DD233373A5 - PROCESS FOR THE PREPARATION OF IMIDAZOLIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of imidazolidine derivatives of the general formula I in which n is 0, 1, 2, 3 or 4 and R is optionally substituted by one or more halogen atom (s) lower alkyl, halogen, nitro, di (lower -Alkyl) -amino, carboxamido or lower alkylamino (restriction 1: if n 2 and one R 3-fluoro, the other R is not 4-methyl; restriction 2: if n 2 and one R 4-fluoro, the other R is not 3-methyl, 3-nitro or 3-chloro). Several variants of the method are given. For example, 2-methyl-4-chloro-phenyliminodithiocarbonic acid dimethyl ester is reacted with ethylenediamine to give 2- (2-methyl-4-chloro-phenylimino) -imidazolidine. The process is easily feasible with easily accessible starting materials also large-scale. The process also includes the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula I, especially the fumarates. Formula I

Description

For this 3-page formulas

Field of application of the invention

The invention relates to a novel, improved process for the preparation of Imidazolidinderivaten of the general formula I and the pharmaceutically acceptable acid addition salts thereof, wherein

η is 0,1,2,3 or 4;

R optionally substituted by one or more halogen atoms) substituted lower alkyl; or halogen, nitro, di- (lower alkyD-amino, carboxamido or lower alkynoylamino,

with the proviso that if η = 2 and one R is 3-fluoro, the other R is other than 4-methyl and with the further restriction that if η = 2 and one R is fluoro-4, the other R is from 3 Methyl, 3-nitro or 3-chloro is different.

Characteristic of the known technical solutions

The compounds of general formula I are known. Some members of this group of compounds exert a selective effect on the function of a-adrenoreceptors and Η receptors. Other compounds of the general formula I possess valuable hypotensive, diuretic, intraocular pressure-lowering and anovulatory properties. For the preparation of the compounds of general formula I, several methods are known.

According to US Pat. No. 4,287,201, an amine of general formula VI, wherein R and η are as defined above, is reacted with 2-chloroimidazolidine. This method has several disadvantages. The 2-chloro-imidazolidine used as the starting material is on the one hand very difficult to access and on the other hand capable of alkylating the resulting compound of general formula I, resulting in the formation of difficult to remove by-products.

Another method (US Patent 4290971, BE-PS 877428, JP-PS 8094370 or DE-OS 2900538) is an acylated isothiourea of the general formula VII, wherein R ³ and R ^{4 are} lower alkyl and R and η have the above meaning have reacted with ethylenediamine mon-p-toluenesulfonate. This method also has several disadvantages. The reaction time is long and the reaction proceeds only at elevated temperature, resulting in the formation of decomposition products which are difficult to remove.

According to another known method (NL-PS 6411 516, NL-PA 7710061 and 7710072, DE-PS 1 313141, 1303930 and 1795517, DE-OS 2446758, JP-PS 75154246, FR-PS 1 566035, BE-PS 623305, US Pat. No. 2,899,426 and ZA-PS 7707418), the compounds of the general formula I are prepared by reacting isothiourea salts of the general formula VIII in which H is halogen and R and η are as defined above, with ethylenediamine. The disadvantage of this method is that the starting materials of general formula VIII are very difficult to access and must be prepared using toxic isothiocyanates.

In DD-PS 68511 a method analogous to the above method is described. An isothiourea of general formula IX, wherein R and η have the above meaning, is reacted with ethylenedioamine mono-p-toluenesulfonate. The starting materials of the general formula IX are also difficult to access and the yields are low.

According to BE-PS 872581 and NL-PA 6411 516, the compounds of general formula I are prepared by reacting an isothiocyanate of the general formula X with ethylenediamine and treating the resulting thiourea derivative of the general Foremi Xl mt lead tetraacetate. In the above formulas, R and η are as defined above. The disadvantage of this method is that the very toxic isothocyanates of the general formula X and the toxic lead tetraacetate must be used.

