SU670219A3 - Method of producing carbostyril- or 3,4-dihydrostyril derivatives - Google Patents

Description

(54) METHOD FOR OBTAINING CARBOSTYRILILES 3,4-DIHYDROCARBOSTERILYL DERIVATIVES

The mixture is stirred for 20 hours. To the reaction mixture is added 500 ml of a 10% aqueous solution of hydrochloric acid and the nitrobenzene is removed by steam distillation. After cooling the mixture, the precipitated crystals are collected by filtration, which are then washed with 30 ml of hot water. By recrystallization from methanol, 14.0 g of 5-chloroacetyl-3-oxycarbostyryl are obtained with m.p. 285-287 ° C (with decomposition) in the form of pale yellow crystals.

Example 2 20 g of aluminum chromium was added to 5.0 g of 8-hydroxycarbostiryl and the mixture was thoroughly mixed. 10 g of chloroacetic acid chloride are added to the mixture while cooling with ice. The mixture is heated for 2 hours at 40-45 ° C to obtain 8-chloroacetoxycarbostyril, and then stirred for 3 hours at. After cooling, the precipitated crystals are collected by filtration, the crystals are washed with 300 ml of water, then by recrystallization from methanol, 2.6 g of 5-chloroacetyl-8-hydroxycarbosyryl are obtained as pale yellow crystals with m.p. 285-287 ° С (with decomposition).

In addition, a portion of the resulting 8-chloroacetoxycarbostyril is separated and recrystallized from acetone to obtain pale yellow crystals. The melting point of these crystals is 248-250 ° C (with decomposition).

Example 3. 1.5 g of chloroacetic acid chloride and 20 ml of carbon disulfide were added to 0.5 g of 8-hydroxycarostyryl, and 2 g of aluminum chloride was gradually added to the resulting solution while cooling with ice. After thorough mixing, the mixture is gradually heated and boiled for 30 minutes. After cooling, unreacted chloroacetic acid chloride and carbon disulfide are removed, and crushed ice is added to the resulting residue to crystallize the product. The resulting crystals are gnawed with water and then recrystallized from acetone to obtain 0.45 g of 8-chloroacetoxycarbostyril as pale yellow crystals with mp. 2 4 8-251 ° С (with decomposition). Prymer420 g of aluminum chloride and 10 g of chloroacetic acid chloride are added to 10 g of 8-chloroacetoxycarbostyril (see Example 3) and the mixture is heated at 75-85 ° C for 1 hour. washed with water and recrystallized from methanol to obtain 3.7 g of 5-chloroacetyl-8-к xycarbostiril as pale yellow crystals with mp. 285-287 ° С (with decomposition).

Example 5..7.3 g of 8-hydroxycarbostyril and 12.5 g of chloroacetic acid chloride were added to 70 ml of nitrobenzene, and 30 g of aluminum chloride was gradually added to the resulting solution while stirring and cooling with ice. The mixture was stirred at 50-55 ° C for 6 hours, then poured into ice water. The precipitated crystals are filtered, washed with methanol, recrystallized from acetone, and 3.5 g of 5-chloroacetyl-8-chloroacetoxycarbostyril are obtained as pale yellow crystals with m.p. 239-241С (with decomposition).

Example 1.7 g of 5-chloro-acetyl-8-chloro-acetoxycarbostyril obtained in Example 5 is added to 50 ml of a 10% aqueous solution of hydrochloric acid, and then stirred at 95-100 seconds for 2 hours. After cooling, the precipitated crystals filtered off, washed with water, recrystallized from methanol and obtain 1.1 g of 5-chloroacetyl-8-oxycarbostyril in the form of pale yellow crystals with so pl. 285-28b ° C (with decomposition).

Example 7 2.5 g of 5-chloroacetyl-8-chloroacetoxycarbostyril prepared in Example 5 was added to 30 ml of 5% aqueous potassium hydroxide.

then stirred at 20-25 C for 30 minutes The resulting solution was adjusted to pH 2-3 with dilute hydrochloric acid while cooling. The precipitated crystals are filtered, washed with water, recrystallized from methanol and 1.7 g of 5-chloroacetyl-8-hydroxycarbostyril are obtained in the form of pale yellow crystals with m.p. 285-287 ° С (with decomposition).

Example8. To a mixture of 4.5 g of 8-hydroxycarbostyril and 10 g of chloroacetic acid chloride are gradually added, with stirring and cooling with ice, 220 g of aluminum chloride. The resulting mixture was stirred at 55-60 ° C for 8 hours to form 5-chloroacetyl-8-chlorodetoxycarbostyril. Then, 40 ml of 5% potassium hydroxide was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. In addition, a 10% hydrochloric acid aqueous solution is added to acidify the solution and form crystals. The precipitated crystal is filtered, washed with water, then recrystallized from methanol to obtain 2.3 g of 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with mp. 285-286 C (with decomposition).

A portion of this reaction mixture, before the addition of 5% potassium hydroxide, is removed and poured into ice water. The precipitated crystals are filtered off, washed with methanol, recrystallized from ethyl acetate to give 5-chloroacetyl-3-chloroacetoxycarbostyril as pale yellow crystals with m.p. 238-241 ° С (with decomposition).

Sample 12, b g of 5-chloroaceti-8-hydroxycarbostyril (see Example 4 or 8), suspended in 130 ml of isopropanol, and 2515 g of isopropylamine are added dropwise to the resulting suspension with stirring. The reaction mixture is then stirred at 55 ° C for 3 hours. After cooling, concentrated hydrochloric acid is added to the mixture to bring the mixture to pH 2-3, and the precipitated crystals are filtered, washed with acetone, and recrystallized from methanol-dimethylformamide (1: 1 by volume) and get 6.5 g of 5-isopropylaminoacetyl-8-hydroxycarbostyryl hydrochloride in the form of pale yellow crystals with so pl. 28-288С (with decomposition).

Example 10 8, O g of 5-chloroacetyl-8-hydroxycarbostyril (see Example 4 or 8) —substituted in 100 ml of ethanol and 10 g of tert-butylamine added dropwise to the suspension after transferring -BO ° C for 5 hours. After that, the mixture is concentrated to half the volume and then concentrated hydrochloric acid is added to bring the mixture to a pH of 2-3. The precipitated crystals are filtered, washed with acetone, recrystallized from ethanol, and 4.1 g of 5-tert-butylamino-acetyl-8 -oxycarbostyryl are obtained in the form of pale yellow crystals with mp. 291-293 0 (with decomposition).

Example 11. 4.3 g-5-chloroaceti-8-hydroxycarbostyril (see Example 4 or 8) is suspended in 50 ml of ethanol and to the resulting suspension, 5 g of fluorobutlamine is added dropwise to the suspension, with stirring C for 5 hours. After cooling, the mixture is adjusted to pH 3 with concentrated hydrochloric acid. The precipitated crystals of the filters were washed with acetone, recrystallized from methanol-ethanol (1: 1 by volume) and 2.9 g of 5-sec-butylamino-acetyl-8-hydroxycarbostyryl hydrochloride were obtained as pale yellow crystals with mp, 289- 291 ° С (with decomposition).

Example 12. The south of 5-chloroaceti-8-hydroxycarbostyril (see Example 4 or 8) is suspended in 30 ml of benzene and 10 ml of piperidine is added to the suspension, after which the mixture is heated under stirring at reflux temperature for 6 hours. The reaction mixture is filtered to part the reaction product, which is then washed with benzene and then 50 ml of isopropanol. The resulting insoluble material is dissolved in 150 MP aqueous hydrochloric acid. The solution is concentrated to dryness under reduced pressure, and the resulting residue is recrystallized from ethanol to obtain 7.5 g of white amorphous 5-piperidino: acetyl-8-hydroxycarbostyryl hydrochloride hemihydrate, mp. 239-242 ° С (with decomposition).

Example 13. South of 5-chloroacetyl.-8-hydroxycarbostyril (see Example 4 or 8) is suspended in. 60 ml of benzene and 9 ml of morpholine are added to the suspension, after which the mixture is heated with stirring and at reflux temperature for 4 hours. The reaction mixture is cooled and (The resulting precipitate is filtered. The precipitate is dissolved in 60 ml of isopropanol and a solution of t to pH 2-3 with

concentrated hydrochloric acid. The resulting acidic solution is cooled.

0 with ice and the precipitate formed is filtered off and then recrystallized from ethanol. The precipitate is dissolved in 20 ml of water and the solution is adjusted to pH 7.5-8.0 with sodium bicarbonate.

5 with ice cooling. The precipitate, formed on cooling, is filtered and recrystallized from ethanol to obtain 2.4 g of white amorphous 5-morpholinoacetyl-8-hydroxy carbostyril with mp. 238-2 39, 5С (with decomposition), The resulting product is identified by IR and NMR spectral and elemental analyzes.

Example 14, 120 ml of benzylamine was added to 15 g of 5-chloroacetyl 3-ok5 Sicarbostyril (see Example 4 or 8) and the mixture was stirred at room temperature for 1 hour. A precipitate that forms when petroleum ether is added to the reaction

0 mixtures are dissolved by adding dilute hydrochloric acid and the solution is filtered to remove any insoluble matter. The acidic layer is then concentrated.

5 to dryness, and the residue is recrystallized from methanol and receive 16.4 g of substance with so pl. 274-279 C (with staining and decomposition), The resulting product is identified by NMR and IR

0 spectral and elemental analyzes as monohydrate 5-benzylaminoacetyl-8-hydroxycarbostyryl hydrochloride.

Example 15. The south of L-chloroacetyl-8-hydroxycarbostyril is dissolved in 50 ml of ethanol and to the solution dropwise

5, 25 g of 1-phenethylamine is added, and then stirred for 4 hours. Ethanol is then distilled off, and the precipitate is washed with diethyl ether and dissolved in isopropanol to remove any insoluble matter. Isopropanol layer is concentrated to approximately 1/3 of the original volume and adjusted to pH 4 with concentrated hydrochloric acid. Forming 5 with the precipitate is recrystallized from

mixtures of ethanol and acetone and get 9.8 g of substance with so pl. 246-249C. The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-phenethylaminoacetyl) -8-hydroxycarbostyryl hydrochloride,

Example 16 40 ml of 1,1-dimethylphenethylamine are added to 5 g of 5-chloro-ethyl-8-hydroxycarbostyril and the mixture is stirred at room temperature in the dark for 5 hours. The precipitate that forms upon the addition of petroleum ether to the reaction mixture is washed with diethyl ether and dissolved in methanolic hydrochloric acid to remove any insoluble material. The methanol is then distilled off, and the residue is recrystallized from methanol and obtain 6.1 g of substance with m.p. 246247 C (with staining and decomposition) The resulting product was identified by NMR and G spectral analyzes as 5- {1,1-dimethylphenethylaminoacetyl) -8-hydroxycarbostyryl hydrochloride hemihydrate.

