HU183306B - Process for the purification of ergometrine - Google Patents

Abstract

The present invention relates to a method for purifying an ergometer or acid addition salt by preparing a base with carbon tetrachloride, wherein according to the invention, a) ergometrine or ergometric acid addition salt containing less polar alkaloid contaminants than ergometrine is used for the ergometry when the ergometric acid addition salt is used. in known manner, after liberation with or with a base, in a C 1 -C 4 alkanol and / or C 3-7 aliphatic ketone and / or C 4 -C 7 aliphatic carboxylic acid ester to form an ergometrine carbon tetrachloride base by addition of carbon tetrachloride and finally ergometrin from the ergometric carbon tetrachloride base. in the form of an acid addition salt, as is known in the art, b) an ergometric or ergometer acid containing more polar alkaloid impurities than ergometrics in the case of purification of the salt, the crude ergometrine, when used with the ergometric acid addition salt, is dissolved in a known manner, with or without a base, in a mixture of C 1 -C 4 alkanol and / or C 3-7 aliphatic ketone and water and / or formamide; an ergometric carbon tetrachloride base is then added to the carbon tetrachloride, and ergometrin is recovered from the ergometric carbon tetrachloride base, if desired in the form of an acid addition salt, in a manner known per se. The advantage of the process is that it can be used to produce ergometers that are virtually free of escaping impurities from good ergonomics with less polar and more polar impurities than ergometers. -1-

Description

The present invention relates to a process for the purification of ergometrine or its acid addition salts, in particular to the removal of alkaloid impurities.

There are several known methods for producing ergometrine. Thus, U.S. Patent No. 150,631 describes the preparation of ergometrine by fermentation. The production of mother rust is described in Hungarian Patent Nos. 125,398 and 155,942. The most up-to-date process based on fermentation broth processing is disclosed in Hungarian Patent No. 164,658. This patent does not address product quality issues because the process was designed to produce the product as described in Hungarian Patent Specification No. 115 025, via an ergometrine-chloroform base, in accordance with the current pharmaceutical specification.

However, recent editions of some pharmacies contain stricter quality standards for ergometrine. For example, IX. The Japanese Pharmacopoeia provides an upper limit of 0.1% for the total amount of co-alkaloids. Ergometrine of this purity was only obtained by recrystallization several times at extremely high losses of 50-70%.

The crude ergometrine or its acid addition salt formed during large-scale production, depending on the various production methods, contains from 1% to 7% impurity, which consists in part of more polar components than ergometrine such as lysergic acid amide and partly less polar components such as ergomethrinine and peptide alkaloids. Removal of less polar components than ergometrine can be accomplished through ergometrine-chloroform base formation at relatively low losses. However, impurities that are more polar than ergometrine can only be removed successfully in solvent systems from which ergometrine chloroform base can only be obtained in poor yield.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a purification method that can be used to purify ergometrine in good yield and to remove accompanying impurities even when ergometrine also contains polar alkaloid impurities.

In our experiments, it was surprisingly found that ergomethrin, although practically insoluble in carbon tetrachloride, forms an ergometrine carbon tetrachloride base which is significantly less soluble than ergomethrin chloroform base. The ergometrine carbon tetrachloride base crystallizes from a variety of solvents or solvent systems in the presence of a sufficient amount of carbon tetrachloride. Elemental analysis, derivatographic and gas chromatography tests confirm the 1: 1 molecular ratio.

The formation of the ergometrine carbon tetrachloride base provides a good opportunity to purify ergometrine, since due to its poor solubility, it can be recrystallized in good yields even from relatively dilute solutions, with the extraordinary advantage that the purification effect of crystallization substantially outweighs the polar component. crystallization of ergometrine-chloroform base.

According to the invention, the process is carried out by:

(a) in the case of purification of ergometrine or ergometric acid addition salt containing only less polar alkaloid impurities than ergometrine, using ergometrine in the presence of a known C 1 -C 4 or aliphatic C in an ketone and / or a C4-C7 aliphatic carboxylic acid ester, by adding carbon tetrachloride to form an ergometric carbon tetrachloride base, and finally ergometrine from the base ergometrine carbon tetrachloride, optionally in the form of an acid addition salt,

(b) in the case of purification of ergometrine or ergometric acid addition salt containing alkaloid impurities more polar than ergometrine, crude ergometrine, after the simultaneous or conventional release of ergometrine with a base and / or alkanol containing 1 to 4 carbon atoms; It is dissolved in a mixture of a C3-C7 aliphatic ketone and water and / or for 15 amide and then added with carbon tetrachloride to form an ergometrine carbon tetrachloride base, followed by recovery of ergomethrin carbon tetrachloride base, optionally in the form of an acid addition salt.