According to another method (DE-PS 842065, JP-PS 79117474 and NL-PA 6411 516), the compounds of general formula I are prepared by reacting a thiourea derivative of general formula XII, wherein R and η have the above meaning, with ethylenediamine heated to boiling for a long period of time (more than 30 hours), and cyclizing the formed thiourea derivative of general formula XI in the above manner with lead tetraacetate. This process also has serious disadvantages, such as the use of very toxic reagents, very long reaction times, etc.

connected.

According to a further process (British Pat. Nos. 1,382,752 and 1 506913, International Pat. No. 44579, European Pat. No. 63913, German Pat. No. 3,520,337, German Offenlegungsschriften Nos. 2,316,377 and 2,505,297 and European Pat. No. 7707418), the compounds of general formula I are prepared, by reacting an amine of the general formula VI with an imidazolidinone of the general formula XIII in the presence of phosphorus oxychloride and removing the acyl group from the resulting acylated imidazoiidine derivative of the general formula XIV by hydrolysis.

In the formulas XIII and XIV is lower alkyl or phenol, while R and η have the above meaning. Because of the extremely corrosive properties of the phosphoroxychloride used, this method can be realized in operation only in a complicated and costly way.

According to a further method (HU-PS 155329, FR-PS 1 566036 and 1 577128, DD-PS 71 554, GB-PS 1 229993, DE-OS 2446758 and ZA-PA 7 707 418), the compounds of general formula I. by reacting an isocyanic dihalide of the general formula XV in which X is halogen and R and η are as defined above, with ethylenediamine. The disadvantage of this method is that the starting materials of the general formula XV are very toxic and the Tionylchlorid Sulfurylchlorid used in the preparation of the same is very corrosive.

According to a further process (ES-PS 409418, DD-PS 68509 and FR-PS 1 577217), the compounds of the general formula I are prepared by reacting a cyanamide of the general formula XVI, wherein R and η have the above meaning, with ethylenediamine. The disadvantage of this method lies in the difficulty of accessibility of the starting materials of general formula XVI.

According to GB-PS 889706 and JP-PS 75101 357, the compounds of general formula I are prepared by reacting an amine of general formula VI with an alkylthiomidazolidine of general formula XVII, wherein R ^{6 is} lower alkyl. However, the starting materials of general formula XVII are difficult to access in industrial quantities and the necessary, relatively high reaction temperature leads to the formation of by-products.

According to JP-PS 7376870, the compounds of the general formula I are prepared by reacting Karbaminsäureestem of the general formula XVIII, wherein R ^{7 is} lower alkyl and R and η have the above meaning, prepared with ethylenediamine. This process is also associated with several disadvantages, such as long reaction time, low yield and high reaction temperature.

According to DD-PS 68510, the compounds of general formula I are prepared by reacting a guanidine derivative of general formula XIX, wherein R and η have the above meaning, with ethylenediamine or its mono-p-toluenesulfonate. However, the reaction can be carried out only at a higher temperature with a long reaction time and the achievable yields are low.

Object of the invention

The aim of the present invention is to eliminate the disadvantages of the known processes and to provide a novel process for the preparation of the compounds of the general formula I, which uses readily available starting materials and is also industrially favorable and economical to carry out.

Explanation of the essence of the invention

The process of the invention, the compounds of general formula I and the pharmaceutically acceptable acid addition salts thereof are prepared by reacting a dithioester of general formula II or a diester of general formula III or an imino ether of general formula IV or a semiconductor halide of general formula V, wherein R ^{8 is} lower alkyl, aryl-lower alkyl or aryl, R ^{9 is} lower alkyl, X is halogen and R and η have the above meaning, with ethylenediamine and, if desired, a compound of general formula I thus obtained in a pharmaceutically acceptable acid addition salt transferred.

The term "lower alkyl" means straight-chain or branched alkyl groups having 1-6, preferably 1-4, carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, etc. The lower alkyl groups may optionally be substituted by one or more halogen atom (s), for example chloromethyl, bromomethyl, trifluoromethyl, etc.

The term "halogen" includes the fluorine, chlorine, bromine and iodine atoms. By the term "lower alkanoyl" are meant the acid radicals of lower aliphatic carboxylic acids, e.g. As formyl, acetyl, propionyl, butyryl, etc., to understand. The term "aryl group" is to be understood by one or more, the reaction not influencing substituent (s) substituted phenyl or naphthyl groups.

