NO784350L - PROCEDURE FOR ALKYLATION OF 4 (5) -MERCAPTOMETHYL-IMIDAZOLES WITH AZIRIDINE DERIVATIVES - Google Patents

Description

The present invention relates to a method

for the alkylation of 4(5)-mercaptomethylimidazoles with derivatives of aziridine, whereby valuable, biologically active compounds of the formula are formed

where R is an alkyl residue with no more than 3 carbon atoms in the chain, i.e. methyl, ethyl, propyl or isopropyl.

The compounds of the general formula I are thus far

have been prepared according to three different methods (Drugs of the Future I, 1976, no. 1, page 13) according to the scheme indicated below. These methods are described, among other things, in DE-OS 2,344,779 and in US-PS 3,876,647 (left side of the form) as well as in FR-PS 2,199,467 (the vertical part of the form) and in NL-PS 73,12198 (right page of the form).

The compound with the formula I and their tautomers with the formula Ia are prepared according to the invention by alkylation of compounds with the formula II

which can exist in the form of the free base or in the form of a salt. Because of the economic advantages, the salts of the hydrohalic acids are preferred, e.g. the hydrochloride or hydrobromide. Other salts can also be used, e.g. sulfates or picrates, which, however, makes the isolation of pure compounds of the formula I and Ia respectively more difficult. The compounds with the formulas II and IIa respectively are new and have been patented in a separate patent application.

The compounds with the formulas I and II are generally always present in a mixture with the corresponding tautomeric compounds Ia and Ila. When in the following it is a question of one or the other tautomeric form, this always means the mixture.

The alkylation of the compound of formula II takes place according to the present invention with aziridine derivatives of formula III

where R has the same meaning as stated above. The reaction is preferably carried out in a polar solvent, e.g. lower alcohols, dimethylsulfoxide, dimethylformamide, acetonitrile or HMPTA (hexamethylphosphoric acid triamide). From an economic standpoint, methanol, ethanol and dimethyl sulfoxide have been found to be preferred. The reaction takes place at temperatures of

between 0 and 80°C, preferably between 0 and 20°C.

The nucleophilic ring opening of the aziridine usually takes place best in an acidic medium (protic acids or Lewis acids as catalysts).

If the free base of compound II is used, it is preferably carried out with the addition of a Lewis acid, preferably boron trifluoride diethyl etherate. It is therefore advisable to work in an aprotic solvent, preferably in acetonitrile, methylene chloride, tetrahydrofuran or dioxane.

However, it has been shown that the reaction between the compounds of the general formula III and the compounds of the formula II takes place with an even higher yield in basic environments, i.e. in a medium where sulphide anions of the compound II are formed.

It surprisingly turned out that the formation of anions of the compound II takes place best under the influence of an alkali alcoholate solution. The best results were obtained with sodium methylate in methanolic solution. It turned out that the aziridine derivatives with the formula III are activated by the cyanomethylimine group for the ring opening, and that the sulphide anion, the strongest nucleophilic reactant in the solution, as the most reactive reactant causes the ring opening of the aziridine.

The compounds with the general formulas II and III and their preparation are described for the first time in CH-PS

......... (Swiss Patent Applications 5236/78 and 5237/78).

The yields of the compounds of the general formula I

when produced in an acidic medium is from 70 to 90%, when working in an alkaline medium between 94 and 98%, i.e. that they are practical

quantitatively speaking. In both embodiments, the yields are higher than according to the above-mentioned known methods. Moreover, the present method is significantly more economical due to the fact that the known methods all use cysteamine hydrochloride (HS-Cf^CH^-NH,, .HCl), which is a relatively

show expensive product.

According to the experimental experiences, the yields are too

the vertical and the right side of the form significantly lower than the yields for the left side. These are therefore not specified. These yields are also not specified in the above-mentioned patents.

In contrast, the yield of the method according to the present invention, calculated from 4(5)-thiomethyl-5(4)-methyl-

imidazole, up to from 94 to 98%, and instead of expensive cysteamine hydrochloride, very cheap ethanolamine or ethylene imine is used.

