SU542475A3 - Method for producing ergot alkaloids - Google Patents

Description

(54) METHOD FOR OBTAINING SPORN ALKALOIDS

one

This invention relates to a process for the preparation of healthy alkaloids, for example alkaloids of an ergotamine or ergotoxin group.

A known method for producing ergot alkaloids of the general formula I

ABOUT

II

s-: nA

EI-: No.

where XY is —CHj — CH or —CH C;

R is hydrogen, lower alkyl, alllyl 20

or benzyl;

- N Н -А - cyclic polypeptide residue of the type of polypeptide residues contained in the structure of peptide alkaloids of ergot by interaction of hydrochloride 25

lysergic acid acids with the salt of the main peptide component of alkaloids in an inert organic solvent B in the presence of an acid acceptor.

However, the known method is complicated.

In order to simplify the process, a compound of formula II is provided.

From the UN

where CGU is the group CH-CH C:, C CH-CC or iCH-CHg-CHi; R - as indicated above, treat with salt of the compound

formulas

H - NH - A

where —NH-A is as defined above, B is an inert solvent medium in the presence of N-di (lower) -alkyl substituent amide of aliphatic monocarboxylic acid with 1–3 carbon atoms, chlorinating or brominating agent, for example oxalyl chloride, thionyl chloride or phosgene, and an acid acceptor , for example pyridine, followed by separation of the target product in a known manner. Of the inert organic solvents, acetonitrile, chloroform, methylene chloride and dimethylformamide (DMF) are most suitable. The reaction is usually carried out at (-10) 20 ° C. As a starting compound, you can use a mixture of 1-R-lyserginic, 1-R -isolizierginic and iK -6S 9 -metal-D-ergolane-8-carboxylic acids, which can be obtained directly but by saprophytic dilution of strain NB RL 3080 of the genus Ceoiviceps paspa 8i Stevens et HaE. Example 1 Ergotamine and Nin Ergotami, 40 ml of oxalyl chloride (3.18 (25 mmol) oxalyl chloride) cooled in -10 C absolute DMF for 5 minutes with vigorous stirring, are added dropwise in 5 ml at absolute temperature, 5.36 are added. g (20 mmol) of an anhydrous mixture of 40% 6-methyl-D®-ergolen-8-carboxylic acid, 40% lysergic acid and 20% isoisergic acid, the resulting dark brown suspension is stirred for 5 min at -0-C, 40 ml of absolute pyridine, maintaining the temperature not higher than -10 ° C, a suspension of 3.86 g (10 mmol) is introduced ( 2 R, 5 5, Yu 5, lObS) -2-amino-5-benzi-3, 6-dioxo-1O b -hydroxy-2-methyl octahydro-8H-oxazolo 3,2-a-pyrrolo-2, 1 -e-pyrazine hydrochloride in 40 ml of absolute DMF and stirred for 2 hours at -10 ° C. Then dilute 5OO ml of methylene chloride and extract with 2OO ml of 2N sodium carbonate, extract the aqueous phase 3x with methylene chloride, dry the combined organic phases are over sodium sulfate, the solvents are distilled off in vacuo, traces of pyridine with toluene (2 x 200 ml) are distilled off and the residue is recrystallized from a bright ocher color from 50 ml of methanol to obtain a pure red ergotaminin-crystal, m. pl. 236-237 ° С (decomp.) + 3750С (с 0.5, chloroform). The mother liquor is evaporated to dryness, the residue is treated with a mixture of 4O ml of methanol and 7 ml of glacial acetic acid containing 0.25 g of sulfuric acid in a small amount of methanol, kept in the refrigerator for 2 hours and brown shiny crystals of ergotamine sulfate, m.p. . 201-203 C, which are treated with a 5% aqueous solution of ammonia and chloroform, dried over sodium sulfate and activated carbon, mixed with a theoretical amount of d-tartaric acid in methanol, concentrated and an almost white ergotamine tartrate is obtained. The mother liquor, after isolation of ergotamine sulfate, is concentrated in vacuo, the sulfate is converted into base, chromatographed on a 30-fold amount of alumina (1 st.act.), Eluted with methylene chloride, and pure ergotamine is obtained. When eluted with methylene chloride containing 0.5% methanol, an additional amount of ergotamine is obtained. Ergotamine is dissolved in a double amount of glacial acetic acid, a theoretical amount of sulfuric acid and a tenfold amount of methanol are added, kept at room temperature, and ergotamine sulfate is obtained. Example 2 Ergostin. From 3.18 g (25 mmol) oxalyl chloride, 5.36 g (2 O mmol) anhydrous mixture of 4 O% 6-methyl-l-ergol-8-carboxylic acid, 40% lysergic acid and 20% zolosergic acid and 5.56 g (10 mmop) (2 R, 5 S, 10a S, 10 1) S) -2-amino2-ethyl-5-benzyl-3, 6-dioxo-10 L-hydroxy octahydro-8H-oxazolo-3,2-a -pyrrolo-2,1-e-pyrazine-hydrochloride in dioxane gives the desired product as in Example 1. Example 3. Ergokristin. Ergocristin is prepared as in Example 1, from 3.18 g (25 mmol) oxalyl chloride, 5.36 g (20 mmol) of an anhydrous mixture of 40% 6-methyl-ergol-8-carboxylic acid, 40% lysergic acid and 20% isoiziergic acid and 4.7 g (10 mmol) (2 R, 5 5, Yua S, 10 t S) -2-amino-5-benzi; -3,6-dioxo-10 b -hydroxy-2-isopropyl octagidro-8H-oxazolo-3,2-a pyrrol-2,1-e-pyrazine hydrochloride in DMF. Example 4. Ergovalin. Ergovalin is synthesized as in Example 1, using 3.18 g (25 mmol) of oxalyl chloride, 5.36 g (20 mmol) of anhydrous mixture of 4O% 6-methyl-D-ergol-8-carboxylic acid, 40% lysergic acid and 2% izolisergic acid and 3.2 g

