CS223993B2 - Method of making the ergot-alcaloid - Google Patents

Abstract

Rye ergot alkaloids (I) (where R is isopropyl, sec. or isobutyl; including salts and mixts. are prepd. (A) of epimerisation of corresp. C-8-epimers of formula (II) in presence of acid and organic solvents; (B) by sepn. of ergot alkaloids (I), and opt. (II), from mixt. contg. in addn. alkaloids of ergotamine gp. and/or ergoxine gp. and opt. epimerising (II). In the process, (a) in the epimerisation of (II), opt. contg. (I), and in the epimerisation and sepn. of mixt. contg. (I) and (II) and also ergotamine and/or ergoxine gp. alkaloids the mixt. of alkaloids is treated in presence of water and organic solvents, (a1) by phosphoric acid or mixt. of acid phosphate or tartrate or tartaric acid and another acid, followed by removal of solvent and leaving opt. concd. reaction mixt. at pH 1.8-4 and sepg. (I), pptd. as its salts and conversion to base; or (a2) by treating in phosphoric acid or tartaric acid, eliminating solvent, adjusting pH to 1.8-3.5 and pptg. (I) as salt and opt. liberating free base, or (a21) the first mother liquor is obtd. by sepn. of the salts which is adjusted to pH 5.5-10, (5.5-7), and pptd. (II), opt. contg. (I), ergotamine and/or ergoxine cpds., are isolated and treated by variant (a1) or (a22) pH of first mother liquors obtd. by sepn. of salts is adjusted to pH 1.9-4.0, esp. 2.1-4.0 to ppte. ther ergoxine gp.; then pH of 2nd mother liquors is adjusted to 2.5-5.5 (3.5-5.5), and pptd. ergotamine alkaloids are removed, third mother liquors contg. mostly alkaloids (II) may then be treated as in (a1). (b)For sepn. of.

Description

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

CH ₃ / * '

wherein R is an isopropyl, sec-butyl or isobutyl group, a salt thereof. or dark. These compounds are obtained by epimerization of ergot-alkaloids of formula II

wherein R is as hereinbefore defined, optionally also comprising ergot-alkaloids of the formula I, in the presence of organic solvents and acids, or by separating the ergot-alkaloids of the formula I and optionally of the formula II from the throat which also contains ergotemin alkaloids; and / or ergoxin alkaloids and optional epimerization of the compounds of formula (II) above.

The compounds of formula (I), i.e. ergol, alpha-rrgocryptine and brta-rrgocryptine, as well as the thrombocryptine formed with ergocriitirea (ergot.O3clin), are primarily used to soothe blood circulation and as an anti-migraine agent. headache.

The compounds of formula II are inactive C-8-epimers of the compounds of formula I. These inactive epimers are formed. In order to increase the yield of alkaloids, modern methods for producing the inactive compound of the formula (II) into the compounds of the formula (I) and / or are separated from the active compounds by chromatography or fractional crystallization.

In the preparation of the compounds of formula (I), often also, at least a few percent, the rothalium and / or alkoxide alkaloids are also used. As used herein, ergotimine alkaloids are ergotimine, ergosine and their C-8-rpiarry, and epoxin alkaloids are ergomine, ergoptin, ergostone, and C-d-epimers thereof. Ergotamine alkaloids must also be separated from the alkaloid growth because, according to the drug regulations, the ergotoxin must not contain more than 0.5% of other alkaloids and may contain at least 2% of the total alkaloids. total

It is an object of the present invention to provide a method for separating ergot-alkaloids, wherein the compounds of formula II can be separated into compounds of formula I, as well as separating them from ergotaaline and / or epoxide alkaloids in one step and in a simple manner.

It is known that by treating certain inactive C-8-epiaery ergot-alkaloids with certain acids or sulphates, these can be rendered effective for active C 8 -alkalides.

F. Kraft (Arch. Pherm. 244 336 (1906)) elaborated a method for the synthesis of acetic acid and an alcohol with sodium sulfate, FH Carr had the same compound in a salt of alcohol and phosphoric acid (J. Chem. Soc. 337). (1907)) and obtains an ergotoxin.

