FR2477155A1 - Ergocornine, alpha and beta ergocryptine prodn. - by epimerisation of C-8 epimers, ergocornine and ergocryptine(s) with acid in organic solvents - 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

où R représente un groupe isopropyle, butyle secondaire ou isobutyle, ou de leurs sels ou de leurs mélanges. On obtient ces composés - par épimerisation, effectuee en présence de solvants organiques et d'acide, d'alcalotdes de l'ergot de seigle qui répondent a la formule générale (II) ci-dessous, et contiennent éventuellement également des alcaloïdes de l'ergot de seigle de formule générale (I)

The present invention relates to a process for the production of ergeal alealofdes of general formula (I)

where R represents an isopropyl, secondary butyl or isobutyl group, or their salts or their mixtures. These compounds are obtained - by epimerization, carried out in the presence of organic solvents and of acid, of ergot alkaloids which correspond to the general formula (II) below, and possibly also contain alkaloids of the ergot of general formula (I)

R having, in formula (II), the same meaning as in formula (I), or - by separation of the alkaloids of the rye of rye of general formula (I) and optionally of general formula (II) from a mixture also containing, also, alkaloids from the group of ergotamine and / or ergoxine and optionally carrying out an epimerization of the compounds of general formula (II).

 The compounds of general formula (I), that is to say ergocornine, a-ergocryptine and S-ergocryptine as well as their mixture (ergotoxin) formed with ergocristine, are used in the first place as hemostatic agent and as an agent against migraine.

The compounds of general formula (II) are the inactive C-8 epimers of the compounds of general formula (I).

These inactive epimers are formed during the production of ergot alkaloids, at the same time as the active compounds of general formula (I). To increase the alkaloid yield, in modern production processes, the compounds of general formula (II) are epimerized into compounds of general formula (I) and / or they are separated by chromatography or by fractional crystallization of the active compounds.

During the production of the compounds of general formula (I), alkaloids from the group of ergotamine and / or ergoxine are frequently obtained in an amount of a few percent. By alkaloids: Ldes from the ergotamine group, in the present description is meant erootamine, ergosine and their C-8 epimers, by alkaloids from the ergoxine group, is meant ergonine, ergoptine, ergostin and their epimers C-8. Alkaloids of the ergotamine group must also be separated from alkaloids of the ergotoxin group, since according to Codex requirements, ergotoxin must not contain more than 0 , 5% of other alkaloids and not more than 2 8 total impurities.

 The object of the present invention is to provide a process for the separation of alkaloids from rye ergot, in which the epimerization of the compounds of general formula (II) into compounds of formula can be carried out in a single stage. general (I), as well as possibly their separation from alkaloids of the group of ergotamine and / or ergoxine.

It is known that epimers can be epimerized
C-8 inactive alkaloids of ergot rye in alkaloS- des ergot corresponding active, by action of specific acids or sulfates.

F. Kraft [Arch.Pharm.244 336 (1906) 7 has epimerized ergotinin in a mixture of acetic acid and alcohol with sodium sulfate; F.H.Carr epimerized the same compound in alcohol with phosphoric acid [J. Chem.

Soc. 337 (1907) 7 and obtained ergotoxin.

 In accordance with British Patent No. 445,325 (1935), ergometrinine can be epimerized to ergometrine, in an aqueous medium or in the presence of a solvent, under an atmosphere of inert gas, using phosphoric acid.

A. Stoîl and E. Burckhard / Zeitschrift Physiol.
Chemie 250 1-7 (1937)] have epimerized in phosphoric acid in alcoholic solution, ergocristinine in ergocris tinte. A.Stoll and A. Hofman Helv.Chim.Acta 26 1570 (194317are prepared in organic solvents, alkalot tartrates and have shown that the three alkalotids forming the ergotoxin can be separated from each other by fractional crystallization, in the form of their di-p-toluyltartrates.

 Two years later, A.Stoll ZHelv.Chim.Acta 28 1283 (1945t7 published other observations concerning the salts of ergotamines. He prepared ergotamine phosphate in alcohol, ergotamine sulfate in a mixture of methanol and glacial acetic acid.

