CS223994B2 - Method of cleaning the ergot.alcaloids - Google Patents

Description

(54, A method for purifying ergot-alkaloids

The invention relates to a process for the preparation of ergot-alkaloids of the formula I

wherein R is an isopropyl, sec-butyl or tert-butyl group, salts or mixtures thereof. According to the invention, these compounds are obtained by separating the ergot-alkaloids of the formula I from a mixture which in addition contains ergotamine alkaloids and / or ergoxin alkaloids.

The compounds of formula (I), i.e. ergocornin, alpha-ergocryptine and beta-ergocryptine, as well as mixtures formed with ergocristin (ergotoxin), are primarily used to soothe blood circulation and as a remedy for migraine headaches.

In the preparation of the compounds of the formula I, ergotamine and / or eggotoxin alkaloids are often produced in amounts of several percent. As used herein, ergotamine alkaloids are ergotamine, ergosine and their C-8-epimers, and ergotoxin alkloids are ergonine, ergoptin, ergostin and their C-8-epimers. Ergotamine alkaloids must also be separated from ergotoxin alkaloids, as according to the drug regulations the ergotoxin must not contain more than 0,5% by weight of other alkaloids and may contain a maximum of 2% by weight of total impurities.

It is an object of the present invention to provide a simple method for separating ergot-alkaloids from ergotamine and / or ergoxin alkaloids in one step.

A. Stoli and A. Hofman (Helv. Chim. Acta 26 1 570 (1943)) describe the production of alkaloid tartrates in organic solvents and demonstrate that the three ergotoxin-forming alkaloids can be separated by fractional crystallization in the form of their di-p-toluyltartrates .

A. Stoli published (Helv. Chim. Acta 28 1 283 (1945)) further findings on salts of ergotamine. He prepared ergotamine phosphate in alcohol and ergotamine sulfate in a mixture of methanol and acetic acid.

Hungarian Patent Specification No. 142095 (1951) discloses the treatment of a mixture consisting of alkaloids of formula I and their epimers of formula II

wherein R is as defined above.

Alcoholic phosphoric acid is added to a solution of a mixture of alkaloids in acetone, whereupon most of the alkaloids of the formula I precipitate in the form of phosphate, while the alkaloids of the formula II can be obtained from the mother liquor. When the mother liquor is allowed to stand, about 50% by weight of the compounds of formula II in the epimerized form as alkaloids of formula I are excreted within two weeks. When a small amount of iodine is added to the mother liquor, epimerization proceeds more rapidly, however, two weeks of reaction is also required.

Hungarian Patent Application Publication No. RI-620 discloses a method for epimerizing various ergotalkaloid epimer pairs in the presence of organic solvents and alkali metal hydrogen sulfates or ammonium hydrogen sulfate.

Hitherto known methods are suitable for the separation or epimerization of a single pair of epimers. When the starting mixture of alkaloids contains multiple pairs of epimers, the ratio of the amounts of the individual alkaloids is shifted during epimerization, first of all, the loss of alpha-ergocryptin and beta-ergocryptin is too great. It is also problematic that ergotamine and ergoxin alkaloids behave exactly as ergotoxin compounds of the formulas I and II in the media examined. This means that they cannot be separated from these during epimerization.

It has now been found that it is also possible to epimerize mixtures containing multiple pairs of epimers without shifting the proportions for the individual epimer pairs. This procedure is described in our related patent specification 223 993.

SUMMARY OF THE INVENTION The present invention provides a novel process for the preparation of ergot-alkaloids of the formula I in which R is an isopropyl, sec-butyl or tert-butyl group or salts and mixtures thereof by separating the ergot-alkaloids of the formula I from a mixture further comprising ergotamine and / or ergoxin alkaloids. The reaction mixture is treated in the presence of an organic solvent and water with phosphoric acid or tartaric acid or a mixture of dihydrogen phosphate or tartrate and an alkanoic acid, in particular acetic acid, optionally removing the solvent from the reaction mixture, adjusting the pH or concentration of the reaction mixture to 2-5. this mixture is allowed to stand until the compounds of the formula I precipitate in the form of their salts. The salts are then separated and, if appropriate, the base is liberated therefrom in a manner known per se.

The starting mixture for the process according to the invention is a mixture of ergotemin and / or ergoxin alkaloids and compounds of the formula I.

The starting alkaloid mixtures may optionally contain some organic substances which are of plant origin or which are derived from fermentation.

In the process according to the invention, the reaction medium consists of organic solvents, water and salt-forming acids. Suitable solvents are alkanols having 1 to 4 carbon atoms (e.g. methanol or ethyl alcohol) or their esters with lower saturated carboxylic acids, furthermore aliphatic ketones having 3 to 8 carbon atoms (e.g. acetone, methylisobutyl ketone), hydrocarbons (such as hexane , heptane, benzene, toluene, xylene, gasoline, petroleum ether and the like) or carbon tetrachloride. Said organic solvents may be used in admixture with acid amides or sulfoxides such as formamide, dimethylformamide or dimethylsulfoxide. The latter solvent can also be used alone.

The reaction medium in the process of the invention comprises an organic solvent and water. The amount of water is in the range of 10 to 95% by weight, preferably 50 to 80% by weight.

As the salt-forming agent, phosphoric acid or tartaric acid is used to form salts of the compounds of formula I which are very poorly soluble in the reaction medium. Both salts are equally suitable for salt formation.