According to British Patent No. 445,325 (1935), it can be adsorbed in an aqueous medium or a solvent medium using an inert ataosphere and phosphoric acid to form a micrometry.

A. Stoo and E. B. Brckhard (Zeetsechift Plhsiol., Chemie 250 1-7 (1937)) have been described for epimerization in the case of alcohol in phosphoric acid. A. Stooi and A. Hof '3 man (Helv. Chim. Acta 26 1570 (1943)) describe the production of alkaloid tartrates in organic solvents and it is claimed that the three ergotoxin-forming alkaloids can be in the form of their di-p-toluyltartrates from to separate the fractured crystallization.

Two years later, A. Stooi (Helv. Chim. Acta 28 1 283/1945 //) published further assurances about ergotamine salts. Prepares ergotamine phosphate in alcohol and ergotamineUphate in the mixture of alcohol and acetic acid ·

Hungarian patent S. 142 095 (1951) discloses the treatment of the artesides associated with alkaloids of the formula I and their epimers of the formula II. Alcoholic phosphoric acid is added to a solution of a mixture of alkaloids in acetone, whereby 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, within about two weeks about 50% of the mono-mono-compounds of the formula II fall out in epimerized form as alkaloids of the formula I. When little iodine is added to the mother liquor, it proceeds. However, two weeks of reaction are also required for useful yield.

L. Wichlinsky (Acta Poloniae Pharm. 22 (3) 327 (1965)) reported the epimmelization of ergotamine in a mixture of acetic acid, methanol and phosphoric acid, sulfuric acid or tartaric acid to the corresponding salt of ergotamine.

Hungarian Patent Application Publication No. RI-620 discloses a process for epimerizing various ergotalkaloid epimeric pairs using organic solvents and alkali metal hydrogen sulphates or ammonium hydrogen sulphates.

The methods known to date are suitable for separating or epoxy-forming processes. one pair of epimers. When the starting mixture of alkaloids contains multiple pairs of epimers, the epidemiological ratios of other alkaloids are shifted during epimerization, first of all, the loss of alpha-trichloro-crystals and beta-epocryptin is too great. It is furthermore problematic that ergotamine and ergosine alkaloids are processed in the media already investigated in exactly the same way as the ergotoxin compounds of the formulas I and II, i.e. they are not separated from these during epimerization.

It has been found that it is also possible to treat sidis containing several pairs of epimers without a sauna. the ratio of amounts for other epimeric vapors in a manner known per se by means of phosphoric acid or tartaric acid, when the reaction medium also contains organic solvents. water. When iilydrogen phosphate and acid, or tartaric acid and tartaric acid, are used instead of phosphoric acid, epimeric activity also takes place while maintaining the proportions of amounts. The isolation is expediently carried out at a pH of from 1.8 to 4.

Further, it has been found that ergotamine and ergosine alkaloids remain in solution in this medium, while alkaloids of formula I fall out of solution as salts. The compounds of the formula I can thus be separated from ergotamine and / or ergosine alkaloids in this way. This separation is expediently carried out at a pH of between 1.8 and 5.

When the mixture of alkaloids to be treated contains the compounds of the formulas I and II and, in addition, the ergotamine and / or ergosin alkaloids, there are several ways to obtain the compounds of the formula I.

One možnoot consists in that the reaction mixture is allowed to stand so long until the alkaloids of the general formula II {^ ^ l ^ i ^ eeis ^ v ^ ^u: I on alkaloids of the general formula I. In this case, there are obtained compounds of formula II as compounds of formula (I), or as salts thereof. Ergotamine and / or ergoxin alkaloids are contained in the remaining mother liquor after separation of the crystallized salts.

Another possibility is to allow the reaction mixture to stand until the main compound of the formula I precipitates in the form of its salts. After separation of the salts, the remaining mother liquor contains the remainder of the alkaloids of the formula I, the epimers of the formula II, and the ergotamine and / or ergoxin alkaloids. This process has the advantage that, in the first step, the main amount of the compounds of the formula I is separated and the separation itself can take place with a considerable amount of material and thus better use of the apparatus.

