HU181097B - Method and sheeting device for constructing linear reinforced concrete construction of closed section particularly public tunnel - Google Patents

Description

The present invention relates to a process for the preparation of the N-cyano / N '- / 2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea bridate and its hydrogen halides.

The hydrate or hydrogen halides of the compound of formula (I) are N-cyano-N '- [2 - ((5-methyl-4-imidazolyl) methylthio] ethyl] -N' -methyl-guanidine (cimetidine) having gastric ulcer activity. The hydrate as well as the hydrogen halides can be synthesized under better reaction conditions in better yields than the known base of formula (I) and can be easily prepared from high quality cimetidine.

The compound of formula (I) can be prepared from the salt of 4-hydroxymethyl or 4-halomethyl-5-methylimidazole according to the first known process in three steps.

The first step is described in Hungarian Patent No. 164,509, according to which 4-hydroxymethyl or 4-chloromethyl-5-methylimidazole hydrochloride is reacted with cysteamine hydrochloride in the presence of an acid. The reaction gives 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole dihydrohalide.

The acid present in the above reaction may be acetic acid, aqueous hydrochloric acid, or hydrobromic acid in acetic acid. The reaction partners in the acid are refluxed for 7-17 hours and the product is obtained in a yield of 83-93% which can be isolated from the reaction mixture in the form of dihydrochloride or dihydrobromide, depending on the acid present. The product of the first step, the dihydrogen halo181097 genide, cannot be directly reacted further, and the appropriate base must first be liberated.

The second step, the base release, is not described in the literature, but it should not pose a particular problem to one of ordinary skill in the art. The literature so far does not disclose the physical constants of the base obtained in Step 2.

The third step is protected by Belgian patent specification No. 804,144. According to p. 4 - [(2-Aminoethyl) thiomethyl] -5-methylimidazole base is reacted in ethanol with dimethyl ester of V-cyano-imidodithioic acid to give the cimetidine intermediate of formula (I) in 73% yield.

Assuming 100% yield, the three steps can be accomplished with a 64% overall yield.

In our experiments we have found that the product of the first step, 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole dihydrogen halide, is not only from 4-hydroxymethyl or 4-halomethyl-5-methylimidazole, but also from the corresponding 4- (lower) alkoxymethyl derivative and from a mixture of the starting materials listed above in good yield and in very pure form by reaction with cysteamine hydrogen halide. The reaction proceeds without the addition of an acid, which is a major advantage, particularly in terms of corrosion. The reaction may be carried out in a melt or in the presence of water as a solvent.

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Among the starting materials, the 4-hydroxymethyl and 4-halomethyl derivatives are described in Hungarian Patent Specification No. 164,509, the 4- (lower) alkoxymethyl derivatives of which are disclosed in Hungarian Patent Application No. 174,840, the 4-hydroxymethyl and 4-hydroxymethyl derivatives. A mixture of alkoxymethyl derivatives is disclosed in U.S. Patent 4,055,573.

It is surprising to find that the mixed thioether type 4 - {(2-aminoethyl) thiomethyl] -5-methylimidazole dihydrogen halide can be prepared from a mercaptan type compound (cysteamine) and an alcohol type

By reaction of 4-hydroxymethyl-5-methylimidazole without promoting the reaction under vigorous conditions or by adding acid.

Reactions of mercaptans and alkylating agents have been described in the literature for the preparation of mixed thioethers [Houben-Weyl, Methoden dérorganchen Chemie IX. 94, 1955]. Reactions of alcohols and mercaptans, in which the water exits in the vapor phase at 350-400 ° C in the presence of catalysts, are also known (cited, p. 117). Further, the reaction of some active phenylcarbinol with mercaptans in the presence of hydrochloric acid is known. The reaction of such compounds in acetic acid with addition of dry hydrochloric acid gas is also known (cited, pp. 117-118). Based on these, it was not expected that cysteamine and 4-hydroxymethyl-5-methylimidazole would react well in either melt or aqueous media.

To the best of our knowledge, mixed thioethers with ethers and mercaptans have not yet been prepared. It is therefore surprising to discover that the reaction between mercaptan-type cysteamine hydrogen halide and ether-type 4-alkoxymethyl-5-methylimidazole hydrogen halide provides a simple method for the preparation of the mixed thioether type 4 - [(2-amino) ethyl) thiomethyl] -5-methylimidazol-dihidrogénhalogenid.

It has also been found that the preparation of the 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole dihydrogen halide obtained in the first step is unnecessary, and that the corresponding base can be liberated in the reaction mixture itself. If the first reaction step is carried out in the presence of water, the base is liberated without the addition of water, and if the first reaction step is carried out in a melt, the base can be liberated in the presence of water.