Dihydrogen phosphate may also be used in place of phosphoric acid in the presence of another acid. Alkali metal dihydrogen phosphates and ammonium dihydrogen phosphate are preferred. Instead of a mixture of tartaric acid and another acid, a mixture of an alkali metal tartrate and an organic acid, preferably acetic acid, may also be used.

The starting alkaloid mixture is dissolved or suspended in the reaction medium. The solubility of the compounds of formula I and their salts in the reaction medium is less due to the addition of water. Suitably, the starting alkaloid mixture is dissolved in an organic solvent or organic solvent mixture, which solution is then mixed with a salt-forming agent, and then the solution is supersaturated for salts of the compounds of formula I. That is, except for acid amides and sulfoxides, evaporation or extraction.

The solubility of the salts of the compounds of formula I also depends on the pH of the reaction medium. When working with concentrated solutions, it is expedient to separate the salts of the compounds of formula I in a lower pH range, whereas in the case of low concentrated solutions, the separation of salts near the upper limit of said pH range is preferable.

The salts of the compounds of formula I are separated from the reaction mixture by crystallization. Optionally, the reaction mixture is partially evaporated before crystallization.

If desired, the base (optionally a base mixture) can be liberated from the salt obtained in a known manner. The base is preferably liberated in a mixture of water and chloroform by adjusting the pH to about 8.

The composition of the ergot-alkaloid base mixture is determined by chromatography (Varian 8500 LC Chromatograph, adsorbent: Liehrosorb S 1 60 5, eluent: n-hexene / chloroform / acetonitrile 7: 1.5: 1.5, flow rate 100 ml / h, wavelength of detection waves 280 nm).

The process according to the invention is explained in more detail in the following examples without being limited thereto.

Example 1

The starting material used is 10 g of a base mixture of the following composition:

% by weight (0.00798 mol) 25% by weight (0.00437 mol) 10% by weight (0.00175 mol) 4% by weight (0.000698 mol) 16% by weight ergocornin, elfa-ergocryptin, beta-ergocryptin, ergotamine and unidentified substances of plant origin.

The mixture is suspended in a mixture of 100 ml of methanol and 3.5 ml of formamide. 2.45 g (0.0163 mol) of d-tartaric acid and 100 ml of water are added with stirring. The reaction mixture was concentrated in vacuo at a maximum temperature of 30 ° C to a total volume of 30 mL and then allowed to stand at -5 ° C for 2 hours. The precipitated product is filtered off, washed twice with 10 ml of water and dried at 40 DEG C. in vacuo. 10.45 g of a mixture of ergot-alkaloid tartrates are obtained. A base mixture of the following composition is released from this salt mixture:

22% by weight

9.1% by weight 0.2% by weight ergocornine, alpha-ergocryptine, beta-ergocryptine and ergotamine.

Yield of alkaloids 94%.

Specific rotation of the base mixture: [α] D = -185 ° (c = 1, chloroform). Example 2

10 g of ergot-alkaloid mixture are used as starting mixture, the bushes were obtained by fermentation and which has the following composition: 38 % by weight (0.00674 mol) ergokorninu, 23 % (0.00402 mol) alpha-ergocryptine 12 % by weight (0.00209 mol) beta-ergocryptine, 18 % by weight (0.00312 mol) ergonin a 9 % by weight. unidentified impurities.

This mixture was dissolved in 500 mL of ethyl acetate. The solution obtained is first extracted once with 100 ml and then four times with 20 ml each of formamide: water: phosphoric acid in a ratio of 10: 87: 3 at a pH of 1.8. The aqueous phases are combined and the ethyl acetate is extracted from the aqueous phase by addition of 50 ml of carbon tetrachloride. The pH of the aqueous phase free of ethyl acetate is adjusted to 3.5 by the addition of concentrated ammonia with vigorous stirring. Phosphates of ergotoxin alkaloids immediately begin to secrete and, after standing for 10 hours at a temperature of 5 ° C, virtually their major amount is eliminated. The precipitated salt mixture is washed twice with 20 ml of water and then dried under vacuum at a maximum of 40 ° C. The mother liquor obtained during filtration is further processed. 8.9 g of a mixture of phosphates are obtained, the liberated bases having the following composition:

% by weight 26% by weight 15% by weight 1% by weight ergocornin, elfa-ergocryptine beta-ergocryptine ergonin.

Specific rotation of the base mixture: Η ρθ = -183 ⁰ (c = 1, chloroform).

The pH of the mother liquor after filtration of the phosphate mixture was adjusted to 7 with concentrated ammonia. A precipitate formed which was washed twice with 20 ml of water each time and dried in vacuo at a maximum temperature of 40 ° C. 2.28 g of a base mixture are obtained, containing predominantly ergoxin alkaloids having the following composition:

% by weight 4% by weight 2% by weight ergonin, ergocornine, alpha-ergocryptine and beta-ergocryptine.

Claims (1)

SUBJECT OF THE INVENTION A process for the purification of ergot-alkaloids of the formula I in which R is an isopropyl, sec-butyl or tert-butyl group, or a salt thereof, a mixture of compounds of the formula I or a mixture of salts thereof, wherein R is as hereinbefore defined, and the ergotamine and / or ergoxin alkaloids act in the presence of organic solvents and water with phosphoric acid or tartaric acid, or a mixture of dihydrogen phosphate or tartrate and an alkanoic acid, especially acetic acid, The pH of the optionally concentrated reaction mixture is adjusted to a range of 2 to 5, and this mixture is allowed to stand until the compounds of formula I wherein R is as defined above precipitate in the form of their salts, then the salts are separated and optionally release the bases.