SU1222198A3 - Method of producing ergoalkaloids (versions) - 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

where R-iso-propyl I BTOR-butyl, m-butyl,

or their salts, mixtures of their compounds or their salts by separating the precipitation of ergo apcaloids of general formula T in the presence of organic solutions of the bodies and an alcoholic solution of phosphoric acid from a mixture containing ergoalkaloids of formulas I and

 -

when, if desired, epimerising compounds of the formula P, characterized in that, in order to simplify the process, the initial mixture containing alkaloids of the general formula T and / or M, as well as ergotamine and / or ergoxin, is subjected to separation by precipitation or in the presence of 20 - 95 wt.% water in the reaction mixture, after which, if necessary, the solvent is partially removed by evaporation, the thickened reaction mixture is removed for 1-7 days, and the compounds of general formula I precipitated as salts are separated om their base.

one

The invention relates to an improved method for the creep of ergoalkaloids of the general formula T

HX. , to-n; H JV-1

-N

, c-i.o

. H i

H

known pharmacologically active compounds, and its variant.

The purpose of the invention is to simplify (the process due to the conservation of the quantitative pairs of epimeric alkaloids in the feedstock.

Example 1. As the starting material take 10 g of a mixture of ergoapcaloids of the following composition, ergokorninin 53 (0.0094 mol); ergocryptinin 24 (0.0042 mol),) 5-ergocryptinin 13 (0.0023 mol); non-resident 11- plant substances 10, The mixture is dissolved in a mixture of 100 ml of methanol, .2 ml (0.0345 mol) 85% aqueous phosphoric acid and 6 ml form. amide, the Solution is mixed with 50 ml of water. The reaction mixture is extruded.

under reduced pressure and up to a volume of 40 ml and then left at room temperature for 7 days in the dark. The precipitated crystals are filtered, washed twice with 10 ml of water and dried at 40 ° C under vacuum. The mixture of bases liberated from salts has the following composition, May,%:

Ergokornin 48 O1-Ergokriptin 22 p-Ergokriptin 12 Use of alkaloid: 94% (a mixture of phosphates: 10.3 g), Specific rotation of a mixture of bases: 1s -180 (, chloroform). Example 2. South of a mixture of ergo-alkaloids of the following composition, wt.%: Argocornine 39 (0.00692 mol); oi. ergocriptine 15 (0.00263 mol); p-ergocryptin 3 (0.000520 mol); ergoorninin 27 (0.00479 mol); p-ergocryptin 2; unidentified substances of plant origin 7 - dissolved in a mixture of 100 ml of acetone, 7 ml of formamide and 6 ml (0.104 mol) of a 5% aqueous phosphoric acid solution, 100 mp are added to the solution

water. The mixture is then evaporated under reduced pressure to a volume of 50 ml. The thickened mixture is left for 3 hours at 80 ° C, then for 24 hours at room temperature. The product is described3

and in example 1. 9.8 g of ergoalkapoid phosphate mixture are obtained. The base mixture liberated from it has the following composition, wt%:

Ergokornin 61 o.-Ergokriptin. 20

r-ergocryptin 4

Alkaloid use: 98%,

The specific rotation of the mixture of bases 185 ° (1, chloroform).

Example 3. As a starting material, take 10 g of a mixture of ergo-alkaloids of the following composition, wt.% Ergocornine 39 (0.00619 mol); d-ergocryptin 15 (0.00260 mol); fs-ergocryptin 3 (0.000520 mol); ergocornine 27 (0.00479 mol); o (- Ergocryptinin 7 (0.00122 mol); o (. - ergocryptine 2 (0.00035 mol); unidentified substances of plant origin 7. 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 (0.0647 ml) of sodium dihydrogen phosphate is added to the solution with stirring and the reaction mixture is stirred at 35-40 ° C for 2 hours. Then the mixture is stirred with 80 ml of water and evaporated at 50 C in vacuo to a volume of 70 ml. The condensed mixture is left at room temperature for 24 hours, and then the product is separated in the manner described in Example 1. uchayut 10.6 g of a mixture of phosphate release from it a mixture of ergot alkaloids - base has the following composition, wt.%:.