According to one embodiment variant of the process according to the invention, a dithioester of the general formula II is reacted with ethylenediamine. The reaction is carried out in an inert solvent as a medium. Alkenols (for example methanol, ethanol, n-butanol), ethers (for example diethyl ether, tetrahydrofuran, dioxane) or aromatic hydrocarbons (for example benzene, toluene or xylene) may be used as the reaction medium. But it is also possible to use an excess of ethylenediamine used for this purpose. The reaction can be carried out at a temperature between 20 ⁰ C and the boiling point of the reaction mixture. Preferably, one works at 60-80 ⁰ C.

According to another embodiment of the method according to the invention, a diester of the general formula III is reacted with ethylenediamine. The reaction is carried out in an inert solvent as a medium. Alkanol (for example methanol, ethanol, n-butanol), ethers (for example diethyl ether, tetrahydrofuran, dioxane) or aromatic hydrocarbons (for example benzene, toluene or xylene) may be used as the reaction medium, if not used an excess of the ethylenediamine used for this purpose. The reaction can be carried out at a temperature between 2O ⁰ C and the boiling point of the reaction mixture. Preferably, working at 60-80 ° C.

According to a further embodiment of the process according to the invention, η_P imino ether of the general formula IV is reacted with ethylenediamine. The reaction is carried out in an inert solvent as a medium. In turn, alkanols (eg, methanol, ethanol, n-butanol), ethers (eg, diethyl ether, tetrahydrofuran, dioxane), or aromatic hydrocarbons (e.g., benzene, toluene, or xylene) can be used as the reaction medium. Again, it is possible to use an excess of ethylenediamine used for this purpose. The reaction can be carried out at a temperature between 20 ° C and the boiling point of the reaction mixture, it is expedient to operate at 60-80 ° C.

According to a further embodiment variant of the process according to the invention, a halo-per-generalgen of the general formula V is reacted with ethylenediamine. Halbedterchloride can preferably be used as starting material (X is chlorine). The reaction is carried out in an inert solvent as a medium. As reaction medium alkanols

(eg, methanol, ethanol, n-butanol), ethers (eg, diethyl ether, tetrahydrofuran, dioxane) or aromatic hydrocarbons

(eg benzene, toluene or xylene), or an excess of the ethylenediamine used can be used for this purpose. The reaction can be carried out at a temperature between 20 ⁰ C and the boiling point of the reaction mixture. Expediently carried out at 60-80 ⁰ C.

The reaction may preferably be carried out in the presence of an acid binder. For this purpose, trialkylamines, such as triethylamine, can be used with advantage, and an excess of the ethylenediamine can serve as an acid binder.

The above reactions can be followed very well by thin layer chromatography. The reactions can be carried out economically and do not require any special equipment.

The compounds of the general formula I can be isolated in the form of the free base or a salt. If desired, a compound of the general formula I can be converted into a pharmaceutically suitable acid addition salt. The salt formation and isolation of the final product can be carried out by methods known per se.

For salt formation, pharmaceutically suitable inorganic acids, for. Hydrochloric acid, hydrogen bromide, nitric acid, sulfuric acid, etc., or organic acids, e.g. As acetic acid, malic acid, maleic acid, fumaric acid, lactic acid, succinic acid, etc. are used. The fumarates are z. B. suitable salts.

According to a particularly advantageous embodiment of the process according to the invention, the 2- (2-methyl-4-chlorophenyliminoHmidazolidin or a pharmaceutically acceptable acid addition salt thereof is prepared.

According to another advantageous embodiment of the method according to the invention, the following compounds are prepared:

2- (2-ethyl-4-chloro-phenylamino) imidazolidine,

2- (2-chloro-5-irifluoromethyl-phenyliniino) -imidazolidine,

2- (2,6-Dichloro-phenylimino) imidazolidine,

and pharmaceutically acceptable acid addition salts thereof.

The advantage of the method according to the invention is that it can be carried out economically using readily available starting materials even on industrial scales.

The starting materials of the general formulas M-V are known compounds and can be prepared in a simple manner by known methods.