The process according to the invention for the production of compounds with the formula I and Ia, respectively, is based on previously undescribed and readily available compounds and is more economical than known methods in that a process step is saved, due to the fact that cheap and commercially available reaction participants are used and due to the fact that higher yields of the desired product are obtained.

The compounds of the formula I are useful in medicine as agents for the F₂ receptor blockade, i.e. for the therapy of ulcers in the stomach and in the duodenum.

In what follows, conditions and working methods are stated

for illustration of the connection.

Preparation: 4(5)-methyl-5(4)-mercaptomethylimidazole-

hydrochloride A 4.5 percent solution of KHS in absolute ethanol was prepared by introducing dry hydrogen sulphide into an alcoholic solution of potassium ethylate. This solution was added dropwise to a solution of 4(5)-methyl-5(4)-chloromethyl-imidazole hydrochloride (15 g, 0.09 mol) in absolute ethanol (140 mL) at 0-

5°C with stirring. It was then stirred for 2 hours and there-

after adding a hydrogen chloride solution in isopropanol to

achieve a pH value of approx. 1. The rinsed inorganic salts were filtered off, the filtrate evaporated to dryness and the residue dissolved in ethanol (300 ml) under heat. After adding activated charcoal, it was filtered, evaporated to dryness again, whereby the crude product crystallized out. Melting point: 283-285°C (14.5 g). After recrystallization from isopropanol

(60 ml), 11.2 g of pure product were obtained. Melting point: 290-291°C. IR (KBr): 2800-3200 (broad), 1640, 1530, 1480, 1440, 1095, 815 cm<-1>.

Example 1

N"-cyano-N<1->methyl-N-{-2- [(5-methyl-1H-imidazol-4-yl)-methyl]-thioethyl}-guanidine

To 1.64 g (10 mmol) of 4(5)-methyl-4(5)-mercaptomethyl-imidazole hydrochloride in methanol was added while stirring a solution of 1.48 g (12 mmol) of N"-cyano-N -methyl-N'-ethyleneguanidine in 50 ml of methanol at 0° C. After stirring for 6 hours, 10 ml of a methanolic ammonia solution was added, the solvent was evaporated,

and the residue crystallized from isopropanol. The compound was obtained in 75-80 percent yield. Melting point: 141-143°C.

Example 2

N"-cyano-N'-methyl-N{-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-thiethyl];-guanidine

The procedure was as described in example 1, but dimethylsulfoxide was used as solvent instead of methanol. The reaction was carried out during 2 hours at 20°C, after which the solvent was evaporated to dryness under vacuum. The residue was recrystallized from isopropanol-acetonitrile, whereby the compound was obtained in 70-75% yield. Melting point: 141-143°C.

Example 3

N"-cyano-N'-ethyl-N-{-2-[(5-methyl-1H-imidazol-4-yl-methylj-thioethyl]t-guanidine

6.5 g (0.05 mol) 4(5)-methyl-5(4)-mercaptomethylimidazole

was dissolved in 80 ml of tetrahydrofuran, after which a solution of 8.28 g (0.06 mol) of N"-cyano-N-ethyl-N'-ethyleneguanidine in 40 ml of tetrahydrofuran was added. Then 0.05 mol of a boron trifluoride-diethyl etherate solution added dropwise at 10-15°C, and the reaction mixture was stirred for 4 hours. The work-up proceeded as described in Example 1. The pure product was obtained, in a yield of 80-85%. Melting point: 117-19° C.

Example 4

N"-cyano-N1-methyl-N-[2-(5-methyl-1H-imidazol-4-yl)-methyl-thioethyl]-guanidine

13.8 g (84 mmol) of 4(5)-thiomethyl-5(4)-methylimidazole hydrochloride was dissolved in 200 ml of absolute methanol, and under a nitrogen* atmosphere at 0°C over 15 minutes it was added dropwise 3.17 ml of a 28.5 percent solution of sodium methylate in methanol. Then, 9.93 g (80 mmol) of N"-cyano-N'-methyl-N-ethyleneguanidine, dissolved in 100 ml of absolute methanol, was added dropwise, also while cooling. The reaction was carried out with stirring for from 10 to 12 hours at room temperature, and the reaction was followed by thin-layer chromatography (elution mixture: acetonitrile-acetic ester-methanol-concentrated ammonia = 10:5:2:1). At the end of the reaction, practically only spots of the product could be seen in the chromatogram, while no spots of the starting compounds appeared.Then the precipitated inorganic precipitate was filtered off, the filtrate was evaporated to

