HU192986B - Process for production of imidasodiline 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

The present invention relates to a novel and improved process for the preparation of imidazolidine derivatives.

The present invention relates to a process for the preparation of imidazoKdin-B derivatives of formula (I) and pharmaceutically acceptable salts thereof, wherein n is 0, 1, 2, 3

R is 1-4 alkyl, optionally substituted with 1-5 halo, alkyl, halo, nitro, carbamoyl or 1-4 alkanoylaminoceopor, provided that when n is 2 and one of R's is 3-fluoro, the other R is different from 4-methyl and provided that when n is 2 and one of R's is 4-fluoro, the other of R's is 3-fluoro. other than methyl or 3-nitro or 3-chloro.

Compounds of formula (I) are known derivatives which are selective in their effect on alpha-adrenoceptor and H-receptor function, while others have antihypertensive, diuretic, intraocular pressure or anovulatory activity.

Several processes are known in the literature for the preparation of compounds of general formula (I).

No. 4,287,201. U.S. Pat.

The disadvantage of the process is that the 2-chloroimidazolidine used as starting material is very difficult to access and, in addition, is able to N-alkylate the resulting compounds of the formula I, which results in difficult to remove by-products.

No. 4,290,971. U.S. Patent No. 877,428; Belgian Patent No. 8,094,370. Japanese Patent Specification No. 2,900,538; According to German Federal Patent Publication No. ^4, acylated isothiourea of general formula (VII) (wherein R ³ and R ⁴ 'are alkyl and R and n are as defined above) is reacted with ethylenediamine mono-p-toluenesulfonate. This process has the serious disadvantages of having a long reaction time and reaction at higher temperatures only, which leads to the formation of decomposition products which are difficult to remove.

No. 6,411,516. U.S. Patent Nos. 7,710,061 and 7,710,062. U.S. Patent Nos. 1,313,141; 1,303,930; and 1,795,517. German Patent Specification No. 2,446,758. German Federal Public Works Publication No. 75,154,246 bz. Japanese Patent Publication No. 1,566,035; French Patent No. 623,305; Belgian Patent No. 2,899,426; U.S. Pat. According to a South African patent, compounds of formula I are prepared by reaction of isothiourea salts of formula VIII (wherein X is halogen and R and n are as defined above) with ethylenediamine. A disadvantage of this process is that the compounds of formula VIII are synthesized through the use of toxic isothiocyanates which are difficult to access.

U.S. Patent No. 68,511 discloses a process analogous to that described above for reacting an isothiourea of Formula IX (wherein R and n are as defined above) with ethylenediamine mono-p-toluenesulfonate. The disadvantage of the method is that the compounds of general formula (IX) are difficult to obtain and the yield obtained is low.

No. 872,581. Belgian Patent Specification No. 6,411,516; According to the Dutch patent, compounds of formula (I) are prepared by reacting an isothiocyanate of formula (X) with ethylenediamine and reacting the resulting thiourea derivative of formula (XI) with lead tetraacetate. In the above formulas, R and n are as defined above. A major drawback of this method is the use of highly toxic isothiocyanates of formula X or lead tetraacetate.

No. 842,065. German Patent Publication No. 79 117 474 Japanese Patent Specification No. 6,411,516; According to the Dutch patent, compounds of the formula I can be prepared by boiling a thiourea derivative of the formula XII with ethylenediamine for a very long time, more than 30 hours, and then forming the thiourea compound of the formula XI. derivative is cyclized by treatment with lead tetraacetate in an analogous manner to the preceding procedure. The disadvantages of the process are the use of highly toxic reagents and the very long reaction time.

Λζ No. 1 382 752 British Patent No. 1,506,913; British, No. 44,579; Israeli, No. 63,913; Romanian, No. 325,037; Austrian Patent Specification Nos. 2,316,377 and 2,505,297; German Federal Public Service Company No. 7,707,418. According to South African Patent Application, compounds of formula (I) may be prepared by reacting an amine of formula (VI) with an imidazolidinone of general formula (XIII) in the presence of phosphorus oxychloride and then forming a compound of formula (XIV) from the acylated imidazolidine derivative, the acyl-c sweep is removed by hydrolysis. In the above formulas, R and n are as defined above and R ^s is alkyl or phenyl ezénatomszámú ESL. The disadvantage of the process is that its high degree of corrosivity in the process makes it difficult and costly to implement in industry.