Ergokornin 61 oi. Ergocryptin 20 r ergriptin 5

Use of alkaloids: 98%.

Specific rotation of the base mixture

about 13

ten

-183 (with 1, chloroform);

Example4. As a starting material, 10 g of a mixture of ergoalkaloids is taken, which has the following composition, wt%: ergokorninin 45 (0.00798 mol); oi - ergocryptine 23 (0.00402 mol); p-ergocriptine .. 12 (0.0021 mol); unidentified substances of vegetable origin 20. 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 potassium dihydrogen phosphate are added and the mixture is stirred at 40 C for 2 hours. The mixture is then stirred with 80 ml of water and evaporated in vacuo at 45 ° C to

221984

. volume of 70 ml. The thickened mixture was left at room temperature for 24 hours. The product was separated by the method described in Example 1. Obtain 11.9 g of a 5 phosphate mixture of ergot alkaloids. The liberated mixture of bases has the following composition, wt.%: Ergokornin 37 Y-Ergokriptin 19 10 - p-Ergriptin 10

Use of alkaloids: 98%; Specific rotation of a mixture of bases: -186 ° (s 1, chloroform).

j Example5. As the starting material, 10 g of a mixture of bases of the following composition is taken, wt%: ergocornine 45 - (0.00798 mol); ot-ergocryptin 25 (0.00437 mol); p-ergo-2p kriptin 10 (0.00175 mol); ergotamine 4 (0.000698 mol); unidentified substances of vegetable origin 16. The mixture is suspended in. mixtures of 100 ml of methanol and 3.5 ml of form-25 amide. With stirring, 2.45 g (0.0163 mol) of D-tartaric acid and 100 ml of water are added to the suspension. The reaction mixture was evaporated in vacuo at max. 30 ° C to a volume of 30 ml and then left at -5 C for 2 hours. The product is separated as described in Example 1. 10.45 g of a mixture of ergoalkaloid tartrates are obtained. The free mixture of bases from this mixture of salts has the following composition:., 5 wt.%:

Ergokornin 41 0 - Ergocryptin 22 - Ergocryptin 9.1 Ergotamine 0.2 Alkaloid use: 94%.

The specific rotation of the mixture of bases: -185 (with I, -chloroform)

PRI me R 6, 10 g obtained as the starting material are obtained by fermentation of a mixture of ergo apcaloids of the following composition, wt.%, Ergocore; Nin 38 (0.00674 mol); o1-ergocryptin 23 (0.00402 stranded); ergocryptin 12 (0.00209 mol); ergonin 18 0 (0.00312 mol); unidentified impurities 9; The mixture is dissolved in 500 ml of ethyl acetate. The solution is extracted once with 100 ml, then four times, each time with 5 for 20 ml of a mixture of formamide: Vrda, phosphoric acid in a ratio of 10: 87: 3 with a pH value of 1.8, The aqueous phases are combined and ethyl acetate extracted from water

thirty

phase with the addition of 50 ml of carbon tetrachloride. The pH of the ethyl acetate-free aqueous phase is adjusted with vigorous stirring with concentrated ammonia to 3.5. Phosphates of ergotoxin alkaloids begin to precipitate immediately, and at 10-hour exposure at the main amount precipitates. The precipitated mixture of salts is washed twice with 20 ml of water and then dried under vacuum as much as possible with AO C. The mother liquor obtained during filtration is recycled. 9.8 g of a phosphate mixture are obtained, in which the bases are distributed as follows, wt%:

Ergokornin 45

about (.- ergokriptin 26

E-ergocryptin 15

Ergonin 1

Specific, rotation of the mixture of bases -183 ° (1, chloroform).

