SU950188A3 - Process for producing derivatives of 4(5)-mercaptomethylimidazoles - 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

This invention relates to a novel process for the preparation of 4 (5) -mercaptomethyl or imidazole derivatives.

 -S-рСНз-к а у

 IIftfm-l. -V -k.- .rnvvW 1.

CHj $ CH2 CH2T HC "HR J i -jTdHjSCiigCHjUHCNira ,,. 1.-vD-CH3 where R is an alkyl residue with 1 to 3 carbon atoms in the chain, which are valuable biologically active compounds and are used to treat stomach and duodenal ulcers. Methods are known for preparing compounds of General Formula I or I and by three methods according to the scheme ijf 2J, 3 and UJ. The purpose of the invention is to increase the yield of the target product and simplify the process. The goal is achieved by the method of obtaining compounds of total

Formula I or 1a, comprising the compound of formula

f -СНз Т-СП2 & 11

1 | II or I I

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andI

n

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Pa or its salt is reacted with a compound of the formula C 3: pir-C-irH-R (where R is as defined above, to isolate the desired product. The reaction is carried out preferably in methanol, ethanol or dimethyl sulfoxide at -5 - 80 ° C. If the free base of compound II is used, the process is preferably carried out in an aprotic solvent with the addition of a Lewis acid, such as boron trifluoride ethyl ether, at 0-20 sec. The formation of anions of compound II is best effected by the action of an alkali methane alcohol solution. The best results are obtained when using sodium methoxide at -5-20 ° C in an inert atmosphere. The yield of the proposed method calculated for 4 (5) -thiomethyl-5 (4) -methylimidazole is almost quantitative, and very cheap ethanolamine is used instead of expensive cysteamine hydrochloride or ethyleneimine. Thus, in the proposed method, cheap and readily available reagents are used and the desired product is obtained in higher yields. The compounds of the formula I are used in medicine as a means for blocking the H receptors, i.e. for the treatment of gastric and duodenal ulcers. In the examples, the conditions and methods of carrying out the method are shown to illustrate the invention, but without any limitation thereof. Preparation of 4 (5) -methyl-5 (4) -mer captomethylimidazole hydrochloride. A 4.5% solution of KHS in absolute ethanol is prepared by passing dry hydrogen sulfide through (an alcoholic solution of potassium ethylate. This solution is added dropwise to a solution of 4 (5) -methyl-5 (4) -chloromethylimidazol hydrochloride (15 g , 0.09 mol) in absolute ethanol (140 ml) at 0-5 ° C with stirring. Then it is stirred for another 2 h, then a solution of hydrogen chloride in isopropanol is added until the pH reaches approximately 1. The isolated inorganic salts are filtered , the filtrate is evaporated to dryness, and the residue is dissolved in ethanol (30 0 ml) with heating. After the addition of activated carbon, it is filtered, evaporated again to dryness, and the crude product is crystallized, mp 283-285 ° C (14.5 g). After recrystallization from isopropanol (60 ml), 11.2 are obtained. g of pure product. So pl.290291 C, IR (KVg): 2800 to 3200 (wide), 1640, 1530, 1480, 1440, 1095, 815 cm-H, example 1. N-cyano-N-methyl- N-2- (5-methylimidazolyl-4-methylmercapto) -ethylJ-guanidine K 4 (5) -methyl-4- (5) -mercaptomethylimidazole hydrochloride (C) OXLopropyl (1.64 g, 10 mmol in methanol;); -cyano-N-methyl-N-ethylenediamine (1.48 g, 12 mmol) in methanol (50 ml with stirring nii. After six hours of stirring, 10 MP of methanolic ammonia solution is added and the solution is evaporated and the residue is crystallized from isopropanol. The yield of 75-80% So pl.141-143s. ,, Example 2. H-cyano-N-methyl-N - {. 2- (5-methylimidazolyl-4-methylmer capto) -ethyl-guanidine. . The method is carried out analogously to example 1, but dimethyl sulfoxide instead of methanol is used as a solvent. The reaction is carried out for 2 hours at which time the solvent is evaporated to dryness in vacuo. The residue is recrystallized from isopropanol acetonitrile. The product yield 70-75%. M.p. 141-143c. PRI me R 3. N-iano-N-ethyl-N-2- (5-methylimidazolyl-4-methylmercapto) ethyl-guanidine. 4 (5) -Methyl-5 (4) -mercaptomethylimidanol (6.5 g; 0.05 mol) was dissolved in tetrahydrofuran (80 ml) and a solution of n-cyano-M-ethyl-M-ethyleneguanidine- ( 8, 28 g, 0.06 mol) in tetrahydrofuran (40 ml). A solution of diethyl ether of boron trifluoride (0.05 mol) is then added dropwise at 10-15 ° C and the reaction mixture is stirred for 4 hours. The treatment is carried out according to Example 1. Yield 80-85%. Mp.117-119 C, Example 4. N-cyano-N-methyl-N- 2- (5 Methylimidazolyl-4-methyl mercaptoethyl-guanidine. 13.8 g (84 mmol) 4 (5) -thiomethyl) are dissolved -5- (4) -methyl-imidazole hydrochloride in 200 ml of absolute methanol and 3.17 ml of a 28.5% solution of sodium methylate in methanol are added dropwise in a nitrogen atmosphere at 15 minutes, then added dropwise. still with cooling, 9.93 g (80 mmol.) and -cyano-N -methyl-L-ethyleneguanidine dissolved in 100 ml of absolute methanol. The reaction is carried out with stirring for 1012 hours at room temperature and using a thin The reaction was monitored by oi chromatography (mixture of eluents: acetonitrile / ethyl acetate / methanol / concentrated ammonia 10: 5: 2: 1). spots of starting compounds. After that, the precipitated inorganic precipitate is filtered, the filtrate is evaporated to dryness, and the residue is dissolved in hot propanol. -methyl-N- 2- (5-methylimide zolyl-4-methylmercaptoethyl) -guanidine with m.p. 141-143 ° C, and subsequent concentration and crystallization of the mother liquor, this product is obtained in a total yield of 90-96%. Example 5. N-cyano-N-methyl-N-2- (5-methylimidazolyl-4) -methyl mercaptoethyl-guanidine. The process is carried out analogously to example 4, but acetonitrile is used as a solvent instead of methanol, which can also be mixed.

