DK144565B - PROCEDURE FOR PREPARING 1-BENZOYL-2- (2,6,6-DICHLORPHENYLAMINO) -2-IMIDAZOLINE AND ITS SALTS - Google Patents

Description

/ A ^ (O1 »(19) DENMARK Vfee i r ^ i

02) PRESENTATION WRITING (11) 144565 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 35 * 3 / Ί S (51), ntC, .3 q q? q 233/50 (22) Filing day Aug 6 1976 (24) Race day 6 Aug. 1976 (41) Aim. available Mar 26 1 977 (44) Presented 29 years. 1982 (86) International application no.

(86) International filing day - (85) Continuation day (62) Stock application no.

(30) Priority 25. pep. 1975 # 7355/75, AT

(71) Applicant CHEMIE LINZ AKTIENGESELLSCHAFT, 4020 Linz, AT.

(72) Inventor Rudolf Franzmair, AT.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Process for the preparation of 1- benzoyl-2- (2 ', 6'-dichlorophenyl = amino) -2-imidazoline and its salts.

From Austrian patents Nos. 248,428, 250,344 and 250,345, it is known that 2-arylamino-2-imidazolines, especially the compound 2- (2 ', 61-dichlorophenylamino) -2-imidazoline, have a pronounced high potency. effect, which is paired with a sedative effect.

Further, from Belgian Patent Specification No. 741,947 N-aroyl derivatives of these 2-arylamino-2-imidazolines, e.g. 2-

LfD N-benzoyl- (21,6'-dichlorophenyl) -amino-2-imidazoline, which also has this hypotensive and simultaneously sedative effect. They are obtained by aroylating the free 2-arylamino-2-imidazolines with the to- *

ISLAND

2 144565 corresponding to acid chlorides of aromatic carboxylic acids, the acid residue being exchanged with the H attached to the aniline nitrogen.

It has now been found that upon reaction of 2,6-dichlorophenyl-isocyanide dihalides with N-benzoylethylenediamine, a benzoyl derivative of 2- (2 ', 61-dichlorophenylamino) -2-imidazoline with interesting pharmacological properties is produced, which derivative bears the benzoyl residue, not by the aniline nitrogen, but as is clearly evident from the synthesis, by the imidazoline nitrogen. This compound known from Danish Patent Application No. 941/75 is a structural isomer of the benzoyl derivative described in Belgian Patent No. 741,947, which can be proved by physical measurements of ia, mixture melting point and pKa value.

The invention thus relates to a process for the preparation of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline of the formula σν <3 ...

C6H5 or J, O ___ <1 _ // \ ^! _ (Ib) "" ci <k> thaw, or of its salts, and the process of the invention is peculiar in that a 2,6-dichlorophenylisoyanide dihalide of the general formula 3 (S of acid binding agents, after which the obtained compound of formula (Ia) and (Ib), respectively, is isolated as the free base or salt with inorganic or organic acids.

N-benzoylethylenediamine is known from the literature and can be prepared according to Aspinall, J.Org.Chem. 6,895,899 (1941).

The reactions can in principle be carried out according to all known methods of acylation reactions with the restriction that only the solvents and acid-binding agents which do not react or only react so slowly with an arylisocyanide dichloride of the formula II are used that the desired reaction is not inhibited or only to a small extent inhibited. As the solvent one can use apolar or slightly polar solvents, e.g. benzene, toluene, xylene, cyclohexane, halogenated csrbonic hydrides, e.g. methylene chloride or chloroform, ethers such as e.g. diethyl ether, tetrahydrofuran or dioxane, and esters such as e.g. acetic acid ethyl ester; or one can use polar solvents, e.g. alcohols, preferably having more than 2 C atoms, acetonitrile, dimethylformamide or dimethylsulfoxide.

The reaction can be carried out both homogeneously and heterogeneously. Without heterogeneous conducting of the reaction, as acid binding agents, especially aqueous sodium or potassium hydroxide solutions or NaH are suitable; by homogeneous execution of the reaction, sodium 4 U4565 or potassium alcoholates are suitable.

Since the compound obtained by the process is a weak base, it is preferable to work in such a way that the reaction product, after evaporation and uptake in an inert solvent such as benzene or methylene chloride, is extracted with a dilute acid, preferably with 1N hydrochloric acid, after which the hydrochloric acid extracts are made basic, thereby precipitating the compound as crystals. After filtration, a suitable solvent is recrystallized, e.g. isopropanol, acetonitrile, ethyl acetate, benzene or toluene, after which the compound is in high purity.