Example 17 24.3 g of 8-hydroxy-3, 4-dihydrocarbostyryl and 8 g of chloroacetic acid chloride are added to 130 ml of carbon disulfide and 200 g aluminum chloride. The mixture is stirred for 6 hours at 6070 ° C and carbon disulfide is distilled off. The resulting residue is poured into LOO ml of ice water. The precipitated crystals are filtered, washed with water and recrystallized twice from methanol to obtain 8.0 g of 5-chloroacetyl-8-hydroxy-3, 4-dihydrocarbostyril as pale yellow crystals with mp. 189-191 ° C.

EXAMPLE 18: 13 g of 8-hydroxy-3,4.-Dihydrocarbostyril and 20 g of chloroacetic acid chloride are dissolved in 100 ml of nit robenzene and 40 g of aluminum chloride are slowly added to the mixture, then stirred for 15 h at TO-TZ C. The mixture is then subjected to steam distillation to remove nitrobenzene. After cooling the mixture, the precipitated crystals are filtered off, washed with hot water, recrystallized from methanol to obtain 7.2 g of 5-chloroacetyl 8-oxy-3, 4-dihydrocarbostyryl in the form of light; yellow crystals with TPI. 189-190С.

Example 19. 66 g of chloroacetic acid chloride and 30 ml of nitrobenzene were added to 17 g of 8-methox-3, 4-dihydrocarbostyryl and 100 g of aluminum chloride was slowly added to the mixture under ice cooling, followed by stirring for 30 minutes at room temperature. temperature After that, the mixture is left for another 30 minutes and then poured into 700 ml of ice water. The resulting precipitate is filtered off, washed with ethanol, recrystallized from methanol and 20 g of white needle-like crystals are obtained with m.p. 187-189C. The obtained crystals were identified by NMR and IR spectral and elemental analyzes as 5-chloroacetyl-8-methoxy 3,4-dihydrocarbostyryl.

Example20. 33 g of chloroacetic acid chloride and 80 ml of carbon disulfide are added to 8.5 g of 8-methoxy-3, 4-dihydrocarbostyril and 50 g of aluminum chloride is slowly added to the mixture while being cooled with ice . The carbon disulfide layer is removed by decantation, and crushed ice is added to the remaining solution to crystallize the product. The precipitated crystals thus obtained

0 is filtered off, washed with ethanol, recrystallized from methanol and get 11 g of white needle-like crystals with so pl. 187-188 ° C. The resulting product was identified by NMR and IR spectral and elemental analyzes as 5-chloroacetyl-8-methoxy-3, 4-dihydrocarbostyryl.

Example 21, 24.3 g of 8-hydroxy-3,4-dihydrocarbostyril and 68 g of chloroacetic acid chloride were added to 130 ml of carbon disulfide and 200 g of aluminum chloride was slowly added to the mixture while stirring and cooling ice water. Then after 4 hours of reaction while cooling

5 with ice get 8-chloroacetoxy-3, 4-dihydrocarbostyryl. The reaction mixture is stirred for 2 hours at 60-70 ° C and carbon disulfide is distilled off. The resulting residue is poured into 500 ml.

0 ice water and the precipitated crystals are filtered, washed with water, recrystallized twice from methanol and get 8-, O g 5-chloroacetyl-8-hydroxy-3

with the form of light yellow crystals with so pl.

189-191 ° C. I

8-chloroacetoxy-3, 4-dihydrocarbostyril, obtained by the above procedure as an intermediate

0 product, isolated from aliquot

part of the reaction mixture, and after recrystallization from acetone, it was found that so pl. 183-186 ° C.

PRI me R 22. 40 g chloride

5 aluminum is added to 11.5 g of 8-hydroxy-3, 4-dihydrocarbostyril and the mixture is thoroughly mixed. While cooling with ice water slowly to the mixture, 21 g of chloro-acetic acid chloride was added and the resulting mixture was stirred at 35-40 ° C for 2 hours, after which an excess of chloroacetic acid chloride was distilled off. The resulting residue vyliviot

