CS207750B2 - Method of making the n'-cyano-n'-alcyl-n-2-/5-methyl-1h-imidazol-4-yl/methyl thicethyl guanidines - Google Patents

Abstract

Compounds of the following formula are obtained by reacting 4 (5)-mercaptomethyl-imidazol with aziridin derivates: (FORMULA) in which R is an alkyl group with one to three carbon atoms. Due to its high yield, the cancelling of a step and the utilization of cheaper raw materials, this method is more economical than known methods.

Description

The present invention relates to a process for the preparation of N-cyano-N‘-methyl-N- {2 - [(5-methyl-1H-imidazol-4-yl) methylthioethyl] guanidines of the general formula I or Ia,

C-N-II

C W S CHr CH-NH -C-NH-R K & &

(I) optionally wherein R represents an alkyl radical of 1 or 2; 2 carbon atoms in the chain, which are valuable, biologically active compounds.

The compounds of formula (I) have so far been produced by three different methods (Drugs of the Future I, 1976, No. 1, page 13), and. according to the scheme below. These are described, inter alia, in DOS 2,344,779 and U.S. Pat. No. 3,876,647 (left side of the diagram), as well as in French Pat.

N-C = N II

CWz-S-CW-CH--NH-C-nh-r CH.

(íaJ

2078 5 0>.

ЪГ - '

H iX γ-с ^ он

30-90 ^ ^HCHCH <1 ^{NH 4 Cl} X ^SCH X ^H Z ^NH 1.

w

IXX ^r - ^H i

NCN II CHLSCH.CH.NHC-SCH

CH3SCH2CH3N HC-NHCH.

w

S и chsch.ch. nhc-nhch ^

According to the invention, the compounds of the formula I or their tautomers of the formula Ia are obtained by alkylation of the compounds of the formula II,

optionally Ha

_СНдЗН сн э and H which may be in free base form or in salt form. For economic reasons, hydrohalide salts such as hydrochloride or hydrobromide are preferred. Other salts, such as sulfates or picrans, may also be used, but this makes it somewhat more difficult to isolate the pure compounds of formula (Ia). Compounds of formula (II) or (IIa) are novel.

The compounds of the formulas I and II are always present in a mixture with the corresponding tautomeric compounds of the formulas Ia and IIa, respectively. When one speaks of one or the other tautomeric form in another, it is meant a mixture.

According to the invention, the alkylation of the compounds of the formula II is carried out with the aziridine derivatives of the formula III,

N-C = N (III) wherein R is as previously defined.

The reaction is preferably carried out in a polar solvent such as low alcohols, dimethylsulfoxide, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. Methanol, ethanol and dimethylsulfoxide are preferred for economic reasons. The reaction is carried out at a temperature between 0 to 80 ° C, preferably between 0 to 20 ° C.

The nucleophilic opening of the aziridine ring usually occurs best in an acidic environment (protonic acids or Lewis acids as catalysts).

When 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 recommended to work in an aprotic solvent, preferably acetonitrile, methylene chloride, tetrahydrofuran or dioxane.

However, it has been found that the reaction of the compound of the formula III with the compounds of the formula II proceeds with even greater yield in a basic environment, i.e. in the environment in which the sulfide anions of the compound of the formula II are formed.

The formation of anions of the compound of formula (II) is preferably effected by treatment with an alkali metal alcoholate solution in a polar solvent at a temperature of -5 ° C to + 20 ° C and under an inert atmosphere, preferably under dry nitrogen. The best results were obtained with sodium methylate in methanolic solution. It has been found that the ring-opening aziridine derivatives of formula III are activated by a cyanomethylimino group and that the sulfide anion, the strongest nucleophile in solution, acts as a ring-opening aziridine as reactive.

The compounds of formulas II and III and their preparation were first described in Belgian patents 875 944 and 876 201.

The yields of the compound of the formula (I) are 70 to 90% when prepared in an acidic medium, and 94 to 98% when used in an alkaline medium, i.e. practically quantitative. In both embodiments the yields are higher than in the known methods mentioned above. Furthermore, the process according to the invention is considerably more economical since all known methods use cystamine hydrochloride (HS-CH2CH2-NH2HCl), which is a relatively expensive product.

According to experimental experience, the yields for the vertical part and for the right side of the above scheme are considerably lower than those of the left side and are not reported. These yields are not disclosed in the aforementioned patents.

