GB2103206A - Process for preparing an imidazole derivative - Google Patents

Abstract

A process for the preparation of N-methyl-N'-2-[(5-methylimidazol-4-yl)methylthio]- ethyl-N''-cyanoguanidine, a histamine H-2 receptor antagonist, comprises reacting the compound of formula I or its monohydrate or hydrohalide with methylamine in solution at a temperature between 30 DEG C and the boiling point of the solution, in an aqueous medium and, if desired, the formed N-methyl-N'-2-[(5-methylimidazol-4-yl)methylthio]-ethyl-N''- cyanoguanidine is separated from the reaction mixture in a manner known in the art and dried by means of azeotropic distillation. <IMAGE>

Description

SPECIFICATION Process for preparing an imidazole derivative This invention relates to a process for the preparation of N-methyl-N'-t2-[(5-methylimidazol-4- yl)methylthio]-ethyil-N''-cyanoguanidine (cimetidine), a histamine H-2 receptor antagonist, by the reaction of a compound having formula i or its hydrate or its hydrohalogenide with methylamine and, if desired, separating the product from the reaction mixture.

Several processes are known for the preparation of N-methyl-N'-{2-[(5-methylimidazol-4-yl) methylthio]-ethyl)-N"-cyanoguanidine. From a practical point of view, those described in the Belgian patent Specification No. 804,144 are remarkable. These are as follows: a) the reaction with ethanolic methylamine of N-cyano-N'-(2-[(5-methylimidazol-4-yl)- methylthio]-ethyl}-S-methylisothiourea represented by formula I; b) the reaction of 4-(2-aminoethylthiomethyl)-5-methylimidazole with N-cyano-N',Sdimethylisothiourea in acetonitrile by boiling for a long time; c) the reaction of N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyli-thiourea with lead cyanamide in a mixture of dimethylformamide and acetonitrile.

According to the process b), the product is obtained with a yield of only 20% after purifying with column chromatography [J. Med. Chem.20,901/1977/1. The yield of the process c) (i.e. 40%) also falls below that required in the last step of a reaction sequence. Another disadvantage of process c) is the use of a lead reagent.

Although process a) seems to be problem-free concerning the yield, the carrying out of the reaction and working up of the reaction mixture is rather problematic. According to the Belgian Patent No. 804,144 [Example 1 (c) (ii)], the reaction takes place at room temperature with a large excess of methylamine in ethanol, the mixture is then evaporated and the residue recrystallized from a mixture of isopropanol and petroleum ether. The inconveniences of this method can be summarized as follows.

Methyl mercaptan, arising from the condensation reaction, does not pass out from the system in the course of the reaction carried out at room temperature and as a consequence, the simultaneous leaving of both methyl mercaptan and solvent vapour during evaporation occurs so violently that the collection of these gases cannot be achieved. N-methyl-N'-j2-[(5-methylimidazol-4-yl)-meThylthioj-ethyli-N11- cyanoguanidine, the reaction product, appears as an evaporation residue containing all contaminations and side products. These cannot be removed in the way described in the Example cited from the Belgian Patent No. 804,144; thus, the recrystallization does not result in a product of the required quality.

The object of this invention is to develop the reaction of the compound having the formula I with methylamine in such a way that methyl mercaptan is steadily formed under more simple conditions and the final product can be prepared in a purer form.

It was found that on reacting the compound of formula I or its monohydrate or hydrohalogenide with aqueous methylamine, a temperature range can be found at which methyl mercaptan is evolved at a uniform rate. Thus, the destruction by chemical methods (burning, oxidation by hypochlorite) of the side product can be achieved more simply than in the case when the mercaptan leaves abruptly. The evolution of methyl mercaptan is retarded by methylamine (because of a loose salt formation) at or even above room temperature, while on heating in ethanolic media the methylamine reactant also evaporates to a significant extent. in contrast, when an aqueous medium is used, methyl mercaptan can be eliminated at temperatures (at about 50--600C) far below the boiling point.Thus, methylamine can be used in a lower excess, i.e. more economically: 2-5 moles of it are sufficient for the rapid and complete transformation, as opposed to the 10 moles required according to the literature.

Thus, this invention relates to a new process for preparing N-methyl-N'-{2-[(5-methylimidazol-4yl)-methylthio]-ethyl}-N"-cyanoguanidine by reacting the compound of formula I or its monohydrate or its hydrohalogenide with methylamine in solution, which comprises carrying out the reaction between 300C and the boiling point of the solution, preferably at 40--600C, and most preferably at 50 to 55 C, in aqueous media and, if desired, separating the formed N-methyl-N'-{2-[(5-methylimidazol-4-yl) methylthio]-ethyl}-N"-cyanoguanidine from the reaction mixture in a manner known in the art and, optionally, drying it by means of azeotropic distillation in a butanol-water system.

