CS226930B1 - Method of preparing n-cyan-n(2-(5-methyl-4-imidazolylmethylthio)ethyl)-5-methylisothiourea - Google Patents

Description

The present invention relates to a process for the preparation of N-cyano-N - [2- (5-methyl-4-imidazolylmethylthio) ethyl] -S-methylisothiourea of the formula I

N-CN

XH ^ SCH ^ CH ^ NHC ^ ^X sc ^h 3 ^CH 3 (I)

The compound of the formula I according to the invention is an important intermediate in the production of pharmacologically active substances used, inter alia, in the therapy of gastric ulcers and the like (eg cimetidine).

According to prior literature, the compounds of formula (I) are obtained by reacting 4- (2-aminoethylthiomethyl) -5-methylimidazole of formula (II) with dimethyl cyaniminodithium carbonate of formula (III) in ethanol at room temperature with yields of 70-75% (GJ Duranjt et al. Med. Chem., 20, 901 (1977), T. Brown, G. Shaw, GJ Durant: J. Chem. Soc., Perkin Trans. I, 1980, 2310, with yields of 226930 higher (GJ) being reported in some patents. Durant et al., DOS 2 344 779, 1972; GJ Durant et al., DOS 2 344 833, 1972; GJ Durant et al., US Pat. 4,022,797, 1977; JJ Lewis, RL Webb: Belg. 853,954, 1977, et al.

The required aminoethyl derivative of formula (II) is generally obtained by boiling (18 h) of 4-hydroxymethyl-5-methylimidiazole with 2-aminoethanthiol (cysteamine) in acetic, hydrochloric or hydrobromic acid processes as described in the above literature.

The method for obtaining a compound of formula I, based on the reaction sequence, has the following disadvantages:

1. As one of the reaction components, it uses expensive and unstable cysteamine, which is obtained by the inconvenient reaction of expensive, very toxic and explosive ethylenimine, with hydrogen sulfide in a yield of about 70% (e.g. WO Poye, RN Duvall, J. MiCkles: J. Pharm. Sci. 51, 168 (1962)].

2. The condensation of cysteamine with 4-hydroxymethyl-5-mephthylimidazole requires the long-term heating of both of these reaction components in an aggressive environment of acetic, hydrochloric or hydrobromic acid to 100-120 ° C.

3. The aminoethyl derivative of the formula II obtained is isolated in yields of 70 to 90% in the form of its dihydrochloride or dihydrobromo 226930 du. However, since the aminoethyl derivative II must be used as base in the reaction with dimethyl cyaniminodithium carbonate, it must first be liberated from its salts by aqueous solutions of alkali hydroxides or carbonates. Because of the high solubility of the aminoethyl derivative II in water, the reaction mixture must then be completely evaporated to dryness and the aminoethyl derivative base separated from the inorganic salts by repeated extraction with organic solvents and the extracts recovered, with yields of amine base II not exceeding 90%.

4. The crude compound of formula (I) obtained is finally to be purified by crystallization, for example from 2-propanol and ether.

A procedure based on the condensation of the bases of 4-mercaptomethyl-5-methylimidazole IV and 2-halo-ethylamines has been described for the preparation of aminoeithyl derivative II without cysteamine (B. Jenko, I. Langof: AO CS 214 047, 1981). Both components are reacted in an ethanol medium with the addition of sodium hydroxide and the presence of quaternary ammonium or phosphonium salts at a slightly elevated temperature. The mixture is finally evaporated, the ammonium ethyl derivative II base is separated from the inorganic salts and catalyst by alcohol extraction, the extracts are neutralized with hydrogen chloride gas and evaporated to give the base II dihydrochloride in a yield of about 90%.

The disadvantage of this procedure is that

a] bases of both components IV and V are used in the reaction; the 2-chloroethylamine base is known to be highly unstable even when the room is standing still and to polymerise readily by self-condensation (G. D. Jones et al., J. Org. Chem. 9, 125, 1944); the thiol IV base is readily oxidized to the disulfide;

bj to carry out the reaction, said phase shift catalysts must be added.

It has now been found that by modifying the reaction conditions in the process (Jenko, Langdf), the reaction can be carried out using either the stable salts (hydrochloride or hydrobromide) of thiol IV and 2-halenethylamine, and the quaternary ammonium or phosphonium salts need not be added. In order to prepare the compound of formula (I), it is not necessary to isolate the amide ethyl derivative (II) in the form of the hydrochloride, but then to amine the base of the amine (II) directly to the desired compound (I) according to the scheme:

XCH 2 Cu / M / ¹ * * ³ N&OH

He knows: x = 0r

The necessary reaction components are prepared according to methods described in the literature. Thus, by reaction of cyanamide, carbon disulphide and potassium hydroxide solution, the dipotassium salt of cyaniminodithium carbonate obtained is converted with methyl iodide into dimethyl ester III (A. Hautsch, M. Wolwekamp: Ann. Chem. 331, 281, 1904; T. Heitke, CG McCarthy: J. Org. Chem., 39, 1522 (1974).

