JPH0641096A - N-guanidionthiourea salt and production of 3-amino-5-mercapto-1,2,4-triazole - Google Patents

Abstract

PURPOSE:To easily and safely produce the compound useful as a raw material for pharmaceuticals, agricultural chemicals, etc., by reacting a compound having thiocyanic acid group and aminoguanidine group or reacting a thiocyanic acid compound with an aminoguanidine compound in a polar solvent in the presence of an acid. CONSTITUTION:An N-guanidinothiourea salt is produced by reacting a compound having thiocyanic acid group and aminoguanidine group (e.g. aminoguanidine thiocyanate) or reacting a compound having thiocyanic acid group (e.g. ammonium thiocyanate) with a compound having guanidine group (e.g. aminoguanidine bicarbonate) in the presence of an acid (e.g. hydrochloric acid) in a polar solvent (e.g. deionized water) under heating and refluxing for 1hr. The obtained N- guanidinothiourea salt is alkalinized with 50% aqueous solution of sodium hydroxide and made to react under heating and refluxing for 1.5hr to easily and safely obtain 3-amino-5-mercapto-1,2,4-triazole.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to N-guanidinothiourea salts and 3-, which are useful as intermediate raw materials for pharmaceutical and agrochemical materials.
The present invention relates to a method for producing methyl-5-mercapto-1,2,4-triazole, specifically, a compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and an aminoguanidine group. A method for producing N-guanidinothiourea, which is an intermediate of 3-amino-5-mercapto-1,2,4-triazole, characterized by reacting a compound having Is about

Further, a compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and a compound having an aminoguanidine group,
The present invention relates to a method for producing 3-amino-5-mercapto-1,2,4-triazole, which comprises reacting under heat in a polar solvent in the presence of an acid, and then subjecting the resulting reaction solution to heat reaction under alkaline conditions. It is a thing.

[0003]

2. Description of the Related Art As a method for producing 3-amino-5-mercapto-1,2,4-triazole (hereinafter sometimes abbreviated as ASTA), several methods have been conventionally known, for example, West Germany. Japanese Patent Publication No. 1960981 proposes a method in which aminoguanidine bicarbonate is first dissolved in acetal-dissolved etal, triethylamine is added thereto, and then carbon disulfide is blown in to react. . This reaction is considered to follow the following equations (a) to (c).

[0004]

[Chemical 1]

[0005]

[Chemical 2]

[0006]

[Chemical 3]

In addition, USSR Patent No. 1002291 proposes a method of synthesizing aminoguanidine hydrochloride and thiourea by melting reaction in the absence of solvent as shown in the following formula (D).

[0008]

[Chemical 4]

However, a compound having both a thiocyanate group and an aminoguanidine group, which is the method of the present invention,
Alternatively, a method in which a compound having a thiocyanate group and a compound having an aminoguanidine group are heated and reacted in a polar solvent in the presence of an acid and then heated and reacted under alkaline conditions is not known.

In the method of the first proposal, there are problems such as toxicity of carbon disulfide as a raw material, flammability and explosiveness, and special attention should be paid to the equipment's hermeticity and treatment facilities such as exhaust and drainage. However, in the method of the second proposal, the reaction yield is not always sufficient, and thiourea as a raw material has problems of toxicity and carcinogenicity. Therefore, it has been found that there is a problem that the cost is increased due to the manufacturing facility as in the case of the first proposal.

Further, in JP-A-59-124333, N-guanidinothiourea (hereinafter sometimes referred to as GTU)
A method for synthesizing ASTA by dissolving a hydrochloride in an aqueous solution of sodium hydroxide and reacting with heating is described. However, this proposal does not disclose a method for synthesizing GTU at all, and it goes without saying that a compound having both a thiocyanic acid group and an aminoguanidine group, which is the method of the present invention, or a compound having a thiocyanic acid group and aminoguanidine is used. There is no description or suggestion of a method for producing ASTA using a compound having a group as a raw material.

[0012]

DISCLOSURE OF THE INVENTION The inventors of the present invention have solved the above-mentioned problems of the prior art, and have a safe and inexpensive AS.
As a result of conducting research to develop a TA manufacturing method, for example,
When a compound having an aminoguanidine group such as aminoguanidine bicarbonate and a compound having a thiocyanic acid group such as ammonium thiocyanate are reacted by heating in a polar solvent such as water in the presence of an acid such as hydrochloric acid, GTU hydrochloride, etc. The salt of the intermediate of is formed, and then the resulting reaction solution is made alkaline by adding an aqueous solution of sodium hydroxide or the like, and further heated and reacted to easily and safely obtain the desired ASTA.
Was found to be synthesizable, and further research was conducted to complete the present invention.

