JPH05247004A - Synthesis of 3-amino-5-mercapto-1,2,4-triazole - Google Patents

Abstract

PURPOSE:To safely and inexpensively obtain 3-methyl-5-mercapto-1,2,4-triazole useful as an intermediate for medicines and agricultural chemical materials in easy operation and high yield. CONSTITUTION:(i) >=0.5mol, especially 0.5-2mol thiocyanic acid salt, particularly ammonium thiocyanate based on 1mol aminoguanidine thiocyanic acid salt of formula I is added to the compound of formula I and both components are subjected to heat reaction, normally in solventless and melted conditions, normally at >=130 deg.C, especially at 150-190 deg.C or (ii) the amino guanidine salt and normally 1-20mol, preferably 1-5mol thiocyanic acid salt based on 1mol of the compound are subjected to heat melt reaction, preferably under solventless condition at the above-mentioned temperature condition to advantageously provide the objective compound of formula II. According to the method, problems of a conventional method, e.g. toxicity and danger of raw material, increased cost of production equipment accompanied thereby and insufficient reaction yield can be solved and further, lowering of reaction rate by increase of viscosity of reaction system can be suppressed by use of thiocyanic acid salt.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for synthesizing 3-methyl-5-mercapto-1,2,4-triazole which is useful as an intermediate raw material for pharmaceuticals and agricultural chemicals. A method for synthesizing 3-amino-5-mercapto-1,2,4-triazole, which is characterized by reacting guanidine with heating, and is particularly characterized by reacting an aminoguanidine salt with a thiocyanate salt. The present invention relates to a method for synthesizing -amino-5-mercapto-1,2,4-triazole.

[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 heating the aminoguanidine thiocyanate and the method of reacting the aminoguanidine salt with the thiocyanate, which are the methods of the present invention, are 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 reacting an aminoguanidine salt such as aminoguanidine bicarbonate with a thiocyanate such as ammonium thiocyanate in a solvent-free manner, and further research is conducted to further the present invention. Was completed.

[0011]

The present invention is characterized in that aminoguanidine thiocyanate is reacted by heating.
It is intended to provide a method for synthesizing 3-amino-5-mercapto-1,2,4-triazole, which is characterized by reacting an aminoguanidine salt with a thiocyanate salt.
It is intended to provide a method for synthesizing amino-5-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 by reacting aminoguanidine thiocyanate with heat.

This reaction is considered to proceed as in the following equation (1).

[0014]

[Chemical 5]

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 reaction temperature can be generally 130.degree. C. or higher, but 150.degree. C. to 190.degree. 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.

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

Examples of the above aminoguanidine salts 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.

The formation reaction of aminoguanidine thiocyanate is considered to follow the following formula (2) when guanidine bicarbonate as the aminoguanidine salt and ammonium thiocyanate as the thiocyanate are used.

[0022]

[Chemical 6]

Further, in the present invention, the aminoguanidine salt and the thiocyanate salt are subjected to a melting reaction under heating, preferably in the absence of a solvent, to synthesize 3-amino-5-mercapto-1,2,4-triazole. You can also This reaction also passes through aminoguanidine thiocyanate as a reaction intermediate, but by continuing the heating reaction as it is without isolating the aminoguanidine thiocyanate, the target compound 3-amino-5-mercapto is obtained. -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 formula (3).

[0025]

[Chemical 7]

The above 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 with respect to 1 mol of the aminoguanidine salt, but usually 1 mol-
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 does not become too high or solidify, and the reactivity and stirring property do not deteriorate, 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.

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 charging of the raw materials, the reaction may be carried out by charging only thiocyanate and aminoguanidine salt, but 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 the acid precipitation, water is added to the reaction mixture containing ASTA obtained in the reaction to form a slurry solution, and ASTA and the filtrate in which the residual raw material thiocyanate is dissolved are filtered off by suction filtration. , Furthermore, once dissolve this ASTA in an aqueous solution of alkali metal hydroxide such as sodium hydroxide.
An aqueous solution of ASTA alkali metal salt is prepared, and insoluble matter such as sulfur is filtered off by suction filtration. Then, add an inorganic acid such as hydrochloric acid to the aqueous solution of the ASTA alkali metal salt to adjust the pH to 1-2.
Then, 95% to 99% of ASTA crystals can be obtained by separating the precipitated ASTA by suction filtration and drying.

[0032]

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 Erlenmeyer flask equipped with a thermometer and a stirrer was charged with 20.8 g (0.15 mol) of aminoguanidine bicarbonate and 22.3 g (0.30 mol) of ammonium thiocyanate and heated on an oil bath to melt. The mixture was allowed to react with stirring at 150 ° C. for 16 hours. After completion of the reaction, 31.4 g of water and 0.49 g of 35 wt% hydrochloric acid aqueous solution were added to the reaction mixture, and after cooling to room temperature, the formed ASTA precipitate was suction filtered to obtain 15.7 g of water-containing ASTA.