Preferred alkanols in the process of the invention are methanol or ethanol, aliphatic ketones are preferably acetone or methylethylketone and aliphatic carboxylic acid esters are preferably ethyl acetate.

When an ergometric acid addition salt is used as a starting material, it is known to liberate ergometrine with a base in a known manner. Both organic and inorganic bases can be used for this purpose. When selecting the appropriate base, the primary consideration is not to damage the ergometrine (epimerization, hydrolysis), or to form an insoluble compound with the acid component of the acid addition salt in the solvent or solvent system used, such as trialkylamines or especially triethylamine.

An advantage of the process according to the invention is that it provides ergometrine practically free of contaminants in good yield, both from ergometrine containing only less polar impurities than ergometrine and from impurities more polar than ergometrine or from its acid addition salt.

The following examples illustrate the process of the invention.

Example 1 g of crude ergometrine maleate, prepared as described in Hungarian Patent No. 164,658, having an ergometrine content of 66% and 3% more polar and less polar than alkali50 alkaline impurities, is dissolved in 200 ml of 7: 1: 1: 1 of acetone-formamide-water-triethylamine (200 ml) and carbon tetrachloride (200 ml) was added with stirring. The excellent ergometrine carbon tetrachloride base from the two-phase separation system was allowed to crystallize for one hour at room temperature, then filtered, twice with 20 ml of a 7: 1: 1: 9 mixture of acetone-formamide-carbon tetrachloride and twice with 20 ml of 1: 1 acetone. wash with carbon tetrachloride and vacuum to max. Dry at 40 ° C. This gives 17.7 g of ergometrine carbon 60 tetrachloride base with an ergometric content of 69% and a foreign alkaloid content of 0.15%.

The resulting ergometrine carbon tetrachloride base was then dissolved in ethanol (530 mL), clarified with activated carbon (1.77 g), and filtered. At the same time, 5.9 g of maleic acid is dissolved in 25 ml of ethanol and the

Pour 183,306 into a solution of ergometrine carbon tetrachloride base. Ergometrine maleate crystallizes from the system very rapidly. After standing for one hour, the crystals are filtered off, washed twice with 20 ml of acetone and vacuum dried to max. Dry at 60 ° C to constant weight. 15.8 g of ergometrine maleate were obtained, having an ergometric content of 74% and a foreign alkaloid content of IX. less than 0.1% according to Japanese Pharmacopoeia. Yield: 88.5%.

EXAMPLE 2 Crude ergometrine maleate containing 68% and more than 1% ergometrine in polar and less polar alkaline impurities than in ergometrine was dissolved in 100 ml of a 2: 7: 1 mixture of acetone-formamide-triethylamine and 100 ml of carbon was added with constant stirring. After 1 hour, the ergometrine carbon tetrachloride base which crystallized from the two-phase separation system was filtered off, washed twice with 20 ml of a 2: 7: 9 mixture of acetone-formamide-carbon tetrachloride and twice with 20 ml of distilled water. Dry at 40 ° C. This gives 18 g of ergometrine carbon tetrachloride base with an ergometric content of 70% and a foreign alkaloid content of 0.1%.

This ergometrine carbon tetrachloride base is then

Converted to ergometrine malate as described in Example 1. This gives 16.1 g of ergometrine maleate having an ergometric content of 74% and a foreign alkaloid content of less than 0.1%. Yield: 87.5%.

Example 3 g of crude ergometrine maleate having an ergometric content of more than 65% and 0.5% ergometrine and less polar alkaline impurity than 6.5% was dissolved in 100 ml of methanol / triethylamine 50: 6 and 100 ml of carbon tetrachloride was added with stirring. The ergometrine carbon tetrachloride base which crystallized out of the solution was filtered off after 1 hour, washed twice with 20 ml of acetone and in vacuo to a max. Dry at 40 ° C. This gives 18 g of ergometrine carbon tetrachloride base with an ergometric content of 71% and a foreign alkaloid content of 0.2%.