Hungarian Patent No. 142,095 (1951) describes the treatment of mixtures consisting of alkaloids of general formula (I) and their epimers of general formula (II).

To the solution of the mixture of alkaloids, prepared with acetone, phosphoric acid is added in alcoholic solution, the principal quantity of the alkaloids of general formula (I) then precipitating in the form of phosphate, while one can obtain the alkaloids of general formula (II) from mother-waters. When the mother liquors are left to stand for approximately 50% of the compounds of general formula (II) precipitate in the space of two weeks, in epimerized form, as an alkaloid of general formula (I). When a little iodine is added to the mother liquors as a catalyst, the epimerization begins more quickly, but it also takes two weeks to obtain an acceptable yield.

 L. Wichlinsky Jacta Poloniae Pharm. 22 (3) 327 (1965ss7 epimerized ergotaminine in a mixture of glacial acetic acid and methanol with phosphoric acid, = sulfuric acid or tartaric acid with obtaining the corresponding ergotamine salt.

The published Hungarian Patent Application nORI-620 describes a process for the epimerization of different pairs of epimers of rye ergot alkaloids, in the presence of organic solvents and alkali bisulfate or ammonium bisulfate.

 The methods known up to now are suitable for the separation or epimerization of a single pair of epimers at a time. When the starting alkalode mixture contains several pairs of pimers, the quantitative ratio of the individual alkaloids is modified during the epimerization and in the first place the loss of a-ergocryptine and ss-ergocryptine is very high. The fact that the alca lofes of the group of ergotamine and ergoxine behave exactly like the compounds of ergotoxin which correspond to the general formulas (I) and (II) in the media already examined, that is to say saying that they cannot be separated from them during the epimerization is also a problem.

The Applicant has now found that it is also possible to epimerize mixtures containing several pairs of epimers without modifying the quantitative ratios, with phosphoric acid or dtartaric acid, in the manner known for the individual pairs. epimers, when the reaction medium contains, in addition to organic solvents, also water. When an acid phosphate and an acid are used in place of phosphoric acid, in place of tartaric acid, a tartrate and an acid, epimerization also takes place while maintaining the quantitative ratios. The epimerization is advantageously carried out at a pH of between 1.8 and 4.

 The Applicant has also found that in this medium, the alkaloses of the ergotamine and ergoxine group remain in solution, while the alkaloids of general formula (I) precipitate in the form of salts. The compounds of general formula (I) can thus be separated in this way from the alkaloids of the group of ergotamine and / or ergoxine. Your separation is advantageously carried out at a pH of between 1.8 and 5.

 When the mixture of alkaloids to be treated contains compounds of general formulas (I) and (II) and, in addition, also alkaloids from the group of ergotamine and / or ergoxine, there are several routes for the 'obtaining the compounds of general formula (I).

 One possibility is to allow the reaction mixture to stand long enough for the alkaloids of general formula (II) to be epimerized into alkaloids of general formula (I). In this case, the compounds of general formula (II) are obtained in the form of compounds of general formula (I) and more exactly in the form of their salts. In the mother liquors which remain after the separation of the precipitated salts, there are alkaloses from the group of ergotamine and / or ergoxine.

 Another possibility is to allow the reaction mixture to stand long enough for the main amount of the compounds of general formula (I) to precipitate in the form of salts. The mother liquors which remain after the separation of the salts contain a residue of alkaloids of general formula (I), as well as the epimers of general formula (II) and the alkaloids of the group of ergotamine and / or ergoxine . This procedure has the advantage that in the first stage, most of the compounds of general formula (I) are separated, and that the actual separation can be carried out with smaller quantities of materials and, therefore, with better use of the capacity of the apparatus.