2-Chloro-thylamine hydrochloride V is obtained from ethanolamine after conversion to the hydrochloride by treatment with thionyl chloride (GW Raizis, LW Clemence: J. Am. Chem. Soc. 63, 3126, 1941; GI Braz: Journal of Chim. 25, 763); 1955, K. Ward, Jr., J. Am. Chem., Soc., 57, 915, 1935; PD Jones, Inc., J. Org. Chem., 9, 125, 1944).

2-Bromo-thylamine hydrobromide VI can be prepared by treating ethanolamine with 46-48% hydrobromic acid (F. Cortese et al., Org. Synth., Coll. Vol. 2, 91, 1946). The required 4-mercaptomethyl-5-methylimidazole IV is obtained, for example, by reacting 4-chloromethyl-5-methylimidazole with an alkaline hydrosulfide solution (NaHS, KHS) and isolated as its stable hydrochloride (R. Toso et al .: Gazz. Chim. 109: 529 (1979).

The principle of the novel process for the preparation of the compound of formula I is that a suspension of thiol hydrochloride IV in lower alcohols (1 to 3 carbon atoms) is mixed with a concentrated aqueous or alcoholic alkali hydroxide solution or with an alkoxide solution in alcohol under a nitrogen atmosphere. the hydrochloride first liberates the base of the thiol IV and this is passed under the influence of ab

III Id ιιΙΗ

6 Kali per thiolate. The 2-halo-ethylamine salt V or VI is then added at room temperature, reacted first at room temperature and then at elevated temperature (50-60 ° C) and after cooling the precipitated inorganic fraction is filtered off with suction. It is added dropwise to the alcoholic solution of ester III directly or after evaporation at room temperature and the reaction is completed by standing overnight After partial evaporation the resulting suspension is diluted with water and the substance I is suctioned off. yielding up to 91 why the compound of formula I. If 1-propanol is used as the reaction medium, the compound I in the form of the β-1 solvate is eliminated by the 1-propanol molecule; does not arise.

The compound of formula (I) according to the invention is accessible by the synthetic procedures depicted in the reaction scheme, which are described in more detail in the examples. These examples describe some possibilities of carrying out the preparation of the compound of formula I and do not limit the invention in any way.

Example 1

To a suspension of 8.4 g of 4-mercaptomethyl-5-methylimidazole hydrochloride in 70 ml of ethanol is added under a nitrogen atmosphere 11 ml of 50% aqueous sodium hydroxide solution, cooled to 25 ° C and stirred for 10 min. Then 5.8 g of 2-chloroethylamine hydrochloride are added, stirred for 30 minutes, heated to 50-55 ° C over 25 minutes and stirred at this temperature for 40 minutes. The nitrogen stream is interrupted, the suspension is cooled to below 30 ° C, the precipitated sodium chloride is filtered off with suction and the filtrates are evaporated to a volume of about 50 ml. This solution was added dropwise to a solution of 7.3 grams of cyaniminodithium carbonate dimethyl ester in 50 ml of ethanol over 30 minutes, stirred for 2 hours and allowed to stand overnight. It is evaporated to a volume of about 30 ml, poured into 160 ml of cold water, stirred for 1 hour while cooling with water and ice, the product is filtered off with suction, washed with water and dried. 9.3 g / l of product are obtained, and by evaporation of the mother liquors a further 0.70 g is obtained, a total of 10.0 g (74%) of substance I melting at 145-147 ° C.

For C ₁₀ H ₁₅ N ₅ S ₂ (269.38) calculated:

% C, 44.58;% H, 5.61;% N, 26.00%; Π & ΙβΖΘΠΟ ’

C, 44.79; H, 5.64; N, 25.81; S, 23.78

The procedure was as described in Example 1 except that ethanol was replaced with methanol. 10.5 g (78%) of crude product are obtained, which, after crystallization from 2-propanol, has a melting point of 145-147 ° C; yield 9.0 g (67%).

Example 3

The procedure was as in Example 1 except that ethanol was replaced with 1-propanol; After completion of the reaction, the resulting suspension is concentrated in vacuo to a weight of 30-35 g and 150 ml of cold water are added dropwise with stirring. After stirring for 1 h under cooling with water and ice, it is filtered off with suction, washed with water and dried. 11.5 g of a solvate of compound I with 1 molecule of 1-propanol are obtained.