[0013]

The present invention provides a compound having both a thiocyanate group and an aminoguanidine group, or
A target compound of the present invention, 3-amino-5-mercapto-1,2, characterized in that a compound having a thiocyanic acid group and a compound having an aminoguanidine group are heated and reacted in the presence of an acid in a polar solvent. An object of the present invention is to provide a method for producing an intermediate of 1,4-triazole, N-guanidinothiourea,

Further, a compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and a compound having an aminoguanidine group,
A method for producing 3-amino-5-mercapto-1,2,4-triazole, which comprises heating in a polar solvent in the presence of an acid, and then heating the resulting reaction solution under alkaline conditions. It is intended to be provided.

The present invention will be described in detail below. The present invention is
A compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and a compound having an aminoguanidine group is heated and reacted in a polar solvent in the presence of an acid to give the object compound of the present invention. ASTA intermediate, GTU salt is generated (1st stage reaction),

Next, the present invention relates to a method for producing ASTA, characterized in that the reaction solution containing the GTU salt is heated and reacted under alkaline conditions (second step reaction).

First-Step Reaction Examples of the compound having both a thiocyanate group and an aminoguanidine group that can be used in the first-step reaction of the method of the present invention include aminoguanidine thiocyanate. .

Examples of compounds having a thiocyanate group include ammonium thiocyanate, potassium thiocyanate, sodium thiocyanate, lithium thiocyanate, calcium thiocyanate, magnesium thiocyanate and barium thiocyanate. Among these, it is most preferable to use ammonium thiocyanate from the viewpoints of operability when the reaction is carried out on an industrial scale and easy availability.

Further, examples of the compound having an aminoguanidine group include aminoguanidine hydrochloride, aminoguanidine dihydrochloride, aminoguanidine sulfate, aminoguanidine bisulfate, aminoguanidine carbonate and aminoguanidine bicarbonate. Among these, aminoguanidine bicarbonate is most preferably used from the viewpoints of operability in the case of carrying out the reaction on an industrial scale and easy availability.

In the first-step reaction, when a compound having a thiocyanic acid group, for example, ammonium thiocyanate, or a compound having an aminoguanidine group, for example, aminoguanidine bicarbonate, is used, prior to the reaction with an acid, A method in which these compounds are heated and reacted in a polar solvent to distill off ammonia and carbon dioxide together with water to form aminoguanidine thiocyanate can also be suitably adopted.

The above-mentioned acid that can be used in the first-step reaction in the method of the present invention is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. It is preferable to use hydrochloric acid or sulfuric acid from the viewpoint of good reactivity and easy availability.

The polar solvent that can be used in the method of the present invention is not particularly limited, but from the viewpoints of availability and reactivity, for example, water;
It is preferable to use lower alcohols such as methyl alcohol, ethyl alcohol and i-propyl alcohol;
The use of water is particularly preferred.

The first-step reaction of the method of the present invention is considered to proceed as in the following formula (1).

[0024]

[Chemical 5]

In the above formula (1), X represents an acid residue.

As is clear from the above reaction formula, 1 equivalent of thiocyanic acid group and 1 equivalent of acid are required for 1 equivalent of aminoguanidine group, but 1 equivalent of aminoguanidine group is required from the viewpoint of reactivity. With respect to the thiocyanate group, generally 1 to 5 equivalents, preferably 1 to 2 equivalents, and
The acid is generally used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, particularly preferably 1 to 2 equivalents.

The method of using the acid is not particularly limited, but if necessary, it is preferable to add dropwise to the reaction system at an appropriate concentration with water or the like.

The reaction temperature can be generally 50 ° C. or higher, but it is preferably 80 ° C. to 120 ° C. from the viewpoint of reaction rate, decomposition of raw materials and generated GTU, and suppression of side reactions.

The reaction time is not particularly limited, but it is generally 5 minutes to 4 hours, preferably 10 to 3 hours.

After completion of the reaction, the resulting reaction solution is concentrated if necessary and then cooled to crystallize a GTU salt which is an intermediate of the target compound ASTA of the present invention, and is separated by filtration. Crystals of GTU salt can be obtained. Since GTU salts have some water solubility, a significant amount of GTU is present in the filtrate.
Although the salt is dissolved, the yield of GTU salt can be improved by recycling the filtrate.

The GTU salt is determined by the type of acid used in the first-step reaction, and as mentioned above, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid can be exemplified. Alternatively, a sulfate salt is preferable, and a hydrochloride salt is particularly preferable.