 The mother liquors obtained in the second procedure can be treated in two ways. Either the alkaloids are separated by fractional adjustment of the pH into groups of alkaloids and the group of alkaloids of general formula (II) is epimerized, or the pH of the waters is adjusted to a value between 5.5 and 10 and preferably between 5.5 and 7, and the mixture consisting of alkaloids of the general formulas (I) and (II) is epimerized as well as alkaloids from the group of ergotamine and / or ergoxine, the salts of the compounds of general formula (I) and compounds of general formula (II) transformed into compounds of formula (I) due to epimerization then being deposited in the form of precipitates, while the alkaloids of the ergotamine group and / or of ergoxine remain in the mother liquors and can be obtained from them.

The invention therefore relates to a new process for the production of rye ergot alkaloids of general formula (I), in which R represents an isopropyl group, secondary butyl or tertiary butyl, or their derivatives. salts or their mixtures - by epimerization, in the presence of an organic solvent and of acid, of ergot alkaloids which correspond to the general formula (II) in which R has the same meaning as above , and which optionally also contain rye ergot alkaloids of general formula (I), or - by separation of rye ergot alkaloids, of general formula (I) and optionally of general formula (II), to starting from the mixture also containing alkaloses from the group of ergotamine and / or ergoxine and optionally carrying out the epimerization of the compounds of general formula (II); The characteristic of the process according to the present invention resides in that a) in the case of the epimerization of the ergo alkaloids of rye which correspond to the general formula (II), which optionally also contain ergo alkaloids of rye of general formula (I), or in the case of the epimerization and the separation of a mixture containing rye ergot alkaloids of general formulas (I) and (II) and in addition alkaloids of group of ergotamine and / or ergoxine,
al) treating the mixture of starting alkaloids, in the presence of water and organic solvents, with phosphoric acid or a mixture of acid phosphate or tartrate or tartaric acid and an acid, then separates, if desired, the solvent partially from the reaction mixture and the reaction mixture which is optionally concentrated is allowed to stand at a pH of between 1.8 and 4 until the epimerization is completed and the compounds of general formula are separated (I) precipitated in the form of a salt and, if desired, the bases of general formula (I) are liberated, if desired, from the. salts obtained, or
a2) treating the mixture of starting alkalots, in the presence of water and organic solvents, with phosphoric acid or tartaric acid, optionally removing part of the solvent from the reaction mixture, adjusting the mixture reaction at a pH between 1.8 and 3.5 and then allowed to stand until separation of the major part of the compounds of general formula (I) obtained in the form of salts, the precipitated salts are separated and released, if if desired, the bases of general formula (I), and
a21) the first mother liquors obtained during the separation of the salts are adjusted to a pH between 5.5 and 10 and preferably between 5.5 and 7, and the precipitated mixture which consists of compounds of general formula (II) also containing as impurities alkaloses of general formula (I), as well as alkaloids from the group of ergotamine and / or ergoxine and treatment is carried out, if desired, according to the variant of process a11 or
a22) the pH of the first mother liquors obtained during the separation of the salts is adjusted to a value which is greater than the pH value adjusted during the execution of variant a2 and which is advantageously between 1.9 and 4 , 0, and in particular between 2.1 and 4.0, and the precipitated fraction mainly containing alkaloids is separated from ergoxine, then the pH of the second mother liquors is adjusted to a value between 2.5 and 5.5 and preferably between 3.5 and 5.5, and the precipitated fraction containing mainly alkaloses is separated from the ergotamine group and the fraction is treated, if desired, in accordance with the variant of process a1 consisting mainly of alkaloids of general formula (II), obtained from the third mother liquor, or
b) in the case of the separation of a mixture of compounds of general formula (I) and of alkaloids from the group of ergotamine and / or ergoxine, the mixture of starting alkaloids is treated, in the presence organic solvent and acid, with phosphoric acid or tartaric acid or with a mixture of an acid phosphate or tartrate and an acid, the solvent is optionally partially removed from the reaction mixture, it is adjusted the pH of the reaction mixture possibly concentrated to a value between 2 and 5 and the mixture is allowed to stand until the compounds of general formula (I) have precipitated in the form of their salts, then - the salts are then separated and liberating, if desired, in a manner known per se, the bases from the salts.