The mother liquor obtained in the second process can be further processed further. Either the alkaloids are separated by fractional adjustment of the pH to the individual alkaloid groups and the alkaloid group of the formula II is epimerized, or the pH of the mother liquor is adjusted to 5.5 to 10, preferably to 5.5 to 7, and the precipitated alkaloid mixture of alkaloids of formula I and II as well as of ergotamine and / or ergoxine alkaloids are epimerized, whereby the compounds of formula I and II converted by epimerization into compounds of formula I precipitate, while ergotamine and / or ergoxine alkaloids remain in the mother liquor and can be recovered from there.

Accordingly, the present invention provides a novel process for the preparation of ergo-O-cycloyl compounds of formula (I) wherein R is an isopropyl group, a n-butyl group or an isobutyl group, or a salt thereof and mixtures thereof.

epimerizing the ergot-alkaloids of formula II, wherein R is as hereinbefore defined, optionally in admixture with the ergot-alkaloids of formula I, with one or more organic solvents and acids, by separating the ergo-octloids of formula I and optionally of formula II from the mixture containing, in addition, also ergotamine and / or ergoxin alkaloids and optionally epimerization of the compounds of formula II. The process according to the invention is characterized by the fact that in the case of epicyclic ergot-alkaloids of the general formula II, which may also contain alkaloids of general formula I, or in the case of epimerization and separation of mixtures containing ergot-alkaloids of general formulas I and II and, moreover, also ergotamine and / or ergoxin alkaloids, treat the starting alkaloid mixture in the presence of water and organic solvents with a reagent selected from the group consisting of phosphoric acid, tartaric acid or a mixture of dihydro-phosphoric or tartaric acid or tartaric acid and alkanoic acids, the solvent is partially removed from the reaction mixture and the optionally concentrated reaction mixture is allowed to stand at a pH in the range of from 1.8 to 4 until the epimerization of the ergo-alkali metal compounds of formula II has taken place. The compounds of the formula I precipitated in the form of their salts are separated and, if desired, liberated from the salts obtained in a manner known per se by a base of the formula I in which R is as defined above.

According to a further variant of the process according to the invention, the starting mixture of alkaloids is treated in the presence of water and organic solvents with phosphoric acid or tartaric acid, if part of the solvent is removed from the reaction mixture, the pH or concentration is adjusted to 1.8 to 3. And this is then allowed to stand until the major sub-component of the compounds of formula (I) wherein R is as defined above, in addition to its salts, is separated, and optionally liberates the bases of formula (I) by known methods. The pH of the first mother liquor remaining after the precipitation of the precipitated salts is adjusted to a range of 5.5 to 1.0, preferably 5.5 to 7, and the precipitated mixture melting from the alkaloids of the formula I, the compounds of the formula II as well as ergotamine and / or or ergoxin is isolated and optionally processed according to the first variant. A further possibility is to set the pH of the first liquid liquor obtained after separating the brine to a value higher than that mentioned above, preferably in the range of 1.9 to 4.0, in particular 2.1 to 4.0, and a precipitated fraction, mainly containing The oxine alkaloids are stripped off, then the pH of the second mother liquor is adjusted to a value in the range of 2.5 to 5.5, preferably in the range of 3.5 to 5.5, and the precipitated fraction containing mainly the ergotamine alkaloid fraction. кК ^ ИС. The fraction consisting essentially of the alkaloids of the formula II obtained from the third mother liquor is optionally treated according to the first embodiment.

Suitable starting materials for the process according to the invention are the following mixture of ± alkaloids:

- mixtures of ergotamine and / or ergoxin alkaloids and compounds of formula I,

- including ergotamine and / or ergoxin alkaloids and compounds of formulas I and II,

- mixtures of compounds of formulas I and II,

compounds of formula II.