The starting materials of general formula II can be prepared by reacting the corresponding amine of general formula VI with carbon disulfide, an alkyl, aralkyl or aryl iodide and alkali metal hydroxide at room temperature with a yield of 90% (Rec. Trav. Chim. 74, 126 / 1955 /; Tetrahedron 27, 2893/1971 /).

The starting stage of general formula III can be prepared by reaction of the corresponding benzyl cyanide with hydroxylamine, tosylation of the oxime formed and treatment of the resulting tosylate with the corresponding alkyl, aralkyl or ethyl alcohol (J. Org. Chem. 28 2436/1963 /).

The preparation of the starting materials of general formula IV is in Ber. 32, 495 (1899) and J. Am. Chem. Soc. 26,215 (1904).

The compounds of general formula V can be prepared by the method described in J. Am. Chem. Soc. 16,70,392 (1894).

Further details of the method according to the invention can be found in the following examples, without limiting the scope of protection to these examples.

embodiments example 1

2- (2-Methyl-4-chloro-phenylimino-hamidazolidine 10,0g (0,04 mol) г-Ме ^ уІ-Ф-сЫог-рЬіепуІітіпогігіМокомепзаигеаітеіЬіуІезіег are dissolved in 20 ml of n-butanol, 2,7 ml (0 , 04 mol) Äthylendiamin is added, after which the reaction mixture is heated to boiling for 5 hours.

The mixture is concentrated to dryness under reduced pressure and the residue is recrystallized from isopropanol. There are obtained 5.1 g of the title compound, yield 60.7%.

Q .: 132-135 ⁰ C.

In an analogous manner, the following compounds are prepared:

2- (2,6-dichloro-phenylimino) imidazolidine, m.p .: 135-137 ° C; 2- (2-bromo-6-chloro-phenylimino) -imidazolidine, F .: 134-135 ⁰ C; 2- (2,4,6-trimethyl-phenylimino) -imidazolidine, m.p .: 154-156 ° C; 2- (2,6-dichloro - * - nitro-phenylimino) imidazolidine, F .: 275-277 ⁰ C; 2- (2,6-dichloro-4-formamido-phenyliminoHmidazolidin dihydrochloride, m.p .: 240-242 ⁰ C; 2- (2,6-diethyl-4-acetylamidc-phenyliminoHmidazilidin hydrochloride, m.p .: 265-266 ° C; 2- (2,5-dichloro-4-carboxamido-phenylimino) -imidazolidine, m.:244-245 ° C.

Example 2

2- (2-M ethyl-4-chloro-phenylimino) imidazolidine fumarate The procedure is as in Example 1, with the difference that after completion of the reaction of the solution of 2- (2-methyl-4-hydroxy) formed in butanol. chloro-phenylimino) imidazolidine adds 4.6 g (0.04 mol) of fumaric acid. After cooling the mixture, the precipitated product is filtered off. There are obtained 8.5 g of the title compound. Yield 65.2% F .:

174-176 ° C (after recrystallization from methanol).

In an analogous manner, the following compounds are obtained:

2- (2-ethyl ~ 4-chloro-phenyliminoHmidazolidin fumarate, m.p .: 188-191 ⁰ C; 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidinfumarat, F .: 196-198 ° C.

Example 3

2- (2ßMethyl-4-chloro-phenylimino) -imidazolidin The procedure is as in Example 1, with the difference that dissolving the 2-methyl-4-chloro-phenylimino-dithiokohlensäuredimethylester in 54ml (0.8 mol) of ethylenediamine, the Heat reaction mixture for 2 hours to boiling and evaporated to dryness. The residue is recrystallized from isopropanol. There are obtained 6.5 g of the title compound, yield 77.4%. F .: 133-135 ° C.

The product is identical to the compound prepared according to Example 1.

