CS233426B1 - Preparation method of n-kyan-n-methyl-n-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)-guanidine - Google Patents

Abstract

The invention relates to a process for the preparation of N-cyano- -N * -methyl-N '[2- (5-methyl-4-imidazolylmethylthlo) ethyl] guanidine of Formula I as important drug in gastric therapy ulcers. This substance can be prepared continuously the sequence of the reaction by first condensation salts of 4-mercaptomethyl-5-methylimidazole and 2-halomethylamines in the presence of alkali a solution of the base of 4- (2-aminoethylthiomethyl) -5-methylimidazole obtained by inorganic filtration salts, the filtrate was evaporated and recovered the solution is reacted with an alcoholic ■ cyanimino-dimethyl dimethyl ester solution Dithiocarbonate and the resulting suspension N-cyano-N-2- (5-methyl-4-imidolylmethyl-4) thio) ethyl] -S-isothiourea acts directly methylamine solution, the solution was evaporated and the crude product is crystallized from water, acetonitrile or another suitable solvent, Thus, the compound of formula I is obtained in a yield 65 to 90 ».

Description

The invention relates to a process for preparing N-cyano-N'-methyl-N '* - £ 2- (5-methyl-4-imidazolylmethylthio) ethyl] guanidine of formula I «-r ^CH

H ^X CH, CH ₂ CH ₂ CH ₂ nH-q s N-CN

NHCH->

The compound of formula I according to the invention is an important drug in the treatment of gastric ulcers.

According to literature, X is obtained, inter alia, by reacting N-cyano-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl] -S-methylisothiourea II with a methylamine solution at room temperature (0 J). Durant et al., J. Med Chem 20, 901, 1977;

O. J. Durant et al., DOS 2,344,779, 1972; DOS 2,344,833, 1972; US Pat. 4,022,797, 1977;

J.J. Lewls, R.L. Webb: Belg. U.S. Pat. 853,954,977; JM Grande: Sleep. U.S. Pat. 476,073, 979 e) with yields of 80 to 90%.

The isothiourea derivative of formula (II) is generally prepared by reacting 5-methyl-4- (2-aminoethylthiomethyl) imidazole of formula (III) with dimethyl cyanilminodithiourea (IV) at room temperature in yields of 70 to 75% (GJ Durant et al .: J. Med. Chem., 22, 901 (1977), T. Brown, G. Shaw, GJ Durant, J. Chem. Soc., Perkin Trans., 1980.

310, et al., And in some patents, yields and higher are reported (G. J. Durant et al., DOS 2 344 779, 972; DOS 2 344 833, 1972; U.S. Pat. No. 4,022,797, 1977; J. J. Lewis,

R. L. Webb: Belg. U.S. Pat. 853,954 (1977, et al.).

The required amino derivative of the formula IH is generally obtained by boiling (for 18 hours) of 4-hydroxymethyl-5-methylimidazole with 2-aminoethanthiol (cysteamine) in acetic acid and hydrochloric or hydrobromic processes as described in the literature.

Methods for obtaining a compound of formula I by the reaction sequence have the following disadvantages:

1. As one of the reaction components, they use unstable cysteamine, which is obtained by the inconvenient reaction of expensive, toxic and explosive athylenimine with hydrogen sulfide in yields of about 70% (P0, RN Duvell, J. Mickles, J, Pharm. Sci. 51). , 168, 1962, et al.).

2. Condensation of cysteamine with 4-hydroxymethyl-5-methylimidazole to amine III requires long-term heating in a highly aggressive environment to temperatures of 00 to 120 ° C.

3. The amine III is finally isolated as the hydrochloride or other salts in a yield of 70-90%; for its further reaction with ester IV, the amine must first be liberated by the addition of aqueous solutions of alkali carbonates or hydroxides. Due to the high solubility of the amine III in water, it is necessary to evaporate the mixture completely to dryness and to separate the amine base from the inorganic fractions by uncomfortable repeated extraction with organic solvents and to re-evaporate these extracts, which also results in considerable losses.

4. After the condensation of the amine IH with the ester IV has been carried out, the tsothiourea derivative II is finally isolated and then subjected to the final reaction with methylamine resulting in a compound of formula I.