The compound of formula I used as starting material of the process can be synthetized according to the Belgian Patent No. 804,144.

The monohydrate of the compound of formula I can be obtained in such a way that a mixture of 4-hydroxymethyl-5-methylimidazole hydrochloride (14.8 g, 0.1 mole) with cisteamine hydrochloride (11.3 g, 0.1 mole) is melted and stirred at 1 6O0C for 15 minutes. After cooling, the melt is dissolved in water (75 ml), sodium carbonate (10.6 g, 0.1 mole), then ethanol (50 ml) and methyl-Ncyanoimidodithiocarbonate) 14.6 g, 0.1 mole) are added. The mixture is refluxed for one hour, allowed to cool and stirred at room temperature for 5-7 hours.The precipitated product is filtered, washed with waterflnd dried at room temperature to yield 28 g (80%) of N-cyano-N'-{2-[(5-methylimidazol-4 yl)-methylthio]-ethyI -S-methylisothiourea monohydrate; m.p. 104-1 050 C.

The preparation of the hydrohalogenides of the compound of formula I is illustrated by the synthesis of the monohydrochloride. This is accomplished in the same way as in case of the monohydrate, except that half the amount (0.05 mole) of sodium carbonate is used. The yield is 22.05 g (74.5%) N-cyano-N'-{2-[( 5-methyl i midazol-4-yl)-methylthio]-ethyl }-S-methylisothiourea monohydrochloride; m.p. 220-2220C.

In an aqueous medium, the reaction is carried out in the presence of 2-5 molar equivalents of methylamine at 4O-600C for 2-6 hours. The preferred concentration of methylamine is 2-6 moles/litre in the reaction mixture. The lower limit is necessary to achieve the required reaction rate, while the upper limit is advised to compensate for the considerable losses of methylamine during the reaction. The precipitation of N-methyl-N'-j2-[( E-methylimidazol-4-yl)-methylthio]-ethyl }-N"cyanoguanidine starts in some cases without the formation of a homogeneous solution during the reaction. Thus, when a homogeneous solution is aimed at, it is suitable to heat the reaction mixture to a temperature permitting a complete dissolution during the final period of the reaction.This can be reached at 7090 C. It is undesirable to boil the solution for several reasons, e.g. in order to avoid the accumulation of contaminations, which can be detected by thin layer chromatography.

After ending the reaction, N-methyl-N'-12-[( 5-methyl midazol-4-yl)-methylthio]-ethyl i-N"cyanoguanidine is obtained from the solution, if desired, by crystallisation in a manner known in the art and S,S'-bis-[2-N-cyano-N'-methyl)-guanidinoethyl]-disulphide, represented by formula II

is removed by washing with water. Acid addition salts of the obtained N-methyl-N'-{2-[(5- methylimidazol-4-yI)-methylthio]-ethyli-N"-cyanoguanidine can be formed in a manner known in the art.

The advantages of the process carried out in an aqueous medium concern not only the safety and protection of the environment. Additional advantages are the decrease in the amount of methylamine used and the fact that the N-methyl-N'-(2-[(5-methylimidazol-4-yl)-methylthio]-ethyl i-N"- cyanoguanidine obtained is purer.

The compound of formula II above appears as a side product in the reaction. The preparation of this compound is described in the published German Patent Application No. 2,944,257 (though with an unsatisfactory purity). The contamination with disulphide of cisteamine hydrochloride, used for the precursor of the synthesis, is not necessary for the appearance of the compound of formula 11 as impurity.The formation of this substance can arise from bis-(2-aminoethyl)-disulphide (contaminating the cisteamine), methyl-N-cyanoimidodithiocarbonate and methylamine; however, according to our discovery, it can also arise from splitting the C-S bond in the side chain of N-methyl-N'-I2-[(5- methylimidazol-4-yl)-methylthio]-ethyl }-N"-cyanoguanidine. The interchange of various nucleophils in Mannich type compounds is well known. It was found that the compound of formula il, crystallizing together with the desired product from organic solvents, can be removed by crystallisation from water or, by carrying out the reaction in water and by washing out thoroughly the methylamine with water before drying.On the basis of our experiments, the amount of the compound having formula II considerably increases when the reaction is realized by boiling with the methylamine solution or when the drying is performed in the presence of methylamine. This can be proved by thin layer chromatography on Kieselgel 60F 254 adsorbent, by development with ethyl acetate-acetone-water 5:4:1 system and by evaluation with UV densitometry of the spot appearing with 0.45 Rf value.

