SU645581A3 - Method of obtaining d-2-halogen-6-methyl-8-cyanomethyl- or d-2-halogen-6-methyl-8-carboxamidomethylergolines - Google Patents

Description

(54) METHOD OF OBTAINING 1) -2-HALOID 6-METAL-8 CYANOMETHYL-OR-2-HALOID-6-METHYL-8KARBOXAMIDOMETHYLERGOLINES

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This invention relates to a process for the preparation of novel 2-halide derivatives of D-Q methyl-8-cyanomethyl or / -b-methyl-3-carboxamidomethyl ergolines with high physiological activity.

The halogenation reaction with N-halo-succinimide is known.

For the purpose of synthesizing new halogen derivatives of) -6-methyl-8-cyanomethyl- or D-6-methyl-8-carboxamidomethylergoline, a preparation method based on the known reaction L-2-halo-6-methyl-8-cyanomethyl- or 1 is proposed. ) -2-halo-6-methyl-8-carboxamido ergolines of the general formula

where X is halogen;

R-CHsCN or SNHSOYNg, or their salts, which consists in the fact that D6-methyl-8-cyanomethyl- or O-6-methyl-8 carboxamidomethyl ergoline is subjected to halogenation .N-halo-succinimide, for example: L-chlorosuccinimide, followed by isolation of the target product in in free form or in salt form.

The stereochemistry of the ergoline derivative is identical to that of natural 1) -legic acid. Ergolin salts can be formed

with both organic and inorganic pharmaceutically acceptable acids, for example, sulfuric, acetic, tartaric, and others. The lezerginic and isolic acids are 8-carboxy-6-methyl-A ergoline. Lysergic acid amides, many of which have valuable and exceptional pharmaceutical properties, include natural alkaloids, such as ergocornine, ergocryptin, ergonovine, ergokristin,

ergozin, ergotamine, etc., synthetic compounds such as metergin, as well as a synthetic hallucinogen — lysergic acid diethylamide or LSD. Amides of 6methyl-8-carboxyergoline, known as

dihydroergoalkaloids, possess lower activity, and also lower toxicity, than ergoalkaloidy.

Example 1. Obtaining D-2-chloro-b-methyl-8-cyanomethylene ergoline.

400 mg of N-chlorosuccinimide is dissolved in 30 ml of dioxane, and the solution is added dropwise at 60 ° C to a stirred suspension of 535 mg /) - 6-methyl-8-cyanomethylene ergoline in 25 ml of dioxane, the mixture is heated for 4, 5 hours under the atmosphere nitrogen at 60-65 ° C, cooled, diluted with water, solid sodium bicarbonate added and extracted with chloroform. The extract is separated, dried, and the chloroform is removed in vacuo. The resulting crude residue showed two spots during thin layer chromatography. The residue is dissolved in chloroform and chromatographed on Florisil. Chromatography of each fraction of chloroform extracts shows that fractions 7–12 have the largest amounts of a new component (no initial weight, no evidence). These fractions were combined by thin layer chromatography and the chloroform was removed. From the residue, 165 mg of the desired product was recrystallized from ether; m.p. 270-273 ° C.

Similarly, D-6 - methyl-8-cyanmethylergoline is brominated with N-bromosuccinimide to give D-2 - bromo-6-methyl-8-cyanmethylergoline; m.p. 244-247 ° C (decomposition from ethanol).

Calculated,%: C 59.31; P 5.27; N 12.21; Br 23.21.

Found,%: C 59.33; H 5.37; N 11.96; Br 23.39.

Similarly, replacing N-chlorosucimimide with Niododucimimide, D-2-iodine — 6-methyl-8-cyanomethylergoline is obtained; m.p. 211-213 ° С (decomposition from ether).

Calculated,%: C 52.19; H 4.64; N 10.74; J 32.44.

Found,%: C 51.90; H 4.51; N 10.58; J 32.17.

Example 2. Obtaining D-2 - bromo-6-methyl-8-carboxamidomethyl ergoline.

240 mg /) - 6-methyl-8-carboxamidomethylethergoline is dissolved at 65-70 ° C under nitrogen in 25 ml of dioxane and a solution of 180 mg of N-bromosuccinimide in 20 ml of dioxane is added dropwise, the resulting mixture is heated for 30 minutes at 65-70 ° C with stirring, poured into saturated aqueous tartaric acid, extracted with chloroform and the chloroform layer is discarded. The aqueous layer is filtered, dilute ammonium hydroxide is added to alkaline reactions, and 2-bromo-6-methyl-8-carboxy-dimethyl ergoline is obtained, insoluble in an aqueous-alkaline solution, which is separated, dissolved in chloroform, the chloroform layer is separated, created and remove the solvent in vacuo, get the Target Product; m.p. 238-24ГС (decomposition from ether).

Salts with pharmaceutically applied

prepared by acids, a solution determined

the amount of ergolin base in ether and the addition of an equivalent amount of a pharmaceutically acceptable acid dissolved in ether. The salts obtained are usually not soluble in ether and are isolated.

by filtration and purified by recrystallization. Salts, a solution of ergblin base in ethanol can be obtained and an equivalent amount of a pharmaceutically acceptable acid in an ethanol solution can be added. In this case, the salts are dissolved and separated, removing the solvent in vacuo. The resulting residue, if it is not crystalline, can be easily crystallized from ethanol; or other suitable solvents.