A procedure for the preparation of an amine HI without the need for cysteamine and based on the condensation of the bases of 4-mercaptomethyl-5-methylimidazole V and 2-helogenethylamines VI (B. Jenko, I. Langof:

AO CS 214 047, 1981) appears to be more advantageous for obtaining the amine IH. The bases V and VI are condensed in an ethanolic or aqueous ethanolic medium in the presence of sodium hydroxide solution and addition of quaternary ammonium or phosphonium salts, the mixture is evaporated, the inorganic salts are separated by alcohol extraction and evaporation of the filtrates, neutralized with gaseous hydrogen chloride. yield of about 90%.

This procedure in Sek has the following disadvantages:

1. Both bases V and VI must be used in the reaction; their release from salts is again very uncomfortable due to the high solubility of both bases in water and is therefore associated with losses. In addition, the 2-chloroethylamine base is known to be highly volatile even at room temperature and to polymerise rapidly due to self-condensation, which may be associated with fexposition (GD Jonee et al., J. Org. Chem. G. 125, 1944) ); the base of the thiol V, on the other hand, is rapidly oxidized by air with oxygen to form a disulfide. These properties of the two substances, in particular when operating on a larger scale, in which the individual operation times are necessarily longer, lead to considerable losses and thus to a decrease in yields;

2. the procedure prescribes the use of an addition of phase transfer catalysts which cannot be practically regenerated, thus increasing costs;

3. The amine III is finally isolated in the form of the dihydrochloride, which is disadvantageous for the next step of the synthesis of the compound of formula I due to the need to use the amine III for the reaction with the ester IV in base form.

It has now been found that the compound of formula (I) can be obtained from the thiol V in good yield by a continuous sequence of reactions according to the scheme below, eliminating all the above-mentioned disadvantages; By eliminating the significant losses resulting from the release of water-soluble bases from their salts, the whole process is greatly accelerated, simplified, reduced in energy consumption and greatly increased in the final yield of the compound of Formula I. The advantages of the present process can be formulated as follows:

1. Since it is not based on cysteamine, there is no need to work with ethyleneimine and further condensate cysteamine and 4-hydroxymethyl-5-methylimidazole in an aggressive acid environment to amine III;

2. In the reaction of the thiol V with the halo-ethylamine VI, these components need not be used in the form of bases but of their salts, thereby eliminating the operations associated with the isolation of the bases of these substances. Further condensation of the two components is carried out without the addition of phase shift catalysts;

3. the amine III is not isolated as a salt after the reaction, but is used directly as a concentrated alcoholic solution of its base for condensation with ester IV;

4. The isothinurea derivative II obtained in accordance with point 3 is not recovered but reacted directly in suspension with an aqueous or alcoholic methylamine solution;

5. the yields of the compound of formula I thus obtained are between 65 and 90% calculated on the starting thiol V; as it is a sequence of three reaction stages, the average yield of one reaction stage is between 87 and 97% ·

Thus, the synthesis of the fly of formula I proceeds according to the scheme:

. HX + XCH ₂ CH ₂ NH ₂ . HX + 3 NaOH

X · Cl or Br

Via: X> Cl VlbiX = Br

- *

CH3SCH3CH3NHj + nc-n-c (sch ₃ ) ₂ (IV, dli) (not isolated)

-b ¹ *

(II) (not isolated)

The necessary starting materials IV, V, VIa or VIb are prepared according to methods described in the literature. 4-Mercaptomethyl-5-methylimidezole hydrochloride V (X = Cl) can be obtained, for example, by reacting 4-chloromethyl-5-methylimidezole with alkaline hydrogen sulphide, hydromide of the same flight in V (X = Br), and reacting 4-hydroxyraethyl-5-methylimidazole with a solution. hydrogen bromide in acetic acid (R. Toso et al. (Jazz. chim. ital. 109, 529, 1979, etc.). - 2-Chloroethylamine hydrochloride Via is prepared from ethanolamine after conversion to the hydrochloride and reaction with thionyl chloride (K). Ward, Jr .: J. Am Chem Soc., 57, 915, 1935, GW Ralzis, LW Clemence:

J. Am. Chem. Soc. 65, 3112, 1941; P. D. Jones et al., J. Org. Chem., 2, 125, 944;

G. I. Braz: Journal. village. chim. 25, 763 (1955); 2-Bromoethylemine hydrobromide VIb can be prepared directly by reacting ethanolamine with 48% hydrobromic acid (P. Cortese et al.):

Org. Synth., Coll. Vol. (91, 946). The synthesis of dimethyl cyanimododecarbonate IV is characterized by the reaction of cyanamide, carbonate and potassium hydroxide to prepare the dipotassium salt of said acid, which after isolation is converted to methyl ester IV by treatment with methyl iodide (A. Hantsoh, M. Wolwekamp: Ann. Chem. 331). 281, 1904, T. T. Heltke, CG McCarthy:

J. Org. Chem. 39, 522 (1974)), or said dipotassium salt is not isolated and is converted in solution directly with the dimethyl ester, not the desired ester (fis AO 226 930).