This ergometrine carbon tetrachloride base is then

Converted to ergometrine malate as described in Example 1. This gives 15.7 g of ergometrine maleate having an ergometric content of 74.5% and a foreign alkaloid content of 0.15%. Yield: 89.7%.

Example 4 g of crude ergometrine maleate having an ergometric content of more polar than 65% and 0.5% ergometrine and less polar than 6.5% ergometrine was dissolved in 200 ml of acetone-water-triethylamine (30: 10: 6) and added with stirring. ml of carbon tetrachloride. The ergometrine carbon tetrachloride base which crystallized from the two-phase separation system was filtered off after 1 hour, washed twice with 20 ml of acetone, and in vacuo to max. Dry at 40 ° C. This gives 17 g of ergometrine carbon tetrachloride base, which has an ergometric content of 69% and a foreign alkaloid content of about 0.1%.

This ergometrine carbon tetrachloride base is converted to ergometrine maleate as described in Example 1. This gives 15.5 g of ergometrine maleate having an ergometric content of 75% and a foreign alkaloid content of less than 0.1%. Yield: 84%.

EXAMPLE 5 Ergometrine base containing an ergometric content of more polar than 96% and 0.2% ergometrine and less polar than 1% ergometrine was dissolved in 200 ml of acetone-water (3: 1) and 200 ml of carbon tetrachloride was added with stirring. The ergometrine carbon tetrachloride base which crystallized out of solution was filtered after standing for 1 hour, washed twice with 20 ml of a 4: 1 mixture of acetone-carbon tetrachloride and in vacuo to a max. After drying at 40 ° C, 29.1 g of ergometrine carbon tetrachloride base is obtained, having an ergometric content of 68% and a foreign alkaloid content of 0.1%.

The resulting ergometrine carbon tetrachloride base is then dissolved in 870 ml of ethanol, clarified with 2.91 g of activated carbon and filtered. Simultaneously, 9.7 g of maleic acid is dissolved in 60 ml of ethanol and this solution is added to a solution of ergometrine carbon tetrachloride base. The solution was allowed to crystallize for 1 hour, and the crystals were filtered, washed with ethanol (2 x 30 mL) and vacuum at max. Drying at 60 ° C to constant weight gives 25.6 g of ergometrine maleate having an ergometric content of 73.5% and a foreign alkaloid content of less than 0.1%.

Example 6

The process was also carried out by comparison with chloroform. The procedure was the same as in Example 1, but with the same amount of chloroform instead of carbon tetrachloride. 12.9 g of ergometrine-chloroform base were obtained with an ergometric content of 72% and a foreign alkaloid content of 0.15%.

Ergometrine maleate was also prepared as described in Example 1, having an ergometric content of 73% and a foreign alkaloid content of 0.1%; Yield: 11.7 g.

Claims (4)

A process for the purification of ergometrine or an acid addition salt thereof by preparation of a base with carbon tetrachloride, characterized in that: (a) in the case of purification of ergometrine or ergometric acid addition salt containing only less polar alkaloid impurities than ergometrine, the crude ergometrine, after the ergometric acid addition salt is known, after or concurrently with dissolved in an aliphatic ketone and / or a C4-C7 aliphatic carboxylic acid ester, the carbon tetrachloride is added to form an ergometrine carbon tetrachloride base, and finally the ergomethrin carbon tetrachloride base is recovered in a known manner, optionally in the form of an acid addition salt, 183,306 (b) in the case of purification of ergometrine or ergometric acid addition salt containing alkaloid impurities more polar than ergometrine, using ergometrine after the release of ergomethrin in a known manner, with a base or 5 It is dissolved in a mixture of a C 7 aliphatic ketone and water and / or formamide, and carbon tetrachloride is added to form an ergometrine carbon tetrachloride base, and the ergomethrin carbon tetrachloride base is then recovered, if desired in the form of an acid addition salt, in a known manner. 2. A process according to claim 1 wherein the alkanol is methanol or ethanol. 3. The process of claim 1 wherein the aliphatic ketone is acetone or methyl ethyl ketone. 4. A process according to claim 1 wherein the aliphatic carboxylic acid ester is ethyl acetate.