JPH0625192A - Synthesis of 3-amino-5-mercapto-1,2,4-triazole - Google Patents

Abstract

PURPOSE:To readily and safely obtain the subject compound useful as an intermediate raw material for medicines and agricultural materials by subjecting thiocyanic acid aminoguanidine to heat reaction in the presence of an acid. CONSTITUTION:Thiocyanic acid aminoguanidine or aminoguanidine salt (preferably aminoguanidine hydrocarbonate) is subjected to heat reaction with a thiocyanic acid salt (preferably ammonium thiocyanate) in the presence of an acid (preferably hydrochloric acid or sulfuric acid), preferably at 150-190 deg.C for 14-20hr to provide the objective compound. Furthermore, the thiocyanic acid salt is preferably used in an amount of 1.5-3mol based on 1mol aminoguanidine salt. The catalyst is preferably used in an amount of 1-3 equivalent based on 1mol thiocyanic acid aminoguanidine or aminoguanidine salt.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 3-methyl-5-mercapto-1,2,4-useful as an intermediate raw material for pharmaceuticals and agricultural chemicals.
It relates to a method for synthesizing triazole, and in detail,
A method for synthesizing 3-amino-5-mercapto-1,2,4-triazole, which comprises reacting aminoguanidine thiocyanate, or an aminoguanidine salt and a thiocyanate with heat in the presence of an acid Is.

[0002]

2. Description of the Related Art There are several conventionally known methods for synthesizing 3-amino-5-mercapto-1,2,4-triazole (hereinafter sometimes abbreviated as ASTA), such as 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).

[0003]

[Chemical 1]

[0004]

[Chemical 2]

[0005]

[Chemical 3]

[0006] Also, 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).

[0007]

[Chemical 4]

However, the method of the present invention, that is, the method of heating aminoguanidine thiocyanate or an aminoguanidine salt and a thiocyanate salt in the presence of an acid under heating 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.

[0010]

DISCLOSURE OF THE INVENTION The inventors of the present invention have solved the above-mentioned problems of the prior art and are safe and inexpensive.
As a result of conducting research to develop a synthetic method of ASTA, for example,
It was found that the target ASTA can be easily and safely synthesized by heating and melting an aminoguanidine salt such as aminoguanidine bicarbonate and a thiocyanate such as ammonium thiocyanate in the presence of an acid, and further research is conducted. The present invention has been completed.

[0011]

The present invention is characterized in that aminoguanidine thiocyanate or an aminoguanidine salt and a thiocyanate are heated and reacted in the presence of an acid, 3-amino-5- It is intended to provide a synthetic method of mercapto-1,2,4-triazole.

The present invention will be described in detail below. The present invention is
First, the method for synthesizing ASTA is characterized in that aminoguanidine thiocyanate is heated and reacted in the presence of an acid.

This reaction is considered to proceed as in the following equations (1) and (2).

[0014]

[Chemical 5]

[0015]

[Chemical 6] In the above formulas (1) and (2), X represents an acid residue.

The above reaction usually proceeds in a substantially solvent-free and molten state, and the viscosity of the reaction system gradually increases and the reaction rate tends to decrease. Therefore, for the purpose of suppressing an increase in the viscosity of the reaction system, it is preferable to add the thiocyanate described below in an amount of 0.5 mol or more, particularly 0.5 to 2 mol, based on 1 mol of aminoguanidine thiocyanate as a raw material.

The acid that can be used 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 easy availability. The amount of acid used is generally 1 to 1 mol of aminoguanidine thiocyanate as a raw material.
It is good to use 10 equivalents, preferably about 1 to 3 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 130 ° C. or higher, but 150 ° C. to 190 ° C. is most preferable from the viewpoint of reaction rate, decomposition of raw materials and generated ASTA, and suppression of side reactions.

The reaction time is not particularly limited, but it is generally 15 minutes to 64 hours, preferably 14 to 20 hours.

The aminoguanidine thiocyanate, which is the raw material of the present invention, can be obtained, for example, by reacting an aminoguanidine salt and a thiocyanate in, for example, an aqueous solvent.