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

In the process according to the invention, the reaction medium consists of organic solvents, water and epimerizing or possibly salt-forming acids. Suitable solvents are alkanols having 1 to 4 carbon atoms (for example methanol or ethyl alcohol) or their esters formed with lower saturated carboxylic acids, further aliphatic ketones of 3 to 8 carbon atoms (such as acetone, hydrocarbons (such as hexane, heptane, benzene, toluene, xylene, gasoline, kerosene, and the like)); or organic solvents may be used. in admixture with acid amides or with sulfoxides, such as formamide or dimethylsulfonyl.

The latter solvent can also be used alone.

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

Phosphoric acid or tartaric acid is primarily used as the rio-ionizing agent or the salt-forming agent. When the starting mixture also contains alkaloids of the formula II, these acids act both as an epioeriation agent and as a soH-forming agent. If the starting reaction mixture contains no alkaloids of the formula II, then the function of these acids is limited only to the formation of salts, thereby forming compounds of the formula I which are very poorly soluble in the reaction mmdd. Both salts are equally suitable for salt formation. If the acids also serve for epichlorination, phosphoric acid is preferable. When tartaric acid is used as an epimerizing agent, it is expedient to increase its effectiveness by adding another acid, preferably by adding a lower aliphatic carboxylic acid, preferably acetic acid.

Instead of phosphoric acid, dihydrogen phosphate may also be used in the presence of an acid. Preferred are alkali metal dihydrogen phosphates and ammonium dihydrogen phosphate. Instead of the tartaric acid and the other acid, a mixture of an alkali metal tartrate and an organic acid, preferably acetic acid, can also be used.

V ^ ^{<^} c ^ ^c ^ ² ^^ Mixtures of alkaloids, in reaction Solvent-mmdiu network or suspended. The solubility of the compounds of formula I and their salts in the reaction medium is measured by the addition of water. Suitably, the starting mixture of alkaloids is dissolved in an organic solvent or a mixture of organic solvents, this solution is then mixed with an epimerizing agent, optionally with a reagent, and then the solution is supersaturated for the salt of the compounds of the formula I. and sulfoxides, primarily by removing the organic solvents by 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) at a lower pH range, while at low concentrated solutions the separation of soH near the upper limit of said pH range is preferable.

Alternatively, the alkaloid mixture can be admixed in a mixture of an epimerizing agent (optionally a salt forming agent) and an acid amide (optionally a sulfoxide) before the action is taken. add water.

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

If desired, bases (or mixtures of bases) can be introduced in a manner known per se from the salt obtained. The release of the base is preferably achieved in a mixture of water and chloroform by adjusting the pH to about 8.

The composition of the mixture. base of ergot-alkaloids is determined chromaatorraically. (Variao 8500 LC Chromatograah, adsorbens: Lichrosorb S 1 60 5, eluent: n-hexane / chloroform 7: 1.5: 1.5, flow rate: 100 al / h, detection wavelength: 280 on).

The process according to the invention, without being exemplified by the present invention, will be explained in more detail in the following examples with the aid of examples of anti-rusting.

Example 1

As starting material serve as mixtures of alkaloids of the following composition:

% haoonootic (0.0094 mol)% palpable (0.0042 mol)% haoonootic (0.0023 mol)% haoonootic ergocornins, ergocryptins, beta-ergocryptins and nonidentified plant substances

This mixture was dissolved in a mixture of 100 ml of ethyl alcohol, 2 ml (0.0345 mol) of 85% aqueous phosphoric acid and 6 ml of amide. The solution obtained is then mixed. · With 50 ml of water. The reaction mixture was evaporated under reduced pressure ^P s te ^ ot ¹ 5 ⁰ ° C to a volume of 40 ml and ^p Otom was allowed to stand at room temperature locally for 7 days in the dark. The crystals her twice promyjí.10 ml of water at 40 ° C in ^the VA uu dried. ^{MES b} aci liberated from the obtained sooí oázteduSící composition has:

% haoonootic% haoonootic% hmoonoidic ergocornins, rhf-ergocryathies and beta-ergocryptia

Alkaloid yield: 94% (Smls phosphates: 10.3 g) Base rotation [n] 2 ° = -188 ⁰ ( ^c = 1, ^c hl ^oro for ^a )

Example 2

It is based on a mixture of ergot-alkaloids with the following composition:

% haloootic (0.00692 aol)% hmoonoot (0.00263 aol)% moisture (0.000520 aol)% hmoonoid (0.00479 aol)% hmoonoot% hmoonoot alpha and beta-ergot / betaine, ergocornium, beta-ergocrystalline LS and other substances of plant origin.

g of the above composition is dissolved in a mixture of 100 ml of acetone, 7 ml of formamide and 6 ml (0.104 aol) of 85% aqueous phosphoric acid. To this solution is then added 100 ml of water. The reaction mixture was then evaporated under reduced pressure at ⁵⁰ ° C. to 5 ⁰ al. ^From ahušt ^S n ^and a ^. with ^p ones ^{and p} i ^r i ^t e ^^ about ⁸⁰ ° C ^t1 St ^{and P d} by the OBU ³ hours .a ^p Otom

Ί at room temperature for 24 hours. The product is isolated in the same manner as described in Example 1. 9.8 g of an ergot-alkaloid phosphate mixture are obtained. The base mixture obtained from these phosphates has the following composition:

% by weight% hmoonoot%% hmoonotine, alpha-ergscryptin and beta-ergocryptia.

Yield of alkaloid: 98%, specific base mixture ^{with λθ} = -185 ° ⁽ c = 1, µm ⁰ ).

Example 3

10 g of a mixture of ergot-alkaloids are used as the starting mixture:

% w / w (0.00619 mol) 15% w / w Snow (0.00260 mol)% w / w (0.000520 mol)%. moisture (0.00479 mol)% w / w (0.00122 mol)% w / w (0.00035 mol)% w / w ergocornins, aflo-ergscryptin, beta-ergocryptin, ergocooninin, alpha-ergotryptine, beta-ergotryentinone and o-ergotentypine of origin.

The mixture of the above composition is dissolved at room temperature at room temperature. 100 ml of ethyl alcohol and 8 ml of acetic acid. To a solution -získanému -for stirring with 7.76 g (0.0647 mole) dihydrogeifosf orečnanu solution and the reaction mixture was stirred for two Nidon at a temperature between 35 EŽ 4 ^{0C. p} is Otom Uve ^d ene ^and the reaction mixture was treated with ⁸⁰ ml in ^soil at ⁵⁰ ° C in vacuo odpaaí to 70 ml. The concentrated mixture was then allowed to stand at room temperature for 24 hours. The product was isolated as described in Example 1. 10.6 g of smOs were obtained. of phosphates. The ergot-alkaloid base mixture released from these phosphates has the following composition:

% ^ οΟη ^ ιηί ^% hmoOnootní% hmoOnnostní ergokornine, alpha-ergskryptin a beta-ergskryptin

Alkaloid yield: 98%

Spindle base base = -83 ^{° (} c = 1 chloroform).

Example 4

The starting mixture used is 10 g of an ergot-alkaloid mixture having the following composition:

% w / w (0.00798 mole)% w / w (0.00402 mole)% w / w (0.0021 mole)% w / w ergocorninin, alpha-ergscryptinin, beta-ergocryptia and oentifenting of substances of origin.

The mixture is suspended at room temperature in a network of 100 ml of MeOH and 10 ml of glacial acetic acid. Under stirring, to the suspension was added 11 g (0,0S1 mol) dihydrogertfosforečnanu ^ aselráho and the reaction mixture stirred at ^d dt ^b Vou h te ^p! Hundred 40 ° C. ^The mixture was then treated with 8 ml of water and evaporated in vacuo to a total volume of ⁷⁰ ml at ⁴⁵ ° C.

The concentrated reaction mixture is allowed to stand at οίδύιοοϋ for 24 hours. The resulting product is separated in a sterile manner as described in Example 1.

11.9 g of a mixture of ergot-alkaloid phosphates are obtained. The liberated base mixture has the following composition:

% hormone alpha-ergocryptines, and% alpha-ergocryptine hormones.

Yield of alkaloids: 98%.

Rence SPPE ^c ^ rt emissivities smětei ^b Azi: И θθ = -186 ⁰ (c = 1, chloroform).

