CS264881B1 - Method of isolating ergotamine sulfate - Google Patents

Abstract

Ergotamine sulfate is an important intermediate in the production of therapeutically used ergotamine tartrates and dihydroergotamine methanesulfonate. According to the previously known procedures, ergot was extracted with a suitable solvent and crude ergotamine was prepared from the obtained crude extract, which was converted into ergotamine sulfate in a further step. The procedure allows ergotamine sulfate to be prepared directly from crude ether-ethanol or ether-methanol extract of ergot by mixing the crude extract with an aqueous solution of sulfuric acid and the crystalline ergotamine sulfate is precipitated in the aqueous phase, from which it is isolated by filtration.

Description

The invention relates to a process for the isolation of ergotamine sulfate.

Ergotamine sulphate is a key intermediate for the preparation of therapeutically important ergot alkaloids, ergotaminia mesylate dihydroergotaminium tartrate, which are prepared from it, e.g. No. 219,420.

The prior art processes for preparing ergotamine sulphate from ergot are essentially two-stage.

In the first stage, the ergot is extracted and the extract is converted to the crude ergotamine and in the second stage the crude ergotamine is converted to ergotamine sulphate.

A number of Czechoslovak and foreign inventions deal with the ergot extraction; čs. inventions 85,995, 113,109, 208,351; tajné čs. inventions 1,228, 10,942, 10,944, 10,945; German Patent 47 315; NSR Patents 697,760, 1,125,940, 1,240,871; Polish patents 40,884, 47,405,

719; GDR patents 10,059, 28,275, 91,665; USSR Patent 177,039; Hungarian Patent 152,934; French patent 2,460,955 and US patent 2,120,635.

The different procedures differ both in the type of extraction agent and in the method of processing the extract into a crude alkaloid pool. Pure organic solvents - ether, toluene, acetone, ethyl acetate, dichloromethane, trichlorethylene and chloroform; organic solvent-ether mixtures with aliphatic alcohols; solutions of organic carboxylic acids in organic solvents - tartaric acid in methanol, acetic acid in trichlorethylene or solutions of organic carboxylic acids in a mixture of water with an organic solvent - oxalic acid in aqueous ethanol.

Each extraction agent has its advantages and disadvantages. In addition to alkaloids, nonpolar solvents extract fats, which have an ergot content of up to 30%, but extract few polar ballasts. In polar solvents, on the contrary, they extract little fat but a lot of polar ballasts. This corresponds to the further processing of the crude extract. In the case of water-immiscible nonpolar organic solvents, most of the time, extraction into an aqueous solution of the appropriate acid is followed - either directly or after concentration and precipitation of the crude alkaloid aggregate; sorption to various materials - alumina, silica gel - is often used.

In the case of water-miscible polar solvents, dilution with water is often followed by inflating, alkalizing and extraction into an organic solvent. The crude sum is isolated by precipitation with a suitable solvent (petroleum ether), or the alkaloids are returned to an aqueous acid solution and the crude sum of alkaloids is precipitated.

Adsorption of alkaloids from the aqueous phase to ion exchangers or other sorbents such as bentonite is also often used. The economic factors - the price of raw materials, labor intensity, complexity and availability of production equipment, as well as the availability of raw materials in individual countries at a certain time - often determine the benefits of individual procedures.

The ergotamine sulphate is prepared from crude ergotamine in the next step. The aim of the operation is to convert ergotamine, which always occurs in crude ergotamine to a lesser or greater extent due to epimerization during the isolation process to ergotamine and to remove unwanted minor alkaloids and ballasts into the mother liquors. Essentially, the method of Stoll (Helv. Chim. Acta 28, 1283, (1945)), which has been modified several times (secret US Patent No. 343; Acta Pol. Pharm. XXII, 237 (1965)) is essentially used.

The drawbacks of the known processes are eliminated by the process according to the invention, which consists in mixing the crude extract obtained by battery extraction of ergotamine ergot with a mixture of ether with 5 to 12% by volume of methanol or ethanol with a maximum of one quarter by volume of aqueous sulfuric acid solution. 1 to 1.0%, whereby crystalline ergotamine sulphate precipitates in the aqueous phase which is isolated by filtration.

The process according to the invention makes it possible to obtain ergotamine sulphate directly from the crude ergot extract and does not require the isolation of the crude total alkaloid in the solid state, as required by the known processes. The crude ether-ethanol or ether-methanol extract is obtained by extracting a non-defatted ergot, e.g. No. 85,995, which protects the use of an ether mixture with a maximum of 25% by volume of a lower aliphatic alcohol. The condition for isolating ergotamine sulphate from the crude ether-ethanol or ether-methanol extract according to the process of the invention is an alcohol concentration of 5 to 12% by volume. In such a case, the alkaloid concentration in the extract is 1 to 4 g / l. Upon addition of the aqueous sulfuric acid solution to the crude extract thus prepared, crystalline ergotamine sulphate is separated in the aqueous phase or at the interface. This surprising effect is achieved:

1. high alkaloid content in the crude extract

2. low solubility of ergotamine sulphate in both ether and water

3. appropriate content of ethanol or methanol in the extract

4. an appropriate ratio of the volume of the crude extract to the aqueous sulfuric acid solution

The yield of ergotamine sulphate obtained is 60 to 85% of all alkaloids contained in the crude extract and depends on the alkaloid content of the extract (and hence the ergot) and the alkaloid purity of the crude extract. The accompanying alkaloids, including ergotamine, remain in the mother liquors, especially in the aqueous phase. They can be obtained by known methods and used, for example, for preparing lysergic acid.

The crystalline ergotamine sulphate obtained by the process of the invention is very pure, as evidenced by the quality and yield of the aqueous acetone base obtained therefrom. By way of illustration, the same parameters of the aqueous acetone base obtained from ergotamine sulphate produced by the present process and the aqueous acetone base obtained from ergotamine sulphate produced by the process of the invention.

Both ergotamine sulphates were obtained from the same ergot.

process according to the invention yield of aqueous acetone base 78% 81%

content ergostin 0.7 % wt. 0.6 % wt content ergocristin 0.1 % wt. 0.1 % wt content Of 8-hydroxyergotamine 0.3 % wt. 0.2 % wt content ergotaminin 0.5 % wt. 0.5 % wt

The following example illustrates the process according to the invention.

Example kg of ergot containing 0.60 i. alkaloids, of which 90 wt. % of ergotamine, was ground and moistened with 2 1 5 wt. aqueous sodium carbonate solution. After 4 h, the ergot was divided into 10 parts and extracted by battery procedure with a 9: 1 mixture of ether and ethanol. 30 L of crude extract was obtained. The crude extract was mixed with 3 L of 0.5 wt. aqueous sulfuric acid solution. After stirring for 5 minutes, the phases were separated. The crystalline ergotamine sulfate precipitated in the aqueous phase was filtered off and washed with ether. After drying, 48 g of ergotamine sulfate with a total content of 79.3% ergotamine were obtained.

Claims (1)

SUBJECT OF THE INVENTION Process for the isolation of ergotamine sulphate from the crude extract obtained by battery extraction of ergotamine ergot with a mixture of 5 to 12% by volume of methanol or ethanol, characterized in that the raw extract is mixed with not more than one quarter by volume of 0.1 to 1 aqueous sulfuric acid, 0% by weight, whereby crystalline ergotamine sulphate precipitates in the aqueous phase which is isolated by filtration.