As starting compounds, for the process according to the invention, the following mixtures of alkaloids are taken into account - mixtures of alkaloids from the group of ergotamine and / or
ergoxine and de-compounds of general formula (I) - mixtures of alkaloses from the ergotamine group and / or
ergoxine and compounds of general formulas (I and II) - mixtures of compounds of general formulas (I) and II); '- compounds of general formula (II).

 The mixture of starting alkaloids may possibly also contain other organic substances which are of vegetable origin or which come from fermentation.

 The reaction medium is constituted, in the process according to the invention, by organic solvents, water and by the epimerizing acid or forming a salt.

As organic solvents, alkanols comprising from 1 to 4 carbon atoms (methanol, ethanol) or their esters formed with saturated lower carboxylic acids (ethyl or butyl acetate) are taken into account, as well as aliphatic ketones comprising from 3 to 8 carbon atoms (for example acetone, methyl isobutyl ketone) or hydrocarbons (for example hexane, heptane, benzene, toluene, xylene, petrol, petroleum ether, etc ...) or carbon tetrachloride The solvents listed may other present in admixture with amides or sulfoxides, for example formamide, dimethylformamide or dimethyl sulfoxide. These latter solvents can also be used alone.

 The reaction medium contains, in accordance with the invention, an organic solvent and water. The amount of water is between 10 and 95% and preferably between 50 and 80%.

As reagents for epimerization or for forming a salt, phosphoric acid or tartaric acid is used first. When the starting mixture also contains alkanoYdes of general formula (II), the acids act both as epimerization agents and as desalting agents. When the starting mixture does not contain alkalotdes of general formula (II), the role of the acid is limited to the formation of salts, while salts of the compounds of general formula (I) are sparingly soluble. in the reaction medium. For the formation of a salt, the two acids mentioned are identically suitable. In the case where the acid is also used for epimerization, phosphoric acid is more suitable. In the case of the use of tartaric acid as an epimerization agent, it is advantageous to increase its effectiveness by adding another acid, advantageously by adding a lower aliphatic carboxylic acid, preferably acetic acid.

As phosphoric acid, an acid phosphate can also be used in the presence of an acid. Advantageously, acid phosphates of an alkali metal or monoammonium acid phosphate are used. Instead of a mixture of tartaric acid and another acid, it is also possible to use a mixture of an alkaline tartrate and an organic acid, preferably acetic acid.
The starting alkaloid mixtures are dissolved or suspended in the reaction medium. The solubility of the compounds of general formula (I) and their salts in the reaction medium becomes weaker when water is added. The starting alkaloid mixture is advantageously dissolved in an organic solvent or in a mixture of solvents, the epimerization or salification reagent is added to the solution and water is added and the solution is then supersaturated with regard to the salts of the compounds of general formula (I). This takes place, except for amides and sulfoxides, first by removing the organic solvent by evaporation or extraction.

 The solubility of the salts of the compounds of general formula (I) also depends on the pH of the medium. When operating with concentrated solutions, it is advantageous to separate the salts of the compounds of general formula (I) in the lower region of the pH range indicated, while in the case of less concentrated solutions, the separation is more advantageous near the upper limit of the indicated pH range.

One can also proceed by dissolving the mixture of alkaloids in the mixture of the epimerization (or salification) reagent and an amide (or a sulfoxide) and then only adding water to the reaction mixture.

 The salts of the compounds of general formula (i3 are separated from the reaction mixture by crystallization. Optionally, the reaction mixture is partially evaporated before crystallization.

 If desired, the base (the mixture of bases) can be released from the salt obtained, in a manner known per se. This advantageously takes place in a mixture of water and chloroform by adjusting the pH to approximately 8.

 The composition of the alkaloid base mixture of rye ergot is determined by chromatography (Varian 8500 LC chromatography apparatus, "Lichrosorb" adsorbent S 1 60 5: eluting agents: n-hexane, chloroform and acetonitrile in a ratio of 7: 1.5: 1.5 flow rate: 100 ml / h; detector wavelength: 280 nm).

 In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows.