Example 5

The starting mixture used is a mixture of alkaloids obtained by fermentation in an amount of 10 g, which mixture has. following composition:

% by weight (0.00266 mol)% by weight (0.00192 mol)% by weight (0.003 mol)% by weight (0 ^ 016 mol)% by weight (0.00105 mol)% by weight · (0.00035 mni)% by weight ( 0.00122 mol)% mass (0.000698 mn)

9 wt.% (0.000869 mol)% w / w £ 0000052 mol)% wt (0.000354 mni)% w / w (0.00142 mol)% w / w ergocynins, alpha-ergocryptin, beta-ergocryptin, ergocorninin, alpha-ergotaryptinin, beta- ergocryppinin, ergotamine, ergotaminin, ergonin, ergoninin, BSggoopin, ergooPinin and nonidentifiolar contaminants.

The mixture of this composition is dissolved in the mixture. 100 ml of methyl alcohol, 5 ml of dimethylformamide and 6 ml of concentrated phosphoric acid. To this solution was added 400 ml of water and rises ^{to the} REA was evaporated under sniěenéto tlat and at a maximum temperature of 4 ⁰ C for tilt volume "300 ml. Hodnoíta pH of the crystallizing solution is adjusted to 3 and then the reaction mixture MIC ^{d HA} of ^B to ²⁰ Todina at ^t ^ ^t ^ o epl ^ of 0 ° C. Excluded it taty ^ ^ are filtered off from the ^d vakra ^and T for Yi ° ^{ZDY 20} ml under vacuum and ^dy in the ^y dried at a maximum temperature of 4 ⁰ C. ^The mother liquor obtained after filtration is further used for further processing.

Decanting and drying yielded 5.62 g of ergot-alkaloid phosphate. After the free bases are released, the following are mixed in the mixture:

% by weight of ergocornins,% by weight of aaegegococptins,% by weight of beta-ergo [not] ges;

0.5% by weight of ergoaamine,

0.5% by weight ergonin a

0.3% of mass ergopun.

Specific rotation ^with base: [ ^α ] ^ρθ = -Ί81 ⁰ (c = 1, chloroform).

From the mother liquor obtained above, 4.48 g of a mixture of alkaloids, consisting predominantly of argothylamine and ergoxin tetototinium, having the following composition are obtained as described in Example 6: ergttaminin,% wt ergonin,% wt% wt% wt% wt% wt% wt% wt% wt% wt% wt% ergonomia, ergoptioia, ergskoroia, engskornioia, alpha-ergocriptia, alpha-ergocriptia, alpha-ergocriptia ^y ptiou and beta-ergocryptioia.

Example 6

As a starting material, 10 g of this ergot-alkalside will be used, followed by feroentation which results in the following confusion:

% hot (0.00443 rnol)% thick (0.000530 ool)% w / w (0.000350 ool)% w / w (0.00140 ool)% w / w (0.00266 ool)% w / w (0.00120 ool)% w / w (0.000360 mmol)% (0.000360 mmol)% by ergotium, ergs, ergoptia, ergocorium, αH E E - sk sk ry pt ry iou iou, beta, erg-ergcycyptioim, s erg ident erg erg erg erg erg erg erg erg erg erg erg erg erg erg.

The deer of the cheesecloth was dissolved in a 40 [mu] l solution and 5 [mu] l of a concentrated solution. When all of the ingredients are dissolved, 400 µl of water are added to the solution. The pH of the solution was adjusted to about 3 and added to the concentrate of the isotonic flavor. ^To Saint Rozts ^y lc> ^and enioQU učeosu precipitate was ^plated walnut pstoo St ^and t ^ at ^ pls 0 ps ^d s u ^{b 3} HSDI. PSTs te pevoý product QdUiltkuje twice with breast-ol-20 is always in a vacuum, ^{characterized} in ink rnoxioáloS teplal ^p s 4 ⁰ ° C. ^{There are obtained 5.82} g ^of the ^{ergoforphate salts} which have the following bases:

% by weight% by weight% by weight% by weight ergskoroia, alpha-ergscryptia, betx-ergokr ^y ptiou and ergo and ergQtxoiou as a purification.