Next, this ASTA was dissolved in 58.9 g of a 10% by weight aqueous sodium hydroxide solution, and the insoluble matter was filtered off by suction filtration to obtain 75.7 g of an aqueous sodium hydroxide solution of ASTA. To this, 16.8 g of 35 wt% hydrochloric acid aqueous solution was added to adjust pH to 1-2, ASTA was acid-deposited, and filtered by suction filtration.
7.4 g was obtained. This was dried under reduced pressure at 80 ° C overnight to obtain a purity of 97.2
11.6 g (yield 64.9%) of ASTA crystals with a weight% was obtained. Got
The melting point of ASTA was 300 to 302 ° C, which was in agreement with the standard product.

Example 2 In Example 1, 22.3 g of ammonium thiocyanate was added.
Instead of using (0.30 mol), the reaction and purification were performed in substantially the same manner as in Example 1 except that 34.0 g (0.45 mol) was used, and the purity was
12.5 g (yield 68.9%) of ASTA crystals of 96.3% by weight was obtained. The melting point of the obtained ASTA was 300 to 301 ° C, which was in agreement with the authentic sample.

Example 3 69.2 g of aminoguanidine bicarbonate in a 300 ml eggplant-shaped flask
(0.5 mol), water 50 g and ammonium thiocyanate 38.3 g
(0.5 mol) and put it under reduced pressure with an evaporator at 90-100 ° C.
The carbon dioxide, water and ammonia were removed with to obtain 68.5 g (0.5 mol) of 97.1 wt% aminoguanidine thiocyanate.

Next, in the same apparatus as used in Example 1,
The obtained aminoguanidine thiocyanate (20.0 g, 0.15 mol) and ammonium thiocyanate (23.0 g, 0.30 mol) were charged, and the reaction and purification were carried out in the same manner as in Example 1 to obtain ASTA crystals 11.4 having a purity of 95.8% by weight. g (yield 62.8%) was obtained. The melting point of the obtained ASTA was 299.5 to 302 ° C, which was in agreement with the standard product.

The ammonium thiocyanate in Example 3 acts as a melting medium in the reaction, and if the amount used is reduced, the viscosity of the reaction system during the heating reaction increases, and ASTA
It was also found that the yield of H.

[0039]

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. A salt and a thiocyanate such as ammonium thiocyanate are used. According to this method, various problems in the conventional method, that is, toxicity and danger of raw materials used, cost of manufacturing equipment accompanying this, etc. It is possible to solve the problems such as high and insufficient reaction yield, and inexpensively and safely obtain the target compound 3-amino-5-mercapto-1,2,4-triazole.

In particular, a thiocyanate is added and used in the heating reaction of aminoguanidine thiocyanate, or a thiocyanate is excessively used with respect to the aminoguanidine salt in the reaction of the aminoguanidine salt and the thiocyanate. As a result, the effects of improving the yield and preventing the viscosity of the reaction system from rising excessively and solidifying are recognized.

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[Procedure amendment]

[Submission date] October 23, 1992

[Procedure Amendment 1]

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[Procedure 3]

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[0014]

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[0025]

[Chemical 7]

[Procedure Amendment 5]

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Next, this ASTA was dissolved in 58.9 g of a 10% by weight aqueous sodium hydroxide solution, and the insoluble matter was filtered off by suction filtration to obtain 75.7 g of an aqueous sodium hydroxide solution of ASTA. To this, 16.8 g of 35 wt% hydrochloric acid aqueous solution was added to adjust the pH to 1-2, ASTA was acid-deposited, and filtered by suction filtration to obtain water-containing ASTA 1
7.4 g was obtained. This was dried under reduced pressure at 80 ° C overnight to obtain a purity of 97.2
11.6 g (yield 64.9%) of ASTA crystals with a weight% was obtained. Got
The decomposition point of ASTA was 300-302 ℃, which was in agreement with the standard product.

[Procedure correction 6]

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Example 2 In Example 1, 22.3 g of ammonium thiocyanate was added.
Instead of using (0.30 mol), the reaction and purification were performed in substantially the same manner as in Example 1 except that 34.0 g (0.45 mol) was used, and the purity was
12.5 g (yield 68.9%) of ASTA crystals of 96.3% by weight was obtained. The decomposition point of the obtained ASTA was 300-301 ° C, which was in agreement with the standard product.

[Procedure Amendment 7]

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Next, in the same apparatus as used in Example 1,
The obtained aminoguanidine thiocyanate (20.0 g, 0.15 mol) and ammonium thiocyanate (23.0 g, 0.30 mol) were charged, and the reaction and purification were carried out in the same manner as in Example 1 to obtain ASTA crystals 11.4 having a purity of 95.8% by weight. g (yield 62.8%) was obtained. The decomposition point of the obtained ASTA was 299.5 to 302 ° C, which was in agreement with the standard product.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yasushi Imai 46-31 Mitsuke-cho, Hiratsuka-shi, Kanagawa Lions Mansion Hiratsuka-Mitsuke-cho No. 2213

Claims (2)

[Claims] 1. 3-Amino-5-mercapto-1,2, characterized by reacting aminoguanidine thiocyanate with heat.
Synthesis of 4-triazole. 2. An aminoguanidine salt and a thiocyanate are reacted with each other, 3-amino-5-mercapto-
Synthesis of 1,2,4-triazole.