HU201528B - Process for producing 2-(2,6-dichlorophenylimino)-imidazolidine monohydrochloride - Google Patents

Abstract

2-(2,6-Dichloro-phenyl -imino)-imid-azolidine of formula (I), an anti-hypertensive agent is prepd. from an iso-cyanuric-acid deriv. of formula (II), where X is halogen atom and from ethylene-di:amine in a heterogeneous phase transfer system of a water-immiscible solvent and aq. soln. - of an alkali-hydroxide, with a small excess of ethylene-di:amine acting as phase transfer agent.

Description

The present invention relates to a novel improved process for the preparation of 2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride.

2- (2,6-Dichlorophenylimino) imidazolidine monohydrochloride (clonidine monohydrochloride, hereinafter referred to as the hydrochloride salt) is a known active ingredient in antihypertensive preparations.

The hydrochloric acid salt is prepared from the imidazolidine base of formula (I) by reaction with hydrochloric acid and the quality of the hydrochloric acid salt is essentially determined by the quality of the base.

The known processes for the preparation of the base of formula (I) raise technological problems in part and do not ensure the quality required for the preparation of hydrochloride salt of appropriate quality:

No. 155,329. Hungarian, No. 1,577,128 French, No. 71,554 No. 77,07418 of the GDR South Africa and U.S. Patent No. 1,229,993; According to the processes described in British patents, the isocyanic acid derivative of the formula II is reacted in a homogeneous phase with ethylenediamine to produce the compound of formula (I).

No. 155,329. Hungarian, No. 1,577,128 French, No. 71,554 No. 77,07418 of the GDR A disadvantage of the process of South African patent application is the use of 5-10 molar excess of ethylenediamine in anhydrous medium. The use of a large amount of anhydrous ethylenediamine on the one hand is uneconomical and on the other hand it is difficult to remove a large excess of ethylenediamine and the hydrochloride salt of the appropriate quality cannot be obtained from the base.

No. 1,229,993. In the British patent specification the possibility of using water-miscible and / or water-immiscible solvents is mentioned in the description section.

However, the examples only describe reactions carried out in a homogeneous phase.

Examples of the above description where an anhydrous medium is used have a relatively low yield ranging from 55 to 67%.

The following examples use aqueous dioxane. In this case, the yield is slightly higher, but the purity of the pharmaceutically acceptable hydrochloride salt obtained from the imidazolidine base obtained by the process no longer corresponds to today's requirements. It should also be noted that the removal of dioxane from the mother liquor, due to its equal boiling point, is extremely difficult and environmentally disadvantageous.

The hydrochloric acid salt of the base obtained by both processes has a contamination of more than 0.3% by weight of 2,6-dichloroaniline and N- (2,6-dichlorophenyl) formamide. However, USP XXI (United States Pharmacopoeia) allows up to 0.2% total impurities and up to 0.1% individual impurities in the active ingredient when tested by thin layer chromatography as described below.

Surprisingly, it has been found that all of these drawbacks of the above processes can be easily overcome by preparing the isocyanic acid derivative of formula (II) and ethylenediamine in a heterogeneous mixture of a water immiscible solvent and an aqueous alkali metal hydroxide. It has been particularly surprisingly found that ethylenediamine, up to a maximum of 0.5 mol, is suitable as phase transfer.

The present invention therefore relates to a process for preparing the monohydrochloride of 2- (2,6-dichlorophenylimino) imidazolidine of formula (I) by reacting the isocyanic acid derivative of formula (II) with ethylenediamine in the presence of aqueous alkali metal hydroxide. By reacting the base of formula (I) with hydrochloric acid, using from 1.0 to 1.5 moles of ethylenediamine per mole of the compound of formula (II) and reacting with an aqueous solution of sodium or potassium hydroxide and water. in a mixed solvent mixture in a heterogeneous phase using phase transfer.

As the water-immiscible solvent, polar or non-polar solvents, such as ethers (e.g. diethyl ether, diisopropyl ether), aromatic hydrocarbons (e.g. toluene, xylene), preferably diisopropyl ether or toluene, may be used.

As the aqueous alkali metal hydroxide solution, various concentrations, preferably 10-15% by weight, of aqueous sodium or potassium hydroxide solutions can be used.