The mother liquor obtained with the sodium phosphate salt is then further processed as described in Example 6. This yields also 4.82 g of mostly the above-mentioned formula II and ergonomics. Tats soSs follow the following:

% Hmosnostní% hmosnostní% hшoQnoQtní% hIшnnostníih% hmoQnoQtoí% hшoQnoQSníih% hooQnostníih% hrnosnostních% hmosnostní% hrnosnostních ergQkorriou alpha-engskryptiou, beta-ergokkyppiou, ekgsniou, ergoptiou, ekgokorniniou, xlfx-ergQkr ^y ptininu, BE TA-ergoskrppioiou, ekgsnioiou and ergoptioinu .

g trn ^ Si s above. The cushion is epioedized and is shared with the ecologic and following reagents. Dissolve 10 g of the mixture in 100 ml of teeth-alkanol, 2 ml of 85% aqueous acid and 6 ml of water. To the solution of the solution, 150 µl of inoculum was added.

The reaction mixture was evaporated under reduced pressure at ⁵⁰ ° C to a total volume of ¹⁰⁰ ml and then left to stand in the dark at room temperature for 7 days. The precipitated crystals are filtered off with akṛta ^ ^ ^ i Proi in ¹⁰ ml ^ZDY in ^soil and ^p s ^t e ^p lo ^{I 40} ° C and dried. 6.46 g of ergo alkaloid phosphates are obtained, the base being mixed in a mixture. the following composition:

% w / w 42% w / w 19% w / w% w / w ergokooin) alpha-ergocryptine, beta-ergocryptine and ergosin alkaloids

Claims (4)

SUBJECT OF THE INVENTION In the form of their salts, in the form of their salts, the compounds of the formula I in which R is as defined above are separated and, optionally, the base of the formula I is liberated therefrom. A process for the preparation of ergoo-alkaloids of the general formula I CH. CHi Wherein R is an isopropyl, sec-butyl or isobutyl group, or a salt thereof, a mixture of compounds of formula I or mixtures thereof, by separating the ergoO-alkaloids of formula I and optionally the ergoO-alkaloids R is as hereinbefore defined, including in addition ergotamine and / or ergoxin alkaloids, and in which one or more of the compounds of formula II are treated, characterized in that the starting mixture of alkaloids is treated with an agent selected from phosphoric acid, tartaric acid or a mixture of disodium phosphate or tartaric acid or tartaric acid and alkali acids, in particular acetic acid, with water and organic solvents, optionally removing some of the solvent from the reaction mixture and leaving the optionally concentrated reaction mixture to stand at a pH of 1. 8 to 4 until the epimerization of the .epsilon.-alkaloids in general The compound of formula (II), a compound of formula (I) precipitated in the form of its salts, is separated and optionally liberated from the obtained salts of a base of formula (I) wherein R is as defined above. 2. Process according to claim 1, characterized in that the starting mixture of alkaloids is treated with phosphoric acid or tartaric acid, the pH of the optionally concentrated sidOss is adjusted to a range of 1.8 to 3.5 and is then allowed to stand until the main share 3. Process according to claim 2, characterized in that the pH of the first liquor remaining after separation of the precipitated salts is adjusted to a pH of 5.5 to 10, preferably 5.5 to 7, and a precipitated mixture consisting of: the alkaloids of the formula I, the compounds of the formula II, as well as the ergotamine and / or ergoxin alkaloids, are isolated or further processed as described in point 11. 4. Method according to claim 2, characterized in that the value of the first mother liquor obtained after the separation of the salts is set to a value higher than that of the method according to claim 2, preferably in the range 1.9 to 4.0, in particular 2.1 to 4.0 and the precipitated fraction containing predominantly ergoxin alkaloids is separated, then the pH of the second mother liquor is adjusted to a value in the range of 2.5 to 5.5, preferably in the range of 3.5 to 5.5 and the precipitated fraction, consisting predominantly of the ergotamine alkaloid fraction of formula (II) obtained from the third mother liquor, is optionally treated as described in (1).