In an analogous manner, the following compounds are prepared:

2- (2,6-dimethyl-phenylimino) -imidazolidine, m.p .: 145-146 ° C; 2- (2,6-difluoro-phenylimino) -imidazolidine, m.p .: 161-163 ° C; 2- (2,4,6-trimethyl-phenylimino) -imidazolidine, m.p .: 155-156 ° C; 2- (2-chloro-5-trifluoromethyl-phenylirnino) -irnidazolidin, F .: 123-125 ⁰ C;

Example 4

2- (2-Methyl-4-chloro-phenylimino-himidazolidine The procedure is as in Example 1, except that the starting material is 2-methyl-4-chlorophenyliminodithiocarbonic acid dimethyl ester and dibutyl 2-methyl-4-chloro-phenylimino-dithiocarbonate is used ,

There are obtained 4.6 g of the title compound, yield 54.8%. F .: 132-134 ° C.

The product is identical to the compound prepared according to Example 1.

In an analogous manner, the following compounds are prepared:

2- (2,6-dimethyl-phenylimino-himidazolidine, m.:144-146 ° C; 2- (2-chloro-phenylimino) -imidazolidine, m.:133-132 ° C.

Example 5

2- (2-Methyl-4-chloro-phenylimino) -imidazolidine The procedure is as in Example 1, except that the starting material arsf.tt of 2-methyl-chlorophenyliminodithiocarbonic acid dimethyl ester is 2-methyl-4-chloro-phepylimi- dibenzyl dithiocarbonate used.

There are obtained 4.7 g of the title compound, yield 56.0%, mp. 133-136 ⁰ C.

In an analogous manner, the following compounds are prepared:

2-phenyliminoimidazolidine, m.p .: 135-136 ° C; 2- (2-bromo-6-chloro-phenylimino) -imidazolidine. F .: 133-35 ° C; 2- (2,6-dichloro-phenylimino) -imidazolidine, m.p .: 136-137 ° C.

Example 6

2- (2-Methyl-4-chloro-phenylimino-himidazolidine The procedure is as in Example 1, with the difference that the starting material used instead of the 2-methyl-4-chlorophenyliminodithiokohlensäuredimethylesters the 2-methyl- A- chloro-phenylimino-dithiokohlensäurediphenylester. There are obtained 4.5 g of the title compound, yield 53.6%, mp .: 132-134 ° C. The following compounds are prepared in an analogous manner: 2- (2-chloro-4-methyl-phenylimino) - imidazolidine, F .: 148-150 ^0C; 2- (2,4,6-trichloro-phenyiiminoHmidazolidin, m.p .: 175-176 ° C; 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidine, F .: 123-125 ⁰ C.

Example 7

2- (2-Methyl-4-chloro-phenylimino-himidazolidine The procedure is as in Example 1, except that the starting material is 2-methyl-4-chloro-2-phenyliminodithiocarboxylic acid dimethyl ester of г-МеШуІ- Ыог-рпепуІітіпо-коЫепзаигеаіпШпуІезіег 4.3 g of the title compound are obtained, yield 51.3%, mp 134-135 ° C. The product is identical to the compound prepared according to example 1.

In an analogous manner, the following compounds are obtained:

2- (2-bromo-6-chloro-phenylimino-himidazolidine, m.:135-136 ° C; 2-2,6-dichloro-phenylimino-himidazolidine, m.p. 134-135X; 2- (2,4,6-trimethyl- phenylimino) -imidazolidine, m.:155-156 ° C; 2- (2,6-dichloro-4-nitrophenylimino-himidazolidine, F .: 274-276X.

Example 8

2- (2-ethyl-4-chloro-phenylimino-himidazolidine The procedure is as in Example 3, with the difference that the starting material used instead of the 2-methyl-4-chlorophenyliminodithiokohiensäuredimethylesters the 2-ethyl-4-chloro-phenylimino-carbonic acid dibutyl ester. it will be 4.1 g of the title compound are obtained, yield 45.8%. m.p .: 109-111 ⁰ C.

In an analogous manner, the following compounds are obtained:

2- (2,4,6-trimethyl-phenylimino-himidazolidine, m.:155-156 ° C; 2- (2,6-dichloro-phenylimino) -imidazolidine, m.:135-137 ° C.

Example 9

2- (2-methyl-4-chloro-phenylimino) imidazolidine The procedure is as in Example 3 with the difference that the starting material instead of the 2-methyl-4-chlorphenyliminodithiokohlensäuredimethylesters 2-methyl-4-chloro-phenylimino-carbonic acid diphenyl ester used. There are obtained 4.5 g of the titled compound, yield 53.6%. F .: 133-135 ° C. The product is identical to the compound prepared according to Example 1.