The reaction is carried out at a temperature of between 0 ° C and the boiling point of the solvent used, preferably between +10 and +50 ° C. The reaction time may advantageously range from a few hours to 24 hours.

Surprisingly, and not foreseeably, it has been found that an amide nitrogen, as present in N-benzoylethylenediamine, also reacts using mild acylation methods such as e.g. using Schotten Baumann's reaction, where it readily reacts with a halogen in the aryl isoyanide dihalide.

The compound of formula 1a and 1b, respectively, is a uniform, well crystallizing product. The structure of these compounds cannot be unambiguously determined as it must be open whether the double bond occurs in the imidazoline ring (1a) or exocyclic (1b). The compound in question has very interesting pharmaceutical properties. It even has as good a blood pressure lowering effect as the known compound containing hydrogen instead of the benzoyl group and as the benzoyl derivative substituted by the aniline nitrogen described in Belgian Patent No. 741,947; however, the sedative effect component is significantly less pronounced. Therefore, without using the subject compound as a hypotensive agent, the fatigue which otherwise occurs as an unpleasant side effect lapses.

The lack of sedative or centrally attenuating effect can easily be detected by the finding of carotissin reflex in an anesthetized rabbit after administration of said compound at doses of 100 micrograms / kg. This reflex, on the other hand, is almost completely suppressed by administration of the same dose of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline. The lack of reflex can also be observed by unchanged behavior in awake mice after administration of 5 or 10 mg / kg of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline.

The compound of formula Ia and Ib, respectively, is very suitable for oral administration.

The process for preparing this compound is explained in more detail by the following examples.

EXAMPLE 1 1.64 g (10 mmol) of N-benzoylethylenediamine is dissolved in 100 ml of benzene and 25 ml of water is added and heated to 50 ° C with vigorous stirring; at the same time, a solution of 2.31 g (10 mmol) of 2,6-dichlorophenyl isocyanide dichloride in 20 ml of absolute benzene and 20 ml of 1N NaOH is added dropwise over a period of 75 minutes. After 3 hours, stir at 50 ° C. One is cooled to room temperature and the phases are separated. The aqueous phase is extracted again with 100 ml of benzene. The two benzene phases are mixed and washed with water and extracted 3 times, each time with 75 ml of 1N hydrochloric acid. The hydrochloric acid extracts are mixed, washed once with ether and. is basified with N a C 0 O to give 650 mg (19.4%) of crude 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline.

After recrystallization from isopropanol, 480 mg of product is obtained.

Melting point = 160 - 162 ° C.

Claims (1)

EXAMPLE 2 3.28 g (20 mmol) of N-benzoylethylenediamine are reacted with 4.62 g (20 mmol) of 2,6-dichlorophenylisocyanide dichloride d and 40 ml of IN! NaOH at a temperature of 10 - 15 ° C analogous to Example 1 and worked up. 1.20 g- (18.0% of theory) of crude 1-benzoyl-2- (2 ', 61-dichlorophenylamino) -2-imidazoline are obtained. After recrystallization from isopropanol, 950 mg (14.2 µl of the theoretical yield) is obtained, mp 160 - 162 ° C. Example 3 1.64 g (10 mmol) of N-benzoylethylenediamine is dissolved in 60 ml of absolute tetrahydrofuran. 0.48 g (20 mmol) of NaH is added (acidifying to 0.90 g of a 55% dispersion) and stirred for 30 minutes until gas evolution has ceased. Then, with stirring at room temperature, a solution of 2.31 g (10 mmol) of 2,6-dichlorophenylisocyanide dichloride in 20 ml of absolute tetrahydrofuran is added dropwise to warm the reaction solution to some extent. Stir for another 2 hours at room temperature, and any remaining NaH is gently reacted with water and evaporated. The residue is taken up in methylene chloride and extracted 3 times, each time with 75 ml of 1N hydrochloric acid. The hydrochloric acid extracts are mixed and made basic with a Na 2 CO 2 solution, precipitating a crystalline. This crystalline is filtered and recrystallized in still moist state from isopropanol. 1.02 g of 1-benzoyl-2- (2 ', 61-dichlorophenylamino) -2-imidazoline (30.5% of theory) is obtained, m.p. 160 - 162 ° C. P- ate n t requirements; Process for the preparation of 1-benzoyl-2- (2 ', 6'-dichloro-phenylamino) -2-imidazoline of the formula