Second Stage Reaction The object compound ASTA of the present invention was prepared as described above.
It can be produced by dissolving a salt of GTU in the same polar solvent as described above, adding an alkaline compound to the resulting GTU solution to make the solution alkaline, and then reacting the solution by heating. After completion of the reaction, the reaction solution after completion of the reaction can be used as it is as a GTU solution without separating and recovering GTU salt.

The first-step reaction of the method of the present invention comprises the following formula (2) and
It is thought that it will proceed as in (3).

[0034]

[Chemical 6]

[0035]

[Chemical 7]

In the above formula (2), M represents a monovalent metal.

Examples of the alkaline compound include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide.

As a method of using the alkaline compound, it is preferable to dilute it with water or the like to an appropriate concentration and add it dropwise into the reaction system. The pH of the reaction solution is generally 7-14, preferably about 9-13.

The reaction temperature can be generally 50 ° C. or higher, but it is preferably 80 ° C. to 120 ° C. from the viewpoints of reaction rate, decomposition of intermediate GTU and generated ASTA and suppression of side reactions.

The reaction time is not particularly limited, but it is generally 10 minutes to 6 hours, preferably 1 to 2 hours.

After completion of the reaction, by adding the above-exemplified acids such as hydrochloric acid to the obtained reaction solution to adjust the pH to about 1 to 2, ASTA as the object compound of the present invention can be obtained in high purity. . In addition, when it is desired to obtain a higher-purity product, it can be purified by a method such as column chromatography or acid precipitation.

For acid precipitation, the obtained ASTA is once dissolved in an aqueous solution of an alkali metal hydroxide such as sodium hydroxide to obtain an aqueous solution of an alkali metal salt of ASTA, and insoluble matter such as sulfur is removed by suction filtration. Filter off. And that
Add hydrochloric acid to the aqueous solution of ASTA alkali metal salt to obtain pH 1-2.
Then, the deposited ASTA is filtered by suction filtration and dried to obtain 85 to 100% of ASTA crystals.

[0043]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1 A 100 ml eggplant-shaped flask equipped with a thermometer and a stirrer was charged with aminoguanidine bicarbonate 27.2 g (about 0.2 mol), ammonium thiocyanate 15.2 g (about 0.2 mol) and deionized water 10 g.
And heat it on an oil bath to bring the reaction solution temperature to 108 ° C.
Water, carbon dioxide, and ammonia were distilled off until.

Next, a reflux condenser was set in this apparatus, and the reaction solution was heated to 95 ° C. and stirred, and 35% by weight of hydrochloric acid was 28.0 g.
(About 0.27 mol) was added dropwise over 2 hours, and the temperature was kept at the same temperature for 1 hour. Then, the crystals were crystallized by cooling to room temperature, and the obtained wet crystals were dried under reduced pressure at 50 ° C. overnight. ,purity
16.3 g (about 0.11 mol) of 91 wt% GTU hydrochloride crystals were obtained.
The melting point of the obtained GTU hydrochloride is 195-197 ° C, and
The results of infrared spectroscopy (IR) are shown in FIG.
In addition, 9.3 g (about 0.07 mol) of GTU hydrochloride was dissolved in the filtrate, and the yield of GTU hydrochloride combined with the recovered crystals was about 95% with respect to aminoguanidine bicarbonate.

Example 2 The same apparatus as in Example 1 was used, and aminoguanidine bicarbonate, ammonium thiocyanate and deionized water were charged in the same amounts as in Example 1 and heated in the same manner on an oil bath to prepare water. , Carbon dioxide and ammonia were distilled off. Then, a reflux condenser was set in this apparatus, and the reaction solution was heated to 95 ° C. as in Example 1 and 35% by weight of hydrochloric acid 28.0 g with stirring.
(About 0.27 mol) was added dropwise over 2 hours, and the mixture was kept at the same temperature for 1 hour to obtain a reaction liquid containing GTU hydrochloride.

Next, 18.3 g (about 0.23 mol) of 50% by weight aqueous sodium hydroxide solution was added to the reaction solution to make the reaction solution alkaline, and the mixture was heated to reflux (about 110 ° C.) on an oil bath for 1.5 minutes.
Reacted for hours. After the reaction is complete, cool the reaction solution to room temperature.
Generated by adding 9.5 g of 35 wt% hydrochloric acid to pH 1-2
The ASTA precipitate was filtered off to obtain 24.5 g of hydrous ASTA. This water content A
ASTA with a purity of 97.1% by weight was dried by vacuum drying STA at 50 ° C overnight.
19.2 g of crystals (about 0.161 mol; yield about 80.3% based on aminoguanidine bicarbonate) were obtained. The decomposition temperature of the obtained ASTA is
The temperature was 298 to 301 ° C., and the results of infrared spectroscopic analysis (IR) were as shown in FIG. 2, which were all in agreement with the standard.

