SU1189351A3 - Method of producing 5'-s-(2r-butyl)-peptidergotalkaloid or its additive salts with acids - Google Patents

Abstract

(A) 5'S-(2R-butyl) ergopeptide alkaloids (I), pref. of formula (Ia), and their acid-addn. salts are new (where R1 is Me, Et or i-Pr). (B) 5'S-(2R-butyl) aminocyclols (II) and intermediates of formula (IIa) (IV), (VI), (VII), (VIII) and (IX) are also new. (I) inhibit prolactin secretion, have serotoninergic activity, increase cerebral glucose utilisation and have alpha-sympatholytic and hypotensive activity. (Ia; R1=i-Pr) is generally more active than codergocrine in these respects. (I) are esp. useful for treating senile dementia and hypertension. Effective doses are 0.3-30 (esp. 2-4) mg/day.

Description

1 The invention relates to a process for the preparation of a sporine amide alkaloid (5R, 8R, 10 R) -N- (2R, 5S, 115, 126, 13R) -5- (2-butyl) -octahydro-12-hydroxy-2-isopropyl -3, 6-dio-co-8H-oxazolo z, 2-a-pyrrolo 3,1-c Dipirazinyl-b-methyl-ergolin-8-carboxylic acid HzC CH3 f-sn H -HaC I The purpose of the invention is to obtain a new derivative 5 S- (2R-6yTmT) peptide-ergothalkaloid with increased pharmacological activity. Example. Amide (5R, 8R, 10R) -Nf (2R, 55,115,1 23,13R) -5- (2-butyl) -octagidro-12-OXI-2-IZOPROPSH -3,6-dioxo-8H-oxazolo 3, 2-aZpyrrolo 2,1-d pyrazinylj-6-methylergoline-8-carboxylic acid or (ashes, 1oV) -9,10-DIGIDRO-12-oxy-2 - (1-metsh1atsh1) -5 - G (R) - 1-melshlpropsh1 - ergotamon-3, 6,18-trion. To a mixture of 5.36 g (20 mmol) of anhydrous (5R, 8R, 10H) -dihydrolysis acid, 40 ml of absolute dimethylformamide and 20 ml of absolute acetonitrile, 1.8 ml (22.5 mol) of trifluoroacetic acid was added immediately after that to the mixture was added dropwise at -10 ° C with 2.8 ml (20 mmol) of trifluoroacetic anhydride and 20 ml of pyride. The reaction solution is stirred for 5 minutes at -10 ° C, and the solution is mixed with 3.62 g (10 mmol) of monohydrochloride (2R, 55,115,123,13K) -2-amino-5- (2-butyl-octahydro-12- hydroxy-2-isopropyl-3,6 -dioxo-8H-oxazolo 3,2-aJ pyrrolo 2,1-cj pyrazine and the reaction mixture are allowed to warm up with stirring for 2 hours to 22 C. After the mixture is distributed between methylene chloride and water, organic the phase is dried over sodium sulfate, filtered and evaporated 12. The residue is recrystallized from a mixture of ethyl acetate and diethyl ether. Mp 190-191 s; oi -43.5 ° C (with 0.5 in pyridine). NMR spectrum 360 MHz (CDCP), S, 0.98 million :: (6H, triplet), 1.081, 17 - (bN, quartet), 1.3 (1H, multiplet, C-13-H) .13 C-NMR spectrum 360 MHz (30 mg) 1.5 ml, pD 3.4 (there are no signals with an offset of 16, 4 and 28.6 ppm, which would indicate the presence of 13 9-epimer. Consequently, the reaction mixture does not contain or contains less than 1% of 13 S-epimer. 1 mmol of the obtained base is dissolved in acetone, mixed with 1 mmol of methanesulfonic acid and crystallized by the addition of ethyl acetate. The methanesulfonate of the title compound is obtained. M.p. 227-228 ° C; (from 0.6 in pyridine) .. I Source monohydrochloride (2R, 55, 116, 126, 13K) -2-amino-5- (2-butsh1) -octahydro-10b-hydroxy-2-isopropyl-3, 6 -dioxo-8H-oxazolo 13, -a pyrrolo 2,1-c pyrazine was prepared as follows. a) (36, 8 5,9R) -3- (2-butyl) -hexahydropyrrolo 1,2-a piperazinedione-1, 4. 30 g (229 mmol) (25, ЗR) -L-allo-isoleucine 45 t 2 С (from 5 to 6 M HC8) are dissolved in 300 ml of 6.8N solution of hydrogen chloride in methyl alcohol and the solution is stirred at room temperature for 18 h. Thereafter, the solvent is distilled off, and the residue is extracted using 300 ml of a saturated solution of potassium carbonate and 600 ml of DIETHYL ester. Immediately thereafter, the aqueous phase is extracted three times with 600 ml of diethyl ether. The combined ethereal solutions are dried over sodium sulfate, filtered and evaporated, after which the resulting residue is dried under high vacuum to constant weight. 24.27 g of a clear oily substance are obtained, which is slightly colored yellow.

