CS219418B1 - Method of isolating ergocryptines with the desired ratio of a and β components - Google Patents

Abstract

A method for isolating ergocryptines with a desired ratio of α and β components of 1:1 to 2.5:1, characterized in that the crude mixture of alkaloids, after purification by crystallization and adjustment of the ratio of ergotoxine components to the desired ratio, usually ergoconnine: ergocryptine: ergocristine 1:1:1, is chromatographed on a silica gel column using an elution mixture of chlorinated hydrocarbons, methane or ethane in a ratio of 1:2 to 2:1 with benzene or diethyl ether, or is processed to a pure mixture of? and β ergocryptines, which is crystallized from methanol or ethanol, ethyl acetate, dioxane, benzene, a mixture of methanol or ethanol - water 8:2, most preferably from a mixture of ethyl acetate, methanol, water 10:1:2, or the purified mixture of α and β ergocryptines after hydrogenation of the 9,10-lysergic acid bond is crystallized from dioxane, or ethyl acetate, butyl acetate or aqueous aliphatic alcohol C1 to C3 (8:2).

Description

The invention relates. method of preparation of ct and β ergocryptine in the desired ratio, isolation from the raw mixture of ergocribline ergotoxin group alkaloids, ergocornine, aa β ergocryptine and their mixtures accompanied by a limited amount of ergotamine alkaloids (ergotamine, aa β ergosin) in form of 1-evo , rotating enantiomers and another group of peptide alkaloids of a non-cyclol structure (e.g. N- [N- (d-Lysergyl) -L-valyl] -L-phenyl-alanyl-D-proline lactam, [1- (d-Lysergyl) -L-valyl] -L-leucyl-D-pr L-lactam and Ν- [N- (d-Lysergyl) -L-valyl] -L-valyl-D-proline lactam], their cleavage products and ballasts.

The alkaloid isolation procedure described below allows the desired ratio of the individual ergotoxin alkaloids to be adjusted for the α and β ergocryptine ratio, reliably separates the other accompanying alkaloids and solves the removal of the lactam alkaloids.

Recently, dihydroergotoxin and its salts have been introduced into therapy in a precisely defined composition, practically corresponding to the proportion of dihydroergocristin, dihydroergdkornitine and dihydroergocryptine 33.3% by weight. + 10%, with optimum pharmacological effects being obtained for the substance and the dosage forms prepared therein, in which the dihydroergocryptine fraction comprises η-dihydroergocryptine and β-dihydroergocryptine in a ratio of 1.5: 1 to 2.5: 1 .

The first mention of an alkaloid with very close properties of ergocryptine with the working designation EK 115 was published by Aries and Semonski Cs. Pharmacy 11 (1962). In 1968, Schlientz et al. Pharm. Acta Helvetiae 43,497 [1968] have described the isolation, physical, chemical and pharmacological properties of β -ergocryptine. The crude alkaloid mixture obtained by extraction of Swiss ergot, after separation of the major part of ergocornin containing the predominance of ergocryptine, was converted to the di-p-toluyl-D-tartaric acid addition salt and repeatedly crystallized from aqueous methanol. Concentrated 2-ergocryptine in the mother liquors after purification by silica gel column chromatography was recrystallized from benzene. The fractional crystallization of the mixture carried out in the manner described is labor intensive (preparation of optically active substituted tartaric acid necessary) and labor intensive, and is more useful for laboratory purposes than industrial production.

Partial synthesis of β-ergocryptiin was obtained by Stadler et al., Helv. Chem., Acta 52, 1563 (1969). The reaction mixture was directly crystallized from methanol. Another portion of the mother liquors was isolated after column chromatography on alumina and crystallized from methylene chloride-methanol.

The physical and chemical properties of β-ergocryptin are very close to those of other ergotoxin alkaloids, and in particular of β-ergocryptin itself. However, it is known that in the technology used to purify ergotoxin alkaloids to date, partial separation of β-ergocryptine, along with the accompanying alkaloids, fission products and ballasts into the mother liquors, still occurs. Therefore, a method was first sought to remove the accompanying alkaloids so that the alkaloids including the β-ergocryptine present could be effectively used.

After the removal of the accompanying alkaloids and ballasts, the individual ergotoxin alkaloids were separated and then the methods for separating the α and β-ergocryptine were prepared in order to prepare a base or dihydroergotoxinium salt with the desired ratio of α and β-ergocryptin with the respective proportions. ergotoxin alkaloids.

The present inventors have found that partial enrichment of the β-ergocryptine mixture can be achieved by silica gel column chromatography using a mixture of chlorinated hydrocarbons of methane or ethane with an aromatic hydrocarbon or diethyl ether as eluent.

In the first fractions, mainly the dextrorotatory enantiomers are concentrated, elution is continued with β-ergocryptine, n -ergocryptine, ergocornine and ergocristin. The β-ergocryptine-enriched material obtained can advantageously be used to correct ergotoxin to the desired component ratio.

