SU348002A1 - METHOD OF OBTAINING IMIDAZOZIDIDINONE DERIVATIVES - Google Patents

Description

The invention relates to the field of the preparation of new compounds that are superior in pharmacological properties. The closest analogous compounds have a similar effect.

It is known to use in organic chemistry esters of sulfonic acids as strong alkylating agents of nitrogen-containing compounds, in particular, secondary amines, one of which is piperazine and its derivatives.

Proposed based on the method known in organic reaction chemistry for the preparation of new imidazolidinone derivatives of the general formula

national ester of a compound of the general formula

5HO- (CH), c ;.

where w, RI have the above values, are reacted with a compound of the general formula

15

CH, -CH-GH,

sn.

20

where R2, Rs are as defined above, or with an alkali metal containing compound of formula III, in the presence of a basic condensing agent, followed by isolation of the desired product in free form or in the form of its salts.

dy), and also sulfonic acid esters, for example, methanesulfonic acid ester or Oily ester P-toluenesulfonic acid ester.

in the case of using the compound of the general formula II as the reactive ester of chloride or bromide, the process is carried out in the presence of a catalytic amount of an iodide, for example sodium iodide.

The reaction of the reaction of the ester-reactive compound of the general formula II with the base of the general formula III is carried out predominantly in the presence of a solvent and an acid binding agent.

The solvent used is hydrocarbons (benzene, toluene), halohydrocarbons (chloroform), ethers (ether and dioxane), lower alkanones (methylethyl or diethyl ketone), phosphoric amides (triamide hexamethylphosphoric acid), as well as excess tethered bases.

Alkali metal carbonates, tertiary organic bases, for example, pyridine, triethylamine and, in particular, S, K-diisopropylethylamine, are used as an acid binding agent.

In the case of using, instead of the base of the general formula III, a derivative of the compound of formula III containing an alkali metal, for example sodium or lithium, it is advisable to carry out the reaction in a hydrocarbon (benzene, toluene).

Example 1. 7.8 g (0.048 jol) of 1- (2-chloroethyl) -3-methyl-2-imidazolidinone and 13.3 g (0.040 mol of 5-2-mt IL-3- (1-piperazSl1Il) propyl-5H-dibenz- 6, / - azepine is boiled with 5.5 g (0.040 mol) of carbonate or 0.5 g (0.003 mol) of sodium iodide in 100 ml of diethyl ketone for 20 hours with stirring under reflux After cooling, the precipitate formed is sucked off, then washed with diethyl ketone. The filtrate is freed from the solvent under a water-jet vacuum, the residue is dissolved in ethyl ester of acetic acid. Then, a solution of ethyl acetate and acetic acid washed with water and shaken several times with 2N hydrochloric acid. The combined hydrochloric acid solutions are brought to alkaline with concentrated ammonia, and the liberated base is extracted with ethyl ester of acetic acid. The solution of this ester is washed with water, dried over sodium sulfate and evaporated under water-jet vacuum. The residue (crude base) is dissolved in 80 ml of methyl ethyl ketone, and an excess of ethanolic hydrochloric acid is added to the solution. The separated dihydrochloride is sucked off, washed with methyl ethyl ketone and recrystallized from ethanol-methyl ethyl ketone. 1- {2- {4- 3- (5H-Dibenz & / -azepin-5-yl) -2-methyl1-propyl-1-piperazinyl-ethyl-3-methyl -2-imidazolidinone dihydrochloride is formed. T. dl. 223-224 ° C. Yield 8.9 g (42%).

The starting material, 5- 2-methyl-3- (1-cyperazinyl) -crocyl-5H-dibenz-b, / J-azepine, was prepared as follows: i

57.0 g (0.20 mol of crude 5- (3-chloro-2-methylpropyl) -H-dibenz-6, / j-azenium (see the Swiss patent 374.681, Geigy AG) and 35.0 g (0, 22 mol of 1-piperazincarbic acid ethyl ester is heated with 35.0 g (0.25 mol} potassium carbonate and 1.0 g (0.006 mol} sodium iodide in 120 ml of dimethyl form) for 16 hours to a temperature of 95-. Then the solvent The residue is taken up in a water-jet vacuum. The residue is dissolved in ethyl ester of acetic acid, the solution of this ethyl ester is washed with water and extracted with 2N hydrochloric acid. . Annym ammonia .o alkaline reaction and liberated base was shaken with l1ilovym ester A solution of acetic acid ethyl ester was dried over sodium sulfate and evaporated under a water aspirator vacuum residue nerekristallizovshayut from 95% ethanol;. Complicated pure ethyl

ether (5P-dibenz- &, / -azepin-5-yl) - 2methyl-propyl - pizerazin-1-carboxylic acid, t. Il. 90-92 ,, 20 hours, boiled under reflux with 32.0 g (0.56 mol} of KOP in 320 ml of ethanol. Then ethanol is separated under a water-jet vacuum and the residue is dissolved in ether. The ether solution is washed with a small amount of water, dried over sodium sulfate, and evaporated under a water-jet vacuum.

(crude base), recrystallized from petroleum ether, after which a pure 5-2-methyl-3-1-piperazinyl-propyl 5P-dibenz-b, / -azecine is obtained. T. pl. 77-79 0.

Yield 24 g (36%).

The free base is converted with hydrochloric acid to dihydrochloride, m.p. 168-169 ° C, recrystallization from ethanol.

PRI mme R 2. Similar to Example 1, of 8.5 g (0.05 mol) of 1- (3-chloropropyl) -3-methyl-2-imidazolidinone and 13.3 g (0.040 mol) of 5- 2- methyl 3- (1-piperazinyl) -propyl-5H-dibenz 6, / -azepine to give (5P-dibenz- &, / -azepin-5-yl - 2-methyl-propyl-1-piperazinyl-propyl-3 -methyl-2-amidazolidinone, i.e. 132-135 ° C (from ethyl acetate ester), mp 235-237 ° C digondrochloride.