the crushed ice and the precipitated crystals are filtered, washed with water, recrystallized from acetone, and 5.6 g of 8-chloroacetox-3,4-dihydrocarbostyril are obtained in the form of light yellow crystals with m. gsh  182-184 ° C.  Example 23  13 g of 8-hydroxy-3,4-dihydrocarbostyril and 20 g of chloro acetic acid chloroalkyl are dissolved in 100 ml of nitrobenzene and 40 g of aluminum chloride is slowly added to the mixture, after which it is stirred at 70-75 ° C for 15 h.  Nitrobenzene is then removed by steam distillation.  After cooling the mixture, the precipitated crystals are filtered, washed with hot water, recrystallized from methanol, and 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydr carbostyril are obtained in the form of light yellow crystals with m. square  189-190 ° C.  Example 24  K, 0 g 8-hydroxy-3, 4-dihydrocarbostyril and 15.0 g of acid chloride. and chloroacetic acid is slowly added with stirring and cooling with ice 30 g of aluminum chloride, after which the mixture is stirred at 55-60 ° C for 6 hours and 5-chloroacetyl-8-chloroacetoxy-3, 4-dihydrocarboxylic acid is obtained.  To the reaction mixture, 50 ml of 10% aqueous hydrochloric acid is added, and then stirred for 3 hours at 95-100 ° C. After cooling the mixture, the precipitated crystals are filtered, washed with water, and recrystallized from methanol to obtain 2.7 g 5-chloroacetyl-8-hydroxy-3, 4-dihydrocarbostyril as light yellow crystals with m. square  189-190 ° C.  According to this method, an aliquot of a part of the reaction mixture was taken from the reactor before its hydrolysis with hydrochloric acid and poured into ice water.  The crystals precipitated are filtered off, washed with hot water, recrystallized from dimethylformamide-methanol (1: 1 by volume) and 3-hl-racetyl-8-chloroacetate si-3 4-dihydrocarbostyryl are obtained as light yellow crystals with m. square  206-207 ° C.  Example25.  4g 5-chloroacetyl-8-hydroxy-3, 4-dihydrocarbostyril (see  Example 24) is dissolved in 50 ml of isopr panol and 20 g of isopropylamine is added to the solution, followed by stirring at 60 ° C for 3 hours.  The reaction mixture is concentrated to a volume of 1/3 - 1/4 of the original volume and saturated with dried gaseous hydrogen chloride.  After cooling the mixture, the resulting precipitate is filtered off, recrystallized from ethanol, and 3.5 g of a colorless amorphous substance are obtained with a solid. square  274-275s The obtained substance was identified by NMR and IR spectral and the element T1YM analyzes as b-propylaminoacetyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride.  Example 26, 3g 5-chloroacetyl-8-hydroxy-3, 4-dihydroharbostyril (see  Example 24) is dissolved in 40 N of isopropanol, and 3 g of methylamine is added dropwise to the solution with stirring during 30 minutes.  After the addition is complete, the mixture is stirred for another 1 h, heating at the same temperature.  The reaction mixture is then concentrated to 1/3 of the initial volume and adjusted to pH 1-2 with hydrochloric acid.  The precipitate obtained is filtered off and recrystallized from ethanol to obtain 1.5 g of a colorless amorphous substance with m. Pl. 254256 C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-methylaminoacetyl-8-hydroxy-3, 4-dihydrocarboxyryl hydrochloride.  Example 27  2.54 g of 5-chloroacetyl-8-OXY-3, 4-dihydrocarbostyril (see  Example 24) is dissolved in 30 ml of isopropanol and 2.7 g of ethylamine is added dropwise to the solution with stirring during 20 minutes.  After completion of the addition, the mixture is stirred for more. 40 min, heating at the same temperature.  Then the reaction mixture is concentrated to 1/3 of the initial volume and adjusted to pH 1-2 with concentrated hydrochloric acid. The resulting precipitate is filtered off and recrystallized from ethanol to obtain 1.7 g of a colorless amorphous substance with m. square  258-260 s.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-ethylaminoacetyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride.  Example 28  4 g of 5-chloroacetyl-8-hydroxy-3, 4-dishydrocarbostyril (see  Example 24) is dissolved in 60 ml of isopropanol and 20 g of tert-butylamine is added dropwise to the solution with stirring at 60 ° C over 20 minutes.  After completion of the addition, the mixture is stirred for another 40 minutes, heating at the same temperature.  Then the reaction mixture is concentrated to 1/2 of the initial volume and adjusted to pH 1-2 with concentrated hydrochloric acid. The resulting wasp, dock filtered, re-recrystallized from a mixture of ethanol and acetone (1: 2 by volume) and obtain 2.0 g of a colorless amorphous substance with t. square  253-25 ° C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-tert-butylamino-acetyl-8-hydroxy-3, 4-dihydrocarboxyryl hydrochloride.  Example 29, 3g 5-chloroacetyl-.  -8-hydroxy-3,4-dihydrocarbostyril (see  Example 24) is dissolved in 40 ml of isopropanol and added to the solution with stirring. dropwise 10 g of sec-butylamine at h ° C for 20 minutes.  After completion of the addition, the mixture is stirred for another 2.5 h, heating at the same temperature.  Then the reaction mixture is concentrated to 1/3 of the original volume and the chlorine is saturated with dry hydrogen gas.  The precipitate obtained is filtered off and recrystallized from ethanol to obtain 1.8 g of a colorless amorphous substance with m. square  269-271С The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-sec-butylaminoacetyl-8-OXI-3, 4-digilrocarbostyryl hydrochloride.  Example 30  4 g of 5-chloroacetyl-8-methoxy-3, 4-dihydrocarbostyril (see Examples 19 and 20) are dissolved in BO ml of isopropanol and 20 g of isopropylamine are added to the solution, followed by stirring for 3 hours at 60 ° C.  The reaction mixture is then concentrated to 1/3 to 1/4 of the original volume and saturation with dry gaseous hydrogen chloride.  After cooling the mixture, the precipitate obtained is filtered off, recrystallized from ethanol, and 3.5 g of a colorless, needle-like crystalline substance is obtained with the solid. square  208-209 ° C.  The obtained substance was identified by NMR and IR spectral and elemental angshysis as 5-isopropylaminoacetyl-8-methoxy-3, -; 9I DRO Pbosythylamine.  example 31.  3g 5-chloroacetyl-8-methoxy-3, 4-dihydrocarbostyril (see Examples 19 and 20) are dissolved in 40 ml of isopropanol and 3 g of methylamine is added dropwise to the solution with stirring during 30 minutes.  After the addition is complete, stir the mixture for another 1 hour, heating at the same temperature.  Then the reaction mixture is concentrated to 1/3 of the initial volume and adjusted to pH 1-2 with concentrated hydrochloric acid.  The precipitate obtained is filtered off and recrystallized from ethanol to obtain 1.5, g of a colorless, needle-like crystalline substance with m. square  232-234 C.  The substances obtained are identified by NMR and IR spectral.  and elemental analyzes as 5-methylaminoacetyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride.  EXAMPLE 32, 2.54 g of 5-chloro-8-methoxy-3, 4-dihydrocarbostyril (see Examples 19 and 20) are dissolved in 30 ml of isopropanol and 2.7 g of ethylamine is added dropwise to the solution with stirring during 20 minutes.  After completion of the addition, the mixture is stirred for an additional 40 minutes, heated at the same temperature.  Then the reaction mixture is concentrated to 1/3 of the initial volume and adjusted to pH 1-2 with concentrated hydrochloric acid.  The precipitate obtained is filtered off and recrystallized from ethanol to obtain 1.9 g of a colorless needle-like substance m. square  224-227C.  The resulting product was identified by NMR and IR spectral and elemental analyzes as ethylaminoacetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride.  Example 33  4g 5-chloroacetyl-8-methoxy-3, 4-dihydrocarbostyril (see Examples 19 and 20) are dissolved in 60 MP of isopropanol and tert-butylamine is added dropwise to the solution with stirring during 20 minutes.  After completion of the addition, the mixture is stirred for another 40 minutes, heating at the same temperature.  Then the reaction mixture is concentrated to 1/2 of the initial volume and adjusted to pH 1-2 with concentrated hydrochloric acid.  The precipitate is filtered off, recrystallized from a mixture of ethanol and acetone (1: 2 by volume) and obtain 2.0 g of a colorless amorphous substance with t. square  203-210 ° C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-tert-butylamino-acetyl-8-methoxy-3,4 Dihydrocarboustryl hydrochloride.  Example 34  3g 5-chloro-1-acetyl-8-methoxy-3, 4-dihydrocarbostyril (see Examples 19 and 20) are dissolved in 40 ml of isopropanol and 10 g of sec-butylamine is added dropwise to the solution with stirring at 60 ° C over 20 minutes.  Then the reaction mixture is concentrated to 1/3 of the original volume and saturated with dry gaseous. hydrogen chloride.  The precipitate obtained is filtered, recrystallized from ethanol and 1.8 g of colorless needle-like crystals are obtained with m. square  212-214 C.  The resulting IBO was identified by NMR and IR spectral and elemental analyzes as 5-sec-butylamino-acetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride.  Example of  1g 5-isopropylaminoacetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride (see Example 30) is dissolved in 10 ml of a 47% aqueous solution of hydrogen bromide and the mixture is heated under reflux at a bath temperature of 120-130 ° C for 2.5 hours.  Then, 20 ml of water is added to the mixture and the pH of the mixture is adjusted to 6.5-7.5 with sodium bicarbonate.  The precipitate thus formed is filtered, washed with water and dried.  The resulting material is dissolved in isopropanol and the solution is saturated with dry gaseous hydrogen chloride.  The precipitate is filtered off and recrystallized from ethanol to obtain 0.5 g of a colorless amorphous substance with m. square  274-275 ° C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 3-isopro-shlaminoacetyl-B-hydroxy-3, 4-dihydroxy procarbiril and hydrochloride.  13 Example 36.  O, 7g 5-methylamine acetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride (see example L) races.  create in 10 ml of a 47% aqueous solution of hydrogen bromide and mix the mixture with a reflux condenser at a bath temperature of 120-130 ° C for 4 hours.  Then the reaction mixture is treated as in Example 35 and obtain 0.5 g of a colorless amorphous substance with m. square  254-256®C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-methylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride.   PRI me R 37.  0.9 g of 5-tert-butylamino acetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride is dissolved in 10 ml of a 47% aqueous solution of hydrogen bromide, and then the resulting solution is treated in the same manner as in example 35 and obtain 0.2 g of light yellow amorphous substance with t. square  253255 ° C.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-tert-buty-laminoacetyl-8-hydroxy-3, 4-dihydrocarboxyryl hydrochloride.  Example 38  O, 5 g of 5-sec-butyou aminoacetyl-8-methoxy-3, 4-dihydrocarbostyryl hydrochloride (see Example 34 was dissolved in 10 ml of a 47% aqueous solution of hydrogen bromide, and then the resulting solution was treated in the same manner as in Example 19 and 0.24 g of a colorless amorphous substance was obtained with m. P 269-271 p.  The obtained substance was identified by NMR and IR spectral and elemental analyzes as 5-sec-butylamino-acetyl-8-hydroxy-3, 4-dihydro carbostyryl hydrochloride.  Example 39  50 g of a bromoanhydride of α-bromic acid (U), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide are added to 20 g of 8-hydroxycarbostyril (U1).  The resulting mixture was heated at 50 ° C for 13 hours and the carbon disulfide layer was removed by decantation.  To the residue for crystallization of the product, crushed ice is added and the crystals thus formed are filtered off, washed with water, then recrystallized from methanol and 27 g of 5- (3-bromobutyryl) -8-oxycarbutyry (IV) are obtained. square  218-219 ° С (with oxidation and decomposition).  PRI me R 40.  25 g of acid chloride a.  -Bromobutyric acid (U) and 25 g of anhydrous aluminum chloride are added to 10 g of 8-hydroxycarostyryl (U1) and the resulting mixture is heated for 4 hours with thorough stirring.  To the mixture of crystallizing product, thereafter, crushed ice is added, the crystals thus formed are filtered off from the filter, washed with water, and then recrystallized from methanol to obtain 12.6 g of 5-oi-bromobutyryl) -8-oxycar19 botirile (IV) with m. square  213-219 ° C (with staining and decomposition).  Example 41, 25 g of bromo-anhydrocarboxylic acid (U) and 100 ml of nitrobenzene were added to 10 g of 8-hydroxycarbostyryl, and 25 g of anhydrous aluminum chloride was added to the resulting solution while cooling.  The mixture is heated at 70 ° C for 10 hours, then poured onto crushed ice.  The precipitated crystals are filtered, washed with water, recrystallized from methanol and obtain 11.2 g of 5- (a (. -bromobutyryl) -8-hydroxycarbostyril with t. square  217218, 5 ° C (with staining and decomposition).  Example 42  200 ml of sec-butylamine (III) is added to 10 g of 5- (oC-bromobutyryl) -8-hydroxycarbostyryl (IV) (see examples 39-41) and the resulting mixture is heated at for 20 h, then concentrated to dryness.  The crystals that form when water is added are filtered, dissolved in 50 ml of ethanol, and the resulting solution is adjusted to pH 1 with concentrated hydrochloric acid.  The precipitated crystals are filtered, recrystallized from methanol and 8.3 g of 5- (c. -second-butylaminobutyryl) -8-hydroxycarbostyryl hydrochloride (II) with t. pl, 212-214 ° C (with staining and decomposition).  Example 43  10 ml of isopropylamine (I1) and 50 MG1 of methanol were added to 5 g of 5- (oi-bromobutyryl) -8-hydroxycarbostyryl (IV) (see examples 39-41).  The resulting mixture was heated under reflux for 6 hours and then concentrated to dryness.  Further, the reaction product is treated analogously to example 1 and get 4.2 g of the methanol solvate 5 (ai-isopropylaminobutyryl) -8-oxycarbostyryl (P) with t. square  136-137С (with decomposition and foaming).  TP (example44.  50 g of ai-bromoic acid bromide (U), 50 g of anhydrous aluminium chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (U1).  The resulting mixture is heated at 50 ° C for 13 hours and the carbon disulfide layer is removed by decantation.  To the residue, crushed ice is added to the precipitated crystals, filtered, washed with water and recrystallized from methanol to obtain 27 g of 5- (ot-bromobutyryl) -8-oxycarbostyryl (IV) with m. square  218-219 ° C (with staining and decomposition).  To 5 g of the resulting 5- (ot-bromobutyryl) -B-oxygarbostyril (IV) 100 ml of isopropylamine (III) are added and the mixture is heated at 50 ° C for 4 h, then concentrated to dryness.  The crystals that form when water is added are filtered, taken up in water, and then recrystallized from methanol to give 4.6 g of methanol solvate 5- (oi-isoproplaminobutyryl) -8-hydroxycarbostyryl (I) t. square  136-137 ° C (with decomposition and foaming).  Example 45  25 g of 2-phenethyl on (14) are added to 5 g of 5- {o-bromobutyryl) -8-oxycarbostyryl (IV) (see examples 39.40 or 41) and the mixture is stirred at 30 ° C for 8 hours.  A mixture of diethyl ether and petroleum ether is added to the reaction mixture and the precipitated substance is dissolved in dilute hydrochloric acid to remove any insoluble matter.  The hydrochloric acid layer is concentrated and the precipitate is filtered off and 5.3 g of substance is obtained by recrystallization from ethanol. square  200–201 ° C (with staining and decomposition).  The resulting substance is identified by NMR and IR spectral and elemental analyzes as dihydra. t (2-phenethylamino) butyryl-8-hydroxycarbostyryl chloro hydrate (P).  Example 46  5MP of morpholine (III) is added to 5 g of 5- (° C -bromobutyl) -8-hydroxycarbostyril (IV) (see  examples 39-41) and the mixture is stirred at 40 ° C for 4 hours  Then, the reaction mixture was concentrated under reduced pressure, 100 ml of water was added to the resulting residue.  The mixture is stirred and filtered, after which the filtered mother liquor is concentrated under reduced pressure. The residue is dissolved in acetone and the solution is filtered to remove any insoluble matter.  The filtrate is then concentrated under reduced pressure, adjusted to pH 2-3 with concentrated hydrochloric acid, and the precipitate formed by cooling with ice is recrystallized from this ethanol to give 2.1 g of white amorphous monohydrate 5- (o (α-morpholinobuty Ryl) -B-hydroxycarbostyryl hydrochloride (with t. square  179-182 C (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analyzes.  PRI me R 47.  17.1 o-bromopropionic acid chlorides, 27 g of anhydrous aluminum chloride and 8 nitrobenzene are added to 8 g of 8-meter CI-3,4-dihydrocarbostyril and the mixture is heated at 50–60 ° C for stirring; for 1 h.  The reaction mixture is then poured into 200 ml of ice-cold water and the precipitate formed is filtered off and washed with water.  Then the precipitate is recrystallized from ethanol and 11.5 g of substance are obtained with m. square  15 155 ° C.  The resulting product is identified by NMR and IR spectral and.  Elemental analyzes as.  5 (oC-bromo propionyl) -8-methoxy-3, 4 dihydrocar bostyril.  Example 48, 26.4 g of bromohydride oi-bromo acid, 17.5 anhydrous aluminum chloride and 5 ml of nitrobenzene are added to 5 g of 8-NKToxy-3, 4-dihydrocarbostyril and the mixture is heated at 5060 ° C for stirring 1 hour  The reaction mixture is then poured into 100 ml of ice-cold water, and the resulting precipitate is filtered off and washed with water.  Then the precipitate is recrystallized from ethanol and get 5 g of the substance with t. square  151-152 ° C.  The resulting product was identified by NMR and IR spectral and elemental angles as 5- (cibromobutyryl) -8-methoxy-3, 4-dihydrocarbostyryl.  Example 49  2g 5- (o-bromopropionyl) -8-methoxy-3, 4-dihydrocarbostyril (see Example 47) is suspended in 50 MP of isopropanol and the suspension is stirred for 2 hours at 60 ° C.  The solvent is then distilled off and the resulting residue is dissolved in 5 ml of isopropanol.  The solution is then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed is filtered off and the mixture of acetone and diethyl ether is added to the filtrate.  The precipitate formed is filtered off and 1.5 g of a white amorphous substance is obtained by recrystallization from isopropanol. pl, 172-174C (with decomposition), The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (oi-isopropylaminopropionyl) -8-methoxy-3, 4-dihydrocarboustryl hydrochloride dihydrate.  Example 50  5 g 5- (s: -brompropionyl) -8-methoxy-3, 4-dihydrocarbostyril (see Example 47) is suspended in 50 ml of isopropanol and 10 g of tert-butyl amine is added to the suspension, after which the mixture is dried at 60 ° C for 15 hours.  The solvent is then distilled off and the resulting residue is dissolved in 10 ml of isopropanol.  The solution is then made up to pI 2-3 with concentrated hydrochloric acid.  The precipitate formed is filtered off and acetone is added to the filtrate.  The precipitate formed is filtered off and diethyl ether is added to the filtrate.  The precipitate formed is filtered off and recrystallized from a mixture of isopropanol and diethyl ether to obtain 2.1 g of a colorless amorphous substance with m. square  207-210 s (with decomposition).  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (o -t-butylaminopropionyl) -8-methoxy-3 monohydrate, 4-dihydrocarbostyryl hydrochloride.  Example 51  2 g of 5- (o (-bromobutyryl) 6-methoxy-3, 4-dihydrocarbostyril (see Example 48) is suspended in 50 ml of isopropanol and 5G of isopropylamine is added to the suspension, after which the mixture is stirred at 4 hours.  The solvent is then distilled off and the resulting residue is taken up in 5 ml of isopropanol.  The solution is then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed is filtered off and recrystallized from a mixture of isopropanol and acetone to obtain 1.7 g of a colorless amorphous substance with m. pl, 204-206 С (with decomposition).  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (oi-isopropylaminobutyryl) -8-methoxy-3 monohydrate, 4-dihydrocarbostyryl hydrochloride, Example 52.  3g of 5- (oi-bromobutyryl) -8-methoxy-3, 4-dihydrocarbostyril (see Example 48) is suspended in 50 ml of isopropanol and 9 g of tert-butylginin is added to the suspension, which is then stirred at 19 hours.  The solvent is then distilled off and the resulting residue is dissolved in 5 ml of isopropanol.  The solution is then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed is filtered off and acetone is added to the filtrate.  The precipitate formed is filtered off and diethyl ether is added to the filtrate.  The precipitate is filtered off and recrystallized from isopropanol to obtain 1.6 g of a colorless amorphous substance with t. square  160-162 ° C (with decomposition) The resulting product was identified by NMR and IR spectral and elemental analysis and as 5- (o-tert-butylaminobutyryl) -8-methoxy-3 monohydrate, 4-dihydrocarboxyryl hydrochloride.  Example 53  1.5 g 5- (o-isopropylaminopropionyl) -8-methoxy - 3, 4-dihydrocarbostyril (see  Example 50) was dissolved in 15 ml of 47% aqueous hydrogen bromide and the solution was boiled for 15 hours, heating at 140 ° C.  The reaction mixture was concentrated and acetone was added to crystallize the product.  The product is then recrystallized from a mixture of ethanol and acetone to obtain 1.1 g.  substances with t. square 223-226 ° C (with decomposition), The resulting product was identified by NMR and IR spectral and elemental analyzes as 5-Сe (-isopropyl aminopropionyl) -8-hydroxy-3, 4-dihydrocarbostyryl bromohydrate.  Remark p 54.  1.5 g of 5- (c-isopropylaminobutyryl) -8-methoxy-3, 4-dihydrocarbostyril is dissolved in 15 ml of 47% aqueous hydrobromic acid and the solution is boiled for 15 hours, heating at 130-140 °.  The reaction mixture is concentrated and acetone is added to the crystallization of the product to the reaction mixture.  The product is then recrystallized from a mixture of ethanol and acetone, and 1.0 g is obtained with t. square  165 GB8 p.  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (o-isopropylaminobutyryl) -8-hydroxy-3 hemihydrate, 4-dihydrocarbostyrylbromohydrate.  example 55.  1g of 5- (c-tert-butylaminopropionyl) -8-methoxy-3, 4-dihydrocarbostyril, obtained from monohydrate hydrochloride, prepared as in Example 50, is dissolved in 15 ml of 47% aqueous hydrobromic acid and the solution is boiled over 15 h, heating at 140-150C.  