3

As a result of the additional three-time extraction of the aqueous phase with methylene chloride, an additional 2.68 g of methyl ester is obtained.

wi in +45 C (with 3 in methylene chloride) J

NMR spectrum 100 MHz (CDCB,),, 0.81 - 1.01 million :: (6H, 4 peaks,

SNAC: —w, sn, sng-s-3), s, 4b (1n,

J 4 Hz, C-2-H), 3.71 (ЗН, 5, СООСНз).

Condensation with BWC-L-proline.

The solution obtained in this way methyl ester. (29, 3R) -L-allo-isoleucine (22.95 g of 158, 3 mmol) in 155 ml of tetrahydrofuran is added dropwise to a mixture prepared in the following manner,

40.35 g (161.5 mmol) of 25-carbobenzoxy-b-proline are dissolved in 600 ml of tetrahydrofuran, after which 26.15 g (161.5 mmol) of K, Li are added to the resulting solution with stirring in solid form. -carbonyldiimidazole. After 5 minutes, carbon dioxide deactivation is stopped, the mixture is slightly yellow, and it is further stirred at room temperature for 1 hour. After the addition of the methyl isoleucine ester, the mixture is stirred for 2 hours at room temperature. In a separating funnel, the reaction mixture is treated with 1 l of diethyl ether, washed twice with 1 l of water, after which it is extracted with 1 l of diethyl ether.

After drying over sodium sulfate, the combined organic solutions are filtered, evaporated, and the residue is dried under high vacuum at 30 C. 54.4 g of a clear oily substance slightly colored in yellowish are obtained.

Cleavage of the CCD-protective group.

A solution of 64 g (170 mmol) of the resulting product in 800 ml of methyl alcohol is added to a pre-hydrogenated mixture consisting of 12.0 g of 10% palladium on carbon in 500 ml of methyl alcohol. During the hydrogenation process, 2.9 l of hydrogen are absorbed (room temperature, 757 mm Hg, reaction time h). After that, the reaction mixture is filtered on hyflo, about 893514

wash with 1 l of a mixture of methylene chloride and methyl alcohol (1: 1) and dry. 55 g of a yellow, viscous, oily substance are obtained.

Cyclization to form diketopiperazine.

Immediately thereafter, the resulting crude product is heated to 0 under high vacuum for 1.5 hours at. The resulting mixture of oily and crystalline substance is first mixed with diethyl ether and, after adding hexane by filtration, the mixture is separated into crystalline (8.66 g) and oily components (27.4 g).

The oily component is again heated to cyclization. As a result, 17.47 g of a colorless crystalline substance are obtained (a total of 21.29 g). After recrystallization from a mixture of 5 diethyl ether and hexane, 17.87 g of a colorless product with needle-like crystals are obtained. M.p. 132-135 ° Ci

od -156 ° С (with 1 in chlorine; that is, methylene).

IZ-spectrum 360 MHz (CDC,), S 0.80 million: (ZN, d, J 6.5 Hz, SN, -C-9), 0.98 (ZN, t, J 7 Hz, SN , -CH2-C-9). 1.42 (2Nt), 1.92 (1H, ha), 2.45 (2H, t), 2.38 (2H, t), 3.52-3.59 (2H, t), 4.08 (2H, t).

B) Ethyl ether (2R, 55, 116, 125, 13К) -5- (2-butyl) -octagidro-12-OXI-2-IZOPROPIL-3, 6-dioxo-8HP-oxazolo 3,2-aJ pyrrolo 2,1 -cj pyrazin-2-carboxylic acid,