Example 3 In the step of producing a reaction solution containing GTU hydrochloride of Example 2, instead of using 28.0 g (about 0.27 mol) of 35 wt% hydrochloric acid, 13.2 g (about 0.13 mol) of 98 wt% concentrated sulfuric acid was used. ASTA crystals 16.8 g (0.138 mol; ratio to aminoguanidine bicarbonate 70.5%) were obtained in the same manner except that was used. The decomposition temperature of the obtained ASTA was 295-299 ℃, which was almost the same as the standard.

Example 4 In a 5 liter separable flask equipped with a thermometer and a stirrer, 1382 g (about 10 mol) of aminoguanidine bicarbonate, 767 g (about 10 mol) of ammonium thiocyanate and 500 g of deionized water.
And heat it on an oil bath to bring the reaction solution temperature to 108 ° C.
Water, carbon dioxide, and ammonia were distilled off until.

Next, a reflux condenser was set in this apparatus, and the reaction solution was heated to 95 ° C. with stirring and 1247 g of 35 wt% hydrochloric acid.
(About 12 mol) was added dropwise over 2 hours, and at the same temperature 1
After holding for a period of time, a reaction solution containing GTU hydrochloride was obtained.

Next, 650 g (about 6.5 mol) of 40% by weight sodium hydroxide aqueous solution is added to the obtained reaction solution to make the reaction solution alkaline, and the mixture is heated under reflux on an oil bath (about 110 mol).
C) for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 383 g of 35 wt% hydrochloric acid was added to adjust the pH to 1-2, and the formed ASTA precipitate was filtered off to obtain 1296 g of hydrous ASTA. This water-containing ASTA was dried under reduced pressure at 50 ° C overnight to obtain a purity of 95.8.
935 g (about 7.71 mol; yield about 77.1% based on aminoguanidine bicarbonate) of ASTA crystals of weight% were obtained. The decomposition temperature of the obtained ASTA is 295 to 297 ° C, and the infrared spectroscopy (I
The results of (R) are as shown in FIG. 2, and all were in agreement with the standard.

[0052]

INDUSTRIAL APPLICABILITY The method of the present invention is a raw material which has never been used in the conventional method, and is a compound having both a thiocyanate group and an aminoguanidine group, such as aminoguanidine thiocyanate, or a raw material which is not in the conventional method. A combination of a compound having an aminoguanidine group such as aminoguanidine bicarbonate and a compound having a thiocyanate group such as ammonium thiocyanate is heated in a polar solvent in the presence of an acid. -Related to the production of guanidinothiourea salts,

Further, a compound having both a thiocyanic acid group and an aminoguanidine group, or a compound having an aminoguanidine group and a compound having a thiocyanic acid group is used and reacted by heating in a polar solvent in the presence of an acid. The present invention relates to the production of 3-amino-5-mercapto-1,2,4-triazole, which is characterized in that the resulting reaction solution is heated and reacted under alkaline conditions.

According to this method, various problems in the conventional method, that is, the problems such as toxicity and danger of raw materials used, high cost of manufacturing facilities and insufficient reaction yield, etc., are solved. Thus, the target compound, 3-amino-5-mercapto-1,2,4-triazole, and its intermediate, N-guanidinothiourea salt, can be produced on an industrial scale inexpensively and safely.

[Brief description of drawings]

FIG. 1 is an IR chart of N-guanidinothiourea hydrochloride, which is an intermediate of 3-amino-5-mercapto-1,2,4-triazole, a target compound of the method of the present invention.

FIG. 2 is an IR chart of 3-amino-5-mercapto-1,2,4-triazole, a target compound of the method of the present invention.

Claims (2)

[Claims] 1. A method of reacting a compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and a compound having an aminoguanidine group with heating in a polar solvent in the presence of an acid. Characteristic N
-A method for producing a guanidinothiourea salt. 2. A compound having both a thiocyanate group and an aminoguanidine group, or a compound having a thiocyanate group and a compound having an aminoguanidine group is heated and reacted in a polar solvent in the presence of an acid, and then, A method for producing 3-amino-5-mercapto-1,2,4-triazole, which comprises subjecting the resulting reaction solution to a heating reaction under alkaline conditions.