(10 mmol) (2 R, 5 S, lOa S, lOtS) -2-amino-2-methyl-5-isopropyl-10 t) -hydroxy-3, 6-dioxooctahydroxazolo- 3,2- -a -pyrrole - 12.1-c-pyrazine-hydrochloride da.

Similarly to Examples 1-4, ergocornine, ergocryptin and ergonin are obtained.

Example 5 Ergotamine and erghetamine.

A mixture of 10 ml of absolute DMF and 30 ml of absolute methylene chloride is cooled to -10 ° C, 2.14 g of thionyl chloride in 10 ml of methylene chloride is added dropwise to a solution, 4 are added at -10 ° C, O2 g is dried under high vacuum 4 - lysergic acid and stirred for 5 min at -10 ° C. Then 3.68 g (2 R, 5S, lOaS, lots) -2-amio-2-methyl-5-benzyl-10 b -hydroxy-3,6-dioxooctahydroxazolo-Gz, 2-aj-pyrrolo-2D is added. -C-pyrazine hydrochloride, 10 ml of absolute pyridine is added dropwise during 15 minutes while stirring and -10 ° C and stirred in the dark for 0.5 hour at and within 1.5 hours at room temperature. The reaction mixture is diluted with 500 ml of methylene chloride, treated with 250 ml of 4N potassium carbonate, the aqueous phase is extracted with 3 x 500 ml of methylene chloride, the extract is washed with a dilute solution of sodium chloride, dried over sodium sulfate, the solvent is removed, the brown residue is crystallized from 40 ml of methanol and isolate ergotamine, m.p. 225 ° C 227 ° C (decomp.). After recrystallization from a mixture of methylene chloride-methanol, m.p. 231 ° C (decomp.); loif ° + 375 ° C (with 0.5 chloroform).

The mother liquor after separation of the ergamine is evaporated to dryness, the residue is dissolved in a small amount of aqueous acetone and the ergotamine crystallizes, m.p. 172-175 ° C (decomp.); 1-7.7 ° (c 1, pyridine).

Example 6. 1-Methyl ergotamine and 1 methylergoaminine.

5.95 g of thionyl chloride are dripped into the cooled 5 ° C solution of 5 O ml of absolute DMF in 150 ml of absolute methylene chloride for 5 minutes while stirring, stirred for 5 minutes, 14.1 g of 1-methyl-5 are added at -10 ° C. α-liageric acid, stirred for 5 minutes, 30 ml of absolute pyridine were added dropwise to the resulting brown solution at -10 ° C and stirred for 5 minutes, and 9.2 g (2 R, 5 S, lOa 5, lObS) was added -amino-2-methyl-5-benzyl-10 L-hydroxy-3, 6-dioxooctahydroxazolo-3,2-a-pyrrolo-2,1-e-pyrazine hydrochloride, stirred for 0.5 hour at 0 ° C and 3 hours at room temp ture was diluted with ethyl acetate 7OO mL, ekstragiruyut50O ml

20% potassium carbonate solution, the aqueous phase is extracted with 3 X 700 ml of ethyl acetate, the combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and poured into

vacuum. The residue is chromatographed on 500 g of alumina (1 st.act.), Eluting with methylene chloride containing 0.1% methanol, and 1-methylergo-aminine is isolated, which is crystallized from methylene chloride-methanol, m.p. 219-220 ° C (decomp.); + 390 ° (with 0.5, pyridine). When eluted with methylene chloride containing 0.2% methanol, 1-methylergotamine was isolated. After crystallization from a mixture of methylene chloride-methanol, m.p. 167-170 ° C

(different); ° -163 ° (with 0.5, chloroform).