The reaction mixture was concentrated and acetone was added to the reaction mixture to crystallize the product.  Product then overwrite.  Talsed from a mixture of ethanol and acetone and obtains 0.7 g of substance with t. square  224-227 ° С (with decomposition).  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (L-tert-butylamino -; propionyl) -8-hydroxy-3, 4-dihydrocarbostyrylbromohydrate monohydrate.  Example 56.  1.5 g of 5- (oC-tert-butylaminobutyryl) -8-methoxy-3, 4-dihydrocarbostyril, obtained from monohydrate hydrochloride, prepared as in Example 52, is dissolved in 47% aqueous hydrobromic acid and the solution is boiled over 19 h at 140-150 ° C.  The reaction mixture was concentrated and acetone was added to the reaction mixture to crystallize the product.  The product is then recrystallized from a mixture of acetone and ethanol to obtain 1.1 g of the substance with m. square  144-146 ° C (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analysis. 1 as 5- (s-tert-butylaminobutyryl) -8-hydroxy-3, 4-d11 hydrocarboxyrylbromohydrate dihydrate.  Example 57  5 g of 5- (ot-6pOM propionyl) -8-hydroxy-3, 4-dihydrocarbostyril are suspended in 30 ml of benzene and 4.2 ml of morpholine are added to the suspension, after which the mixture is heated at.  boiling point for 4 hours.  The reaction mixture is filtered and the filtrate is washed with water, then concentrated under reduced pressure to completely remove the remaining water.  The resulting residue is dissolved in.  .  50 ml of isopropanol and the solution was adjusted to pH 2-3 with concentrated hydrochloric acid.  The viscous precipitate formed by cooling with ice is separated and dissolved by heating in acetone.  After cooling the solution, the precipitate formed is dissolved in 30 ml of water and adjusted to pH 7.5-8 with sodium bicarbonate.  The precipitate formed upon cooling is filtered and dissolved in 10 ml of 47% aqueous hydrobromic acid, and then concentrated under reduced pressure.  The residue obtained is washed with 10 ml of ethanol, recrystallized from ethanol, and 2.6 g of white amorphous monohydrate of 5- (o (-morpholino) -propionyl-8-oxy-3, 4-dihydrocarbostyryl bromohydrate with t are obtained. square  23b-23bc (with decomposition).  Example 58  30 ml of nitrobenzene and 70 MP of chloroacetic acid chloride are added to 40 g of 1-methyl-8-methoxycarbostyril and 130 g of chlorine chloride are slowly added to the mixture while cooling with ice water, after which the mixture is stirred for 4 h.  The reaction mixture is then poured into 1 liter of ice water to precipitate the product.  Sediment from. filtered, washed with diethyl ether, recrystallized from a mixture of chloroform and ethanol (2: 5 by volume) to obtain 32 g of white amorphous 1-methyl-5-chloroacetyl-8-methoxycarbostyril with m. square  204-205,5 ° C.  The resulting product was identified by elemental analysis and IR and NMR spectral analyzes.  Example 59  40 ml of nitrobenzene and 12 ml of monochloroacetic acid chloride are added to 7.4 g of 1-methyl-8-hydroxycarbostyryl and 20 g of aluminum chloride is slowly added to the mixture while cooling with ice water, after which the mixture is stirred at 60 ° C for 18 h.  The reaction mixture is then poured into 500 ml of ice water to precipitate the product.  The precipitate is filtered off, washed with diethyl ether and ethyl ether, recrystallized from a mixture of ethanol and dimethylformamide (1: 1 by volume) to give 2.8 g of white amorphous 1-methyl-5-chloroacetyl-8-hydroxycarboxyryl with m. square  287-289 ° (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analyzes.  For example.  2.7 g of 1-methyl-5-chloroacetyl-8-methoxycarbostyril, prepared analogously to example 58, is dissolved in 40 ml of isopropanol and 9 g of isopropylamine is added to the solution by heating the solution at 55-60 ° C. .  After the addition is complete, the mixture is stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and the resulting residue is dissolved in 40 ml of isopropanol.  Then the solution is filtered to completely remove non-soluble substances and the filtrate is adjusted to pH 2, -3 with concentrated hydrochloric acid.  The mixture is cooled with ice and the precipitate formed is filtered off and recrystallized from ethanol to obtain 0.4 g of white amorphous 1-methyl-5-isopropylamino acetyl-8-methoxycarbostyryl hydrochloride.  The resulting product is identified by IR spectral and elemental analyzes.  Ex. 61. 10 ml of isopropanolamine was added to 1/6 g of 1-methyl-5-chloroacetyl-8-hydroxycarbostyril, prepared as in Example 59, and mixture 9 was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation with ethanol to dryness.  The resulting residue is dissolved in 20 ml of ethanol and the solution is filtered to recover insoluble substances, which are then dissolved in hot ethanol.  The solution is adjusted to pH 2-3 with concentrated hydrochloric acid and cooled with ice.  The precipitate formed is filtered off and dissolved in 20 ml of water.  The solution is adjusted to pH 6.5-7.5 with sodium bicarbonate and the precipitate formed is filtered off, -, recrystallized from ethanol, and 1.1 g of a white, amorphous 1-methyl-5-isopropylaminoacetyl-8-oxycarboxylic 116-138 ° C are obtained (with with t. square  zheniem).  Example 62  2.0 g of 1-methyl-5-isopropylamino-acetyl-8-methoxycarbostyryl hydrochloride (see Example 60) is dissolved in 30 ml of a 47% aqueous solution of hydrobromic acid and the solution is heated on an oil bath at 120-130 ° C for 8 hours at reflux.  Then, 10 ml of water was added to the reaction mixture, after which it was concentrated by distillation.  Again, 10 ml of water was added to the mixture, followed by concentration.  After cooling the mixture, the precipitate formed is filtered and dissolved in 60 ml of water with heating.  The resulting solution is adjusted to pH 6.5-7.5 with sodium bicarbonate and the filter cake is formed.  By recrystallization of the precipitate from ethanol. JET 0.45 g of white amorphous 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril with m. square  136-138 with (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analyzes.  Example 63  1.0 g of 5-isopropylaminoacetyl-8-hydroxycarbostyryl hydrochloride (see  Example 9) is dissolved in 40 ml of water and 0.5 g of gesh on carbon is added to the resulting solution as a catalyst.  The resulting mixture is heated to 35-40 ° C with stirring to absorb hydrogen.  After completion of the reduction reaction, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure.  Ethanol is added to the residue and then re-concentrated to dryness to completely remove the water.  The residue is crystallized from acetone and recrystallized from a mixture of ethanol and acetone (1: 1 by volume) to obtain a pale yellow amorphous 5- (1-hydroxy-2-isopropylamino) ethyl 8-hydroxycarbostyryl hydrochloride with t. square  210-212С (with decomposition).  Example 64  2, O g of the free base of 5-sec-butylamino-acetyl-8-oxycarbo steryl (see  Example 11) is dissolved in lOO ml of methanol, and 0.8 g of sodium borohydride is gradually added to the resulting solution with stirring and cooling, the resulting mixture is stirred at the same temperature for 15 minutes, and then further stirred at room temperature. for another 1 hour  Concentrated hydrochloric acid is added to the mixture to bring the mixture to a pH of 1.5-2, and the solvent is removed by distillation under reduced pressure.  30 ml of ethanol was added to the residue and then the mixture was concentrated to dryness under reduced pressure to remove water.  The residue is dissolved in 50 MP absolute ethanol and an ethanolic solution of sodium hydroxide is added to the resulting solution in order to bring the solution to a pH of 7-8, b.  The precipitates that form are filtered off, and the filtrate is concentrated to dryness under reduced pressure.  The residue is then extracted with 50 ml of absolute ethanol and hydrogen chloride is passed through the extract and the extract is concentrated to dryness under reduced pressure, the residue is recrystallized from isopropanol to obtain 1.3 g of pale yellow amorphous monohydrate 5- (1-hydroxy-2-sec-butylamino) - ethyl 8-hydroxycarbosothyryl dichlorohydrate with t. square  143-144 ° (with decomposition).  Example 65  1.5 g of 5-tert-butylamino-acetyl-8-hydroxycarbostyril (see Example 10) is dissolved in 100 ml of methanol and 0.7 g of sodium borohydride is slowly added to the resulting solution while stirring and cooling.  Stirring is continued at the same temperature for 15 minutes and at room temperature for another 1 hour. The reaction product is treated in the same manner as in Example 2, and then, by recrystallization from ethanol, 0.9 g of pale yellow amorphous 5- (1-hydroxy-2-tert-butylamino) -ethyl-8-hydroxycarbostyryl hydrochloride with t is obtained. square  242-244 C (with decomposition).  Example 66  2.0 g of 5-piperidinoacetyl-8-hydroxycarbostyryl hydrochloride (see  Example 12) is dissolved in 200 ml of methanol and 2.0 g of sodium borohydrate is added to the solution while cooling with ice, and the mixture is stirred for 2 hours.  The mixture is adjusted to pH 2-3 with concentrated hydrochloric acid, and the mixture is left for 1 h at room temperature, then filtered.  The filtered reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30 ml of ethanol.  The solution is filtered to completely remove insoluble substances, and the filtrate is concentrated under reduced pressure.  These operations (dissolution in ethanol, filtration and concentration) are repeated three times.  The resulting residue is dissolved in acetone by maturing and the precipitate formed upon cooling is filtered off and the isopropanol is recrystallized, and 0.6 g of white amorphous one-and-a-half-hydrate 5- (1-hydroxy-2-piperidine ethyl 8-hydroxycarboxyryl hydrochloride with t is obtained. square  146-148 C (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analyzes.  According to the method described in Example 61, the following compounds can be obtained from the corresponding 5- (heterocyclic amino) ethanoylcarbostyryl compounds: 5- (1-hydroxy-2-piperazino) ethyl-8methoxycarbostyryl dihydrochloride having a melting point (decomposed) 177-179 seconds (water is recovered from the water-methanol mixture).  5- (1-hydroxy-2-pyrrolidino) ethyl-8methoxycarbostyryl hydrochloride having a melting point (with decomposition) of 150-151 ° C.  (precipitated from isopropyl-acetone mixture).  Example 67.  1.0 g of the 5-morpholinoacetyl-8-hydroxycarbostyril prepared in Example 13 is dissolved in 100 ml of methanol and 1.2 g of sodium borohydride is added to the solution, followed by stirring for 2 hours.  The reaction mixture is adjusted to pH 2-3 with concentrated hydrochloric acid and the mixture is left for 1 hour at room temperature.  Then the reaction mixture was filtered off and the filtrate was concentrated under reduced pressure.  The residue is dissolved in 20 MP of ethanol and the solution is filtered to completely remove insoluble substances, after which the filtrate is concentrated under reduced pressure.  These operations (dissolution in standard, filtration and concentration) are repeated three times and the resulting precipitate is cristized from acetone.  The precipitated crystals are filtered off and triturated with 20 ml of an aqueous solution of sodium bicarbonate to completely remove soluble substances by filtration, and the insoluble matter is washed with water and dissolved in ethanol with heating.  The resulting solution is adjusted to pH 2-3 with concentrated hydrochloric acid and the precipitate formed upon cooling is filtered to obtain 0.6 g of white amorphous one and a half hydrate of 5- (1-hydroxy-2-morpholino) -ethyl-8-oxycarbstryl hydrochloride with t . square  157-158, (with decomposition).  The resulting product is identified by NMR and IR spectral and elemental analyzes.  Example 68  50 ml of methanol was added to 5 g of the free base of 5-benzylamino-acetyl-8-hydroxycarbostyril (see Example 14) and to the solution while cooling with ice and stirring, 3 g of sodium borohydride are slowly added, after which the mixture is stirred at room temperature for 1 hour.  The resulting mixture is adjusted to pH 1 with concentrated hydrochloric acid, and the resulting precipitate is filtered. The filtrate is concentrated to dryness and crystallized from acetone.  The resulting crystals are adjusted to pH 8 with an aqueous solution of sodium hydroxide, the resulting precipitate is filtered and washed with water.  The precipitate is adjusted to pH 1 with dilute hydrochloric acid and concentrated to dryness.  The residue obtained is recrystallized from a mixture of methanol and acetone to obtain 4.2 g of a white amorphous substance with m. square  120-121 ° C.  The resulting product was identified by NMR and IR spectral and elemental analyzes and as 5- (1-hydroxy-2-benzyalmino) ethyl-8 hydroxy carbostyryl hydrochloride dihydrate.  Example 69 1g L- {1-phenethyl, minoacetyl) -8-hydroxycarbostyryl chlorohydrate prepared in Example 15 is dissolved in 50 ml of methanol and the solution is converted to a weakly basic solution with a methanolic solution of sodium hydroxide.  Then, 0.5 g of sodium borohydride is slowly added to the mixture while cooling with ice, and the mixture is then stirred at room temperature for 1 hour.  The precipitate, which is formed by adding concentrated hydrochloric acid to pH 3, is filtered off and the filtrate is concentrated to dryness.  The resulting residue is dissolved in absolute ethanol and the solution is adjusted to pH 9 with an ethanolic solution of sodium hydroxide.  The precipitate is filtered off and the filtrate is concentrated to dryness.  The residue is crystallized from acetone and washed with water.  The resulting crystals are dissolved in isopropanol and the solution is saturated with gaseous hydrogen chloride, then cooled.  The precipitate formed is filtered off and recrystallized from isopropanol to give i 0.77 g of a white amorphous substance with m. square  1b2-1b4 ° C.  The resulting product was identified by NMR and IR spectral and elemental analyzes as digirate 5-1 - OXI-2- (1-phenethylamino) ethyl 8-hydroxycarbostyryl chlorohydroate.  Example 70  0.1 g of platinum oxide and 50 ml of water are added to 0.5 g of 5-benzylamino-acetyl-8-hydroxycarbostyryl hydrochloride monohydrate prepared in Example 14, and the mixture is shaken at room temperature and atmospheric pressure under a hydrogen atmosphere in for 24 hours  After the reduction is complete, the catalyst is filtered off and the aqueous portion is concentrated to dryness.  The residue is recrystallized from a mixture of methanol and acetone to obtain 0.25 g of white amorphous 5 (1-hydroxy-2 amine 6) ethyl 8-hydroxycarbostyryl hydrochloride with m. square  261-262 ° С (with decomposition).  The resulting product is identified by NMR and IR spectral and lement analyzes.  Example 71  1.5 g of 5- {1,1-dimethylphenethylaminoacetyl) -8-oxycarbostyril is dissolved in 50 ml of methanol. 1 g of sodium borohydride is slowly added to the solution under cooling with ice water and stirring, after which 1 hour  The resulting mixture was then adjusted to pH 1 with concentrated hydrochloric acid, and the mixture was concentrated to dryness.  The residue is dissolved in ethanol and the insoluble materials are completely removed by filtration.  The ethanol layer is concentrated to dryness and the residue is dissolved in isopropanol.  The isopripole layer is concentrated and acetone is added to crystallize the product.  Recrystallization of the product from a mixture of methanol and acetone gives 1.4 g of a white amorphous substance with m. pl, 167-1b8 s (with staining and decomposition).  The obtained substance was identified by NMR and IR spectral and elemental analyzes as (1,1-dimethylphenethylamino) 1-hydroxy ethyl-8-hydroxycarbostyryl hydrochloride dihydrate.  Example 72  2.5 g of chloranil and 20 ml of xylene are added to 2.2 g of 5- (1-hydroxy-2-amino -) - ethyl-8-hydroxy-3, 4 dihydrocarbostyryl and the mixture is heated at reflux temperature for 24 h .  Then the reaction mixture is concentrated to dryness and the residue is thoroughly washed with carbon tetrachloride.  The residue is then dissolved in 30 ml of methanol and the solution is brought to pH 1 by passing gaseous hydrogen chloride into the solution and then cooled.  The precipitated crystals were filtered off by recrystallization from methanol to obtain 1.5 g of the substance with m. pl, 261262 С (with decomposition).  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-hydroxy-2-amino) ethyl-8-hydroxycarbostyryl hydrochloride, Example 73.  200 ml of water, 0.9 g of sodium hydroxide and 4.3 g of Rene nickel are added to 4.3 g of dihydrate (1,1-dimethylphenethylamino) -1-hydroxyethyl-8-hydroxy-3, 4-dihydrocarboustryl hydrochloride and the mixture heated at reflux for 15 h.  The reaction mixture is then filtered to remove the catalyst, and the filtrate is concentrated.  The resulting precipitated crystals are recrystallized from water and obtain 2.6 g of the substance with m. square  167-168s (with decomposition).  The resulting product was identified by NMR and IR spectral and elemental analyzes as monohydrate of 5-12- (i, 1-dimethylphenethylamino) -1-hydroxy-ethyl-8-hydroxy-carbostyryl hydrochloride.  Analogously to Example 10, 5- (2-isopropylamino-1-hydroxy) -ethyl-8-hydroxycarbostyryl hydrochloride is obtained with m. square  210-212 ° C (with decomposition), Example 74.  2, O g of 5-isopropylaminoacetyl-8-hydroxy-3, 4-dihydrocarbo styryl hydrochloride (see Example 3L) is dissolved in 40 ml of water and 0.5 g of palladium black is added to the solution as a catalyst.  The mixture is stirred at TO-VSC and atmospheric pressure in the presence of hydrogen gas (to absorb hydrogen).  After the reduction is complete, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure.  The water that remains in the resulting residue is then completely removed using ethanol, then acetone is added to the residue to crystallize the product.  Recrystallization from a mixture of ethanol and acetone (1: 2 by volume) gives 1.1 g of a colorless amorphous substance with m. square  199-201С.  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-hydroxy-2-isopropylamino) ethyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride.  Example 75  1.5 g of 5-tert-butylamino-acetyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride (see Example 37 was dissolved in 35 ml of water and 1.0 g of palladium on carbon was added to the solution as a catalyst. The mixture is shaken at 50-C 0 under a pressure of 4-5 atm in the presence of hydrogen gas (to absorb hydrogen).  After completion of the reduction, the cat agitator is filtered off and the filtrate is concentrated to dryness under reduced pressure.  Acetone is added to the residue to crystallize the product.  By recrystallization from a mixture of methanol and acetone (1: 2 by volume), 0.8 g of a colorless amorphous substance with m is obtained. square  240-241 ° C.  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-hydroxy-2-tert-butylamino) ethyl-8-hydroxy. -3, 4-dihydrocarboxyryl hydrochloride.  Example 76. 2.0 g 5-sec-butylamino-acetyl-8-hydroxy-3, 4-dihydrocarbostyril (see  Example 29) is dissolved in 100 ml of methanol and 0.8 g of sodium borohydride is slowly added to the solution while stirring and cooling with ice.  The mixture was then stirred at the same temperature for 15 minutes and then at room temperature for 1 hour.  The mixture was adjusted to pH 1.5 with 2 hydrochloric acid, and then the solvent was distilled off under reduced pressure.  Then 30 ml of ethanol was added to the residue and the mixture was again concentrated to dryness under reduced pressure to remove water.  926 50 ml of absolute ethanol was added to the obtained residue and the mixture was adjusted to pH 7-8.5.  The precipitate is filtered off and the filtrate is concentrated to dryness under reduced pressure.  The residue is extracted with 50 ml of absolute ethanol, and gaseous chloride is passed through the extract.  The extract is then concentrated to dryness under reduced pressure, and the residue is recrystallized from a mixture of methanol and acetone (1: 2 by volume) to obtain 1.3 g of a colorless amorphous substance with m. square  183-184 ° C.  The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (2-sec-butylamino-1-hydroxy) ethyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride.  Example 77.  0.7 g of palladium black and 130 ml of water are added to 1.5 g of 8-hydroxy-5- (-methylbenzylaminoacetyl) -carbostyryl hydrochloride and the mixture is shaken at 60 ° C under a hydrogen pressure of 4 atm.  After completion of the reaction, the catalyst is filtered off and the aqueous filtrate is concentrated to dryness.  Acetone is added to the residue to crystallize the product.  The product is then washed with 100 ml of ethanol and recrystallized from a mixture of methanol and ethyl acetate to obtain 0.8 g of white amorphous 5- (1-hydroxy-2-benzylamino) -ethyl-8-oxy-3, 4-dihydrocarbostyryl hydrochloride.  The resulting product is identified by NMR and IR spectral and elemental analyzes.  Example 78  0.1 g of palladium black and 50 ml of water are added to 0.4 g of 5- (1-hydroxy-2-benzylamino) ethyl-8-hydroxycarbostyryl chlorohydrate dihydrate. And the mixture is shaken at room temperature and atmospheric pressure in a hydrogen atmosphere for 8 hours .  After completion of the reaction, the catalyst is filtered off and the aqueous filtrate is concentrated to dryness.  The residue obtained is recrystallized from a mixture of methanol and acetone to obtain 0.2 g of white amorphous 5- (1-hydroxy-2-amino) ethyl-8-hydroxycarbostyryl hydrochloride.  The resulting product is identified by NMR and IR spectral and elemental anschism.  Example 79  0.7 g 5-pallas of wild black and 100 ml of water add 1.4 g of 5- (about {. -benzyl-1 inoacetyl) -8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride and the mixture is reduced at 60 ° C under a hydrogen pressure of 4 atm.  After the reduction is complete, the catalyst is filtered off and the resulting aqueous filtrate is concentrated to dryness.  Acetone is then added to the residue to crystallize the product.  The resulting crystals are washed with 100 ml of ethanol and recrystallized from a mixture of methanol and ethyl acetate to obtain 0.7 g of a white amorphous 5- (1-hydroxy-2-amino) ethyl-8-hydroxy-3, 4-dihydrocarbenyl hydrochloride.  The resulting product is identified by NMR and IR spectral and elemental analyzes.