The principle of the novel process for the preparation of formula I consists in mixing a suspension of the thiol salt V in low-alcohol alcohols with an aqueous or alcoholic alkali hydroxide solution or an alcoholic alkoxide solution under a nitrogen atmosphere, thereby first liberating the thiol V base and passing it in excess alkali to alkali thiolate. At room temperature, 2-halo-ethylamine salt VIa or VIb is added and allowed to react first from room temperature and then at a slightly elevated temperature (40-60 ° C). The precipitated inorganic salt is filtered off, the filtrate is concentrated and added dropwise to an alcoholic solution of ester IV at room temperature and the reaction is allowed to complete by standing overnight, whereupon the orthothiourea derivative II is formed. An aqueous or alcoholic methylamine solution is then added dropwise either directly or after concentration to the suspension obtained at room temperature; The precipitated II is gradually introduced into the solution and the reaction is again completed by standing the reaction mixture for 24 to 48 h. The filtered solution is finally evaporated to dryness and the residue is crystallized from water, acettaitrile or another suitable solvent. According to the embodiment, the solvent and the quantity used and the concentration of the methylamine solution in the last reaction step, the yield of formula I is obtained in a yield of 65 to 90%.

The advantage of this process is, inter alia, that thiol hydrochloride can be processed

Vis content over 50%.

Accordingly, according to the present invention, the compound of formula I is obtained by the processes depicted in said reaction scheme; the foregoing examples illustrate some of the possibilities of preparation and embodiments of the invention and are not intended to limit the invention in any way.

He did

To a suspension of 11.6 g of 71% of 4-methylmercapto-5-methylimidazole in 80 ml of anhydrous ethanol under nitrogen was added dropwise 11 ml of 50% aqueous sodium hydroxide solution, cooled to 23 ^N C and stirred 15 min. Then 5.8 g of 2-chloroethylamine hydrochloride Via are added, stirred for 40 min, then heated to 50 ° C for 40 min, cooled to below 30 ° C, the precipitated sodium chloride is filtered off and the filtrate is evaporated in vacuo to a mass of 35-45. g. The resulting solution was added dropwise over 25 min to a stirred solution of 7.3 g of dimethyl ester IV in 50 ml of ethanol, stirred for a further 4 h and allowed to stand overnight. Thereafter, 11 g of methylamine as a 30-40% ethanol solution are added dropwise to the suspension over a period of 40 minutes and stirred for a further 5 hours; the solution is filtered, evaporated and the residue is dissolved in 30 to 40 ml of water and the solution is left to crystallize in a refrigerator for 24 hours. The precipitated product is filtered off with suction, washed with water and ether and dried. Yield 9.4 g (74.6%) of the compound of formula I melting between. in the range of 65 to 75 ° C and then melts at 139 to 141 ° C.

Example 2

To a suspension of 10.3 g of 80% hydrochloride V in 70 ml of 2-propanol was added dropwise under a nitrogen atmosphere, 11 ml of 50% sodium hydroxide solution, the mixture was cooled to below 25 ° C, stirred for 10 min. Stir for 30 min at room temperature and then for 45 min at 52 ° C, cool, filter out sodium chloride and evaporate the filtrates to a weight of 35 to 45 g. This solution is added dropwise to a stirred solution of 7.3 g of ester IV in 35 min. 50 ml of 2-propanol is then stirred for 4 hours and allowed to stand overnight. To the suspension was added dropwise 15.3 g of methylamine as a 40% aqueous solution over 15 min, stirred for 7 h and allowed to stand overnight. The filtered solution was evaporated to dryness and the residue was crystallized from acetonitrile. Yield: 8.3 g (65.8%) of the formula (I), m.p. 140-142 ° C.