The invention will be better understood with the aid of the additional description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

It should be understood, however, that these examples of implementation are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.

EXAMPLE 1
As starting material, 10 g of the following mixture of rye ergot alkaloids are used: 53% by weight (0.0094 mole) of ergocorninine, 24% by weight (0.0042 mole) of ergocryptinine, 13% by weight (0.0023 mole) of ss-ergo-cryptinine and 10% of unidentified vegetable substances.

The mixture is dissolved in a mixture of 100 ml of methanol, 2 ml (0.00345 mole) of phosphoric acid in 85% aqueous solution and 6 ml of formamide. 50 ml of water are added to the solution. The reaction mixture is concentrated under reduced pressure at 500C to a volume of 40 ml and then left to stand at room temperature for 7 days in the dark. The precipitated crystals are separated by filtration, washed twice with 10 ml of water and dried under vacuum at 400C. The mixture of bases released from the salts has the following composition:. 48% by weight of ergocornine,. 22% by weight of a-ergocryptine, 12% by weight of ss-ergocryptine.

The use of alkaloids: 94% (mixture of phosphates: 10.3 g).

Specific rotary power of the base mixture
Z 720 = 1880 (c = 1, chloroform).

EXAMPLE 2
10 g of a mixture of rye ergot alkaloids having the following composition are dissolved: 39% by weight (0.00692 mole) of ergocornine, 15% by weight (0.00263 mole) of a- ergocryptine, 3% by weight (0.000520 mole) of ss-ergocryptine, 27% by weight (0.00479 mole) of ergocorninine, 2% by weight of ss-ergocryptinine and 7% by weight of unidentified substances of vegetable origin, in a mixture of 100 ml of acetone, 7 ml of formamide and 6 ml (0.104 mole) of phosphoric acid in 85% aqueous solution. 100 ml of water are added to the solution.

Then, the mixture is concentrated under reduced pressure to a volume of 50 ml. The concentrated mixture is left to stand for 3 hours at 800C, then for 24 hours at room temperature. The product is isolated as described in Example 1. 9.8 g of a mixture of phosphates from the ergo alkaloids are obtained. The mixture of bases which is released from the above-mentioned mixture has the following composition
61% by weight of ergocornine,
20% by weight of a-ergocryptine,
4% by weight of B-ergocryptine.

Use of alkaloids: 98%
Specific rotary power of the base mixture La, 720 = -1850 (c = 1, chloroform).

EXAMPLE 3
As starting material, 10 g of a mixture of rye ergot alkaloids are used which has the following composition: 39% by weight (0.00619 mole) of ergocornine, 15% by weight (0.00260 mole) of a-ergocryptine, 3% by weight (0.000520 mole) of 6-ergocryptine, 27% by weight (0.00479 mole) of ergocorninine, 7% by weight (0.00122 mole) of -ergocryptinin, 2% by weight (0.00035 mole) of ss-ergocryptinin and 7% of unidentified substances of plant origin. The mixture is dissolved at room temperature in a mixture of 100 ml of methanol and 8 ml of glacial acetic acid. 7.76 g (0.00647 mole) of monosodium acid phosphate is added to the solution with stirring and the reaction mixture is stirred at 35-40 C for 2 hours, then 80 ml of water is added to the mixture and evaporates at 500C under vacuum until a volume of 70 ml is obtained. The concentrated mixture is allowed to stand at room temperature for 24 hours. Then, the product obtained is separated, as described in Example 1. 10.6 g of phosphate mixture are obtained. The mixture of alkaloid bases of ergot which is released from the mixture of phosphates, has the following composition
61% by weight of ergocornine,
20% by weight of a-ergocryptine,
5% by weight of B-ergocryptine.

Use of alkaloids: 98%
Specific rotary power of base mixture Z 720 = -1830 (c = 1, chloroform).