Example 80. 0.05 g of palladium black and 100 ml of water add 1 g of 5- (1-hydroxy-2-amino) ethyl-8-hydroxycarbostyryl / orhydrate and, with shaking, restore the mixture under hydrogen pressure at 2 atm. 50 ° C for 10 hours. After the completion of the reduction, the catalyst is filtered off and the aqueous filtrate is concentrated to dryness. The precipitate obtained is recrystallized from a mixture of methanol and acetone, and 0.9 g of amorphous white 5- (1-hydroxy-2-amino) - is obtained. Ethylene-8-oxy-3,4-dihydrocarbostyryl-. hydrochloride with so pl. 270-272 ° C. The resulting product is identified by NMR and IR spectral and elemental analyzes.

Example 81. About 5 g of palladium black and 50 ml of water are added to 2 g of 5- (1-hydroxy-2-isopropylamino) ethyl-8-hydroxycarbostyril and the mixture is restored under atmospheric pressure in a hydrogen atmosphere at 70 ° C under shaking for 8 hours. After the reduction is complete, the catalyst is filtered off and the aqueous filtrate is concentrated to dryness. The precipitate obtained is recrystallized from a mixture of methanol and acetone to obtain 1.7 g of a white, amorphous 5- (1-hydroxy-2-isopropylamino) -ethyl-8-oxime-3,4-dihydrocarbostyryl hydroxide. The resulting product is identified by NMR and IR spectral and elemental analyzes.