In an analogous manner, 2- {2-chloro-phenylimino / -imidazolidine) F. 131-132 ° C is prepared.

Example 10

2- (2-Chloro-5-trifluoromethyl-phenylimino) imidazolidine The procedure is as in Example 1, with the difference that instead of 2-methyl-4-chloro-phenylimino-dithiokohlensäuredimethylesters the 2-hydrochloro-5-trifluoromethyl used phepylamiopoimiopolokhylacetic acid ether. There are obtained 3.9 g of the title compound, yield 36.9%, mp .: 124-125 ° C.

In an analogous manner, the following compounds are prepared:

2- (2,6-Dimethyl-phenylimino) -imdazolidin, F .: 144-145 ⁰ C; 2- (2,6-dichloro-phenylimino-himidazolidine, Mp .: 136-137 ° C; 2- (2-methyl-4-chloro-phenylimino) -imidazolidine, m.p .: 134-135 ° C; 2- <2- ethyl 4 ~ chloro-phenyliminoHmidazolidin, F .: 109-110 ⁰ C.

Example 11

2- (2-Chloro-5-trifluoromethyl-phenylimino-himidazolidine The procedure is as in Example 3, except that 2-chloro-5-trifluoromethyl-phenyiamino-imino-carbonic acid ethyl ether is used as the starting material in place of the methyl gamma-methyl-D-sulfophenyliminodithiocarbonate . There are obtained 4.1 g of the compound named in the title, yield 38.9%. m.p .: 123-125 ⁰ C.

In an analogous manner, 2- <2-ethyl-4-chloro-phenylimino-hmidazolidine F: 108-109X is prepared.

Example 12

2- (2-Methyl-4-chloro-phenylimino) imidazolidine The procedure is as in Example 3, except that the starting material is the gamma-meta-p-poro-mogramme_eplutate in place of the 2-MeIhYl ^ ChIOr-PhOnYUmJnO-dithiokohlensäuredimethyiesters. imino-carbonyl butyl ether used. There are obtained 3.8 g of the title compound, yield 45.3%. F .: 133-135 ° C.

In an analogous manner, 2- (2-chloro-4-methyl-phenylimino-halidazolidine F. 148-150X is prepared.

Example 13

2- (2-Methyl-4-chlorophenyl-imino) imidazolidine To a solution of 3.0 g (0.05 mole) of ethylenediamine and 5.06 g (0.05 mole) of triethylamine in 30 ml of benzene are added 10 while stirring at room temperature , 9g (0.05 mol) of 2-methyl-4-chloro-phenylimino-chloro-kohiensäuremethylester added dropwise, whereupon the reaction mixture is heated to boiling for one hour. After cooling, 40 ml of water are added to the reaction mixture. The phases are separated and the benzene layer is dried over magnesium sulfate and evaporated. After recrystallization of the residue from isopropanol, 5.4 g of the title compound are obtained, yield 51.5%. F .: 133-135 ° C.

In an analogous manner, the following compounds are prepared:

2- (2,6-dichloro-phenylimino) -imidazolidine, m.p .: 136-137 ° C; 2- (2,6-dichloro-4-nitro-phenylimino) -imidazolidine, m.p. 275-277 ° C; 2- (2-bromo-6-chloro-phenylimino) -imidazolidine, F .: 134-135 ⁰ C; 2- (2,4,6-trimethyl-phenylimino) -imidazolidine, m.p .: 154-155 ° C;

Example 14

2- (2-methyl-4-chloro-phenylimino) -imidazolidin

The procedure is as in Example 13, with the difference that instead of the triethylamine as the acid binder and the benzene as the reaction medium, the reaction in an excess of ethylenediamine (30.0 g, 0.5 mol) performs. There are obtained 5.8 g of the title compound, yield 55.3%. F .: 134-135 ° C.

In an analogous manner, the following compounds are prepared:

2- <2,6-difluoro-phenylimino-hmidazolidine, m.p .: 145-146 ° C;

2- {2-chloro-5-trilfuormethyl-phenyliminoHmidazolidin, F .: 123-125 ⁰ C.