Examples of the above aminoguanidine salt include aminoguanidine hydrochloride, aminoguanidine dihydrochloride,
Examples thereof include aminoguanidine sulfate, aminoguanidine bisulfate, aminoguanidine carbonate, aminoguanidine bicarbonate, and the like. Among these, operability in the case of carrying out the reaction on an industrial scale, easy availability, etc. Most preferred is the use of aminoguanidine bicarbonate.

Examples of the thiocyanates include ammonium thiocyanate, potassium thiocyanate, sodium thiocyanate, lithium thiocyanate,
Calcium thiocyanate, magnesium thiocyanate,
Examples thereof include barium thiocyanate, and of these, ammonium thiocyanate is most preferable from the viewpoints of operability when the reaction is carried out on an industrial scale and easy availability.

Further, in the present invention, the aminoguanidine salt and the thiocyanate salt are subjected to a heat-melting reaction, preferably without using a solvent, and then the reaction mixture is subsequently subjected to a heat reaction in the presence of an acid to give a 3-amino acid. It is also possible to synthesize -5-mercapto-1,2,4-triazole. Also in this reaction, aminoguanidine thiocyanate is used as a reaction intermediate, but the target compound can be obtained by continuing the heating reaction in the presence of an acid as it is without isolating the aminoguanidine thiocyanate. -amino-
5-Mercapto-1,2,4-triazole can be synthesized.

The reaction when aminoguanidine bicarbonate is used as the aminoguanidine salt and ammonium thiocyanate is used as the thiocyanate is considered to proceed according to the following formulas (4) and (5).

[0026]

[Chemical 7]

[0027]

[Chemical 8]

The above-mentioned reaction of the present invention also usually proceeds in a substantially solvent-free and molten state. In this reaction, the amount of the thiocyanate used is theoretically 1 mol per 1 mol of the aminoguanidine salt, but usually 1 mol to
20 mol, preferably 1 mol to 5 mol, particularly preferably 1.5 mol to 3 mol. When the amount of the thiocyanate used is at least the lower limit value, the reaction system viscosity is not excessively high and solidification is not caused, and the reactivity and the stirring property are not deteriorated, which is preferable. If it is at most the upper limit value, the operability will not be deteriorated even during filtration when purifying the target compound ASTA, which will be described later, and the economy will be excellent, which is preferable.

Further, as the acid which can be used here, the same ones as those used in the above-mentioned heating reaction of aminoguanidine thiocyanate can be exemplified, but hydrochloric acid or sulfuric acid is preferably used for the same reason. The amount of the acid used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 mol of the aminoguanidine salt.

The reaction temperature can be generally 130 ° C. or higher, but 150 ° C. to 190 ° C. is most preferable from the viewpoints of reaction rate, decomposition of raw materials and produced ASTA, and suppression of side reactions.

The reaction time is not particularly limited, but it is generally 15 minutes to 64 hours, preferably 14 to 20 hours.

Regarding the raw material charging, only the thiocyanate and aminoguanidine salt may be charged and the reaction may be carried out. However, considering the operation and stirring at the initial stage of the reaction, a slight amount of water may be added when the thiocyanate is charged. The operability may be improved by adding methanol, ethanol, acetone or the like.

Thus, the target compound of the present invention is obtained.
ASTA can be obtained, but if a higher purity is desired, it can be purified using a method such as column chromatography or acid precipitation.

For acid precipitation, water is added to the reaction mixture containing ASTA obtained in the reaction to form a slurry solution, and ASTA, the thiocyanate as a residual raw material and the ammonium salt as a by-product are dissolved by suction filtration. The filtrate is separated by filtration, and this 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 filtered off by suction filtration. To do. Then, an inorganic acid such as hydrochloric acid is added to the aqueous solution of the ASTA alkali metal salt to adjust the pH to 1-2, and the precipitated ASTA is filtered by suction filtration and dried to obtain 95-99%
ASTA crystals can be obtained.