Neutralization of both addition acid molecules in the starting material is required to liberate the base. It has been found that if only one molecule is bonded to an acid, the resulting monohydrogen halide is also suitable as a starting material for Step 3. Either the base or the monohydrogen halide are prepared, each of which can be directly reacted further with dimethyl ester of N-cyanimidodithioic acid. When the N-cyanimidido-dithiocarboxylic acid dimethyl ester is reacted with 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole base in the presence of water, the hydrate of the compound of formula (I). when reacted with the monohydrogen halide of 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole, the monohydrogen halide of the compound of formula (I) can be isolated from the reaction mixture. Any of the products obtained can be converted into the base of formula (I) by methods known per se.

The variant of the third step, wherein the N-cyanimidido-dithiocarboxylic acid dimethyl ester is reacted with the monohydrogen halide of 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole, is surprising in light of the prior art. Known [J. Org. Chem. 35, 2067 (1970)] that N-cyanoimidodithiocarboxylic acid dimethyl ester can be converted to N-cyanoisothiourea derivatives with amines. In our own experiments, however, N-cyanoimidodithioic acid dimethyl ester was not similarly reacted with acid addition salts of various amines; the reaction occurred only in the case of amines liberated from their acid addition salts. Thus, the third variant of the reaction described in this case is an exception.

The advantages of the process according to the invention can thus be briefly summarized as follows:

1. The reaction steps 3 can be carried out in a single apparatus without preparation of the intermediates.

2. Each of the 3 steps can be carried out under mild reaction conditions, if desired in an aqueous medium.

3. No. 804,144. According to a Belgian patent, the base of formula (I) can be prepared in 64% yield. By the present process, the hydrate to be substituted for the base of formula (I) is 80%, respectively. Chlorohydrate was obtained in 74.5% yield. The hydrate can be converted to the base of formula (I) in 100% yield and the chlorohydrate in 90% yield.

4. The products were found to be completely uniform, pure material by thin layer chromatography, and high quality cimetidine was obtained directly therefrom.

The present invention therefore relates to a process for the preparation of hydrate and halides of N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea of formula (I). converting any of the obtained products to a base of formula (I) with a 4-substituted-5-methylimidazole salt with a cysteamine salt of formula (III) wherein X is halogen and then liberating the base from the resulting compound with N-cyanimidodithioic acid. by reacting a dimethyl ester with one or more compounds of formula (IV) as a salt of 4-substituted-5-methylimidazole

Y is halogen, hydroxy, or

C 1 -C 4 alkoxy and X is halogen - optionally in the presence of water, followed by reaction with N-cyanimidodithioic acid dimethyl ester

(a) carrying out the base obtained from the salt of formula (II) wherein X is a halogen atom in the first reaction step in the presence of water and recovering the hydrate of the compound of formula (I), or

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b) with the monohydrogen halide obtained from the salt of the formula II and recovering the monohydrogen halide of the compound of the formula I and converting the product obtained by any of the processes a) or B into the base of the formula I if desired.

According to the process of the present invention, one of the starting materials is one or more of Formula IV. compound.

The one or more compounds of formula (IV) are reacted with a compound of formula (III). The reaction is carried out in a melt or in the presence of water as a solvent. The latter is the preferred solution. The reaction, both in the melt and in the presence of water, is carried out at 100-180 ° C, preferably 110-170 ° C, in the first case at atmospheric pressure and in the second case at the system's own pressure.

The dihydrogen halide of formula (II) formed in the reaction does not need to be isolated from the reaction mixture, but can be directly processed according to process (a) or (b).

According to process (a) of the invention, a hydrate of the compound of formula (I) is prepared. In the preparation of the hydrate, the corresponding base of the dihydrogen halide of formula (II) obtained in the first step is liberated. The reaction is conveniently carried out in the presence of water by addition of an inorganic base, preferably an alkali metal carbonate, followed by addition of the liberated base in water, or preferably in a mixture of C1-C3 alkanol and water, with N-cyanimidodithiocarboxylic acid dimethyl ester. At a temperature of between about 0 ° C. The reaction forms a hydrate of the compound of formula (I), e.g. can be isolated by filtration.

According to process b) of the invention, the monohydrogen halide of the compound of formula I is prepared. In this case, the corresponding monohydrogen halide is liberated from the dihydrogen halide of formula (II) obtained in the first step. The reaction is conveniently carried out in the presence of water by addition of a calculated amount of an inorganic base, preferably an alkali metal carbonate. The resulting monohydrogen halide is reacted with dimethyl ester of N-cyanoimidodithioic acid. The reaction is carried out in a solvent, preferably water, or a mixture of water and a C 1 -C 3 alkanol at a temperature of from 20 to 100 ° C, preferably from 70 to 90 ° C. From the reaction mixture, the monohydrogen halide of the compound of formula (I) is precipitated.