Further details of the invention are given in the following non-limiting Examples.

Example 1 N-cyano-N'-(2-[(5-methylimidazol-4-yI)-methylthio]-ethyl )-S-methylisothiourea monohydrate (14.35 g, 0.05 mole) is suspended in distilled water (50 ml), stirred and heated. At a bath temperature of 500C, aqueous methylamine solution (18.5 ml containing 411 g/litre of methylamine, i.e. 0.245 mole equal to 4.9 equivalents) is added. The evolving gas is led to an equipment for destruction (annihilation). The reaction mixture is kept on a bath of 50--550C for 2.5 hours. Initially, the mixture becomes considerably thinner, then, in most cases, N-methyl-N'42-[(5-methylimidazol-4-yl)- methylthio]-ethylj-N"-cyanoguanidine begins to precipitate without a complete solution being formed.

The mixture becomes thicker and eventually the stirring is stopped. After 2.5 hours, the mixture is rapidly heated to 800C and stirred at this temperature for 30 minutes. The substance goes into solution. The heating bath is removed. The mixture is allowed to cool to 600C whereupon a voluminous precipitate appears. It is kept in a refrigerator overnight.

The precipitate, occluding the mother liquor, is evenly spread out onto a filter and filtered by suction. The mother liquor should be thoroughly removed. The washing can be performed with distilled water (3x20 ml) of a temperature of 0--50C. This is carried out in all cases as follows. The suction is stopped, the substance is stirred up on the filter, the washing liquid is applied, transformed to a uniform paste and filtered again by suction.

The effectivity of washing is examined on a small sample, taken from the precipitate, by means of thin layer chromatography method described above. When 300 micrograms of product are applied (with 100 micrograms of dry product), the intensity of the spot having 0.45 Rf value should not be above the intensity of 100 micrograms of a substance containing this impurity in an amount of 0.3%.

The weight of the filter-wet N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyll-N"- cyanoguanidine is 32.7 g. After drying to constant weight, the yield is 11.77 g (93.33%); m.p. 142- 1440C. This product contains 0.14% of impurity with 0.45 Rf.

Example 2 The method described in Example 1 is used up to the drying of the substance. The filter-wet product (35.8 g) is placed in a 100-ml round-bottom flask fitted with a stirrer, n-butanol (35 ml) is added, a uniform paste is formed by stirring and the solvent is distilled off under reduced pressure (4000 Pa, 30 Hgmm). The receiver is cooled by ice. The highest temperature of the heating bath is 600 C; the azeotropic mixture of butanol with water distills at 300C. The distillate separates to two layers. The recovered butanol amounts to 30 ml. The distillation residue, containing a small amount of butanol and less than 1% of water, is recrystallized from isopropanol (45 ml) to yield 10.21 g (80.96%) of N-methyl-N'-{2-[(5-methylim idazol-4-yl)-methylthio]-ethyl }-N"-cyanoguanidine; m.p. 141-1 C.

Example 3 N-Cyano-N'-{2-[( 5-methylimidazol-4-yI)-methylthio]-ethyl )-S-methylisothiou rea hydrochloride (3.05 g, 0.01 mole) is reacted with an aqueous methylamine solution (14 ml containing 8.43 moles/litre of methylamine) according to the method described in Example 1. After cooling, washing and drying 2.31 g (91.7%) of N-methyl-Nl-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N cyanoguanidine are obtained; m.p. 141-1430C.

Claims (7)

Claims

1. A process for the preparation of N-methyl-N'-j2-[(5-methylimidazol-4-yl)-methylthioj-ethyli- N"-cyanoguanidine by reacting the compound of formula I or its monohydrate or its hydrohalogenide with methylamine in solution, which comprises the steps of carrying out the reaction between 300C and the boiling point of the solution in an aqueous medium and, if desired, separating the formed N methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-Nn-cyanoguanidine from the reaction mixture in a manner known in the art and optionally drying it by means of azeotropic distillation.

2. A process as claimed in Claim 1, wherein the methylamine is used in an excess of 1 to 4 moles per mole of the compound of the general formula

3. A process as claimed in Claim 1 or 2, wherein the reaction temperature is from 40 to 600 C.

4. A process as claimed in Claim 3, wherein the reaction temperature is from 50 to 550C.

5. A process as claimed in any of Claims 1 to 4, wherein the reaction is carried out for from 2 to 6 hours.

6. A process as claimed in any one of Claims 1 to 5, substantially as hereinbefore described in any one of Examples 1 to 3.

7. N-methyl-N'-f2-[(5-methylimidazol-4-yl)-methylthio]-ethyli-N11-cyanoguanidine when made by a process as claimed in any one of Claims 1 to 6.