqueous ammonia solution, and the solution was passed through a column of 25 g of alumina (Reanal) under gentle lower extraction. The column was then washed with 30 ml of an aqueous ammonia solution of the same concentration. The bulk of the filtrate, along with the column wash obtained, was evaporated on a rotary evaporator (40 ° C bath), under a vacuum pump, to a small volume (ca 20 ml) and stored in a refrigerator at 5 ° C. After crystallization was complete, D-lysergic acid was aspirated and washed with a small amount of chilled water. 3.35 g of D-lysergic acid with a content of 95.5% in a solvent-free substance were obtained. The total yield of D-lysergic acid calculated on the D-lyeergic acid content in the crude sulphate is 73% ·

Claims (1)

Process for the purification of crude D-lysergic acid contaminated with organic and inorganic substances obtained, for example, by liberation from a crude salt of D-lysergic acid, e.g. its sulphate, or obtained by another isolation process, characterized in that the crude D-lysergic acid is dissolved in dilute aqueous ammonia solution and the solution thus obtained are passed through a column of alumina, after which the filtrate is treated with D-lyeergic acid, e.g. by concentration and separation of the crystallized acid.