As the phase transfer, various carbon quaternary ammonium salts such as triethylbenzylammonium chloride, tetrabutylammonium bromide, tricaprylmethylammonium chloride are preferred, but preferably 0.05-0.5 molar excess of ethylenediamine. used.

The reaction is carried out at 5-80 'C, preferably at 20-30' C,

The reaction is carried out with stirring for 1 to 10 hours, preferably 2 to 4 hours.

The recovery of the product of formula (I) is very simple, after separation of the phases, washing of the organic phase with water, evaporation of the solvent in vacuo and recrystallization of the residue.

The conversion of the base of formula (I) into the monohydrochloride can be carried out in a manner known per se. Thus, it is reacted with hydrochloric acid in an inert solvent, preferably acetone. In this way, 2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride is obtained according to USP XXI.

A further advantage of the process, apart from the purity of the product obtained, is the high yield that it is simple to carry out, it does not require any special equipment for the reaction, it can be carried out at room temperature and is suitable for aqueous ethylenediamine.

1-9. Example 4 below describes the

2- (2,6-dichlorophenylimino) imidazolidine.

From the product obtained in any one of the Examples, 2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride can be obtained by the method of Example 10, which is in all respects in compliance with USP XXI.

Specifically, the USP XXI thin-layer chromatography assay was performed as follows and its results are given.

For reference ("reference"), reference is made to U.S. Patent No. 1,229,993. 2- (2,6-dichlorophenylimino) imidazolidine prepared according to Example 3 of British Patent Application Example 3, 2- (2,6-dichlorophenylimino) imidazolidine monochloride prepared according to Example 10 herein. .

Running Plate: 100 x 200 mm Merc Kieselgel GF-254

Running mixture: toluene / dioxane / ethanol / ammonium hydroxide

10: 8: 2: 1 by volume

Quantity of sample applied: 10 micrograms

Development: After chlorination, spray with potassium iodide / starch solution

HU 201528 Β

Rating: Pollution (%)

Rf own reference 2,6-dichloroaniline 0.7 <0.1 0.4 N- (2,6-dichlorophenyl) - formamide 0.57 <0.1 0.3 (clonidine 0.52) From the table It can be seen, that the substances tested

Only the quality of the product produced by our process meets the requirements of USP XXI, that is, the amount of each impurity is less than 0.1% by weight.

The invention is further illustrated by the following non-limiting Examples.

Example 1

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

To a solution of 40.0 g (1 mol) of sodium hydroxide in 300 ml of water was added 30.1 g (0.5 mol) of ethylenediamine and 2.3 g (0.01 mol) of triethylbenzylammonium chloride and added dropwise with vigorous stirring. A solution of 121.5 g (0.5 mole) of 2,6-dichlorophenyl isocyanic acid dichloride in 400 ml of diisopropyl ether. Meanwhile, the temperature of the slightly exothermic reaction mixture was maintained at 20 ° C with water cooling. After the dropwise addition, the reaction mixture was stirred at room temperature for an additional 3 hours, the layers were separated, and the ether layer was washed with water (200 mL) and evaporated to dryness in vacuo. This gives 110 g (96%) of crude 2- (2,6-dichlorophenylimino) imidazolidine, which is dissolved in 500 ml of hot acetone, decolorized with charcoal, filtered and allowed to crystallize in a refrigerator. 100 g (87%) of pure 2- (2,6-dichlorophenylimino) imidazoline are obtained, m.p.

Example 2

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

In all of Example 1, except that 3.2 g (0.01 mol) of tetrabutylammonium bromide was used in place of triethylbenzylammonium chloride catalyst and 500 ml of diethyl ether in place of diisopropyl ether solvent, the reaction temperature was 20 '. Instead of C, the reaction is maintained at 5 ° C with ice-cold cooling, and the reaction is completed at room temperature with stirring for 10 hours instead of 3 hours. 105 g (91.3%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p.

Example 3

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

In all the procedures of Example 2, except that the reaction solvent was 400 ml dibutyl ether instead of diethyl ether, the reaction was carried out at 30 ° C and completed by stirring at room temperature for 3 hours. This gives 99 g (86%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p. 140-142 ° C.