On the other hand, the yield of the process according to the invention, calculated on 4 (S) -thiomethyl-5 (4) -methylimidazole, is up to about 94 to 98%, using very cheap ethanolamine or ethyleneimine instead of expensive cystamine hydrochloride.

The novel process for the preparation of the compounds of the formula I or Ia according to the invention is based on novel, hitherto undescribed and readily accessible compounds and is more economical than the hitherto known processes, since one synthesis step is saved, inexpensive and commercially available reactants are used and higher yields of the desired product.

The compounds of the invention of formula (I) are useful in medicine as agents for blocking the .alpha.-receptor, i.e., for the treatment of ulcers in the stomach and the gastricum.

In order to illustrate the invention, the following examples and conditions are given without limiting the invention.

Preparation:

4 (S) -Methyl-5 (4) -mercaptomethyl-imidazole hydrochloride.

A solution (4.5%) of KHS in absolute ethanol is prepared by introducing dry hydrogen sulfide into an alcoholic solution of ethyl acetate · potassium. This solution was added dropwise to a solution of 4 (S) -methyl-5 (4) -chloromethylimidazole hydrochloride (15 g, 0.09 mol) in absolute ethanol (140 mL) at 0-5 ° C with stirring. After stirring for 2 hours, a solution of hydrogen chloride in isopropanol was added to bring the pH to about 1.

The precipitated inorganic salts are filtered off, the filtrate is evaporated to dryness and the residue is dissolved in ethanol (300 ml) with heating. After addition of activated carbon, it is filtered, concentrated to dryness again, and the crude product crystallizes. Melting point: 283-285 ° C (14.5 g). After recrystallization from isopropanol (60 ml), 11.2 g of pure product is obtained. M.p .: 280-291 ° C.

IC (KBr): 2800 to 3200 (wide waist), 1640, 1530, 1480, 1440, 1095, 815 cm4

Example 1 a d 1

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

To 4 (S) -methyl 1-4 (S) -mercaptomethylimidazole hydrochloride (1.64 g, 10 mmol) in methanol at 0 ° C was added a solution of N &apos; -cyano-N-methyl-N &apos; -ethyleneguanidine (1) with stirring. (48 g, 12 mmol) in methanol (50 mL). After stirring for 6 hours, 10 ml of a solution of ammonia in methanol are added, the solvent is evaporated and the residue is crystallized from isopropanol. The title compound was obtained in 75 to 80% yield. Melting point; M.p. 141-143 ° C.

Example 2

N, N-Cyano-N-methyl-N - N - [(5-methyl-1H-imidazol-4-yl) methyl] thioethyl] guanidine

The procedure is as described in Example 1, but instead of methanol, dimethylsulfoxide is used as the solvent. The reaction is carried out for 2 hours at 20 ° C, then the solvent is evaporated to dryness in vacuo. The residue was recrystallized from isopropanol-acetonitrile to give the pure title compound. Yield 70-75%. M.p .: 141-143 ° C.

Example 3

N '-cyano-N‘-methyl-N- (2 - ((5-methyl-1H-imidazo-1-ylmethyl) thioethylfguamido)

Dissolve 4 (S) -methyl-5 (4) -mercaptomethylimidazole (6.5 g, 0.05 mol) in tetrahydrofuran (80 mL) and add a solution of N-cyano

N-ethyl-N‘-ethyleneguanidine (8.28 g, 0.96 mol) in tetrahydrofuran (40 mL). A solution of boron trifluoride diethyl etherate (0.05 mol) was then added dropwise at 10-15 ° C and the reaction mixture was stirred for 4 hours. It was worked up as described in Example 1. The yield of pure product was 80-85%. Melting point: 117-119 ° C.

Example 4

N'-Cyano-N‘-methyl-N-β - [(5-methyl-1H-imidazol-4-yl) methyl] thioethyl | guanidine

13.8 g (84 millimoles) of 4 (S) -thiomethyl-1-5 (4) methylimidazole hydrochloride are dissolved in 200 ml of absolute methanol and 3.17 ml of a 28.5% solution are added dropwise over 15 minutes at 0 ° C under nitrogen. sodium methylate in methanol. 9.93 g (80 millimoles) of N &apos; -cyano-N &apos; -methyl-N-ethylenguanidine dissolved in 100 ml of absolute methanol are then added dropwise while cooling. The reaction is carried out with stirring at room temperature for 10-12 hours and the conversion is monitored by thin layer chromatography (eluent: acetonitrile-ethyl acetate-methanol-concentrated ammonia 10: 2: 1).