Claims (1)

Claim 1. The method of obtaining derivatives of 4 (5) -mercaptomethylimidazoles of the general formula I K — I — CHj ίί-CaN II ’II. BH> -CH ₂ $ ss ₂ ch ₂ brcnhr t Η where R is an alkyl residue with 1–3 aTo ^J carbon atoms in the chain, characterized by the fact that, or laК-С = К 'II. sn ₂ $ СН ₂ СМ ₂ »НС KHR sn ₃ I and with the aim of increasing the yield of the target product and simplifying the distillation of formula I I of the process CH ₂ 6I I and OR, the e-salt is subjected to the interaction of the formula III £> -C-NH-R or di80 ^d C. from the case where r has the indicated meanings, with the isolation of the target product. · 2. The method according to claim 1, o t and h a ^J y with the fact that the process is carried out in methanol, ethanol, methyl sulphoxide at -5 3. The method according to claims 1 and 2, characterized in that when compound II is used in the form of a free base, the process carried out in an aprotic solvent with the addition of a Lewis acid such as boron trifluoroidethylether at 0-20 ° C. The method of Pop. 1, distinguished by the fact that the process is carried out with a polar solvent of up to 4. u and th are added. alkali metal alcoholate, mainly sodium methylate, at a temperature of -5 - 20 ° С in an inert atmosphere .. Priority on points: 12.30.77 according to claims 1-3, 10.16.78 according to claim 4.