EXAMPLE 4
As starting material, 10 g of a mixture of rye ergot alkaloids is used which has the following composition: 45% by weight (0.00798 mole of ergocorninine, 23% by weight (0.00402 mole ) of α-ergocryptinin, 12% by weight (0.0021 mole) of 8-ergocryptine and 20% of unidentified substances of plant origin. The mixture is suspended at room temperature in a mixture of 100 ml of methanol and 10 ml of glacial acetic acid, while stirring, 11 g (0.081 mol) of monopotassium phosphate are added and the mixture is stirred at -400C for 2 hours, then 80 ml of water is added to the mixture and concentrated under vacuum at 450 ° C. to a volume of 70 ml. The concentrated mixture is left to stand at room temperature for 24 hours. The product obtained is separated as described in Example 1. 11.9 g of a mixture of phosphates of the alkaloids of ergot of rye. The mixture of bases which one releases from it has the following composition
37% by weight of ergocornine,
19% by weight of a-ergocryptine,
10% by weight of 8-ergocryptine.

Use of alkaloids: 18%.

Specific rotary power of base mixture Z 720 = -186 (c = 1, chloroform).

EXAMPLE 5
As starting material, 10 g of a mixture of bases is used which has the following composition: 45% by weight (0.00798 mole of ergocornine, 25% by weight (0.00437 mole) of α-ergocryptine, 10 % by weight (0.00175 mole) of B-ergocryptine, 4% by weight (0.000698 mole) of ergotamine and 16% of unidentified substances of vegetable origin The mixture is suspended in a mixture of 100 ml of methanol and 3.5 ml of formamide.

2.45 g (0.0163 mole) of d-tartaric acid and 100 ml of water are added to the suspension, with stirring. The reaction mixture is concentrated in vacuo to 30 ml at a maximum temperature of 300C and then allowed to stand for 2 hours at -5 ° C. The product obtained is separated, as described in Example 1. 10.45 g of mixture of tartrates of the alkaloids of rye ergot are obtained. The mixture of bases which is released from this mixture of salts has the following composition
41% by weight of ergocornine,
22% by weight of a-ergocryptine,
9.1% by weight of ss-ergocryptine,
0.2% by weight of ergotamine.

Use of alkaloids: 94%
Specific rotary power of the basic mixture g 720 = -185 (c = 1, chloroform).

EXAMPLE 6
As starting material, 10 g of a mixture of rye ergot alkaloids obtained by fermentation and having the following composition are used: 38% by weight (0.00674 mole) of ergocornine, 23% by weight (0.00402 mole) of a-ergocryptine, 12% by weight (0.00209 mole) of ss-ergocryptine, 18% by weight (0.0312 mole) of ergonine and 9% by weight of unidentified components .

The mixture is dissolved in 500 ml of ethyl acetate and the solution is extracted once with 100 ml, then 4 times with 20 ml of a formamide / phosphoric acid mixture 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 the addition of 50 ml of carbon tetrachloride. The pH of the aqueous phase freed from ethyl acetate is adjusted, with vigorous stirring, using ammonia concentrated to 3.5 The phosphates of the alca ergotoxin bids immediately begin to separate and after standing from 10 hours at 5 ° C, most of it has practically precipitated. The precipitated salt mixture is washed twice with 20 ml of water and then dried under vacuum at 400C maximum. The mother liquors obtained during filtration are put aside for further processing. 8.9 g of a mixture of phosphates are obtained in which the bases are distributed as follows
45% by weight of ergocornine,
26% by weight of a-ergocryptine,
15% by weight of 8-ergocryptine,
1% by weight of ergonine.

Specific rotary power of the basic mixture Za ~ 7D = -183 (c = 1, chloroform).

The pH of the mother liquors is adjusted to 7 with concentrated ammonia, the precipitate obtained is filtered, it is washed twice with 20 ml of water and it is dried under vacuum at 40 ° C. maximum. 2.28 g of a mixture of bases mainly containing alkaloids from the ergoxine group are obtained, having the following composition
72% ergonine,
7% ergocornine
4% of a-ergocryptine
2% B-ergocryptine.