No. 155,329. Hungarian, l 566 036 and

577,128 thousand. French, with 71,554 thousand. German Democratic Republic and Decree No. 1 229 993 British patents; and

No. 446,758 Federal Republic of Germany 7 707 418 thousand. In South Africa, the compound of formula I is prepared by reaction of isocyanic acid dihalides of formula XV (wherein X is halogen and R and n are as defined above) with ethylenediamine. A disadvantage of this process is that the starting materials of formula XV are highly toxic and highly corrosive to thionyl chloride and sulfuryl chloride.

No. 409,418 bz. Spanish, No. 68,509 German Democratic Republic; and U.S. Patent No. 1,577,217. According to French patent specification, compounds of formula (I) are prepared by reaction of cyanamides of formula (XVI) (where R and n are as defined above) with ethylenediamine. A disadvantage of this method is the difficult availability of the starting materials of the formula XVI.

No. 889,706. British Columbia 75 101 375 According to the Japanese patent, compounds of formula (I) are prepared by reaction of amines of formula (VI) with alkylthioimidazolidines of formula (XVII) (wherein R * is C 1 -C 4 alkyl).

The disadvantage of this process is that the starting materials of formula (XVII) are difficult to access on an industrial scale and lead to the formation of relatively high reaction temperature by-products.

That's 7,376,870. According to Japanese Patent Application, compounds of formula I are prepared by reaction of carbamic acid esters of formula XVIII (wherein R ⁷ is lower alkyl and R and n are as defined above) with ethylenediamine. The disadvantage of this process is its long reaction time, low yield and high reaction temperature.

In U.S. Patent No. 68,510, the compounds of formula (I) are prepared by reacting a guanidine B derivative of formula (XIX) (wherein R e and n are as defined above) with ethylenediamine or its mono-p-toluene. sulfonate. However, this process can only be carried out at elevated temperatures with a poor reaction time and the resulting yield is also low.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the above drawbacks of the immersed processes by providing a process for the preparation of compounds of formula I from readily available starting materials, which can be carried out on an industrial scale.

According to the process of the present invention, the compounds of formula I and their pharmaceutically acceptable salts are prepared by:

a) (II) ditioéeztert formula [wherein R ⁸ is lower alkyl, aryl (PA szénatomezámú) alkyl or as sending arilceoport R and n are as defined above] is reacted with ethylene diamine; obsession

b) reacting a diethyl ether of formula III (wherein R ⁸ , R and n are as defined above) with ethylenediamine; obsession

c) reacting an imino ether of formula IV (wherein R ⁸ is lower alkyl and R and n are as defined above) with ethylenediamine; obsession

d) reacting a semi-ester halide of formula V (wherein X is halogen and R ⁸ , R and n are as defined above) with ethylenediamine;

and optionally converting the compound of formula (I) thus obtained into a pharmaceutically acceptable salt.

According to process (a) of the present invention, a dithioester of formula (II) is reacted with ethylenediamine. The reaction is carried out in an inert solvent medium. The reaction medium may be an alkanol (e.g. methanol, ethanol, n-butanol), an ether (e.g. diethyl ether, tetrahydrofuran or dioxane), an aromatic hydrocarbon (e.g. benzene, toluene or xylene). However, excess ethylene diamine may also serve as a reaction medium. The reaction may be carried out at a temperature between 20 ° C and the boiling point of the reaction mixture, preferably at a temperature of 60-30 ° C.

According to process b) of the present invention, the diester of formula III is reacted with ethylenediamine. The reaction is carried out in an inert solvent medium. The reaction medium may be an alkanol (e.g. methanol, ethanol, n-butanol), an ether (e.g. diethyl ether, tetrahydrofuran or dioxane) and an aromatic hydrocarbon (e.g. benzene, toluene or xylene). However, the reaction medium may be loaded with an excess of ethylenediamine. The reaction may be carried out at a temperature between 20 ° C and the boiling point of the reaction mixture, preferably at 60-80 ° C.

According to process c) of the present invention, the imino ether of formula IV is reacted with ethylenediamine. The reaction is carried out in an inert solvent medium. The reaction medium may be an alkanol (e.g. methanol, ethanol, n-butanol), an ether (e.g. diethyl ether, tetrahydrofuran or dioxane), an aromatic hydrocarbon (e.g. benzene, toluene or xylene). However, excess ethylene diamine may serve as the reaction medium. The reaction may be carried out at a temperature between 20 ° C and the boiling point of the reaction mixture, preferably at 60-80 ° C.