Example 3

To a suspension of 113.6 g of 88% thiol hydrochloride V in 500 ml of 2-propanol is added dropwise 1 <20 ml of 50% sodium hydroxide solution over 20 minutes under nitrogen, cooled to 2.0 ° C, stirred for 10 minutes and added 71 0 g of Via hydrochloride. The reaction mixture is stirred for 30 min at room temperature and 50 min at 53 ° C, cooled, the precipitated sodium chloride is filtered off with suction, the filtrates are evaporated to a weight of about 200 g and added dropwise over 35 min to a stirred solution of 88.2 g of ester IV in 300 ml. Of 2-propanol. The suspension was stirred for 4 h and allowed to stand over noo. The next day 96.3 g of methylamine as a 30-35% solution in 2-propanol are added dropwise over 60 minutes, stirred for a further 8 hours and then left to stand overnight. The solution is filtered, the filtrates are evaporated to dryness, the residue is dissolved in 1500 ml of boiling acetonitrile, filtered while hot. and crystallize in the fridge for 4 days. The product is filtered off with suction, washed with 100 ml of acetone and dried. Yield 136.2 g (89%) of the compound of formula lot. mp 137-140 ° C.

Example 4

To a suspension of 10.0 g of 82% thiol hydrochloride V in 70 ml of 2-propanol was added dropwise 11 ml of 50% sodium hydroxide solution over 15 minutes under a nitrogen atmosphere, cooled below 25 ° C and stirred for 10 minutes. Then 10.25 g of 2-bromoethylamine hydrobromide VIb is added and stirred first at room temperature for 40 min and then at 50 ° C for 35 min and cooled below 20 ° C. The inorganic salt is filtered off with suction, the filtrates are evaporated, filtered from subsequently precipitated sodium bromide and evaporated to a mass of 30 to 35 g. This solution is then added dropwise to a solution of 7.3 g of ester IV in 50 ml of 2-propa233426. overnight. The resulting slurry was weighed to a weight of 46 to g and, after cooling, 13.75 g of methylamine as its 35% solution in 2-propanol was added dropwise and dissolved. Stir for 4 h at room temperature, allow to stand overnight, filter and evaporate. The residue is dissolved in 50 ml of boiling water and left to crystallize in the refrigerator for 48 hours. After aspiration and washing with water, 10.0 g (80 #) of the compound of formula I are obtained.

Example 5

To a suspension of 117.6 g of 85 # thiol hydrochloride V in 550 ml of 2-propanol was added dropwise under nitrogen atmosphere 116 ml of 50 # sodium hydroxide solution, cooled to 24 ° C, stirred for 15 min, 71.0 g of hydrochloride 2 were added. -chlorethylamine VIa, stirred for 30 min at room temperature and 45 min at 50-55 ° C, cooled to below 25 ° C and the inorganic fraction was filtered off with suction. The filtrate was weighed to a weight of 200 g and was added dropwise at room temperature to a solution of 88.2 g of ester IV in 320 ml of 2-propanol, stirred for 5 hours and allowed to stand overnight. 132 g of methylamine as a 40% aqueous solution were added dropwise over 45 minutes, stirred for 8 hours, allowed to stand for 48 hours, filtered and evaporated to dryness. The residue is dissolved in 1600 ml of boiling acetonitrile, the hot solution is filtered from the remainder of the inorganics and the filtrate is cooled in a refrigerator for 3 days. The crystallized solid is filtered off with suction, washed with ether and dried. There was thus obtained 114.3 g (74.7%) of the compound of formula I, m.p. 137-140 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of N-cyen-N'-methyl-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl-3-guanidine of formula I (I) by reacting 4-mercaptomethyl-5-methylimidazole with 2-haloethyl amines wherein halogen denotes chlorine or bromine, followed by reaction of the resulting 4- (2-aminoethylthiomethyl) -5-methylimidazole with dimethyl cyaniminodithium carbonate to give N-cyano-N '- [2- (5-methyl-ε-imidazolylmethylthio) ethyl] -S- methylthiourea which is reacted with methylamine (characterized in that both starting materials are used in the form of piglets, preferably hydrochlorides or hydro-bromides, the bases being released therefrom by the addition of an aqueous solution of an alkali hydroxide or an alcoholic solution of an alkoxide, alcohols are understood to be lower alcohols having 1 to 3 carbon atoms and, as alkoxides, preferably sodium alkoxide or potassium alkoxide having 1 to 3 carbon atoms, the reaction mixture is filtered off by inorganic salts, the filtrate is evaporated and the latter is evaporated. the solution is treated directly with a lower alcohol cyaniminodithium carbonate solution of the same meaning as above, and the resulting isothiourea derivative is treated directly with an aqueous or alcoholic methylamine solution, the solution is evaporated and the crude product is crystallized from a suitable solvent, preferably from a solvent. water or acetonitrile.