EXAMPLE 7
As starting materials, 10 g of a mixture of rye ergot alkaloids obtained by fermentation and having the following composition are used: 15% (0.00266 mole) of ergocornine, 11% (0.00192 mole ) of a-ergocryptine, 17% (0.003 mole) of B-ergocryptine, 6% (0.0016 mole) of ergocorninine, 9% (0.00105 mole) of a-ergocryptinine, 2% (0.00035 mole) of B-ergocryptinine, 7% (0.00122 mole) of ergotamine, 4% (0.000698 mole) of ergotamine, 5 (0.000869 mole) of ergonine, 3% (0.00052 mole) of ergoninin, 2% (0.000354 mole) of ergoptin, 8% (0.00142 mole) of ergoptinin and 11% of unidentified impurities. The mixture is dissolved in a mixture of 100 ml of methanol, 5 ml of dimethylformamide and 6 ml of concentrated phosphoric acid in aqueous solution. 400 ml of water are added to the solution. Then, the mixture is concentrated under reduced pressure at 40 ° C. maximum to a volume of 300 ml.

The pH of the solution which crystallizes is adjusted to 3, then the mixture is stirred at O * C for 20 hours. The crystals are separated by filtration, washed twice with 20 ml of water and dried in vacuo at 40 ° C maximum. The mother liquors obtained after filtration of the crystals are set aside for further processing.

5.62 g of a mixture of alkalose phosphates of 11 rye ergots are obtained. The bases are present in the following report in this mixture
29% ergocornine
22% of a-ergocryptine
31% ss-ergocryptine
0.5% ergotamine
0.5% ergonine
0.3% ergoptin.

Specific rotary power of base mixture Z 720 = -181 (c = 1, chloroform).

From the mother liquors, 4.48 g of an alkaloid mixture containing mainly derivatives of the group of ergotamine and ergoxine and having the following composition are obtained in the manner described in Example 6
9% ergotamine,
8% ergotaminine,
8% ergonine,
8% ergoninine,
7% ergoptin,
13% ergoptinin,
2% ergocornine,
7% ergocorninine, -.

1% of α-ergocryptine,
16% of a-ergocryptinine,
1% ss-ergocryptine,
2% B-ergocryptinine.

EXAMPLE 8
As starting material, 10 g of a mixture of rye ergot alkaloids obtained by fermentation and having the following composition are used: 25% (0.00443 mole) of ergocornine, 3% (0.000530 mole ) of ergonine, 2% (0.000350 mole) of ergoptin, 8% (0.00140 mole) of ergocorninine, 15% (0.00266 mole) of -ergocryptinin, 7% (0.000020 mole) of B-ergocryptinine, 2% (0.000360 mole) of ergoninine, 2% (0.000360 mole) of ergoptinine and 12% of unidentified impurities. The mixture is dissolved in a mixture of 40 mol of formamide and 5 ml of concentrated phosphoric acid. After all the material has dissolved, 400 ml of water are added and the pH of the solution is adjusted to 3 using concentrated ammonia with vigorous stirring. The solution containing the precipitate at OOC is left to stand for 3 hours. Then the solid product obtained is filtered off, washed twice with 20 ml of water and dried under vacuum at 40 ° C maximum. 5.82 g of the phosphate mixture of rye ergot alkaloids are obtained. The basics are present in the following report
40% ergocornine
21% of a-ergocryptine
17% ss-ergocryptine
2% ergoxine and ergotamine as impurities.

The mother liquors obtained during the separation by filtration of the mixture of phosphates, in the manner described in Example 6, are treated. 4.82 g of a mixture containing mainly compounds of general formula (II) and alkaloids from the ergoxine group.

The mixture has the following composition
2% ergocornine
2% of a-ergocryptine
2% 8-ergocryptine
5% ergonine
4% ergoptin
14% of a-ergocorninine
29% of a-ergocryptinine,
13% B-ergocryptinine,
4% ergoninine,
5% ergoptinin.

 10 g of this mixture are epimerized and the alkaloids from the ergoxine group are separated, as follows. The 10 g are dissolved in a mixture of 100 ml of methanol, 2 ml of 85% aqueous phosphoric acid and 6 ml of formamide. To this solution is added 150 ml of water.