Example 7 9,10-Dihydroergotamine.

1O, 8 g (40 mmol) of 9,10-dihydrolisergic acid are suspended in 1OO ml of absolute DMF, cooled to -10 ° C, 4.72 g (40 mmol) are dropped in within 5 minutes

thionyl chloride, stirred for 30 minutes at -5 ° -O 4, 4O ml of absolute pyridine was added, at -15 ° C and strong stirring was added 7.36 g (20 mmol) (2 R, 5S, 10aS, 10bS) -2-amino -2-methyl-5-benzyl-10 b -hydroxy-3,6-dioxooctahydroxazolo-G3,2-a} -pyrrolo-2,1-cj-pyrazine hydrochloride formed

a lot of brick color is stirred for 100 min at -5 - O C, the formation of a honey-yellow mass is observed, which is diluted with 500 ml of chloroform, treated with 300 ml of 2N ammonia and the aqueous phase is extracted with 3 x 20O ml of chloro-j form containing 5% methanol. The combined organic phases are washed with water, dried over sodium sulfate, the solvent is removed in vacuo, the remaining yellow foam is dried for 2 hours in high vacuum

5pri 100 C, in high vacuum, so pl. 235-239 ° C (decomp.); Ld. -65 ° (s

dg 1, pyridine).

Example 8. 9,1O-Dihydro ergocryptin.

6Я 10.8 g (4O mmol) of 9,10-dihydrolisergic acid are suspended in 100 ml of absolute DMF, cooled to -10 ° C, 4.72 g (40 mmol of thionyl chloride) are added dropwise in 5 minutes, stirred for 30 minutes

Claims (1)

b 5-0 ° C, 40 ml of absolute pyridine are added, and with stirring, 7.24 g (20 mmol) (2 R, 5 S, 10a S, 10 bS) -2-amino-2-isopropyl- 5-isobutyl-10 b -hydroxy-3,6-dioxooct-hydroxazolo-3,2-a-pyrrolo-G2D-c-pyrazine hydrochloride and stir the resulting mass of brick color at -5 ° C for 10 ° C, a transition is observed brick color in honey yellow. The reaction mixture is treated as in Example 7, but recrystallization is performed with 9,10-β-dihydro-ergocryptin from 60 ml of ethyl alcohol, dried for 2 hours under high vacuum at 10 ° C, so pl. 230-235 ° C (decomp.); 41 ° (with 1, pyridine). Example 9. 9,10-Dihydroergocristin. From 10.8 g (40 mmol) of 9,10-dihydrolisergic acid in 10 O ml of absolute DMF, 4.72 g (40 mmol) of thionyl chloride, 40 ml of absolute pyridine and 7.96 g (20 mmol) of 2 amino-2-isopropyl -5-benzyl-10 b -hydroxy-3,6-dioxooctahydroxazolo-3,2-a-pyrrolo-2,1-cj-pyrazine hydrochloride, similarly, when measure 8 after recrystallization from 60 m of acetone, 9,10-dihydroergocris- Tin, which is dry for 2 hours at 10 ° C under high vacuum, so pl. 178-180 C g) t 2O ОO -64 ° (c 1, pyridine (group of claims) 1. Method for producing spore alkaloids spores of the general formula I T G-CH 3 7S CHUS-CH or -CH 2; E is hydrogen, lower alkyl , allyl, or benzyl; - NH - A- cyclic polypeptide residue of the type of polypeptide residues contained in the structure of peptide spore alkaloids, characterized in that, in order to simplify the process, the compound of general formula II where IX Y is CH-CH SLS / C CH or CH-CHs. -sna; R has the above meanings, is reacted with a salt of a compound of the general formula III H-NH-A, where is NH-A - as indicated further, in an inert solvent in the presence of N -dg1- (lower) -alkyl-mixed amide of aliphatic monocarboxylic acid with 1-3 carbon atoms, chlorinating or brominating agent, for example oxalic chloride, thionyl chloride or phosgene, and an acid acceptor, for example pyridine , followed by isolation of the target product in a known manner. 2, A method according to claim 1, characterized in that a mixture of 1-R-lehrgne, 1-R-isolyzergin and 1-R-6-methyl-ergol is used as the starting compound -8-carboxylic acids.