[0036]

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

Example 1 Into a 1000 ml Erlenmeyer flask equipped with a thermometer and a stirrer, 276.0 g (about 2.0 mol) of aminoguanidine bicarbonate and 305.0 g (4.0 mol) of ammonium thiocyanate were charged and heated on an oil bath. The mixture was melted and maintained at 150 ° C. with stirring, and 432.3 g (about 4.1 mol) of 35 wt% hydrochloric acid was added dropwise over 15 hours to cause a reaction. After the reaction was completed, 500 g of water was added to the reaction mixture and cooled to room temperature, 2.9 g of 35 wt% hydrochloric acid aqueous solution was added to acidify the aqueous solution, and then the formed ASTA precipitate was suction-filtered to obtain water-containing crude ASTA. 264.9 g were obtained.

Next, this ASTA was dissolved in 221.3 g of a 15% by weight aqueous sodium hydroxide solution, the insoluble matter was filtered off by suction filtration, and the resulting filtrate was adjusted to pH 1-2 with 35% by weight hydrochloric acid. An aqueous solution was added to acidify ASTA, and filtered by suction filtration to obtain 346.4 g of water-containing ASTA. This was dried under reduced pressure at 50 ° C. overnight, and 94.4 g (yield 78.8%) of ASTA crystals having a purity of 94.2% by weight.
Got The decomposition temperature of the obtained ASTA is 300 to 302 ° C,
In addition, the results of infrared spectroscopic analysis (IR) were all in agreement with the standard. The IR chart is shown in FIG.

Example 2 Aminoguanidine bicarbonate 277.
2 g (about 2.0 mol), 100 g of water and 160.2 g (about 2.1 mol) of ammonium thiocyanate were put in, and carbon dioxide, water and ammonia were removed at 90 to 100 ° C under reduced pressure by an evaporator to obtain 81.0% by weight of thiocyanic acid. Aminoguanidine 328.
2 g (about 2.0 mol) were obtained.

Next, in the same apparatus as used in Example 1,
The obtained aminoguanidine thiocyanate 328.2 g (about 2.0
Mol) and 155.0 g (about 2.0 mol) of ammonium thiocyanate were charged and the reaction and purification were carried out in the same manner as in Example 1 to obtain 178.3 g (yield) of ASTA crystals having a purity of 95.0% by weight.
73.0%). The decomposition temperature of the obtained ASTA is 299.5-302
C, which was in agreement with the standard.

Ammonium thiocyanate in Example 2 acts as a melting medium in the reaction, and if the amount used is reduced, the reaction system viscosity during the heating reaction increases, and ASTA
It was also found that the yield of H.

[0042]

INDUSTRIAL APPLICABILITY The method of the present invention uses aminoguanidine thiocyanate, which is a raw material that has not been used in the conventional method, or a combination of raw materials, which is not in the conventional method, such as aminoguanidine bicarbonate. This is a method in which a salt and a thiocyanate such as ammonium thiocyanate are used to carry out a heat reaction in the presence of an acid. According to this method, various problems in conventional methods, that is, toxicity and danger of raw materials used In addition, by solving the problems such as high cost of manufacturing facilities and insufficient reaction yield, the target compound 3-amino-5-mercapto-1,2,4- is inexpensive and safe. A triazole can be obtained.

In particular, when aminoguanidine thiocyanate is heated and reacted in the presence of an acid, a thiocyanate is added and used together, or when an aminoguanidine salt and a thiocyanate are heated and reacted in the presence of an acid, aminoguanidine is used. By using an excess amount of thiocyanate with respect to the salt, the effects of improving the yield and preventing the viscosity of the reaction system from increasing excessively and solidifying are also recognized.

[Brief description of drawings]

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

Claims (1)

[Claims] 1. Aminoguanidine thiocyanate, or
A method for synthesizing 3-amino-5-mercapto-1,2,4-triazole, which comprises reacting an aminoguanidine salt and a thiocyanate salt in the presence of an acid with heating.