NO135214B - - Google Patents

Description

The present invention relates to a process for the production of substituted arylamino-2-imidazolines of the general formula:

where R^-R^ each denote a hydrogen or chlorine atom or a methyl group, and which may be the same or different, at least two denote hydrogen, as well as acid addition salts thereof. Numerous processes for the preparation of arylamino-2-imidazolines of a general formula I have previously been described. Thus, compounds of this type can be prepared by heating analogously substituted isothiuronium salts or thiourea derivatives with ethylenediamine, or via pyrolysis to cyclize N-aryl-N^-aminoethyl-urea or -thiourea (see, for example, U.S. Patent No. 2,899.< 1>+26, 3,202,660, British Patent No. 1.035-!-.938). Various compounds have been prepared by reacting ethylenediamine or salts thereof with substituted phenyl-imino-carboxylic acid derivatives in the presence of suitable solvents (see, e.g., U.S. Patent No. 3, K68,887), substituted phenylguanidines or substituted phenylcyanamides (see eg D.D.R. patent document 68,509).

Compounds of the general formula I can also be prepared via reactions between ethylenediamine and cub-substituted phenyl isocyanide dichlorides (see e.g. Dutch Patent Bknad No. 65,10117, U.S. Patent No. 3A68,887, British Patent No. 1,229,993).

In connection with the methods indicated above, it has been possible to prepare compounds of the general formula I first via several synthesis steps, whereby the yield has simultaneously decreased.

Najer et al. has in the publication Bull. Soc. Chim. France 1961, 211Li-2126 continued p. a. following two procedures for the preparation of compounds of general formula I. Methyl mercapto-2-imidazoline hydroiodide was reacted with substituted anilines (see e.g. B.D.R. patent document no. 539.179) or N,N<1->bis-(imidazolidinyl) -1-one-2)-phosphoryl chloride is reacted with corresponding anilines.

Blue. from the above-mentioned article it appears that the dividends in

large extent depends on the position of the substituents in the aromatic ring and that e.g. 2,6-substituted anilines react poorly or do not react at all under the conditions stated in the article. 2,6-substituted compounds of the general formula I

has therefore not been able to be produced according to these methods.

The present invention relates to a simple process for the preparation of compounds of the general formula I. The process is characterized in that a substituted aniline of general

formula:

where R^-R^ when the previously stated meanings are reacted with an equivalent amount of 2-imidazolidone of formula:

in the presence of an excess of phosphorus oxychloride, and that the reaction is carried out'

in an anhydrous, inert, aromatic hydrocarbon at. its reflux temperature. Suitable solvents are e.g. benzene, toluene, xylene or the like. Suitable reaction temperature is 80-150°C and the reaction time is 10-20 hours.

Via this entrance see; .compounds of the general formula I can be prepared in a simple manner and with satisfactory yields. The yield varies between approx. 5° and 6% depending on the substituents in the phenyl ring, whereby the yield is at least in connection with 2,6-substituted anilines (see e.g. example 3). ■ •-.

The obtained imidazoline bases can be easily transferred to corresponding acid addition alters by the action of inorganic or organic acids, e.g. hydrochloric acid, nitric acid or picric acid.

All compounds have been identified on the basis of IR and NMR spectra as well as with the help of gas chromatography and blaride melting point determinations. Certain of the compounds produced here have been shown to exhibit valuable pharmacological properties, i.a. blood pressure lowering properties.

The invention is illustrated in more detail in the following example. Temperatures are given in degrees Celsius.

EXAMPLE 1

g (0.1 mol) phosphorus oxychloride in 10 ml anhydrous benzene was added with stirring at 10-15°C to a suspension of 17.2 g (0.2 mol) 2-imidazolidone in 50 ml anhydrous benzene, after which the mixture was allowed to stand for 2 hours at room temperature. 9.3 g (0.1 mol) of aniline in 20 ml of anhydrous benzene were then added with stirring and the mixture was refluxed for 15 hours.

The mixture was cooled and the benzene was decanted off.

The oily residue was taken up in water, and the aqueous solution was washed with benzene and made strongly alkaline by the addition of h0% ± g sodium hydroxide solution. The mixture was extracted 2-3 times with benzene and the extracts combined and washed with water and treated with activated charcoal and dried with anhydrous magnesium sulfate.

The solution was evaporated to a small volume in vacuo and

was diluted with 5 volumes of petroleum ether (b.p. 60-80°), with which phenylamino-2-imidazoline is precipitated.

The mixture was allowed to stand in a refrigerator overnight and the product was filtered off, washed with petroleum ether (b.p. H-0-60°C) and dried in a vacuum desiccator.

The impure product was recrystallized from chloroform, whereby 7.1 g (hh% of theory) of pure phenylamino-2-imidazoline were obtained. Melting point 131-132°C.

EXAMPLE 2

The reaction was carried out as described in example 1, but instead of aniline, 12.1 g (0.1 mol) of 2,4-di-thylaniline was used as starting material. The alkaline aqueous solution was extracted with benzene and then with ether. The extracts were combined and treated as in Example 1. The crude product was recrystallized from a mixture of cyclohexane and benzene C+:1), after which the yield was 3.8 g (20$ of theory) of 2,<>>+- ditnethylphenylamino-2-imidazoline. Melting point 10^-105°C. ;■ EXAMPLE ;The reaction was carried out as described in example 1 using 16.2 g (0.1 mol) of 2,6-dichloroaniline as starting material, and anhydrous toluene was used as solvent, whereby 2,6- dichlorophenylamino-2-imiduzoline as the final product. The yield for recrystallization from toluene was 1.*+ g (6.1$ of theory). Melting point 137-138°C.

The base can easily be converted to the hydrochloride by heating dry ether and then acidifying the solution with ethanol-HCl. After recrystallization from methanol-ether, the yield is approx. 90$ of theory.

and the melting point 303-305°C.

EXAMPLE h - l1 )

The following compounds of general formula I were prepared in an analogous manner:

Claims (1)

Procedure for the preparation of arylamino-2-imidazolines of general formula: where R-^-P-^ each denotes a hydrogen or chlorine atom or a methyl group, and which may be the same or different, but where at least two denote a hydrogen atom, characterized by -at a substituted aniline of the general formula: where R--R^ have the previously indicated meanings, is reacted with an equivalent amount of 2-imidazolidone of formula: in the presence of an excess of phosphorus oxychlorine in an anhydrous, inert, aromatic hydrocarbon at its reflux temperature in the course of 10-20 hours, after which the compounds thus obtained are, if desired, transferred to acid addition alternators of inorganic or organic acids.