According to process (d) of the present invention, a semi-ether halide of formula (V) is reacted with ethylenediamine. Preferably, the foil ether chlorides containing X are chlorine. The reaction is carried out in an inert solvent medium. The reaction medium may be an alkanol (e.g. methanol, ethanol, n-butanol), an ether (e.g. diethyl ether, tetrahydrofuran or dioxane), an aromatic hydrocarbon (e.g. benzene, toluene or xylene).

However, excess ethylene diamine may also serve as a reaction medium. The reaction may be carried out at a temperature between 15 ° C and the boiling point of the reaction mixture, preferably at 60-80 ° C. The reaction is preferably carried out in the presence of an acid acceptor. Trialkylamines (such as triethylamine) are preferably used for this purpose, but excess ethylenediamine may also serve as an acid scavenger.

The above reactions can be well monitored by TLC and do not require any special equipment or use.

The resulting compound of formula (1) may be recovered in the form of its base or a salt thereof. If desired, a compound of formula (I) may be converted into its pharmaceutically acceptable salt. The salt formation and isolation of the final product can be carried out by known methods.

Pharmaceutically acceptable salts of the compounds of formula I with pharmaceutically acceptable inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, etc.) or organic acids (e.g., acetic acid, malic acid, maleic acid, fumaric acid, 40 lactic acid). , succinic acid, etc.). Fumarates are particularly preferred.

In a more preferred embodiment of the process of the present invention, the following compounds of formula (I) are prepared;

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

2- (2-Ethyl-4-chloro-phenylimino) -imidazolidine

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine 50

2- (2,6-dichlorophenylimino) imidazolidine and their pharmaceutically acceptable salts, in particular their fumarate.

The present invention provides compounds of formula (I) according to the invention in the preparation of compounds of formula (II), (III), (IV) 55 and 55, respectively. Compounds of formula (V) are novel processes not known in the literature.

The advantage of our process is that it does not use high reaction temperatures, long reaction times, toxic cyanide and the like. lead compound, two of which are known in the art.

No. 4,290,971. U.S. Patent No. 877,428, Belgian Patent No. 877,428, states 8,094,370. In the Japanese patent, acylated isothiourea is reacted with ethylenediamine mono-p-toluenesulfonate. The reaction is carried out at 140 ° C for 20 hours and results in the formation of difficult to remove decomposition products. No. 68,511. In the GDR patent, an isothiourea derivative is reacted with ethylenediamine mono-p-toluene sulfonate.

The disadvantage of the process is that toxic isothiocyanates are formed and the reaction is carried out at 140 ° C.

No. 872,581. in the Belgian description and in U.S. Patent No. 6,411,516. The processes mentioned in the Dutch patent produce highly toxic isothiocipnets and lead tetraacetate.

No. 409,418. Spanish, No. 68,509; GDR and 1,577,217 bz. In the processes mentioned in French patents, it is formed on very toxic chlorine or bromine.

No. 889,706. Great Britain, and 75 1C1 357; According to Japanese Patent Specification, the compounds of formula (I) are formed at a reaction temperature of 140 ° C with 30% yield of by-products.

No. 7,376,870. In the Japanese patent, the compounds of the formula I are prepared at 200 ° C for 8 hours.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

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

10.0 g (0.04 mol) of 2-methyl-4-chlorophenylimino-dithioic acid dimethyl ester are dissolved in 20 ml of n-butanol. Ethylenediamine (2.7 mL, 0.04 mol) was added to the solution and refluxed for 5 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallized from isopropanol. This gave 5.1 g (60.7%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 132-135 ° C.

Following the procedure of Example 1, the following compounds were prepared: 2- (2,6-Dichlorophenylimino) -imidazolidine, m.p. 135-137 'C

2- (2-Bromo-6-chlorophenylimino) -imidazolidine, m.p. 134-135 ° C

2- (2,4,6-Trimethyl-phenylimino) -imidazolidine, m.p. 154-156 ° C

2- (2,6-dichloro-4-nitrophenylimino) imidazolidine, m.p.

2- (2,6-Chloro-4-formamidido-phenylamino) -imidazolidine.2HCl m.p. 2- (2,6-Diethyl-4-acetylamido-phenylimino) -imidazolidine.HCl, m.p. 2- (2,6-dichloro-4-aminocarbonyl-phenylimino) -imidazolidine, m.p.