21 g (100 mmol) (35, 8S, 9R) -3- (3-butyl) -hexahidropyrrol-1, 2-a piperazinedione-1,4 are mixed under nitrogen atmosphere with 200 ml of absolute dioxane, 57.3 ml ( mmol) N-ethyldiisopropylamine and 53.32 g (178.6 mmol) of ethyl 5 - (+) - 2-benzyloxy-2-chlorofor0 mil-3-methyl butyric acid, after which the mixture is heated for 3 hours at boiling point with reflux. After cooling, the reaction mixture was partitioned twice between 1 l of ether and cooled 1N. hydrochloric acid, then washed twice with a saturated solution of potassium hydrogen carbonate. after which the aqueous phase is extracted with 1 l of diethyl ether. The combined organic solutions are then dried over sodium sulfate, filtered and evaporated. 61.2 g of an oily substance are obtained, which is yellow in color. Received. The product was added to a pre-hydrogenated mixture of 10 g of 10% palladium on carbon in 2.6 liters of absolute ethyl alcohol and hydrogenation was carried out at atmospheric pressure for 18 hours. After the vanilla filter on the hyphlo, evaporation of the filter and drying under high vacuum, a cloudy yellow oily substance (49.6 g) is obtained, from which, after recrystallization from a mixture of diethyl and petroleum ether, 29.76 g of a crystalline substance are obtained, m.p. 95-96 ° C, D + 9s (with 1 in ethyl alcohol). with). (2R, 55, 115, 125, 13R) -5- (2-butyl) -octahydro-12-hydroxy-2-isopropyl-3, 6-dioxo-8H-oxazolo {3,2-a pyrrolo 2,1- cj pyrazin-2-carboxylic acid. - S. 28.64 g of the product obtained in accordance with paragraph b are suspended in 20 ml of methyl alcohol. 172 ml of 1 and are added to the prepared suspension. sodium hydroxide solution, after which the colorless solution is stirred for 18 at room temperature. Immediately after this, the reaction cm is washed twice with 50 ml of diethyl ether and the combined organic solutions are extracted with water. The aqueous phase is acidified at 0 ° C by the addition of 103.2 ml of 2N. hydrochloric acid solution. At the same time, the precipitate is precipitated with acid as an oily substance. As a result of stirring in an ultrasonic bath, a crystalline substance is obtained, which is dried for 24 hours under high vacuum at 50 ° C. As a result, 24.24 g of a colorless substance with needle-like crystals is obtained. . M.p. 114-115 ° C, the second crystalline form has so pl. 172173 ° Ci Wv - -11.7 ° С (with 1.5 in the feast day). d). Hydrazide (2R, 55, 116, 125, 1ZK) -5- (2-butyl) -octagidr6- .12-hydroxy-2-yzopropyl-3,6-dioxp-8H-oxazolo-3, 6-dioxo-8H- oxazolo f3,2-a | pyrrolo 2,1-cJ pyrazin-2-carboxylic acid. 23.36 g (65.8 mmol) of the acid obtained in accordance with paragraph C are introduced in solid form into a mixture prepared in advance as follows. A solution of 9.04 ml of dimethylformamide in 132 ml of methylene chloride is prepared. At -10 ° C, a solution of 8.37 ml of oxalyl chloride in 33 ml of methylene chloride is added. A white suspension is formed, which is further stirred for 15 minutes at -10 ° C. After the addition of acid. The temperature rises to -6 ° C. The clear solution colored in light yellow is stirred for 30 microns at -10 ° C. A solution of 42.9 g of sodium azide is then poured into the prepared solution for 4 minutes. in 204 ml of water. At the same time, the temperature rises to 5 ° C, and the reaction solution is colored reddish. After stirring for a further 15 minutes, the reaction mixture is diluted in a separating funnel with 900 ml of methylene chloride, after which it is extracted with ice and a saturated solution of potassium hydrogen carbonate. The aqueous phase is then extracted twice with 800 ml of methylene chloride. The combined organic solutions are dried over sodium sulfate, filtered, evaporated, and the residue is dried under high vacuum. The resulting residue is recrystallized from a mixture of diethyl ether and methylene chloride. 16.62 g of a colorless crystalline substance are obtained. M.p. 175 C (with decomposition). e). Benzyl ether (2R, 55, 115, 125, lЗR) -5 - (2-butyl) -octahydro-12-hydroxy-2-isopropyl-3, 6-dioxo-8H-oxazolo 3,2-a pyrrolo 2, 1-C-pyrazin-2-carbamic acid. To a solution of 16.5 / g (43.6 mmol) of the acid hydrazide obtained in

Claims (2)

The method of obtaining 5'5 “(2K-butyl) -peptidergotalkaloid formula or its additive salts with acids, which consists in the fact that the compound of the formula • HC1 SNS condense with reactive acid derivatives of the formula <p in the form of a mixed anhydride with trifluoroacetic acid and the obtained target product is isolated either in free form or in the form of an additive salt with acids, and isolated in the form that does not contain a 25-butip-epimer. one 1189351 2