The reaction mixture is concentrated under reduced pressure at SO * C to a volume of 100 ml and then left to stand for 7 days in the dark. The precipitated crystals are filtered off, washed twice with 10 ml of water and dried at 400C. 6.46 g of a mixture of phosphates of the alkaloids of rye ergot are obtained. The basics are present in the following report
21% ergocornine
42% of a-ergocryptine
19% ss-ergocryptine
2% of ergoxine alkaloids.

As is apparent from the above, the invention is in no way limited to those of its implementation, production and application nodes which have just been described more explicitly; on the contrary, it embraces all the variants which may come to mind for the technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims (1)

Claim b) in the case of the separation of a mixture of compounds of general formula I and of alkaloids from the group of ergotamine and / or ergoxine, the mixture of starting alkaloids is treated in the presence of solvents organic and acidic with phosphoric acid or tartaric acid or a mixture of an acid phosphate or tartrate and another acid, the solvent is optionally partially removed from the reaction mixture, the pH of the optionally concentrated reaction mixture, at 2-5, the mixture is allowed to stand until the compounds of formula) have precipitated in the form of their salts, the salts are then separated and, if desired, released in a manner known the bases from the salts. a22) the pH of the first mother liquors obtained by separation of the salts is adjusted to a value which is higher than that of the pH adjusted in variant a2 and which is advantageously between 1.9 and 4.0, and in particular between 2.1 and 4.0 and the precipitated fraction containing mainly alkaloids from the ergoxine group is separated, then the pH of the second mother liquors is adjusted to 2.5-5.5 and preferably to 3.5 -5.5, and separating the precipitated fraction containing mainly alkaloids from the group of ltergotamine and then treating, if desired, according to the process variant a1, the fraction consisting mainly of alkaloids of general formula (I3, obtained from the third mother liquor, or a21) the first mother liquors obtained during the separation of the salts are adjusted to a pH between 5.5 and 10 and preferably between 5.5 and 7, and isolated the precipitated mixture which consists of compounds of general formula (II) also containing as i impurities of the alkaloids of general formula (i), as well as by alkaloids from the group of ergotamine and / or ergoxine and, if desired, treated according to process variant a1, or a2) or by phosphoric acid or tartaric acid, then the solvent is optionally partially removed from the reaction mixture, the reaction mixture which is optionally concentrated is adjusted to a pH of between 1.8 and 3.5 and then allowed to stand until precipitation of the main quantity of the compounds of general formula and I) obtained in the form of salts, the precipitated salts are separated and the bases of general formula are freed, if desired, and if desired, a1) by phosphoric acid or a mixture of acid phosphate or tartrate or tartaric acid and another acid, then the solvent is optionally partially removed from the reaction mixture and the optionally concentrated reaction mixture is left to stand at a pH between 1.8 and 4 until the end of the epim erection and separating the compounds of general formula (I) precipitated in the form of their salts and releasing, if desired, from the salts obtained, the bases of general formula (i) in a manner known per se, a) in the case of the epimerization of the ergot alkaloids of general formulaCII) possibly also containing ergot alkaloids of formula (I) or in the case of the epimerization and separation of a mixture containing ergot alkaloids of general formulas (I) and (II) and furthermore alkaloids from the ergotamine and / or ergoxine group, the starting alkaloid mixture is treated in the presence of water and organic solvents - by separation of the rye ergot alkaloids of general formula (I) and optionally of general formula II from a mixture also containing alkaloids from the ergotamine group and / or l ergoxin and optionally carrying out an epimerization of the compounds of general formula t which proc edé is characterized in that in which R has the same meaning as above, possibly also containing ergot alkaloids of general formula tIX, or - by epimerization in the presence of organic solvents and alkaloid acid of l 'pin of general formula (II) below :: R represents an isopropyl, secondary butyl or isobutyl group, or their salts or mixtures of these compounds or their salts in which  1 - Process for the production of ergot alkaloids which correspond to the general formula (I) below