For C ₁₃ H ₂₃ N ₅ S ₂ O (329.47} calculated:

C 47.39, H 7.04, N 21.26, S 19.46; found:

H, 7.11; N, 20.98; S, 19.20.

The substance first melts in the range of 60-70 ° C, then crystallizes and finally melts at 145-147 ° C. The obtained 11.5 g solvate corresponds

9.40 g of compound I and thus a yield of 70%. He attaches

16.6 g of 4-mercaptomethyl-5-methylimide / hydrochloride hydrochloride are stirred in 140 ml of 2-propanol, 22 ml of 50% aqueous sodium hydroxide solution are added under nitrogen, cooled to 25 DEG C. and stirred for 10 minutes. Then 11.6 g of 2-chloroethylamine hydrochloride are added, stirred for 30 min at room temperature and 40 min at 50-60 ° C, cooled below 30 ° C, the precipitated sodium chloride is filtered off with suction, washed with 2-propanol and The filtrates are evaporated to a weight of 60 to 70 g. This solution is added dropwise to a solution of 14.6 grams of cyaniminodithithiocarbonic acid dimethyl ester in 100 ml of 2-propanol over 50 minutes, rinsed with 15 ml of 2-propanol and stirred for 3 hours at room temperature. then stand overnight, with the substance excreted. The suspension is evaporated to a volume of 70 to 80 ml, after cooling 300 ml of water are added dropwise thereto, and it is then stirred for 1 hour while cooling with water and ice. The material is filtered off with suction, washed with water and dried. 12.3 g (91.3%) of pure material are obtained. mp 144-146 ° C. The substance does not form a solvate with 2-propanol.

Example 5

The procedure was as in Example 4 except that the solution obtained by dissolving 28.8 g of 80% potassium hydroxide in 25 ml of water was used instead of sodium hydroxide for alkalization.

Example 6

The procedure is as described in Example 4 except that a solution of 7.8 g of sodium in 2-propanol is used as the alkalizing agent.

Example 7

16.5 g of 4-mercaptomethyl-5-methyl-imidazole hydrochloride are stirred in 150 ml of 2-propanol, 22 ml of 50% aqueous sodium hydroxide solution are added dropwise under cooling under nitrogen and stirred for 12 minutes at 25 degrees Celsius. 20.5 g of 2-bromoethylamine hydrobromide are then added, first stirred for 40 min at room temperature, heated to 50-55 ° C over 30 min and stirred at this temperature for a further 40 min, and finally the suspension is cooled below 30 ° C. The precipitated sodium bromide was filtered off with suction and washed with 2-propanol / ether (3: 7). The combined filtrates are evaporated to a small volume, the second portion of precipitated sodium bromide is filtered off with suction, washed with the same mixture, and the combined filtrates are evaporated to a weight of 60 to 70 g. This solution is added dropwise over 40 min to a solution of 15.4 g of cyaniminodithium carbonate. Of 2-propanol, stirred at room temperature for 3 h and allowed to stand overnight, whereupon compound I precipitates. The suspension is evaporated to a volume of 70-90 ml, 300 ml of cold water are added dropwise, stirred for 1 hour under cooling with water and ice, the product is filtered off with suction, washed with water and dried. Yield 24.4 g (90.5%) of pure substance of m.p. 145-147 ° C.

Claims (1)

Process for preparing N-cyano-N - [2- (5-methyl-4-imidazolylmethylthio) ethyl] -S-methylisothiourea of formula I NN ~ CN ^ H SCH? CH ^ NH ^ \ CH _of m. by reacting 4-mercaptomethyl-5-methylimidazole with 2-halo-ethylamines where halogen is chlorine or bromine, followed by reacting the resulting 4- (2-aminoethylthiomethyl) -5-methylimidazole with dimethyl cyaniminodithium carbonate, characterized in that both starting materials are used in the in the form of salts, preferably hydrochlorides or hydrobromides, the bases are only liberated therefrom in the reaction itself by treatment with aqueous or alcoholic solutions of alkali hydroxides or alcoholic solutions of alkoxides, the alcohols being lower alcohols having 1 to 3 carbon atoms and as alkoxides preferably sodium alkoxide; from 1 to 3 carbon atoms, the inorganic salts are filtered off, the solvents are evaporated, and the residue is reacted directly with a solution of dimethyl cyaniminodithium carbonate in a lower alcohol, preferably 1-propanol or 2-propanol, at room temperature.