Example 82. 0.1 g of palladium black and 30 ml of water are added to 1 g of 5- (1-hydroxy-2-sec-bu ylamino) ethyl-8-hydroxycarbostyryl and the mixture is shaken under pressure of hydrogen to 3 bar. for 10 hours. After completion of the reduction, the catalyst is filtered off and water ;; the filtrate is concentrated to dryness. The precipitate obtained is recrystallized from a mixture of methanol and acetone to obtain 0.6 g of 5- (1-hydroxy-2-sec-butylamino) ethyl-8-oxyl-3, 4-dihydrocarbostyryl hydrochloride. The resulting product is identified by NMR and IR spectral and elemental analyzes.

As an example 83. 0.5 g of 10% palladium on carbon and 50 ml of water are added to 1.5 g of 5- (1-hydroxy-2-tert-butylamine) ethyl ethyl-8-hydroxycarbostyryl hydrochloride and the mixture, while shaking, is set under hydrogen pressure of 5 atm. for 16 hours. After the reduction is complete, the catalyst is filtered off and the aqueous filtrate is concentrated to dryness ... The precipitate is recrystallized from a mixture of acetone and methanol and 1.1 g of white are obtained Amsrfnogo 5- (1-hydroxy-2-tert-butylamino) -ethyl-8-hydroxy-3, 4-dihydrocarbostyril with so pl. 2404lc. The resulting product is identified by NMR and IR spectral and lement. analyzes.

Example 84. 100 M7J of palladium black and 50 ml of water are added to 300 mg of 5-1-hydroxy-2- (1,1-dimethylphenethylamine) monohydrate ethig5-8-hydroxycarbohydrylhydrate monohydrate and the mixture is reduced under 2.5 atm. 45-50s for 8 hours. The catalyst is filtered off and the filtrate is concentrated to dryness. The residue is recrystallized from water and obtain 260 mg of an amorphous substance with so pl. 120-121 ° C. The resulting product was identified by NMR and IR spectral and elemental analyzes as 5-1-hydroxy-2- (1,1-dimethylphenethylamino) ethyl-8-hydroxy-3 dihydrate, 4-dihydrocarboxyryl hydrochloride dihydrate.

Example 85. About 2 g of platinum oxide and 5 p ml of water are added to 1, O g of 5- (1,1-dimethylphenethylaminoacetyl) -8-hydroxycarbostyryl hydrochloride hemihydrate and the mixture is reduced by pressure of 5 atm of hydrogen at 20 ° C for 20 hours. The catalyst is filtered off and the filtrate is concentrated to dryness. The resulting residue is recrystallized from water to obtain 0.8 g of a white amorphous substance with m.p. 120-121 ° C. The resulting product was identified by NMR and IR spectral and elemental analyzes as 5-1-hydroxy-2- (1,1-dimethylphenethylamino) ethyl ethyl 3,4-dihydrocarbostyryl hydrochloride a dihydrate.

PR and G4 e p 86. 1.5 g of 5-piperidinoacetyl-8-hydroxycarbostyryl hydrochloride are dissolved in 100 ml of water and 0.5 g of palladium on coal and 0.2 g of palladium black are added to the solution, after which the mixture is added is boiled for catalytic reduction at a pressure of at atmospheric pressure in a hydrogen atmosphere for 4 days at 70 ° C. After the reduction is complete, the reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness under reduced pressure. The resulting residue is dissolved by heating in acetone, after which the solution is cooled. The precipitate formed upon cooling is recrystallized from isopropanol to obtain 0.8 g of white c1 morphic 5- (2-piperidino-1-hydroxy) ethyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride hemihydrate with mp. 13G-139 ° C (with decomposition). The resulting product is identified by NMR and IR spectral and elemental analyzes.