dry state and the residue was dissolved in hot propanol. Precipitated salt was filtered off again, and the product crystallized on cooling to 0°C. 70-80% of pure N"-cyano-N<1->methyl-N-[2-(5-methyl-1H-imidazol-4-yl)-methylthioethyl)-guanidine was obtained. Melting point: 141-143 °C, and by subsequent evaporation and crystallization of the mother liquor, a total yield of 90-96% of this product was obtained.

Example 5

N"-cyano-N'-methyl-N-[2-(5-methyl-1H-imidazol-4-yl)-methylthioethyl!-guanidine

The work was carried out as in example 4, but as solvent instead of methanol acetonitrile was used, which can also be mixed with water. The reaction was carried out during 10 hours at 20°C, after which the solvent was evaporated to dryness under vacuum and the residue recrystallized from isopropanol-acetonitrile, whereby the pure compound was obtained in a yield of 80-85%. Melting point: 141-143°C.

Example 6

N"-cyano-N'-ethyl-N-[2-(5-methyl-1H-imidazol-4-yl)-methylthioethyl]-guanidine

6.5 g (0.05 mol) 4(5)-methyl-5(4)-mercaptomethylimidazole

was suspended in 80 ml of tetrahydrofuran, and a 28.5% solution of sodium methylate in methanol (2.5 ml) was added dropwise. Then 8.28 g (0.06 mol) of N"-cyano-N'-ethyl-N-ethyleneguanidine in 40 ml of tetrahydrofuran were added. The reaction

was carried out within 10-20 hours at room temperature. Work-up took place as described in example 1. A pure product was obtained with a yield of 80-85%. Melting point: 117-119°C.

Example 7

The procedure was as described in example 4, but the preparation of the reaction mixture took place as follows: The inorganic salt was filtered off, the filtrate was evaporated to a volume of 10-15 ml and the solution was introduced into a silica gel column (360 g silica gel, Merck 80 -325 mesh, elution mixture: acetonitrile-acetic ester, methanol-concentrated ammonia = 10:5:2:1). By column chromatography, 94% pure N"-cyano-N'-methyl-N-[2-(5-methyl-1H-imidazol-4-yl)-methylthioethyl]-guanidine was obtained. Melting point: 141-143°C after recrystallization from isopropanol.

Example 8

In the same way as described in the examples above, the corresponding compounds where R is methyl, ethyl, propyl or isopropyl were prepared.

Claims (7)

1. Process for the preparation of compounds of the general formula I where R is an alkyl residue with no more than 3 carbon atoms in the chain, characterized in that a compound with the formula II as a free base or in the form of a salt, is reacted with a compound of the formula III where R has the same meaning as stated above. 2. Process in accordance with claim 1, characterized in that the reaction takes place in methanol, ethanol or dimethyl sulfoxide at temperatures of between -5 and 80°C, preferably between 0 and 20°C. 3. Process in accordance with claim 1 or 2, characterized in that the compound II is used in the form of the free base, and that the reaction preferably takes place in an aprotic solvent with the addition of a Lewis acid, preferably boron trifluoride diethyl etherate, and at temperatures of 0- 20°C. 4. Method in accordance with claim 1, characterized in that the reaction takes place in a polar solvent with the addition of an alkali metal alcoholate at temperatures of between -5 and 20°C in an inert atmosphere. 5. Method in accordance with claim 4, characterized in that a sodium methylate solution in methanol is used as the alcoholate. 6. Method in accordance with claim 4 or 5, characterized in that the reaction is carried out under dry nitrogen. 7. Method according to one of claims 1-6, characterized in that the compound with the formula II or Ila respectively is used in the form of its salt with a hydrohalic acid, preferably HCl or HBr.