Preparation of salts. 560 mg of D-2-bromo-b-methyl-8-cyanomethylene ergoline is dissolved in 40 ml of tetrahydrofuran (THF). - 10 ml of a solution of 1 g of maleic acid in 50 ml of THF are added with stirring to a solution of ergoline base, 200 ml of ether are added and the resulting precipitate is filtered off. Preparing: 1) -2-bromo-6-methyl-8-cyanomethylergoline acid maleic ester; m.p. 207-209 ° С (decomposition).

In a similar manner, maleic acid D-2-chloro-b-methyl8-cyanomethyl ergoline acid ester is obtained; m.p. 204-206 ° C (decomposition).

Similarly, 320 mg of (2) chloro-6-methyl-8 cyanomethyl ergoline was dissolved in 15 ml of THF. To the solution obtained, a solution of methanesulfonic acid in a solution is added in the

THF until precipitation occurs. The THF solution is diluted with ether and filtered to give () - 2-chloro-6-methyl-8 cyanomethyl ergoline methanesulfonic acid salt, m.p. 295 ° С (decomposition from ethanol - ether).

Calculated,%: C 54.61; H 5.60; N 10.61; C1 8.95; S 8,10.

Found,%: C 54.43; H 5.79; N 10.86; C1 9.22; S 8.18.

Similarly, 220 mg (2) - 2-chloromethyl-8-cyanomethyl ergoline is dissolved in 15 ml of THF. The resulting gelatinous precipitate slowly crystallized, diluted with ether and filtered, the isolate D-2-chloro-b-methyl-8-cyanomethyrolgoline tartaric acid salt; m.p. 247-249 ° C (from ethanol-ether).

Calculated,%: C 60.88; H 5.65; N 11.21; C1 9.46. Found,%: C 60.66; H 5.41; N 11.41;

C1 9.49.

Example 3. Obtaining -2-chloro-6-methyl-8-cyanomethylene ergoline depending on the halogenating agent. A. L-6-methyl-8-cyanmethylergoline (8X

HU mg) is suspended in 50 ml of acrylonitrile, the suspension is cooled from -5 to 0 ° C, 1.25 ml of boron trifluoride etherate is added and a solution of 0.27 ml of sulfuryl chloride in 200 ml of methylenedichloride is added dropwise, the mixture is stirred, cooled for 30 minutes, diluted ammonium hydroxide and extracted with a mixture of chloroform - isopropanol (3: 1). The organic layer is separated, washed with a saturated aqueous solution of sodium chloride, dried and nary. Chromatography of the residue on fluorosilicate using chloroform containing 2% methanol as the elution solvent yields 600 ml (72%) of the desired product; m.p. 268-27GS (decomposition). Similarly, get the target product, but using nitromethane instead of acrylonitrile as a solvent.

B. 625 mg of D-6-methyl-8-cyanomethylene ergoline is dissolved in 50 ml of dimethylacetamide (DMAA) and a solution of 770 mg of N-chloro-3,4,5,6-tetrachlorophthalimide in 30 ml of DMAA is added dropwise; heated for 35 minutes at 55 ° C, cooled and poured into an aqueous solution of ammonium. The ammonium solution is extracted with ethyl acetate, the organic layer is washed with water, dried and evaporated.

64% of the expected product are obtained by analogous chromatography on fluorosilicate.

B. Similarly, the desired product is obtained using 405 mg of 1-chlorobenzotriazole; yield 56%.

G. 2.25 g /) - 6-methyl-8 - cyanmethylergoline is dissolved in 175 ml of DMAA, a solution of 2.6 g of M-chloro-2,6-dichloro-4-nitroacetanilide in 50 ml of DMAA is added dropwise, a mixture stirred for 20 minutes at room temperature, poured into tartaric acid, extracted with ethyl acetate, and the extract was discarded. Then the tartaric acid solution is neutralized with ammonium hydroxide and again extracted with ethyl acetate. Organic

the layer is separated and treated as in item A, the residue is recrystallized and the desired product is obtained; yield 55%; m.p. 263-266 ° C.

D. 1.19 g of 1) -6-methyl-8-cyanomethylene ergoline is dissolved in 70 ml of dioxane, then a solution of 1.29 g of M-chloro-2, 4,6-trichloroacetanilide in 30 ml of dioxane is added dropwise, the mixture is treated as in p. G and get

target product, yield 46% (620 mg of lergotril).

Claims (1)

Invention Formula The method of obtaining D-2-halo-6-methyl-8 cyanomethyl- or D-2-halo-6-methyl-8-carboxamidomethyl ergolins of formula where X is halogen; R-CHaCN or SNGSOMNg, or their salts, characterized by by that that /) - 6-methyl-8 - cyanomethyl ergoline or /) - 6-methyl - 8 - carboxamidomethylegroline is subjected to halogenation with an appropriate halogenating agent, such as NX-succinimide, sulfuryl chloride, N-X-acetanilide, NX-phthalimide, 1-chlorobenzene. X-3,4,5,6-tetrachlorophthalimide, where X has the indicated meanings, with the subsequent selection of the target product in free form or in the form of a salt.