The reaction was monitored by TLC (adsorbent: silica gel, Kieselgel 60, eluent: dichloromethane-methanol-0.1 N aqueous hydrochloric acid 15: 9: 1).

The hydrate obtained in process variant a) can be converted into the base of formula I by methods known per se. The removal of bound water can be effected e.g. Heat treatment at 50-105 ° C or recrystallization from an organic solvent. The recrystallization is preferably carried out in nitromethane, isopropanol or other suitable method.

The monohydrogen halide obtained in process variant b) may conveniently be converted to the base hydrate of formula I with an inorganic base, preferably an alkali metal carbonate.

The invention is further illustrated by the following non-limiting examples.

]. example

Preparation of N-Cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea hydrate

Method A)

A mixture of 14.8 g (0.1 mol) of 5-methyl-4-hydroxymethylimidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydrochloride was melted and stirred at 160 ° C for 15 minutes. The progress of the reaction is monitored by thin layer chromatography. Cooling

After 20 °, the melt was dissolved in water (75 ml) and sodium carbonate (10.6 g, 0.1 mol) was added followed by ethanol (50 ml) and dimethyl ester of N-cyanimidodithiocarboxylic acid (14.6 g, 0.1 mol). . The reaction mixture was refluxed for 1 hour. The mixture was allowed to cool and stirred at room temperature for an additional 5-7 hours. The precipitated product was filtered off, washed with water and dried at room temperature.

Yield: 23 g (80%) of N-cyano-N '- / 2 - [(5-methyl-4 _{30-imidazolyl)} methylthio] - ethyl / -S-methylisothiourea hydrate.

104-106 ° C.

Characteristic bands NMR in ppm (Varian EN-360, _DMSO-d6 (TMS): 2.13 s (3H), 2.56 s (3H), 2.4-2.9 ₃₅ t (2H); 3.3-3.9 m (2H), 3.66 s (2H), 5-7 b (2H),

7.46 s (1H).

Characteristic IR bands cm ^"in1 C = N 2160; CH ₂ - (S), CH ₃ - (S) 2600-2800: NH-3280; imidazole skeletal vibrations 1293, 768, OH 3510:

Elemental Analysis for the OS2 CioH ₁₇ N ₅ O:

date:

found:

Method B

C = 41.79%, N = 24.37%, C = 41.93%, N = 24.60%,

H = 5.96%, S = 22.31%, H = 5.70%, S = 22.57%.

Method A is followed by adding a concentrated (50%) aqueous solution of 5-methyl-4-hydroxymethylimidazole hydrochloride to the melt of cysteamine hydrochloride.

Yield: 23 g (80%).

104-106 v.

Method C

14.8 g (0.1 mol) of 5-methyl-4-hydroxymethylimidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydro chloride ₆₀ are dissolved in 75 ml of water and the solution is pressurized to 15 ° C. for 130 hours at 130-140 ° C. The progress of the reaction was monitored by TLC. After cooling to room temperature 10.6 g (0.1 mole) of sodium carbonate and ₆ ml of ethanol and 50 5-N-3181097 ciánimido-dithio carbonic acid dimethyl ester (14.6 g, 0.1 mol) was added to the reaction solution and then stirring and refluxing for 1 hour and finally stirring at room temperature for a further 5-7 hours. The precipitate was filtered off, washed with water and dried at room temperature.

Yield: 22.5 g (78.3%).

104-105 ° C.

Method D

15.9 g (0.1 mol) of a mixture of 50-60% 5-methyl-4-hydroxymethylimidazole hydrochloride and 50-40% 5-methyl-4-ethoxymethylimidazole hydrochloride; A mixture of cysteamine hydrochloride (3 g, 0.1 mol) was melted and stirred at 160 ° C for 15 minutes, and the melt was dissolved in water. Hereinafter, method A) will be followed.

Yield: 23 g (80%).

104-105 ° C.

Method E:

hydrochloride and cysteamine hydrochloride (11.3 g, 0.1 mol) were melted and stirred at 160 ° C for 15 minutes and then allowed to cool. The progress of the reaction is monitored by thin layer chromatography. The melt was dissolved in water (75 mL), treated with sodium carbonate (5.3 g, 0.05 mol) and then worked up as monohydrochloride according to Example 1 (A).

Yield: 22.05 g (74.5%) of N-cyano-N '- [2 - [(519-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea monohydrochloride.

Mp 220-222 ° C.

Typical NMR bands in ppm [Varian EN-360, 15 Pyr-d (TMS)]: 2.26 s (3H); 2.66 s (3H); 2.93 t (2H): 3.82 m (2H); 3.9 s (2H); 7.92 s (1H); 9.66 (2H).