The pH of the mother liquor is adjusted to 7 with concentrated ammonia, the precipitated precipitate is filtered off, washed twice with 20 ml of water and dried under vacuum at maximum. 2.28 g of a basic mixture of ergoxine alkaloids of the following composition are obtained,%:

Ergonin 72

Ergokornin 7: s1-Ergokriptin 4

R-Ergokriptyn 2

Method 7: 10 g obtained as the starting material were obtained by fermentation of a mixture of ergoalkaloids of the following composition,%: Ergocornine 15 (0.00266 mol); ot-ergocriptine 11 (O, 00192 mol); p-ergocriptine 17 (0.003. mol); ergocorninin 6 (0.0016 mol); oi-ergocryptinine 9 (0.00105 mol); p-ergocriptine 2 (0.00035 mol); ergotamine 7 (0, mol); ergotamine 4 (0.000698 mol); ergonin 5 (0.000869 mol); ergoninin 3 (0.00052 mol); ergoptin 2 (0.000354 mol); ergoptinin 8 (0.00142 mol); unidentified impurities. 11. The mixture is dissolved in a mixture of 100 ml of methanol, 5 ml of dimethylformamide and b ml of concentrated aqueous phosphoric acid. 400 ml of water are added to the solution. Then the mixture is evaporated under reduced pressure at maximum 40 ° C to a volume of 300 ml. The pH of the crystallized solution is adjusted to 3, then the mixture is stirred at 20 hours. The crystals are filtered, washed twice with 20 ml of water and dried under vacuum at maximum. The mother liquor obtained during the filtration of crystals napa, 0, is equal for further processing. 5.62 g of ergoalkaloid phosphate mixture is obtained. The bases are in this mixture in the following ratio,%:

5 Ergokornin 29 d, - Ergokriptin 22 (5-Ergokriptin 31 Ergotamine 0.5 Ergonin 0 | 5 0 Ergoptin 0.3

The specific rotation of the mixture of bases: -181 ° (1, chloroform). From the mother liquor using the method described in example 6, 4.48 g 5 are obtained that contain: mainly ergotamine and ergoxin components of the mixture of alkaloids of the following composition,%: Ergotamine 9 Ergataminine 8 0 Ergonin 8

Ergoninin 8.

Ergoptin 7 Ergoptinin 13 Ergokornin 2 Ergokorninin 7 d-Ergokriptin 1 d-Ergokriptinin 16 p-Ergokriptin I - Ergokriptinin 2

Example8. 10 g obtained by fermentation of a mixture of ergoalkaloids of the following composition,%, are used as the starting material: Ergokornin 25 (0.00443 mol); ergonin 3

 (0.000530 mol); ergoptin 2 (0.000350 mol); ergocornin 8 (0.00140 mol); o-ergocriptine 15 (0.00266 mol); 1-ergocryptine 7 (0.00120 mol); ergoninin 2

0 (0.000360 mol); ergoptinin 2

(0.000360 mol); unidentified impurities 12. The mixture is dissolved in a mixture of 40 ml of formamide and 5 ml of concentrated phosphoric acid. After

40 ml of water are added to dissolve completely, the pH of the solution with vigorous stirring is adjusted to 3 with concentrated, and ammonia content. Contained 40 21 17

The precipitating solution is left to stand for 3 hours. Then the solid product is filtered off, washed twice with 20 ml of water and dried under vacuum at maximum 40 ° C. 5.82 g of ergot alkaloids fofate mixture are obtained. The bases are in a mixture in the following ratio,%:

Ergokornin

d-ergocriptine

Ergocryptin

Ergoxin and

ergotamine 2

The stock solution obtained by filtering out the phosphate mixture is recycled in the manner described in Example 6. Obtain 4.82 g containing mainly the compounds of general formula P and ergoksin-alkaloids mixture The mixture has the following composition,%:

Ergokornin 2 gokripin tin 2 jp-Ergokriptin 2

Ergonki 5

Ergoptin 4 oL-Ergokornin 14 oL-Ergokriptinin 29

Ergkriptinin 13

Ergonknin 4 Ergoptinin 5

10 g of the mixture is epimerized and separated from ergoxine-alkaloids, and they act in the following manner, 10 g of the mixture is dissolved in a mixture of 100 ml of methanol, 2 ml of 85% aqueous phosphoric acid M, Tsitskina Order 1623/61

Compiled by And Fedoseev

Tehred; G.Gerber Proofreader A

Circulation 379 Subscription

VNIIPI USSR State Committee for Inventions and Discoveries 113035, Moscow, Zh-35, Raushsk nab ,, d, 4/5

Branch ShSh Patent, g, Uzhgorod ,, st. Project, 4

You and 6 ml of formamide, 150 ml of water are added to the solution. The reaction mixture is concentrated under reduced pressure to a volume of 100 ml and then left. They are kept for 7 days in the dark. The precipitated crystals are filtered, washed twice with 10 ml of water and dried at 40 ° C. 6.46 g of ergot alkaloid phosphate mixture is obtained. The bases are mixed in the following ratio,%:

Ergokornin d. Ergocryptn j5-Ergocryptin Ergoxine-alkaloids Example 9,

21

42 19

10 g raw base

nor ergoalkaloids, containing, in weight,%: Ergokornin 78 (0.01374 mol); ergokorninin 3; ergometrine 10, dissolved in a mixture of 50 ml of methanol and 3 ml of 85% aqueous phosphoric acid. The solution is diluted, the pH is adjusted to 5.0. Then the reaction mixture is evaporated to 50 ml and held at room temperature for 30 minutes. The product which is separated out is filtered and washed with two 5 ml of water. Yield: 10.1 g of ergocornine phosphate. A base is recovered from it. The resulting ergocornus contains 1% ergocorninin and less than 2% argometrine.

Use of alkaloid: 97%, Specific rotation: -187 ° (s 1, chloroform),

Compiled by And Fedoseev

Tehred; G.Gerber Proofreader A, Obruchar

Claims (2)

The method of obtaining ergoalkaloids of General formula T O II containing, if necessary, ergoalkaloids of the general formula Ϊ, characterized in that, in order to simplify the process, the initial mixture containing alkaloids of the general formula Ϊ and / or 1_1, as well as ergotamine and / or. ergoxin, is subjected to epimerization in the presence of 20-95 wt. 2, water in the reaction mixture, if necessary, the solvent is partially removed by evaporation, the condensed reaction mixture is adjusted to a pH of 1.8-5, maintained for 17 days and the compounds of the general formula are precipitated as salts Ϊ with their subsequent transfer to the grounds. and 1222198 2. A method of producing ergoalkaloids of the general formula J where R is iso-propyl, sec-butyl, butyl or their salts, or mixtures of these compounds or their salts by epimerization in the presence of organic compounds and an alcoholic solution of ergoalkaloids phosphoric acid of the general formula 1_1 where R is njo-propyl, btor-butyl, isobutyl, or their salts, mixtures of their compounds or their salts by separation by precipitation of ergot alkaloids of the general formula 1 in the presence of organic solvents and an alcoholic solution of phosphoric acid from a mixture containing ergot alkaloids of the formulas I and I if desired, the epimerization of compounds of formula 11, characterized in that, in order to simplify the process, the initial mixture containing alkaloids of the general formula T and / or Y, as well as ergotamine and / or ergoxin, is subjected to separation by precipitation or, if desired, epimerization in the presence of 20 95 wt.% Water in the reaction mixture, after which, if necessary, the solvent is partially removed by evaporation, the condensed reaction mixture is kept for 1-7 days, and the compounds of the general formula I are precipitated in the form of salts, followed by their transfer to the base i.