275-277

240-24?

265-266

244-245 'C' C 'C' C

Example 2

2- (2-methyl-4-chlorophenylimino) imidazolidine fumarate

All proceed as in Example 1, except that, after completion of the reaction, fumaric acid (4.6 g, 0.04 mol) was added to a solution of 2- (2-methyl-4-chlorophenylimino) imidazolidine in butanol. After cooling, the precipitated product is filtered off. This gave 8.5 g (65.2%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine fumarate, m.p. 174-176 ° C by recrystallization from methanol.

By following the procedure of Example 2, the following compounds were prepared: 2- (2-ethyl-4-chlorophenylimino) -imidazolidine fumarate, m.p. 188-191 'C

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine

-fumarate op. 196-198 'C

Example 3

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

In each case, Example 1 was performed using ezerine except that the 2-methyl-4-chlorophenyliminodithiocarboxylic acid dimethyl ester was dissolved in ethylene diamine (54 mL, 0.8 mol) and refluxed for 2 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from isopropanol. 6.5 g (77.4%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 133-135 ° C, are obtained.

Example 1.

The following compounds were prepared by the same procedure as in Example 3:

2- (2,6-Diraethyl-phenylamino) -imidazolidine, m.p.

2- (2,6-Difluoro-phenylamino) -imidazolidine, m.p.

2- (2,4,6-Trimethyl-phenylimino) -imidazalidine, m.p.

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p.

145-146 'C

161-163

155-156 'C 45

123-125

2- (2-Chloro-phenylimino) -imidazolidine, m.p. 131-132 'C

Example 5

2- {2-methyl-4-chloro-phenylimino) imidazolidine

All proceed as in Example 1, except that 2-methyl-4-chlorophenylimino-dithioceneBav-dibenzyl ester is used instead of 2-methyl-4-chlorophenylimino-dithioezenoic acid dimethyl ester. This gives 4.7 g (56.0%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 133-136 ° C.

Following the procedure of Example 5 is as follows

compounds live: 2-phenylimino-imidazolidine op. 135-136 'C 2- (2-bromo-6-chloro-phenylimino) imidazolidin op. 133-135 'C 2- (2,6-dichlorophenylimino) - imidazolidin op. 136-137 'C

Example 6

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

All proceed as in Example 1 except that 2-methyl-4-chlorophenylimino-dithiocarboxylic acid diphenyl ester is used instead of 2-methyl-4-chlorophenylimino-dithiocarboxylic acid dimethyl ester. This gave 4.5 g (53.6%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 132-134 ° C, identical to the product obtained in Example 1.

Following the procedure of Example 6, the following compounds were prepared:

2- (2-Chloro-4-methyl-phenylimino) -imidazolidine, m.p. 148-150 ° C

2- (2,4,6-trichlorophenylimino) -imidazolidine, m.p. 175-176 'C

2- (2-methyl-4-chloro-phenylimino) -imidazolidine, m.p. 134-135 ° C

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 123-125

Example 4

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

All proceed as in Example 1, except that 2-methyl-4-chlorophenyliminodithiocarboxylic acid dibutyl ester is used in place of the starting dimethyl ether of 2-methyl-4-chlorophenylimino-dithioic acid. This way

4.6 g (54.8%) of product are obtained, m.p. 132-134 'C, which is identical to the product obtained in Example 1.

Following the procedure of Example 4, the following compounds were prepared: 2- (2,6-Dimethyl-phenylimino) -imidazolidine, m.p. 144-146

Example 7

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

All proceed as in Example 1 except that 2-methyl-455-chlorophenylimino-thiothio-benzoic acid dimethyl ester is replaced by 2-methyl-4-chloro-phenylimino-carbonBav-dimethyl ester. This gave 4.3 g (51.3%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 134-135 ° C, identical with the product obtained in Example 1.

Following the procedure of Example 7, the following compounds were prepared: 2- (2-Bromo-6-chloro-phenylimino) -imidazolidine, m.p. 135-136

2- (2,6-Dichloro-phenylimino) -611

imidazolidin op. 134-135 ° C 2- (2,4,6-trimethyl-phenylimino) - imidazolidin op. 155-156 ° C 2- (2,6-dichloro-4-nitro-phenylimino) - imidazolidin op. 274-276

Example 8

2- (2-ethyl-4-chloro-phenylimino) imidazolidine

All proceed as in Example 3 except that 2-ethyl-4-chlorophenylimino-isonic acid dibutyl ester is used in place of 2-methyl-4-chlorophenylamino-dithioazeneavimethyl-2-ester. This gave 4.1 g (45.8%) of 2- (2-ethyl-4-chlorophenylimino) imidazolidine, m.p. 109-111 ° C.