At the end of the reaction, virtually only spots of the product are visible in the chromatogram, whereas spots of the starting compounds no longer appear. The precipitated inorganic precipitate is then filtered, the filtrate is evaporated to dryness and the residue is dissolved in hot propanol. The precipitated inorganic salt is filtered off once more and the product crystallizes under cooling to 0 ° C. 70-80% of pure N &apos; -cyano-N &apos; -methyl-N- [2- [5-methyl-1H-imidazol-4-yl) methylthioethyl] guanidine is obtained. Melting point: 141-143 [deg.] C., and subsequent concentration and crystallization of the mother liquor gives a total of 90-96% yield.

Example 5

N '-cyano-N‘-methyl-N- | 2 - [(5-methyl-1H-imidazol-4-yl) methyl] thioethyl) guanidine

The procedure is as in Example 4, but instead of methanol acetonitrile is used as the solvent and can also be mixed with water. The reaction is carried out for 10 hours at 20 ° C, then the solvent is evaporated to dryness in vacuo, and the residue is recrystallized from isopropanol-acetonitrile to give the pure title compound in a yield of 80 to 85%. M.p .: 141-143 ° C.

Example 6

N-Cyano-N-methyl-N-} 2 - [(5-methyl-1H-imidazol-4-yl) methyl] thioethylfguanidine

6.5 g (0.05 mol) of 4 (S) -methyl-5 (4) -mercapto-methyldiazole was suspended in tetrahydrofuran (80 ml) and a 28.5% solution of sodium methylate in methanol (2.5 ml) was added dropwise. ). A solution of N &apos; -cyano-N &apos; -ethyl-N-ethylenguanidine (8.28 g, 0.06 mol) in tetrahydrofuran (40 mol) was then added. The reaction is carried out at room temperature for 10 to 20 hours. The work-up is carried out as described in Example 1. A yield of pure product of 80 to 85% is obtained. Melting point: 117-119 ° C.

Example 7

The procedure is as described in Example 4, but the reaction mixture is worked up as follows:

The inorganic salt is filtered off, the filtrate is concentrated to a volume of 10-15 ml and the solution is applied to a silica gel column (360 g silica gel, Merck 80 to 325 mesh, eluent: acetonitrile-ethyl acetate-methanol-concentrated ammonia 10: 5: 2: 1 ). Column chromatography gave 94% pure N '-cyano-N‘-methyl-N- [2- [5-methyl-1H-imidazol-4-yl) methyl] thionyl] guanidine. Melting point: 141-143 ° C after recrystallization from isopropanol.

Claims (7)

OBJECT OF THE INVENTION A process for the preparation of the N '-cyano-N‘-alkyl-N- (2 - [(5-methyl-1H-imidazol-4-yl) methyl] thioethylguanidines of formulas I and Ia, N-tin II ch-ch-nh-c-nh-r (I) N-C = N II CH 2 -S-CH 2 CH 2 NH-C-NH-R ₅ (II) wherein R represents an alkyl radical having 1 or 2 carbon atoms, characterized in that the compound of formula (II) or (IIa) CH ^ SH _сн ъ AND H, as a free base or in the form of a salt, is reacted with a compound of formula III, N-C = N II-n-c-nh-r (III) wherein R is as previously defined. 2. Process according to claim 1, characterized in that the reaction is carried out in methanol, ethanol or dimethyl sulfoxide at a temperature between 0 and 80 degrees Celsius, preferably between 0 and 20 ° C. 3. A process according to claim 1, wherein the compound of formula II is used in the free base form and the reaction is carried out in an aprotic solvent with the addition of a Lewis acid, preferably boron trifluoride diethyl etherate, at a temperature between 0 and 20 ° C. 4. The process of claim 1, wherein the reaction is carried out in a polar solvent with the addition of an alkali metal alcoholate at a temperature between -5 and +20 [deg.] C. under an inert atmosphere. 5. A process according to claim 4, wherein the alcoholate is a solution of sodium methylate in methanol. 6. Process according to claim 4 or 5, characterized in that the reaction is carried out under dry nitrogen. Process according to one of Claims 1 to 6, characterized in that the compound of the formula (II) or (IIa) is used in the form of its salt with hydrohalic acid, preferably hydrochloric or hydrobromic.