SU346869A1 - - Google Patents

Description

METHOD OF OBTAINING IMIDAZOZIDIDINONE DERIVATIVES

where Y is a halogen atom and Ri has the specified value, or its derivative containing an alkali metal, followed by isolation of the target product by known methods in free form or in the form of a salt.

In formula III, Y is preferably chlorine or bromine. The reaction is preferably carried out in the presence of solvents, inert under the reaction conditions: hydrocarbons, for example benzene, toluene or xylene, halohydrogen compounds, example chloroform, ether-like liquids, example ether or dioxane, as well as lower alkanes, for example, acetone, methyl ethylmethane, The reaction temperature is between 50 and 150 ° C, preferably near the boiling point of the solvent used.

In the reaction of 1 mole of precipitation of formula II, 1 mole of urea derivative is cleaved off with 2 moles of the same acid. This acid may be associated with an excess base of general formula II or with a di-basic reaction mixture. An acid binding agent is preferably added to the reaction mixture. Such agents are, for example, alkali metal carbonates, such as sodium or potassium carbonate, tert-organic bases, such as pyridine, triethylamine or N, N-diisopropylethylamine. Excessive grease bases can be used as a solvent.

If a derivative of an alkali metal base, such as sodium, potassium or lithium, is used in the reaction instead of the free base of the general formula II, it is advantageous to carry out the reaction in a hydrocarbon, for example benzene or toluene.

Example 1. A. 2.92 g (0.01 mol) of 8-methyl 10- (1-piperazinyl) -10.11 -dihydro-5H-dibenzo-a, d-cycloheptene is boiled for 12 hours with reflux condenser 2 , 80 g (0.014 mol) of crude 1-methyl- (3,3-bis-2-chloroethyl) -urea and 3.6 g (0.036 mol) of anhydrous potassium carbonate in 36 ml of diethyl ketone. After 4 hours and 8 hours of reaction, 2.4 g (0.018 mol) of potassium carbonate was added. The reaction mixture is cooled, diluted with ether, filtered and the filtrate is evaporated in vacuo. The residue is taken up (5.22 g) with ether and the solution is extracted with 1N. hydrochloric acid, hydrochloric extract is washed with ether and excess sodium carbonate is added to it. The evaporated free base is taken up in ether, the ether solution is washed with water, dissolved over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column (Merek, grain size 0.05-0.2 mm}, which has been soaked in 0.5N sodium hydroxide. Chloroform is used as eluent. The fractions containing raw product are evaporated. The residue is recrystallized from ethyl acetate ester of acetic acid - petroleum ether, followed by pure 1- {2- 4- (8methyl-10, 11-dihydro-5H-dibenzo - a, d-cyclohepten-10-yl) - 1-piperazinyl-ethyl} -3- methyl 2-imidazolidinone melts at 116-117 ° C; yield 2.72 g, 65% of the theoretical.

wives as the starting material can be obtained as follows.

To a solution of 12.1 g (0.05 mol) of 8-metzl-10chlor-III, 11 - dihydro-5H - dibezo-a, d-cycloheptea in 23 ml of benzene was added 23.7 g

(0.15 mol) of 1-piperazinecarboxylic acid ethyl ester and the solution is boiled

24hour with reflux. The reaction mixture is poured onto 200 ml of ice water.

add 25 ml of 2 n. sodium hydroxide solution and the benzene phase is separated. The aqueous phase is shaken with benzene, the organic phases are washed with water, dissolved over magnesium sulfate, the solvent is removed in vacuo and the resulting crude residue is taken up further.

B. 12.9 g of the crude product obtained according to paragraph B is dissolved in 50 ml of absolute ethanol, 10 g (0.15 mol) of potassium hydroxide are added to it and the mixture is boiled.

20 hours with reflux. The reaction solution is cooled, extracted in vacuo, water is added to the residue, and the base is absorbed in benzene. The benzene solution is washed with water until neutral, shaken with 100 ml of 2N. the hydrochloric acid and the acidic aqueous phase are brought to alkaline at nighttime with concentrated sodium hydroxide. The free base precipitated is extracted with benzene, the benzene solution is washed with water, dried over magnesium sulfate and evaporated in vacuo. The crystalline residue is recrystallized from a mixture of ethyl acetate and peptane. Pure 8-methyl-10- (1-piperazinyl) 10, 11-dihydro-5H - dibenzo, and e - cyclohepten

melts at 85-96 ° C; yield 4.4 g, 30% of

theoretical; m.p. bismethanesulfonate

194-196 ° C.

Example 2. A. Analogously to Example 1, prepared from 3.08 g (0.01 mol) of crude 8-methoxy10- (1-piperazinyl) -10, ll-dihydro-5H-dibenzo-a, d-cycloheptene and 3.18 g (0.014 mol) of 1-isopropyl-3,3 - bis- (2-chloroethyl) - urea 2.92 g of 1- {2-4- (8-methoxy-10,11-dihydro-5H-dibenzo-a, g - cyclohepten - 10-yl) -1-piperazinyl-ethyl} -3 - isopropyl-2 - imidazolidinone, which (precipitated and recrystallized from a mixture of ethanol and diethylether) using maleic acid gives the bis-maleate 3/4 hydrate, t. square 125-127 ° C.

B. The 1-isopropyl-3, 3-bis- (2-chloroethyl) urea required as the starting material is prepared as follows. 10.5 g (0.1 mol) of freshly distilled diethanolamine

is dissolved in 100 ml of absolute methylene chloride and 8.95 g (0.105 mol) of isopropyl cyanate dissolved in 20 ml of absolute methylene chloride are added dropwise within 30 minutes. The reaction mixture is stirred

1 hour at room temperature and 1 hour at reflux temperature. After cooling to 0 °, 25.0 g (0.21 mol) of thionyl chloride, dissolved in

After cooling, evaporate g vacuum to dryness and dry in high vacuum at 40 ° C. The resulting residue, oily 1-isopropyl-3,3bis- (2-chloroethyl) -urea, is further processed in the crude state.

Present Invention

The method of obtaining imdazolpdinone derivatives offended by the formula I

m- (sn)

where X is a hydrogen atom, chlorine, methyl-, methoxy group,

.RI is lower alkyl with one to four carbon atoms,

R2 is a hydrogen atom, methyl,

or salts thereof, characterized in that the compound of general formula II

10 where X and Ro have the indicated meanings, or an alkali metal containing derivative thereof, is reacted with a compound of general formula III

YH C-HoC-N —C, 11.

 GH2-Y

M /

R, H

where Y is a halogen atom and Ri has the indicated

value, or its derivative, containing

alkali metal, followed by release

target product known techniques in

in free form or in the form of its salts.

The invention relates to the field of obtaining new compounds, derivatives of i.midazolidinone, which exhibit many-times improved properties as compared with compounds of similar effect and can be used in medicine as pharmaceutical preparations. The proposed method of producing new compounds is based on the reaction of amine with halogen with simultaneous intramolecular condensation, which is known in organic chemistry. A method is proposed for the preparation of new imidazolidinone derivatives of the general formula I NH,) Well, RZ is a hydrogen atom or methylgruium, or their salts, meaning that the compound of the general formula II where X and R2 have the indicated value, or its derivative containing alkali metal is reacted with a compound of the general formula 111 -CH7 CH2-Y / RH