Following the procedure of Example 8, the following compounds were prepared:

2- (2,4,6-trimethyl-phenylimino) -imidazolidine, m.p. 155-156 ° C

2- (2,6-Dichloro-phenylimino) -imidazolidine, m.p. 135-137 ° C

Example 9

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

All proceed as in Example 3 except that 2-methyl-4-chlorophenylimino-enoic acid diphenyl ether is used in place of the dimethyl ester of 2-methyl-4-chlorophenyliminodithiosonic acid. This gives 4.5 g (53.6%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 133-135 ° C, identical with the product obtained in Example 1.

Following the procedure of Example 9, the following compound was prepared: 2- (2-chlorophenylamino) imidazolidine, m.p. 131-132 'C

Example 10

2- (2-chloro-5-lrifluormetil-phenylimino) imidazolidine

In each case, Example 1 was performed using ezerine except that 2-chloro-5-trifluoromethyl-phenylamino-imino-ethyl ester acid was replaced by 2-methyl-4-chloro-femlimino-dithio-2-dimethyl ester. This gave 3.9 g (36.9%) of 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 124-125 ° C.

As in Example 10 acting as described in ai Labbe we have set up chemicals yet live: 2- (2,6-dimethyl-feniliniino) - imidazolidin op. 144-145 'C 2- (2,6-Dichloro-phenylimino) - imidazolidin op. 136-137 'C 2- (2-methyl-4-chloro-phenylimino) - imidazolidin op. 134-135 • C

2- (2-ethyl-4-chloro-phenylimino) -imidazolidine, m.p. 109-110 ° C

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 123-125

Example 11

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine

All proceed as in Example 3 except that 2-chloro-5-trifluoromethyl-phenylamino-imino-benzoic acid is used in place of the dimethyl ester of 2-methyl-4-chloro-phenyliminodithioic acid. This gave 4.1 g (38.9%) of 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 123-125 ° C.

Following the procedure of Example 11, the following compounds were prepared:

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 123-125

2- (2-Ethyl-4-chlorophenylimino) -imidazolidine, m.p. 108-109 'C

Example 12

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

All proceed as in Example 3 except that 2-methyl] -4-chlorophenylamino-iminosenic acid butyl ether is used instead of 2-methyl-4-chlorophenyliminodithiocarboxylic acid dimethyl ether. This gave 3.8 g (45.3%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 133-135 ° C.

Example 12 Using the procedure of ezerine, the following compounds were prepared: 2- (2-methyl-4-chlorophenylimino) -imidazolidine, m.p. 133-135 ° C

2- (2-Chloro-4-methyl-phenylimino) -imidazolidine, m.p. 148-150 ° C

Example 13

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

Ethylenediamine (3.0 g, 0.05 mol) in triethylamine (5.06 g, 0.05 mol) in benzene (30 ml) with stirring at room temperature

10.9 g (0.05 mol) of methyl 2-methyl-4-chloro-phenylimino-chloro-carbonic acid are added dropwise and the reaction mixture is refluxed for 1 hour. After cooling, water (40 ml) was added to the reaction mixture, the phases were separated, and the benzene was dried over magnesium sulfate and concentrated. The residue was recrystallized from isopropanol to give 5.4 g (51.5%) of 2- (2-methyl-4-chlorophenylimino) imidazolidine, m.p. 133-135 ° C.

Following the procedure of Example 13, the following compounds were prepared:

-713

2- (2b-dichlorophenylimino) imidazolidine, m.p. 136-137 'C

2- (2,6-Dichloro-4-nitrophenylimino) -imidazolidine, m.p. 275-277

2- (2-Bromo-6-chloro-phenylimino) -imidazolidine, m.p. 134-135 ° C

2- (2,4,6-Trimethyl-phenylimino) -imidazolidine, m.p. 154-155

Example 14

2- (2-methyl-4-chlorophenylimino) imidazolidine

In all cases, Example 13 was run on ezerine except that the reaction was carried out in excess of 30.0 g (0.5 mole) of ethylenediamine instead of the base of the triethylamine acetic acid base benzene solution. This gave 5.8 g (55.3%) of 2- (2-methyl-4-chlorophenylimino) -imidazolidine, m.p. 134-135 ° C.