Elemental analysis calculated for Ci _O H ₁₆ N ₅ S ₂ Cl:

2o calculated:

found:

C = 39.27%, N = 22.89%, C = 39.38%, N = 22.99%,

H = 5.27%, Cl = 11.59%, H = 5.57%, Cl = 11.41%.

15.9 g (0.1 mol) of 50 -60% 5-methyl-4-hydroxy-2'5-methylimidazole hydrochloride and 50-40% 5-methyl-4-ethoxymethylimidazole hydrochloride A mixture of the mixture containing 10.3 g of cysteamine and 11.3 g (0.1 mL) of cysteamine hydrochloride in 75 mL of water is treated according to Method C into a hydrate.

Yield: 19.3 g (67.5%).

104-105 ° C.

Method F

A mixture of 17.65 g (0.1 mol) of 5-methyl-4-ethoxymethylimidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydrochloride is melted and then worked up according to Method A.

Yield: 22 g (76.7%). 40

104-106 ° C.

Example 3

Preparation of N-Cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea

Method A)

Dissolve 10.0 g of N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea hydrate in 200 ml of nit25 romethane and filter hot. After cooling, the precipitated crystals are filtered off, washed twice with 40 ml of nitromethane and dried. The base obtained has a melting point of 148-150 ° C.

Method B

Method G)

16.7 g (0.1 mol) of 5-methyl-4-chloromethylimidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydrochloride are dissolved in 75 ml of water and heated at 130-140 ° C for 15 hours. At C, the system is kept under its own pressure. The progress of the reaction was monitored by thin layer chromatography. Sodium carbonate (15.9 g, 0.15 mol) was added followed by ethanol (50 ml) and dimeryl cyanodithiimidocarbonate (14.6 g) (0.16 mol), which was subsequently treated with hydrate according to Method C. .

Yield: 22.3 g (77.7%).

104-105 ° C.

Example 2

Preparation of N-Cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl-S-methylisothiocarbamyl monohydrochloride

14.8 g (0.1 mol) of 5-methyl-4-hydroxymethylimidazole10 g of N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea The hydrate was dissolved in 100 mL of iso45 propanol, and after cooling, the crystals which precipitated were filtered off, washed twice with 40 mL of isopropanol, and dried.

147-149 ° C.

Method C

Maintaining N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea hydrate at 105 ° C. it can be converted quantitatively to the appropriate base.

Mp 148-150 ° C.

Method D

2 g of N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea monohydrochloride were triturated with 30 ml of 25% aqueous ammonium hydroxide in a mortar and filter, wash with water and dry gradually at 105 ° C.

Yield: 1.58 g (90%) of base, m.p. 147-148 ° C.

Claims (5)

Patent claims: A process for the preparation of the hydrate and hydrogen halides of N-cyano-N '- [2 - [(5-methyl-4-imidazolyl) methylthio] ethyl] -S-methylisothiourea of formula (I) and optionally products bármelyi- ^one smear of formula (I) in base form shaping, a 4-substituted-5-methylimidazole salt of formula (III) cysteamine salt - wherein X is halogen atom -, and the liberated compound obtained base N-ciánimido by reacting ¹⁵ with -ditioszénsav-dimetilészterrel, characterized in that 4-substituted-5-methylimidazole salt of one or more of (IV) a compound of formula - in this formula ²⁰ Y is halogen, hydroxy, or Is C1-4 alkoxiesoportot and X is halogen - * ⁵ is used optionally in the presence of water, and then the N-dithio carbonic acid-ciánimido reaction dimetilészteres a) the salt of formula obtained in the first reaction of step (II) - wherein X is halogen atom - was carried out in base ³⁰ scarf presence of water and recovering the formula (I) compound hidráját or b) carrying out the monohydrohalide obtained from the salt of the formula II and recovering the mono-hydrohalide of the compound of the formula I and converting the product obtained by any of the processes a) or b) to the base of the formula I if desired. 2. A process according to claim 1 wherein one or more compounds of formula IV are present. wherein X is as defined in claim 1, wherein Y is hydroxy, optionally Y is ethoxy. 3. A process according to any one of claims 1 or 2, wherein the compound (IV) with the compound (III) is at a temperature of 100-180 ° C, preferably 110-170 ° C. reacted. 4. A process according to claim 1, wherein the reaction with N-cyanoimidodithiocarboxylic acid dimethyl ester is carried out in the presence of water or water and a C 1-3 alkanol. 5. A process according to claim 1, wherein the product of step a) is converted to the base of formula I by heat treatment at 50-105 ° C or by recrystallization from an organic solvent.