CS219419B1 - A method for purifying alkaloids of an ergotoxin group from lactam alkaloids - Google Patents

Abstract

A method for purifying alkaloids of the ergotoxine group from lactam alkaloids, consisting in converting the present lactam alkaloids to lysergylvalinamide or lysergylvaline by mixing an ethyl acetate, acetone or ether-acetone solution of a mixture of alkaloids with alkali, preferably with ammonium or calcium hydroxide, the alkaloids isolated from the reaction mixture by extraction into ethyl acetate, ether, chloroform, or precipitation by changing the pH to 7.5 to 8.5, are chromatographed on a silica gel column using an eluent of a mixture of chlorinated hydrocarbons methane or ethane with an aromatic hydrocarbon or ether in a ratio of 1:1 to 2:1, in which case the destruction products of lactam alkaloids are removed by crystallization from ethyl acetate or benzene or by repeated extraction between the aqueous and organic phases, e.g. chloroform - water.

Description

The invention relates to a process for the purification of ergotoxin group alkaloids, ergocristin, ergocornine, and β ergocryptine and mixtures thereof, further accompanied by ergotamine and ergotoxin alkaloids from lactam alkaloids such as

N- [N (d-Lysergyl) -L-valyl-] -L-phenylanynyl-D-proline lactam,

N- [N (d-Lysergyl) -L-valyl-] -L-valyl-D-proline lactam,

N- [N (d-Lysergyl) -L-valyl-] -L-leucyl-D-proline lactam.

Of the three mentioned non-cyclic alkaloids, only the first one has been described in the literature. Stíitz et al., Experientia 29, 936 (1973) described its isolation from ergot including its basic properties, and other physical and chemical properties, destructive products and derivatives described by Černý et al., Collection 41, 3415 [1976] for the other two alkaloids were only the assumption of formation in the blind branch of ergot alkaloid biosynthesis, Fl-oss et al.

The process allows removal of these alkaloids by converting them to the more polar derivatives of lysergylvalinamide or lysergylvaline, which are readily separated by silica gel column chromatography, shaking between the organic and aqueous phases, or crystallization.

Isolation of valinamide from natural material by preparative paper chromatography has been described by Bankovskaya et al., Chim. prirod sojedin. 9 _? 134 (1973).

The invention is of particular importance for the purification of materials derived from mother liquors resulting from crystallization used in the processing of crude summaries of ergotoxin alkaloids into therapeutically useful forms. The technology is also applicable in the direct branch of the ergotoxin group alkaloid processing.

The obtained ergotoxin alkaloids after further purification or catalytic hydrogenation of the bond Δ 9.10 and conversion to salts have a wide therapeutic application and are a very valuable material for the manufacture of medicaments. The elaborated procedure represents significant economic benefits. In attempts to separate lactam alkaloids, we proceeded from the knowledge of their chemical properties. The action of alkali cleaves the peptide bond between valine and the diketopiperazine moiety to form lysergylvaline, and in the case of ammonia, lysergylvalinamide is formed. The higher polarity of the two substances allows their easy separation from the alkaloids of the ergotoxin group.

During the processing of crude summaries of the ergotoxin group alkaloids, the lactam alkaloids are separated and concentrated in the mother liquors. Heretofore, the impure mixtures of alkaloid derivatives of the ergotoxin group have been unprocessable since no prior art processes have been able to be processed in good yield to produce the desired product.

The crude alkaloid mixture containing up to 30% of the lactam structure alkaloids is reacted with alkali at a pH greater than 11 (e.g., ammonium or calcium hydroxide) after dissolution in acetone, ethyl acetate or ether-acetone. After completion of the reaction (0.5 to 4 hours), the alkaloids from the reaction mixture are isolated by extraction into an organic solvent or precipitated by pH adjustment. The resulting alkaloid mixture containing, apart from the ergotoxin group alkaloids, the destructive products of lactam alkaloids, such as lysergylvalinamide, lysergylvaline, and optionally lysergic acid, is subjected to silica gel column chromatography to remove them. The thus purified alkaloid mixture is useful for the preparation of all therapeutic forms of ergot alkaloids.

Example 1 g of homogenization of mother liquors from ergocristine treatment are dissolved in 100 ml of acetone, 10 ml of 26% ammonium hydroxide are added to the homogeneous solution and the reaction mixture is allowed to stand at 20 DEG C. for 0.5 hours.

After completion of the reaction, the solution is added dropwise to 2 l of 0.8% methanesulfonic acid and the pH is adjusted to 4 with ammonium hydroxide, after the ballasts have been filtered off, the pH is adjusted to 7.5 and the precipitated alkaloids are filtered off. After drying, the alkaloid precipitate is converted into hydrophosphate (e.g., by heating the ethanol solution under reflux with phosphoric acid). After liberation of the base, 5.6 g of a residue is obtained which is chromatographed on a silica gel (15) g column using a 1: 1 mixture of chloroform and ether. 0.5% of accompanying alkaloids.

Example 2

100 g bases from mother liquors from the processing of the crude ergotoxin alkaloid sum to ergocristin {total alkaloid content 80%, ergocristin: ergocryptin 7:

(3, lactam alkaloids 23%, ergotamine and ergoxin 5% alkaloids) are dissolved in 300 ml of ethyl acetate and stirred with 50 ml of 26% ammonium hydroxide for 2 hours. After completion of the reaction, 100 ml of water were added to the reaction mixture, and the layers were separated. The aqueous phase is repeatedly extracted with ethyl acetate, the combined organic phases are concentrated to a residue after drying. The destruction products of the lactam alkaloids and ergotamine alkaloids are removed by shaking between chloroform and 0.5% tartaric acid. 55 g of a chloroform residue are obtained, which is further purified by crystallization from ethyl acetate and benzene.

Example 3 g of ergotoxin alkaloid bases containing 20% lactam alkaloids are dissolved in a mixture of 200 ml of acetone and 600 ml of ether, 600 ml of saturated calcium hydroxide solution are added to the homogeneous solution and stirred for 2 hours. After the prescribed time, the phases were separated and the aqueous phase was extracted with ether. The combined organic extracts after concentration to a residue are further processed by one of the methods, see Example 1

Claims (1)

Method for purifying ergotoxin group alkaloids from lactam alkaloids, characterized in that the present lactam alkaloids are converted to lysergylvalinamide or lysergylvaline by stirring an ethyl acetate, acetone or ether-acetone solution of an alkaloid / alkali mixture, preferably with ammonium or calcium hydroxide, isolated from the reaction mixture to ethyl acetate, ether, chloroform of the invention or precipitation by changing the pH of 7.5-8.5, are chromatographed on a silica gel column using a chlorinated hydrocarbon mixture of methane or ethane with an aromatic hydrocarbon or ether in a ratio of 1: 1 to 2: 1, optionally it is freed from the destructive products of the lactam alkaloids by crystallization from ethyl acetate or benzene, or by repeated extraction between the aqueous and organic phases, for example chloroform-water.