Apply p.87. 10 ml of 47% aqueous hydrobromic acid is added to 1 g of 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyryl hydrochloride monohydrate and the mixture is heated at reflux temperature for 15 hours. 29 then concentrated dry up Acetone is added to the residue to crystallize the product, which is then adjusted to pH 8 with dilute aqueous sodium hydroxide solution. The precipitated crystals are filtered, washed with water and dissolved in ethanol. The solution is adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The resulting residue is recrystallized from cm of ethanol and diethyl ether and obtain 0.7 g of substance with so pl. 210-212 (with decomposition). The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-ox-2-isopropyl-amino) -ethyl-8-hydroxycarbo styryl hydrochloride. Analogously to Example 72, the following compounds are prepared from the corresponding 8-methoxy-compounds: 5- (1-hydroxy-2-isopropylamino) ethyl-8-hydroxy-3, 4-dihydrocarboxyryl chloromethyl with mp. 203-204 C (with the decomposition of 5- (1-hydroxy-2-tert-butylamino) -ethi i. -8-hydroxycarbostyryl chlorohydrate-hygiene with mp 244-246 ° С (with the decomposition of 5- ( 1 hydroxy-2-benzylamino) ethyl-8-hydroxycarbostyryl hydrochloride dihydra substance with mp 120-121 ° with 5-1 hydroxy-2- (1,1-dimethylphenethyl but) ethyl 8 hydroxycarbostyryl chlorohydro monohydrate with mp. 167-168 ° С (with decomposition); 5- (1-hydroxy-2-amino) -ethyl-8-hydroxy-3, -dihydrocarbostyryl hydrochloride with mp: 270-272.5 С (with decomposition.) Example 88. 40 ml of methanol was added to 2 g of 5- (o (-isopropylaminobutyryl) -8-hydroxycarbostyryl (P), prepared analogously to Example 43 or 44, and to the During the addition, while stirring and cooling with ice, 2.5 g of sodium borohydrate was added in portions, and then stirred at room temperature for another 1 hour. To adjust the pH to 1, concentrated hydrochloric acid was added to the reaction mixture, and the mixture was concentrated The precipitates are washed with acetone, dissolved in water, and then adjusted to pH 8 with an aqueous solution of sodium hydroxide in order to precipitate crystals. The resulting crystals are collected by filtration, recrystallized from ethanol, and 1.8 g of 5- (1-hydroxy-2-isopropyl-1-amino) -butyl-8-hydroxycarbostyril monohydrate are obtained, mp. 141-142С (with staining and decomposition). Example 89.30 ml of methanol was added to 1.5 g of 5- (o1-sec-butylaminobutyryl) -8-oxycarbostyryl (IIj, see example 42) and 1.5 g of borohydride was added to the resulting solution while stirring and cooling with ice. on three . Subsequently, the stirring was continued at room temperature for another 1 hour. The reaction mixture was then adjusted to pH 1 with concentrated hydrochloric acid, and then concentrated to dryness. The precipitates are filtered, washed with acetone, dissolved in water, and then adjusted to pH 8 with aqueous sodium hydroxide. The precipitated crystals are filtered off, washed with water and again dissolved in dilute hydrochloric acid. The resulting solution was concentrated to dryness, and the precipitates were recrystallized from ethanol to obtain 1.3 g of 5- {1-к-2-sec-butylamino) -butyl-8-hydroxy-carbostyryl hydrochloride monohydrate (1) with mp. 182-183s (with decomposition and foaming). Example 90 20 ml of tetrahydrofuran are added to 1 g of 5 - (.- isopropylaminobutyryl) -8-hydroxycarbostyryl hydrochloride (P; see example 43 or 44) and the resulting mixture is added dropwise to a suspension of 0.12 g of lithium aluminum hydride in 10 ml tetrahydrofuran, stirring at room temperature. After the addition to the reaction mixture is complete, a small amount of water is added to completely decompose the excess lithium aluminum hydride. The reaction mixture is then poured into 50 ml of ice water and the aqueous layer of the resulting solution is separated and concentrated to dryness. The precipitated crystals are filtered, washed with acetone and dissolved in water. The solution is adjusted to pH 8 with aqueous sodium hydroxide in order to precipitate crystals, which are then filtered. recrystallized from ethanol to obtain 0.8 g of 5- {1oxy-2-isopropylamino) -butyl-8-hydroxycarbostyryl monohydrate (1) with m.p. 141-142 ° C (with staining and decomposition). Example 91 1.5 g of the free base of (2-phenethylamino) -butyryl) -8-oxycarbostyryl (P1cm. Example 45) are dissolved in 150 ml of methanol and 2 g of borohydride are slowly added to the solution while cooling with ice water and stirring Sodium, after which continue at room temperature for another 1 hour. The resulting mixture is then adjusted to pH 1 with concentrated hydrochloric acid and the mixture is filtered to remove the precipitate formed. The filtrate is concentrated to dryness and the residue is crystallized by the addition of acetone. An aqueous solution of sodium hydroxide is then added to the crystals to bring the pH to 8. The resulting precipitate is filtered off, recrystallized from ethanol, and 1.3 g of a white amorphous substance are obtained, m.p. 147- “148С (with decomposition and foaming). The resulting product was identified by NMR and IR spectral and elemental analyzes as 5-1-hydroxy-2- (2-phenethyl o no) -butyl J-8-oxycarbo: tiryl (I) trihydrate. Example 92 2.5 g of chloranil and 20 ml of xylene are added to 2.2 g of 5- (1-hydroxy-2-isopropylamino) -propyl-8-hydroxy-3, 4-dihydrocarbostyril (UP and the mixture is heated at boiling point reflux for 24 hours. The reaction mixture is concentrated to dryness and the residue is thoroughly washed with 50 ml of carbon tetrachloride. The residue is then diluted with 30 ml of methanol and hydrogen chloride gas is passed into the solution to pH 1 and then cooled. The precipitated crystals are filtered, recrystallized from methanol and get 1.5 g of substance with so pl. 164-166С (decomposed) The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (1-hydroxy-2-isopropylamino) -propyl-8-oxy-car monohydrate bostyryl hydrochloride (I). Analogously to Example 13, the following compounds (I) of the corresponding 3,4-dihydrocarbostyril compounds (UE): 5- (1-hydroxy-2-sec-butylamino) -butyl-8-hydroxycarbostyryl hydrochloride monohydrate with mp 182-183 ° C (with dilution); 5- (1-hydroxy-2-ethylamino) -butyl-8-hydroxycarbostyryl hydrochloride with m.p., 174-177.5 ° C (with decomposition). Example 93. 10 ml of 47% aqueous hydrobromic acid are added with -1 g of L- (1-hydroxy-2-isopropylamino) propyl-8.-Methoxycarbostyryl hydrochloride monohydrate (And the mixture is heated at reflux temperature for 15 The mixture is then concentrated to dryness. Acetone is added to the resulting crystallization of the product, and then it is brought to pH 8 with a dilute aqueous solution of sodium hydroxide. The precipitated crystals are filtered, washed with water and dissolved in ethanol. The solution is diluted to pH 1 concentrated hydrochloric acid and the resulting residue is recrystallized from a mixture of ethanol and diethyl ether and 0.7 g of material is obtained with mp 164–16 ° C (with decomposition). The resulting product is identified by NMR and IR spectral and elemental analyzes. 5- (1-hydroxy -2-isopropylamino) -propyl-8-hydroxy botiriLchlorohydrate (I). Analogously to Example 14, the following compound (I) is obtained from the corresponding Vidoy 8-methoxy compound JYIII): 5- (1-hydroxy-2- isopropylamino-butyl-8-hydroxycarbostyryl hydrochloride with m.p. 213-214 C (with decomposition), PRI me R 94. 1.0 g, 5- (oC-isopropylaminopropionyl) -8-hydroxy-3, 4-dihydrocarbostyril obtained from bromohydrate hemihydrate prepared analogously to example 54, dissolved in 50 ml of methanol and 0 is slowly added to the solution while cooling with ice. 3 g of sodium borohydride, after which the mixture is stirred for another 1 hour at room temperature. Methanol, which is saturated with hydrochloric acid gas, is then added to the mixture to bring the pH to 1-2. The precipitate formed is filtered off and the filtrate is concentrated to dryness. Then, 1 n is added to the residue to adjust the pH to 7.5-8. an aqueous solution of sodium hydroxide and the precipitate formed is filtered off, dissolved in ethanol and hydrogen chloride gas is passed into the solution. The precipitate formed is filtered off and recrystallized from ethanol to give 0.8 g of a substance with mp. 211-213C. The resulting product was identified by NMR and YUS spectral and elemental analyzes as hemihydrate of 5- (1-hydroxy-2-isopropylamino) -propyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride. Example 95. To 1.0 g of 5- (s-isopropylaminobutyryl) -8-hydroxy-3,4-dihydrocarbostyryl 20 ml of ethanol and 0.05 g of platinum oxide are added and the mixture is reduced under hydrogen pressure of 2 atm at 60 ° C for 10 hours. After the completion of the reduction, the catalyst is removed by filtration and. the filtrate is adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The residue obtained is recrystallized from ethanol to obtain 0.9 g of a substance with so pl. 196198 ° C. The resulting product was identified by NMR and IR spectral and elemental scrolling as monohydrate. 5- (1-hydroxy-3-isopropylamino) -butyl-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride. Example96. K1.0g 5- (o-tert-butylaminopropionyl) .- 8-hydroxy-3, 4 -dihydrocarbostyryl bromohydrate, obtained from the corresponding monohydrate prepared according to example 55, add 50 ml of water and 0.2 g of palladium black and the mixture is reduced at atmospheric pressure for 20 hours. After the completion of the reduction, the catalyst is filtered off and the filtrate is concentrated to dryness. The residue obtained is recrystallized from ethanol to obtain 0.75 g of a substance with so pl. 198-199®C (with decomposition). The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- {1-hydroxy-2-tert-butylamino) propyl-8-hydroxy-3, 4-dihydrocarbostyryl bromohydrate monohydrate. Example 97 K1.0 g 5- (o (-tert-butylaminobutyryl) -8-hydroxy-3, 4-dihydrocarbostyryl bromohydrate obtained from the corresponding dihydrate prepared according to example 56, add 50 ml of water and 0.2 g of palladium black and the mixture is reduced at atmospheric pressure at 80 ° C for 10 days. After the restoration is complete, the catalyst is filtered off and the filtrate is concentrated to dryness. The resulting residue is recrystallized from ethanol to obtain 0.7 g of substance with mp 164-166 ° C (with decomposition) The resulting product is identified by NMR and and spectral and s Cement assays as 5- (1-hydroxy-2-tert-butylamino) -butyl-8-hydroxy-3, 4-dihydrocarbostyri bromine idrat (in the form of a salt of cotton wool). Example98. 8-hydroxycarbostyril was added 0.1 g of palladium black and 50 ml of ethanol and, with stirring, the mixture was reduced under hydrogen pressure of 35 atm at 75 ° C for 15 hours. After the restoration was complete, the catalyst was filtered and the filtrate was adjusted to pH 1 with concentrated salt acid. The mixture is then concentrated to dryness and the resulting residue is recrystallized from ethanol to obtain 1.7 g of 5- (1-hydroxy-2-isopropylamino) -butyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride monohydrate, m.p. 196-198 ° C. Example 99. K1g 5-and-isopropylaminobutyryl) -8-oxycarbostyryl hydrochloride is added with 0.05 g of platinum black and 100 ml of water, and the mixture is reduced under stirring under hydrogen pressure to 40 at 18 hours. After the reduction is completed, the catalyst is filtered and the filtrate is concentrated to dryness. The resulting precipitate is then recrystallized from isopropanol to obtain 0.85 g of 5- (1-hydroxy-2-isopropylamino) -butyl-8-hydroxy-3 monohydrate, 4-dihydrocarboxyethyl hydrochloride, m.p. 196-198 ° C. Example 100. To 0.5 g of 5 - ("t-sec-butylaminobutyryl) -8-oxycarbo steryl, 0.0025 g of palladium black and 15 ml of ethanol are added and the mixture is reduced under grinding at 50 atm under hydrogen pressure for 15 hours. After the completion of the reduction, the catalyst is filtered off and the filtrate is adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The resulting precipitate is then recrystallized with ethanol to obtain 0.45 g of 5- (1-hydroxy-2-sec-butylamino) -buti-8-hydroxy-3, 4-dihydrocarbostyryl hydrochloride monohydrate with mp. 205-207 sec. Example 101. 15 ml of 47% aqueous hydrobromic acid are added to 1.5 g of 5- (1-hydroxy-2-tert-butylamino) -propyl-8-methoxy-3, 4-dihydrocarbostyril and the mixture is heated at a temperature 1 under reflux for 15 hours. After that, acetone is added to the 93 mixture to crystallize the product, and the resulting crystals are recrystallized from a mixture of ethanol and acetone, and 1.4 g of substance are obtained with a mp. 198-199С (with decomposition). The resulting product was identified by NMR and IR spectral and elemental analysis of aNM as 5- (1-hydroxy-2-tert-butylamino) -propyl-8-hydroxy-3, 4-dihydrocarbostyryl bromohydrate monohydrate. Analogously to Example 75, the following compounds were prepared: 5-1-hydroxy-2 - (-2-phenethylamino) -butyl-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride with m.p. 127-129 С (with decomposition); 5- (1-hydroxy-2-morpholinobutyl) -8-hydroxy-3, 4-dihydrocarbostyryl bromohydrate with m.p. 183-185 C (with decomposition). Example 102. To 1.0 g of 5 (o (tert-butylaminobutyryl) -8-hydroxy-3,4-dihydrocarbostyryl bromohydrate, 50 ml of water and 0.2 g of palladium black and a mixture of reduction at atmospheric pressure are added at a temperature for 10 days After the reduction is complete, the catalyst is filtered off and the filtrate is concentrated to dryness. The resulting residue is recrystallized from ethanol to obtain 0.7 g of substance with mp 164166 ° C C decomposition). The resulting product is identified by H1-1R and IR spectral and elemental analyzes as 5- (1-hydroxy-2-tert-butylamino) -. -butyl-8-hydroxy-3, 4-dihydrocarbostyryl bromo hydrate (as ethanol solvate). Example 103: 1.0 g of 5- (2-morpholinobutyryl) -8-hydroxy-3, 4-dihydrocarbostyl yryl bromohydrate aurel is placed in 70 ml of water and 0.2 g of palla is added to the solution. , di on coal, and 0.3 g of palladium black, after which the mixture, with shaking, is subjected to catalytic reduction under hydrogen atmosphere. for 10 days at 70 ° C. the completion of the reduction, the reaction mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness under reduced pressure. The resulting residue is dissolved in acetone by heating, after which the solution is cooled. The precipitate formed upon cooling is recrystallized from ethanol to obtain 0.7 g of a white amorphous 5- (1-hydroxy-2-morpholino) -butyl-8-hydroxy-3 hemihydrate, 4-dihydrocarbostyryl bromohydrate, m.p. 183-185С (with decomposition). The resulting product is identified by NMR and IR spectral and elemental analyzes. Example 104. 0.45 g of the free base of 1-methyl-5-isopropyl-1Minoacetyl-8-hydroxycarbostyril (see Example 60) is dissolved in 50 ml of methanol and slowly added to the solution while cooling with ice and stirring