Example 15

2- <2-chloro-5-trifluoromethyl-phenylimino) -imidazolidin

The procedure is as in Example 14, with the difference that is used as the starting material instead of the 2-methyl-4-chloro-phenyliminochlor-carbonic acid methyl ester, the 2-chloro-5-trifluoromethyl-phenylimino-chloro-carbonic acid butyl ester. There are obtained 5.2 g of the title compound, yield 49.6%. Q .: 123-125 ⁰ C.

In an analogous manner, the following compounds are prepared.

2- <2-Chloro-phenylimino) imidazolidine. F .: 131-132 ° C;

2-phenylimino-imidazolidine, F .: 135-136 ⁰ C.

Claims (14)

claims: A process for the preparation of imidazolidine derivatives of general formula I, wherein η is 0,1,2,3 or 4; R is lower alkyl optionally substituted with one or more halo (s); or halogen, nitro, di- (Nider-Alkyd-amino, carboxamido or lower alkanoylamino; with the proviso that if η = 2 and one R is 3-fluoro, the other R is other than 4-methyl and with the further restriction that if η = 2 and R is 4-fluoro, then other R is different from 3-methyl, 3-nitro or 3-chloro, and pharmaceutically acceptable acid addition salts thereof, characterized by reacting a dithioester of general formula II or a diester of general formula III or an imino ether of general formula IV or a half-ester halide of general formula V, wherein R ^{8 is} lower alkyl, aryl-lower alkyl or aryl; R ^{9 is} lower alkyl, X is halogen and R and η are as defined above, reacted with ethylenediamine and, if desired, converting a compound of the general formula I thus obtained into a pharmaceutically suitable acid addition salt. 2. The method according to claim 1, characterized in that one carries out the reaction of the compound of general formula II with ethylenediamine in a lower alcohol in an aromatic hydrocarbon, in an ether or in an excess of ethylenediamine. 3. The method according to claim 2, characterized in that one carries out the reaction at a temperature between 20 ° C and the boiling point of the reaction mixture. 4. The method according to claim 1, characterized in that one carries out the reaction of the compound of general formula III with ethylenediamine in a lower alcohol, an aromatic hydrocarbon, an ether or an excess of ethylenediamine. 5. The method according to claim 4, characterized in that one carries out the reaction at a temperature between 20 ^c C and the boiling point of the reaction mixture. 6. The method according to claim 1, characterized in that one carries out the reaction of the compound of general formula IV with Äthylendiamin in a lower alcohol, an aromatic hydrocarbon, an ether or an excess of ethylenediamine. 7. The method according to claim 6, characterized in that one carries out the reaction at a temperature between 2O ⁰ C and the boiling point of the reaction mixture. 8. The method according to claim 1, characterized in that one carries out the reaction of a compound of general formula V with ethylenediamine in the presence of an acid binder. 9. The method according to claim 8, characterized in that one uses as the acid binder an excess of ethylenediamine or a tri- (lower-alkyl) amine - preferably triethylamine. 10. The method according to claim 8 or 9, characterized in that one carries out the reaction in an aromatic hydrocarbon, an ether or an excess of ethylenediamine. 11. The method according to any one of claims 8 to 10, characterized in that one carries out the reaction at a temperature between 20 ° C and the boiling point of the reaction mixture. 12. The method according to any one of claims 1 to 11, characterized in that one uses the corresponding starting materials for the preparation of 2- (2-methyl-4-chloro-phenyliminoHmidazolidin and the pharmaceutically suitable acid addition salts thereof. 13. The method according to any one of claims 1 to 11, characterized in that one for the preparation of 2- (2-ethyl-4-chlorphenyliminoHmidazolidin, 2- (2-chloro-5-trifluoromethyl-phenylimino) imidazolidine oder2- (2, 6-DichlorophenyliminoHmidazolidin or the pharmaceutically acceptable acid addition salts thereof used the corresponding starting materials. 14. The method according to claim 12 or 13, characterized in that reacting the prepared base with fumaric acid for the preparation of fumarates.