Following the procedure of Example 14, the following compounds were prepared: 2- (2,6-Difluoro-phenylimino) -imidazolidine, m.p. 145-146 'C

2- (2-Chloro-5-trifluoromethyl-phenylimino) -imidazolidine, m.p. 123-125

Example 15

2- (2-chloro-5-trifluoromethyl-phenylimino) imidazolidine

All proceed as in Example 14 except that 2-chloro-5-trifluoromethyl-phenylimino-chloro-carbonyl butyl ester is used instead of 2-methyl-4-chloro-phenylimino-chloro-carbonic acid methyl ester. 5.2 g (49.6%) of 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidine are obtained, m.p. 123-125 ° C.

Following the procedure of Example 15, the following compounds were prepared: 2- (2-Chloro-phenylimino) -imidazolidine, m.p. 131-132 'C

2-Phenylimino-iroidazolidine, m.p. 135-136

Claims (16)

A process for the preparation of imidazolidine derivatives of the formula I and their pharmaceutically acceptable salts wherein n is 0, 1, 2, 3 and R is C 1 -C 4, optionally Alkyl having 1 to 5 halo substituents, in the case of methyl, substituted with 1 to 3 halo atoms, halogen, nitroceopor, carbamoyl CB or C 1-4 alkanoylamino, provided that when n is 2 and one of R is 3; -fluorine has the same meaning as the other R group other than the 4-raethyl group and provided that when n is 2 and one of the R groups is 4-fluorine, the other R group is 3-methyl or 3-nitro-. other than cB or 3-chloro), characterized in that a) reacting a dithioester of formula II (wherein R ⁸ is lower alkyl, aryl (lower) alkyl or aryl and R and n are as defined above) with ethylenediamine; obsession b) reacting a diester of formula III (wherein R ⁸ , R and n are as defined above) with ethylenediamine; obsession c) reacting an imino ether of formula IV (wherein R 'is lower alkyl and R e n is as defined above) with ethylenediamine; obsession d) reacting a semi-ester halide of formula V (wherein X is halogen and R ⁸ , R and n are as defined above) with ethylenediamine; optionally converting a compound of formula (I) obtained by any of the above processes into a pharmaceutically acceptable salt. Process (a) according to Claim 1, characterized in that the reaction is carried out in an alcohol, an aromatic hydrocarbon, an ether or an excess of ethylenediamine. Process (a) according to claim 1 or process according to claim 2, characterized in that the reaction is carried out at a temperature between 20 ° C and the boiling point of the reaction mixture. Process b) according to claim 1, characterized in that the reaction is carried out in a lower alcohol, an aromatic hydrocarbon, an ether or an excess of ethylenediamine. The process according to claim 4, wherein the reaction is carried out at a temperature between 20 ° C and the boiling point of the reaction mixture. Process c) according to claim 1, characterized in that the reaction is carried out in a lower alkanol, an aromatic hydrocarbon, an ether or an excess of ethylenediamine. A process according to claim 6, wherein the reaction is carried out at a temperature between 20 ° C and the boiling point of the reaction mixture. 8. The process of claim 1, wherein the reaction is carried out in the presence of an acid scavenger. 9. The process according to claim 8, wherein the acid acceptor is an excess of ethylenediamine or a tri (lower carbon atom) amine, preferably triethylamine. -815 10. A 8-9. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in an aromatic hydrocarbon, an ether or triethylamine. 11. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature between 20 ° C and the boiling point of the reaction mixture. 12. A process for preparing 2- (2-methyl-4-chlorophenylimino) -10-imidazolidine and its pharmaceutically acceptable salts according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 13. Process for the preparation of 2- (2-ethyl-4-chlorophenylimino) -15-imidazolidine and its pharmaceutically acceptable salts according to any one of claims 1 to 3, characterized in that the appropriate substances are used. 14. A process for the preparation of 2- (2-chloro-5-trifluoromethyl-phenylimino) -imidazolidine and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 15. Process for the preparation of 2- (2,6-dichlorophenylimio) imidazolidine and its pharmaceutically acceptable salts according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 16. A process for the preparation of the corresponding fumarates according to any one of claims 1 to 3, characterized in that the base obtained is reacted with fumaric acid. 4 drawings