The newly developed crystallization processes in both the non-hydrogenated and hydrogenated ergot alkaloids exhibit a very significant separation effect of .alpha.-3-ergocryptine. Some degree of separation of β-ergocryptine from N -ergocryptine can be achieved by crystallization from methanol, ethanol, benzene, ethyl acetate, dioxane of their mixtures and mixtures with water. Crystallization from aqueous methanol (90%) and a mixture of ethyl acetate, methanol and water seems to be particularly preferred.

and α-3-dihydroergocryptine containing limited amounts of other ergotoxin alkaloids and other accompanying alkaloids can also be separated by crystallization processes using dioxane, methanol or ethanol with water as the crystallization medium; particularly good results can be obtained by crystallization from ethyl acetate. According to the invention, it is possible to process a crude alkaloid composition containing besides α-β-ergocryptine and other ergotoxin components up to 15% by weight. ergotamine alkaloids, 15% lactam structure alkaloids, 5% ergoxin alkaloids in both left and right-handed forms, and up to 30% non-alkaloid ballasts. The aforementioned crystallizations can be carried out after isolation of the pure mixture of .alpha.,. Beta.-ergocryptine devoid of ballasts and other accompanying alkaloids.

The crude alkaloid mixture is converted to a phosphoric acid addition salt, and the liberated base is crystallized from methanol after silica gel chromatography to separate the ergocornin from the other ergotoxin alkaloids. In the mother liquors / concentrated α and β-ergocryptine after recrystallization from benzene, the purity required for the above crystallizations is desired to divide α and β-ergocryptin.

This pure mixture of the two isomers of ergocryptine can be separated after hydrogenation of the Δ 9.10 bond by the above crystallizations.

The described procedures can achieve a shift of the α: β-ergocryptine ratio up to 20: 1 in the crystal and up to 1: 1 in the mother liquors. The concentrates thus obtained can be used, after homogenization with bases of ergocristin and ergocornin, for the preparation of therapeutically effective salts of ergotoximium with a given ratio of ergotoxin components as well as the ratio of β-ergocryptin. The α and β-ergocryptine concentrate can also be used for the preparation of partially-synthetic derivatives of these alkaloids.

The process of the invention is described in more detail in the following examples, but the examples do not limit the scope of the invention.

Example 1 g of a 4: 1 ratio of a: β ergocryptine crude alkaloid mixture after conversion to hydrophosphate and re-release of the base is crystallized from ethyl acetate, the ergotoxin components (ergocristin, ergocornin, ergocryptin) being adjusted to the desired ratio by addition of individual alkaloid bases. The crystal obtained from ethyl acetate is chromatographed on a silica gel column (30 times based on the weight of the initial run in chloroform-diethyl ether 1: 1). Fractions are combined based on thin-layer chromatography analyzes.

In this experiment, 2.9 g of chloroform evaporator 18 to ergotoxin with a ratio of?:?-Ergocryptine were obtained in the first 250 ml of eluate.

2.5: 1 and from the remaining fractions, 3.7 grams of an 8: 1 α: β ergocryptine residue were obtained. After evaporation of the 9, 10 bond, the obtained residue was used to prepare dihydroergotoxinium methanesulfonate.

Example 2 g of a crude alkaloid mixture (total alkaloid content 83% / o, ergocornin: ergocryptin 3: 2, and: β-ergocryptin 3.8: 1, ergotamine 5%, lactam alkaloids 8%) is converted into hydrophosphate and after base release the chloroform residue is chromatographed on a silica gel column (3 times based on the weight of the starting run in chloroform - benzene 4: 1).

A total of 1200 ml of the above mixture was used for elution. The obtained chloroform residue (16 gj deprived of ergotammon alkaloids and partially non-cyclol alkaloids is crystallized from 50 ml of methanol. Concentrated β-ergocryptine (6 gj) crystallizes from ethyl acetate - methanol - water (10: 1) after crystallization from benzene. 2.3 g of a crystal containing about 90% ergocryptine with an a: β ratio of 25: 1 and 1.9 g of mother liquors containing 60% ergocryptine with an a: β ratio of 1: 1 and 40% ergocornin are obtained.

EXAMPLE 3 g of ergocryptine benzene base obtained in the same manner as in Example 2 was crystallized from 70 ml of dioxane after hydrogenation of the Δ9.10 bond by catalytic hydrogenation on Raney nickel. 4.1 g crystal contains 87% ergocryptine with a: β ratio of 35: 1 component in mother liquors (5.6 grams) the α: β-ergocryptine ratio is 1.5: 1, 86% ergocryptine and 34% ergocornine.

Claims (1)

Method of isolating ergocryptins with the desired ratio of α (3 components 1: 1 to 2.5: 1) characterized in that the crude alkaloid mixture after purification by crystallization and adjustment of the ratio of ergotoxin components to the desired ratio, usually ergocornin: ergocryptin: ergocristin 1: 1: 1, chromatographed on a silica gel column using a 1: 2 to 2: 1 mixture of chlorinated hydrocarbons of methane or ethane with benzene or diethyl ether, or worked up to a pure mixture YNALEZ and α and β-ergocryptines which crystallize from methanol or ethanol, ethyl acetate, dioxane, benzene, methanol or ethanol: water 8: 2, most preferably from ethyl acetate, methanol, water 10: 1: 2, optionally with a pure mixture - α and β-ergocryptines, after hydrogenation of the 9,10-lysergic acid bond, crystallize from dioxane or ethyl acetate, butyl acetate or an aqueous aliphatic alcohol C ₁ to C ₃ (8: 2).