SU342347A1 - METHOD OF OBTAINING IMIDAZOZIDIDINONE DERIVATIVES - Google Patents

Description

This invention relates to the preparation of novel compounds which, by their pharmacological properties, are superior to the closest analogues.

A known method for producing N-substituted carbazoles by reacting the corresponding alkyl halides with carbazole in the presence of a condensing agent.

Based on a known reaction method for preparing imidazolidinone derivatives of the general formula

RO RT

ns-sh

-iCH2) -) YN-R,

H G-CH-GHe-i;

SS

where m is 2 or 3, Ri is methyl, ztil, R2, Rs is hydrogen or an additional bond together, and their salts consist in the interaction of a reactive ester of a compound of the general formula

tCH2),

BUT CHf-CH-CH -N CH,

where m and RI are as defined above, with a compound of the general formula

to RT

Gg

nsn nn

where R2 and Rs are as defined above, in the presence of a main condensing agent, followed by isolation of the desired product in free form or in the form of its salt. Alkali metals, for example sodium or lithium, nx amides and hydrides, alkali metal organic bases, for example butyl or phenyl lithium, are used as condensing agents. ABOUT

Example 1. To a solution of 11.3 g (0.03 nil} 1- {2- 4- (2-M € tyl-3-chloropropyl) -1 - piperazinyl-ethyl} -3-methyl-2 - imidazolidinone - dihydrochloride in 15. "L of water, toluene is added and, with ice-cooling, 30 ml of concentrated sodium hydroxide solution. The toluene solution containing the base is separated from the aqueous phase, dried over sodium hydroxide and added dropwise at 75 ° C to the suspension NaO of the 5H-dibenz - (&, /) - azepine derivative obtained from 1.36 g (0.035 mol of sodium amide in 3 ml of absolute toluene and 5.8 g (0.03 mol} 5H-dibenz- (6, f) -a3enHHa in 60 ml of absolute toluene in the absence of moisture and the mixture is heated under reflux for 16 hours, cooled, and washed with water. The organic phase is separated and extracted with 2N hydrochloric acid. ammonium free base and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from ether. Get yellow 1 - {{2- {4- 3- (5H-dibenz- (i, /) - azepin-5 yl) -2-methylpropyl -1-piperazinyl} - ethyl}} - 3 methyl-2-imidazolidinone, m.p. 107-109 ° C. A solution of hydrochloric acid in absolute ethanol is added to a solution of the free base in methyl ethyl ketone and 11.3 g (70.8%) of dihydrochloride are obtained, m.p. 223-224 ° C.

To obtain the starting 1- {2- 4- (2-methyl3-chloropropyl) -1-piperazinyl-ethyl} -3-methyl2-imidazolidinone, 86 g (0.5 mol) of 4-dimethyl-1-piperazine propanol are mixed from absolute pyridine and 61.5 g (0.6 mol) of acetic anhydride are added dropwise at 10-20 ° C. The orange-colored reaction mixture is left to stand for 16 hours at room temperature and then evaporated in vacuo. The residue is cooled with ice the concentrated ammonia is added to pH 9 and the resulting free base is dissolved in ethyl acetate. The solution is dried over sodium sulfate and evaporated in vacuo. The stack is distilled under high vacuum and 101.5 g (94.8%) of 1- (2methyl-3-acetoxypropyl) -4-methylpiperazine, bp 66-69 ° C / 0.03 MM are obtained.

To a solution of 48.8 g (0.46 mol} of bromine cyan in 200 ml of absolute benzene, a solution of 90 g (0.42 mol} 1- (2-methyl-3-acetoxypropyl) -) is added dropwise in 45 minutes while cooling with ice. 4-methylpiperazine in 300 ml of absolute benzene. The reaction mixture is heated under reflux for 75 minutes, cooled, the precipitate is filtered off with suction and washed with benzene. After evaporation of the filtrate in vacuo, 81.5 g of crude 4: (2-methyl-3-acetoxypropyl) -1-piperazinecarbonitrile. 91.0 g of this product and 600 ml of 2 and hydrochloric acid cues for 18 hours under reflux. The resulting solution is evaporated 300 ml of a concentrated solution of potassium hydroxide are added slowly to the residue while cooling with ice and stirring. The upper phase containing the free base is separated and treated with benzene. The benzene solution is dried over sodium hydroxide and evaporated. The residue is distilled under high vacuum, 4-methyl-1-piperazinylpropanol, m.p. 74-78 ° C / 0.007 mm are obtained.

sodium iodide, 7.0 g (0.050 mol) of potassium carbonate and 16.3 g (0.1 mol) of 1- (2-chloroethyl) -3 methyl-2-imidazolidinone. The precipitate was separated on a suction filter, washed with diethylketone and the filtrate evaporated in vacuo. The residue is distilled under high vacuum. Get 1- {2- 4- (2-methyl-3-hydroxypropyl) -1 - piperazinyl-ethyl} - 3 - methyl - 2 - imidazolidinone, t. Kip. 173-180 ° C / 0.008 mm; p 1.5070; yield 26 g (91.5%).

Dry hydrogen chloride is added to a solution of 14.0 g (0.05 mol) of the obtained substance in 40 ml of chloroform.

congo. Then 30 ml (0.41 mol) of thionyl chloride are added dropwise and the mixture is boiled under reflux for 6 hours. 13.4 g (71%) of 1- {2- 4- (2-methyl-3-chloropropyl) -1 - piperazinyl-ethyl} -3 - methyl-2 - imidazole dinone dihydrochloride are obtained, which is washed on the suction filter chloroform. T. pl. 251- 254 ° С (decomposition).