The yield of the free base is 9.0 g (47%).

Example 3. Analogously to example 1 of

(10,11-DITydro-5H - dibenz - b, / azepin-5-yl) -2-methyl-Propyl - 1 - piperazinyl-ethyl-3-methyl-2-imidazolidinone, m.p. 58-63 ° C (from ether, petroleum ether).

T. pl. dihydrochloride 231-234 ° C.

Yield 16.9 g (79%).

5- 2-methyl-3- (1-piperazinyl) - propyl 10, 11-dihydro-5H-dbbepz & -azepin is obtained as follows:

68.5 g (0.33 mol} 10,11-dihydro-5H-dibenz 6, / -azepipa is dissolved in 300 ml of absolute toluene, then in the absence of moisture and 14.0 g of suspension (0.36 mol of amide "atri in 40 ml of absolute toluene. The mixture is heated for 1 hour with stirring to 85 ° C. Then 71.0 g (0.37 mol} 1- (3 -chloro-2-methyl-propyl) -4-methyl-piperazine to the reaction mixture, then heated under reflux for 20 hours. Upon cooling, the reaction mixture is evaporated under a water-jet vacuum .O-statum is dissolved in ethyl ester acetic acid the lots and the resulting solution is washed with water. Then the organic phase is extracted with 1H power of 2N hydrochloric acid. The combined hydrochloric acid extracts are brought to alkaline with concentrated ammonia, and the liberated base is shaken several times with ethyl ester of acetic acid. The acetic acid ester is washed with water, dried over sodium sulfate and evaporated under a water-jet vacuum. The residue is distilled under high vacuum. 5- 2-methyl 3- (4-methyl-1-piperazinyl) - propyl - 10,11 dihydro-5H-dibenz-b, -azepine is formed.

Since 167-168 ° C / 0.005 mm Hg. Art.

The yield is 100.6 g (96.6%).

The resulting base is dissolved in 1000 ml of absolute benzene. This solution at 25 ° C and stirring is added dropwise to a solution of 35 g of cyanogen bromide in 280 ml of absolute benzene. Then the reaction mixture was boiled under reflux for 2 hours, cooled, filtered through a layer of active carbon and then evaporated under a water-jet vacuum. The residue, crude (10,11-dihydro-5H-dibenz-b, / -azepin-5-yl) 2-methyl-propyl - piperazin-1 - carbonitrile, is boiled under reflux for 1000 hours in 1000 ml of 2N hydrochloric acid. Upon cooling, the reaction mixture is brought to a caustic solution with concentrated sodium hydroxide solution, and the free base is extracted with benzene. The benzene solution is dried over solid sodium hydroxide and evaporated in a water-jet vacuum. The residue is crystallized from acetonitrile. 5- 2-methyl-3- (1-nperazinyl) -propyl - 10,11-dihydro-5H-dibenz- & , / -azepin.65

T. pl. 81-83 ° C.

Yield 53 g (44%).

The free base is converted with ethanol hydrochloric acid to dihydrochloride; m.p. 268-270 ° С (from ethanol) with decomposition.

Example 4. Analogously to example 1 of 8.5 g (0.05 mol) of 1- (3-chloro-propyl) -3-methyl2-imidazolidinone and 12.8 g (0.038 mol) of 5 2-methyl-3- (1 - piperazinyl) - propyl - 10,11 dihydro-5P-dibenz - b, azepine is obtained (10,11-DIGIDRO-5H - dibenz-6, / azepin-5-yl) -2-methyl-propyl - 1 - piperazinyl-propyl -Z-methyl-2-imidazolidinone - dihydrochloride.

T. pl. 244-247 ° C.

The yield of 17.6 g (80%).

Example 5. Analogously to example 1 of

9.2 g (0.048 mol) of 1- (3-chloro-propyl) -3-ethyl2-imidazolidinium and 14.3 g (0.042 liters) of 5-2-methyl-3- (1-piperazinyl) -propyl-10, 11 dihydro-5P-dibenz-6, / - azepine is obtained (10,11 - dngydro - 5P-dbbenz, f azep11H-5-yl) -2 - methyl propyl - - piperazinyl-propyl-3-ethyl-2 - imidazolidinone - dihydrochloride.

T. pl. 223-227 ° C. Yield 14.3 g (64%).

Used as starting material, 1- (3-chloro-propyl) -3-ethyl-2-imidazolidinone was prepared as follows.

60.0 g (0.52 mol) of 3-ethyl-2-oxazolidinone and 68.1 g (0.57 mol) of (3-chloro-propyl) isocyanate are mixed with 4.8 g of lithium chloride and the mixture is heated for 90 minutes to 175-180 ° C. Then the reaction mixture is cooled and 300 ml of chloroform is added to it. The chloroform solution is separated, washed three times.

30 ml saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is distilled under high vacuum to obtain pure 1- (3-chloro-propyl) -3-ethyl-2-imidazolidinone.

Since 105-110 ° C / 0.01 mm Hg. Art. P2, 1,4889.

Yield 91.6 g (92.5%).

The invention

The method of obtaining imidazoliss derivatives of dinone with the general formula ,

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

HO- (CH,), c.

Where t, RI are as defined above, with a compound of the general formula

™ 2-CH-CH2-Kf) N-H

sn.

where R2 and Rs have the indicated values, or with a compound of formula III containing an alkali metal, followed by isolation of the target product in free form or in the form of its salt by known methods.