SU493965A3 - The method of obtaining d-2-substituted-6-alkyl-8-substituted ergolin - Google Patents

Description

a suitable inert solvent, such as, for example, methylene chloride. The product of this reaction is a 6-cyano derivative, in which the groups at positions 8 and 2 remain unchanged. Reduction or hydrolysis of this 6-cyano derivative gives the secondary amine of formula III.

The alkylation of this secondary amine is carried out predominantly with a haloalkyl, where the halide is preferably chlorine, bromine or iodine, in a suitable inert solvent, and the desired compounds are obtained. The above procedure is applicable not only to obtain hitherto unknown 6-alkyl ergolines in which the alkyl group is different from methyl, but is also applicable when the alkyl group (R) is methyl, in the preparation of the radiolabeled erolin derivatives of the formula I in which the radioactive label is an C atom located in a Ce-methyl group.

Example 1. Preparation of D-2-chloro-6ethyl-8-cyanmethylergoline.

A solution is prepared containing 6, 11 g of 0-2-chloro-b-methyl-8 - cyanmethylergoline, prepared according to a known method. 13.5 g of cyanogen bromide are added to it and the reaction mixture is stirred in anhydrous deposits for 69 hours. The reaction mixture is poured into an aqueous solution of tartaric acid and the acidic solution is extracted with chloroform. The chloroform layer is separated, washed with water and dried. Evaporation of the chloroform gives a residue containing -2-chloro-6-cyano-8-cyanmethylergoline formed in the above reaction. Recrystallization of this residue from ethanol gives purified () - 2-chloro-6-cyano-8-cyanomethylene ergoline; m.p. 231-232 ° C.

Calculated,%: C 65.70; H 4.87; N 18.03; C1 11.41.

Found,%: C 65.46; H 4.61; N 18.01; C1 11.49.

A mixture of 5.4 g) -2-chloro-6-cyano-8-cyanmethylergoline, 30 g of a zinc powder, 2210 ml of glacial acetic acid and 45 ml of water was heated under reflux under nitrogen for 8 hours. The reaction mixture is filtered and the filtrate is diluted with water, and then alkalinized by the addition of 14 N. aqueous ammonium hydroxide solution. This alkaline solution is extracted with chloroform, the chloroform layer is separated, washed with water and dried, and the chloroform is evaporated by evaporation under vacuum. The resulting residue, containing the D-2chloro-8-cyanomethylene ergoline formed in the above reaction, is recrystallized from ethanol to obtain crystals; m.p. at 228-229 ° С (with decomposition).

Calculated,%: C, 67.24; H 5.64; N 14.70; C1 12.41.

Found,%: C, 66.99; H 5.40; N 14.87; C1 12.42.

About 300 mg (2) - 2-chloro-8-cyanmethylergoline is dissolved in 10 ml of DMF (dimethylformamide). 220 mg of potassium carbonate was added to the reaction mixture, followed by 0.12 ml of ethyl iodide. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 5.5 hours, then it is diluted with water and the aqueous layer is extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, followed by washing with a saturated aqueous solution of sodium chloride, and then dried. Evaporation of ethyl acetate under vacuum gives () - 2-chloro-6-ethyl-8-cyanmethylergoline; m. pl. 225-227 ° С (with decomposition) after chromatography on florisil using chloroform containing 2% ethanol as a washing solvent.

Calculated,%: C 68.89; H 6.42; N 13.39; C1 11.30.

Found,%: C 68.64; H 6.15; N 13.45; C1 11.37.

Following the above procedure, but replacing the corresponding haloalkyl with ethyl iodide, the following compounds were obtained:

) -2-chloro-6-n-propylpropyl-8-cyanmethylergoline; m.p. 185-187 ° C.

Calculated,%: C 69.61; H 6.76; N 12.82; C1 10.81.

Found,%: C 69.57; H 6.98; N 12.59; C1 10.64.

Alkylation of (i) - 2-chloro-8-cyanomethylene ergoline with methyl iodide in the presence of potassium carbonate in a DMF solution gives D2-chloro-6-methyl-8-cyanmethylene ergoline. This compound has properties identical to those of the original substance.

Following the above procedure, D-2-chloro-6-methyl-8-carboxamidomethyl ergoline was demethylated and the resulting secondary amine was alkylated to produce higher alkyl analogs, such as D2-chloro-6-ethyl-8-carboxamidomethyl ergoline and D-2-chloro. -bn-propyl - 8 - carboxamidomethyl ergoline.

Similarly, it is also possible to demethylate 8-cyanmethyl or 8-carboxamidomethyl ergolines having groups in the 2-ergoline ring position other than chlorine, for example 2-bromo-2-iodo, 2-methyl- or 2-cyano derivatives, to give the corresponding secondary amine which in turn, it can be realkylated to produce higher homologues, as in the sequence of the / 2-chloro-8-cyanmethyl reactions described above.

Subject invention

Claims (4)

1. Method for preparing (i) -2-substituted 6-alkyl-8-substituted ergolines of general formula I n - K- -X in which R denotes a primary alkyl group containing 1-4 carbon atoms; X is C1, Br, J, CH3 or CN-rpynny; R CH2-CN or SNG-CO-NHz-rpynny, characterized in that the compound of general formula II H-1 in which X and R have the above meanings, are subjected to de-methylation, and the compound of formula III thus obtained .And-n lit in which X and R are defined above, are alkylated again, after which the desired product is isolated by known techniques. 2. A method according to claim 1, wherein the demethylation is carried out by reacting a compound of formula II with cyanogen bromide and in the resulting 6-cyano-substituted compound, the 6-cyano substituent is removed. 3. A method according to claim 2, characterized in that the 6-cyano substituent is removed by reduction. 4. A method according to claim 2, characterized in that the 6-cyano substituent is removed by hydrolysis.