0.2 g sodium borohydrite. Subsequently, stirring is continued for another 1 hour and the resulting mixture is adjusted to pH 2-3 with concentrated hydrochloric acid. Then it forms a 11; precipitate is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is dissolved in 20 ml of ethanol. The solution is filtered to completely remove insoluble substances. The filtrate is concentrated under reduced pressure, and then 20 ml of ethanol is added, and then filtered to completely remove insoluble substances. The filtrate is concentrated under reduced pressure to dryness and 40 ml of ethanol is added to the residue to completely remove the solubles soluble in ethanol. The ethanol-insoluble material was washed twice with 20 ml portions of cold water, recrystallized from ethanol, and 0.3 g of white amorphous 1-methyl-5- (1-hydroxy-2-isopropylamino) ethyl 8-hydroxy-carbostyryl hydrate with t .pl „202-203,5 ° С (with decomposition) о The obtained product is identified by NMR and IR spectral and elemental analyzes about

Example 105, 1 g of 1-methyl-5. Isopropyl Shnoacetil-8-oxycarboxythryl hydrochloride is suspended in 100 ml of water and 0.1 g of palladium black and 0.1 g of palladium n are added to the suspension. coal, after which the mixture is subjected to catalytic reduction with hydrogen at atmospheric pressure and for 25 hours. After completion of the reduction, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure. The resulting residue is crystallized from acetone and then recrystallized from ethanol to obtain 0.3 g of a white amorphous 1-meth-m-5- (1-hydroxy 2-isopropylamino) ethyl-8 hydroxy-4-dihydrocarboxyryl, m.p. 196-197 ° C (with decomposition). The resulting product is identified by NMR and IR spectral and elemental analyzes.

Example 106. 1.0 g of 5-from-propylaminoacetyl-8-methoxycarbosti

rila is dissolved in 50 ml of methanol and 0.6 g of sodium borohydrate is slowly added to the solution while cooling with ice and stirring, after which the mixture is stirred at room temperature for another 1 hour. The reaction mixture is adjusted to pH 2-3 with concentrated hydrochloric acid. acid and the precipitate formed is filtered off. The filtrate is concentrated to dryness and crystallized from acetone. By recrystallization of the product from ethanol, 0.8 g of the substance is obtained, mp 230-231 0 (with decomposition). The resulting product was identified by NMR and IR spectral and elemental analyzes as monograms, the crate of 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyryl hydrochloride.

Example 107. 2 g of 5-isopropylaminoacetyl-8-methoxy-3, 4-di-. . Hydrocarboxyrol is dissolved in 70 ml of methanol and 1 g of sodium borohydride is slowly added to the solution while cooling it with 5 ice water, then stirred at room temperature for another 1 hour. the precipitate is filtered off. The filtrate is concentrated to dryness and the resulting residue is recrystallized from ethanol to obtain 1.5 g of the substance with so pl. 206208 С (with decomposition). The resulting product was identified by NMR and IR spectral and elemental analyzes as 5- (l-oxy-2-isopropylamino) -ethl-8-methoxy-3, 4-dihydrocarboxyryl hydrochloride.

For example. 108. 3 g of 5- (1-hydroxy-2-isopropylamino) ethyl ethyl-8-hydroxycarostyryl hydrochloride is dissolved in 20 MP of water and 0.9 g of sodium hydroxide is added to the solution. Then, to the solution, while cooling with ice and stirring, Q 1.3 g of dimethyl sulfate are added dropwise during

1h The mixture is stirred for

2 h at 40-50 ° C and the reaction mixture is extracted with chloroform. The chloroform extract is washed with water and dried, and then gaseous hydrogen chloride is passed into the chloroform extract. The precipitated crystals are recrystallized from a mixture of ethanol and acetone, and 2.3 g of material is obtained with a melting point of 235-237 ° C. (with decomposition). The resulting product was identified by NMR and KK spectral and elemental analyzes as monohydrate of 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyl chloride.

Example 109 2.6 g of 5- (1-hydroxy-2-isopropylamino) -ethyl-8-hydroxy-3, 4-dihydrocarbostyryl are dissolved in 30 MP of water and to the solution is added

0.45 g sodium borohydride. Then, 1.3 g of dimethyl sulfate is added dropwise to the solution while cooling with ice and stirring for 1 hour. The reaction mixture is agitated

5 for 2 hours at 40-50 ° C and extracted with chloroform. Chloroform extract is taken with water and dried, and then gaseous chloride is passed into the chloroform extract

0 hydrogen. The precipitated crystals are recrystallized from. ethanol and get 2.2 g of substance with so pl. 206208 ° С (with decomposition). The resulting product is identified by NMR and IR

5 by spectral and elemental analyzes like 5- (1-hydroxy-2-isopropylamino) -ethyl-8-methoxy 3, 4-dihydrocarbostyryl hydrochloride.

Example 110. 10 ml of 47% aqueous hydrobromic acid is added to I g of 1-methyl-5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxy-3, 4-d1.hydrocarboustryl hydrochloride monohydrate and the mixture is heated at reflux temperature for 15 h, then concentrated to dryness. Acetone was added to the residue to crystallize the product, which was then adjusted to pH 8 with dilute aqueous sodium hydroxide solution. The precipitated crystals are filtered, washed and dissolved in ethanol. The solution is adjusted to pH 1 with concentrated hydrochloric acid and concentrated to dryness. The resulting residue is recrystallized from a mixture of ethanol and diethyl ether and obtain 0.7 g of substance with so pl. 198-200 ° C (with decomposition). The resulting product was identified by NMR and IR (spectral and elemental analyzes as 1-methyl-5- {1-hydroxy-2-isopropylamino) -ethyl-8-oxy-3,4-dihydrocarbostyryl hydrochloride.

Claims (1)

Invention Formula The method of obtaining carbostyryl or 3,4-dihydrocarbostyryl derivatives of general formula J yes, an alkyl group, an aralkyl group containing a linear or branched alkyl group Cj-Ci,., or a cycloalkyl group Ci, —C or RZ and Rj together with the nitrogen atom to which they are attached form morpholino, piperidivo, piperazino or pyrrolidino groups, characterized in that 5-alkylaminoalkanoylcarbostyryl- or 5-alkylaminoalkanoyl-3, 4 dihydrocaro-bostyryl proxy compounds of general formula II 15 20 gle R .v .vj .4 R, R, R. and R are specified groups subjected to reduction in the presence of a catalyst or by means of a reducing agent with the isolation of the desired product. 30n.SnmC -o yi ky where, R4 and Well, each represents a hydrogen atom — or an alkyl group C (—C, at least one of the Hc and Rj is a hydrogen atom, and Ra and R, which may be the same or different, each represent a hydrogenPriorite atom 4192/1974; 12953/1974; 15116 / / 19.74; 23604/1974 58315/1974; 58317/1974; 6004/19 74; 67823 / / 1974; 67824/1974; 97660/1974 / 97661/1974; 97663/1974; 129381/1974; 101260/1974 129384/1974; 129382/1974 130718/1974; 130717/1974; 130721/1974; 130719/1974; 13.0722 / 1974; 130724/1974; 130725/1974; 130726/1974; 140339/1974; 140340/1974. M: 01.31.74 dioxane Rg RS H or alkyl 05.02.74 H Rg Rj H or alkyl 02.27.74 Alkyl R H () k, alkyl (C ,.) 05.22.7-5 27, Yu5.74 AlkylR 2 N (C ji. J) R J alkyl 13 „About. 74 (i-h Alkyl (C j.) Ri N. Rj alkyl (i-H) Methyl or 26.OS.74 ethyl H R2 N K} alkyl) 08.26.74 Without solvent, methanol, ethanol, isopropanol, dioxane, diethyl ether, ethyl acetate: tat, benzene, toluene, xiol, acetonitrile Water, methanol, papladiev ethanol, izrobrovenny, Pd on the corner of Renol nickel panol, lithium aluminum hydride, sodium borohydride Methanol, ethanol, isopropanol, alkylamines (i.e., without solvent) Without solvents Lewis acids (A.Ssez, gps.Ea, tel, CSa, nitFeCjta robenzene, diethyl ether, dioxane. H.Water, ethylace-1B. Sodium hydrate, lithium aluminum hydride Water, isopro-palladium panol ethyl black, Pd on coal, acetate – platinum black, Rene Nickel Solvent-free, (amine per se), isopropanol, dioxane, dimethyl ether, ethyl "catat, benzene, H Sources of information taken into consideration during the examination Editor T. Zagrebelna Order 3814/58 Branch PPP Patent, Uzhgorod, Proektna St., 4 1, SA, 62, 16212e, 1965. Compiled by G. Zhukov Tehred 3. Fantasy Corrector E. Papp. Circulation 512 Subscription TSNIIPI USSR State Committee on Inventions and Discoveries 4, Fr. five