Example 2. Analogously to example 1 of 11.3 g (0.03 mol) of 1- {2- 4- (2-methyl-3-chloropropyl) -1-piperazinyl-ethyl} -3-methyl-2 - imidazolidinone dihydrochloride after converting it to the free base and the sodium derivative 10,11-dihydro-5H-dibenz- (6, f) azepine, obtained from 1.36 g (0.035 mol)

sodium amide and 5.85 g (0.030 mol) of 10,11-dihydro-5H-dibenz- (6, /) - azepine, get 1 {{2- {4- 3- (10,11-dihydro-5H- Dibenz - (&, /) - azepin-5-yl) -2-methylpropyl - 1 - piperazinyl} ethyl}} - 3-methyl-2-imidazolidinone, so pl. 58-

63 ° C (ether petroleum ether). T. pl. dihydrochloride 231-234 ° C, yield 7.3 g (53%).

Example 3. To a solution of 14.2 g (0.05 mol) of 1- {2- 4- (2-methyl-3-hydroxypropyl) -1-piperazinyl-ethyl} -3-methyl-2-imidazolidinone in 40 ml of absolute benzene was added under nitrogen and with stirring a dispersion of 1.15 g (0.05 mol) of 1.15 g of paraffin in paraffin and heated to 70-75 ° C for 90 minutes. TO

to the cooled reaction mixture, a solution of 9.5 g (0.05 mol) -tolylsulfonyl chloride in 40 ml of absolute benzene is added dropwise at 0-5 ° C. After stirring for 3 hours at room temperature, filter through

Celite (R) No. 545 (purified diatomaceous earth) and washed with benzene.

A benzene solution containing 1 - {{2- (4 2-methyl-3- (p-tolylsulfonyloxy) -propyl 1-piperazinyl} ethyl) -3-methyl-2-imidazolidinone is added dropwise at 50 ° C to the dispersion of the sodium derivative of 5H-dibenz ({), /) - azepine in absolute toluene, which is obtained from 2.11 g (0.054 mol) of sodium amide

in 4 ml of absolute toluene and 9.7 g (0.050 mol) of 5H-dibenz- (6, /) - azepine in 110 ml of absolute toluene. The reaction mixture is heated under reflux for 16 hours, cooled and water is added. Organic acid and conc. ammonia precipitates the free base, the solution of which in etclacetate is dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from ether to give 1 - {{2- {4- 3- (5H-dibenz- (b, f) -azepin5-yl) -2-methylpropyl -1-piperazinyl} ethyl}} 3-methyl- 2-imidazolidinone, so pl. 107-109 ° C, yield 9.8 g (39%). Example 4. To a suspension of 8.2 g (0.21 mol) of sodium amide in 150 ml of absolute toluene is added dropwise to a line O-10 ° C and stirring, in the absence of moisture and under nitrogen, a solution of 5.0 g (0, 21 mol) 1- {2- 4- (3-hydroxy2-methylpropyl) -1-piperazinyl-ethyl} -3-methyl-2-imidazoleIdinone in 50 ml of absolute toluene. The reaction mixture is heated to 85 ° C for 1 hour, cooled and 40.0 g (0.21 mol) of p-tolylsulfonyl chloride, dissolved in 100 ml of toluene, are added dropwise at O-5 ° C. The mixture is stirred at room temperature for 2 hours and the sodium chloride is separated. The filtrate is a toluene solution of 1 - {{2 {4- 3- (i-tolylsulfonyloxy) -2-methylpropyl -1-piperazinyl} ethyl}} - 3-methyl-2-imidazolidinone. 40.6 g (0.2 mol) of 10,11-dihydro5H-dibenz- (6, /) - azepine are dissolved at 80 ° C in 200 ml of absolute toluene, and suspension 8 is added under nitrogen with stirring and in the absence of moisture, 2 g (0.21 mol) of sodium amide in 30 ml of absolute toluene and heated to 85 ° C for 1 hour with stirring. A toluene solution of 1 - {{2- {4- 3 - ("- tolylsulfonyloxy) -2-methylpropyl-1. Piperazinyl} ethyl}} - 3-methyl-2-imidazolidinone is added dropwise to a suspension of the sodium salt of 10,11-dihydro -5H-dibenz- (&, /) - azepine in toluene. The reaction mixture is boiled under reflux for 24 hours, cooled and evaporated in a vacuum created by a water-jet pump. The residue is dissolved in ethyl acetate and extracted with 2N. hydrochloric acid. To the extract add conc. ammonia to a w / w elk reaction and shake the resulting base with ethyl acetate. The resulting solution is washed with water, dried over sodium sulfate and evaporated in vacuo by a water jet pump. The residue is dissolved in methyl ethyl ketone, an ethanolic solution of hydrochloric acid is added to obtain 1 - {{2- {4- 3 (10, ll-dihydro-5H-dibenz- (6, f) -azepin-5-yl) 2- methylpropyl -1-piperazinyl} ethyl}} - 3 - methyl-2-imidazolidinonon - dihydrochloride, t. pl. 210-216 ° C. The subject of the invention. A process for the preparation of imidazolidinone derivatives of the general formula II HjC -CH-CHrNC - K ar where m is 2 or 3, Ri is methyl, ethyl, R2, Hz is hydrogen or together an additional bond, or their salts, characterized in that in the presence of a basic condensing agent, the reactive ester of a compound of the general formula / h HO — CH j — CH — CH j -}. -iCH2) CH5o where m and RI are as defined above. with a compound of the general formula where Ra and Rs are as defined above, followed by isolation of the target product in free form or in the form of its salt by known methods.