Example 4

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

In each case, the procedure of Example 1 was followed, except that 500 ml of benzene was used as solvent instead of diisopropyl ether. This gives 101 g (88%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p. 140-141 ° C.

Example 5

2- (2,6-Dichloro-phenylimino) -imidazolidine The procedure of Example 1 was repeated except that "Aliqaut 336" (tricaprylmethylammonium chloride) phase transfer catalyst was used instead of triethylbenzylammonium chloride. . This gave pure 2- (2,6-dichlorophenylimino) imidazolidine (g, 86%), m.p. 140-142 ° C.

Example 6

2- (2,6-Dichlorophenylimino) imidazolidine In all the procedures of Example 1, except that 500 ml of toluene was used as the solvent instead of diisopropyl ether and the reaction mixture was completed at room temperature for 2 hours at 80 ° C. stirring. This gives 95 g (82.5%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p. 140-142 ° C.

Example 7

2- (2,6-Dichloro-phenylimino) -imidazolidine In all of the procedures of Example 6, except that 500 ml of xylene was used as the solvent instead of toluene and the reaction mixture was completed at room temperature for 1 hour at 80 ° C. stirring. This gave 93 g (81%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p.

139-141 'C.

Example 8

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

To a solution of 40.0 g (1 mol) of sodium hydroxide in 300 ml of water was added 45.1 g (50 ml - 0.75 mol) of ethylenediamine and ca. A solution of 121.5 g (0.5 mol) of 2,6-dichlorophenyl isocyanic acid dichloride in 400 ml of toluene is added dropwise over 1 hour with vigorous stirring. Meanwhile, the temperature of the slightly exothermic reaction mixture was maintained under water cooling at 30 ° C. After the dropwise addition, the reaction mixture was stirred at room temperature for an additional 3 hours, the layers were separated, the toluene layer washed with water (200 mL) and evaporated to dryness in vacuo. This gives 106 g (92.2%) of crude 2- (2,6-dichlorophenylimono) imidazolidine, which is dissolved in 500 ml of hot acetone, decolorized with charcoal, filtered and allowed to crystallize in a refrigerator. Yield: 101 g (88%) of pure 2- (2,6-dichlorophenylimino) imidazolidine, m.p. 140-142 ° C.

Example 9

2- (2,6-Dichlorophenylimino) imidazolidine The procedure of Example 8 was repeated except that 31.6 g (0%) of ethylene diamine was replaced by 45.1 g (0.75 mole) of ethylene diamine. (53 mol) of ethylenediamine.

100 g (87%) of the title compound are obtained, m.p.

140-142 'C.

Example 10

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

HU 201528 Β

2- (2,6-Dichlorophenylimino) imidazolidine (115 g, 0.5 mole) was dissolved in acetone (750 ml) at 55-60 ° C, and at this temperature, while stirring vigorously, 22 g (18.6 ml) were added. Concentrated hydrochloric acid (0.6 mol) was added dropwise. After addition of the total amount of hydrochloric acid, the mixture was stirred for an additional 1/2 hour, the precipitate was filtered off and washed well with 2 x 50 ml of acetone. There was thus obtained 125.8 g (94%) of 2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride, m.p. 309-312 ° C.

Claims (4)

PATENT CLAIMS Ethylene diamine (1.0-1.5 mol) is used and this reaction is carried out in a mixture of aqueous sodium or potassium hydroxide and a water immiscible solvent, in a heterogeneous phase, using phase transfer. A process for the preparation of 2- (2,6-dichlorophenylimino) imidazolidine monohydrochloride by reacting an isocyanic acid derivative of the formula II with ethylenediamine in the presence of an aqueous alkali metal hydroxide and then reacting the base of the formula I with hydrochloric acid. characterized in that it is prepared per mole of the compound of formula (II) to produce the base Process according to claim 1, characterized in that the water-immiscible solvent is diisopropyl ether, diethyl ether, dibutyl ether, xylene or toluene. 3. Process according to any one of claims 1 to 3, characterized in that the phase transfer is triethylbenzylammonium chloride, tetrabutylammonium bromide, tricaprylmethylammonium chloride. 4. A process according to any one of claims 1 to 4, wherein the phase transfer is 0.05-0.5 mol of excess ethylenediamine based on the compound of formula (Π).