JP3032386B2 - Process for producing N-guanidinothiourea salt and 3-amino-5-mercapto-1,2,4-triazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an N-guanidinothiourea salt useful as an intermediate material for pharmaceutical and agricultural chemical 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 process for producing N-guanidinothiourea, an intermediate of 3-amino-5-mercapto-1,2,4-triazole, which comprises reacting a compound having a compound with a compound having heat in a polar solvent in the presence of an acid. About

Further, a compound having both a thiocyanic acid group and an aminoguanidine group, or a compound having a thiocyanic acid group and a compound having an aminoguanidine group,
A process for producing 3-amino-5-mercapto-1,2,4-triazole, which comprises heating and reacting in a polar solvent in the presence of an acid and then heating and reacting the resulting reaction solution under alkaline conditions. Things.

[0003]

2. Description of the Related Art Several methods for producing 3-amino-5-mercapto-1,2,4-triazole (hereinafter sometimes abbreviated as ASTA) are known in the art. Japanese Patent Publication No. 1960981 proposes a method in which aminoguanidine bicarbonate is first dissolved in ethanol in which acetic acid is dissolved, triethylamine is added thereto, and carbon disulfide is blown into the reaction. . This reaction is considered to follow the following formulas (a) to (c).

[0004]

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[0005]

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[0006]

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[0007] In addition, US Patent No. 1002291 proposes a method of synthesizing aminoguanidine hydrochloride and thiourea by a melt reaction without solvent as shown by the following formula (d).

[0008]

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However, the compound of the present invention, which has both a thiocyanate group and an aminoguanidine group,
Alternatively, a method is not known 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 under alkaline conditions.

[0010] In the first proposed method, there are problems such as toxicity of the carbon disulfide as a raw material, flammability and explosiveness. In addition, the method of the second proposal does not necessarily result in high reaction yield, and the thiourea as a raw material has problems of toxicity and carcinogenicity. As a result, it has been found that there are problems such as an increase in manufacturing equipment costs as in the case of the first proposal.

Further, Japanese Patent Application Laid-Open No. 59-124333 discloses N-guanidinothiourea (hereinafter sometimes abbreviated as GTU).
A method for synthesizing ASTA by dissolving a hydrochloride in an aqueous solution of sodium hydroxide and causing a heat reaction is described. However, this proposal does not disclose a method for synthesizing GTU at all, and naturally, a compound having both a thiocyanic acid group and an aminoguanidine group, or a compound having a thiocyanic acid group and an aminoguanidine which are the methods of the present invention. There is no description or suggestion of a method for producing ASTA using a compound having a group as a raw material.

[0012]

SUMMARY OF THE INVENTION The present inventors have solved the above-mentioned problems of the prior art and have proposed a safe and inexpensive AS.
As a result of conducting research to develop TA manufacturing methods, for example,
When a compound having an aminoguanidine group such as aminoguanidine bicarbonate and a compound having a thiocyanate group such as ammonium thiocyanate are heated and reacted in a polar solvent such as water in the presence of an acid such as hydrochloric acid, GTU hydrochloride, etc. A salt of the intermediate is formed, and then the obtained 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 produce the desired ASTA.
Were found to be able to be synthesized, and further research was carried out to complete the present invention.

[0013]

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

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

Hereinafter, the present invention will be described in detail. The present invention
A compound having both a thiocyanic acid group and an aminoguanidine group, or a compound having an thiocyanic acid group and a compound having an aminoguanidine group are heated and reacted in a polar solvent in the presence of an acid to obtain a compound of the present invention. An intermediate of ASTA, a salt of GTU is formed (first stage reaction),

Next, the present invention relates to a method for producing ASTA, which comprises subjecting a reaction solution containing the GTU salt to a heating reaction under alkaline conditions (second stage reaction).

First Step Reaction Examples of the compound having both a thiocyanic acid group and an aminoguanidine group which can be used in the first step reaction of the method of the present invention include, for example, aminoguanidine thiocyanate. .

Examples of the compound having a thiocyanate group include ammonium thiocyanate, potassium thiocyanate, sodium thiocyanate, lithium thiocyanate, calcium thiocyanate, magnesium thiocyanate, and barium thiocyanate. Among these, use of ammonium thiocyanate is most preferable from the viewpoints of good operability when the reaction is performed on an industrial scale, easy availability, and the like.

Furthermore, examples of the compound having an aminoguanidine group include aminoguanidine hydrochloride, aminoguanidine dihydrochloride, aminoguanidine sulfate, aminoguanidine bisulfate, aminoguanidine carbonate, aminoguanidine bicarbonate, and the like. Among them, the use of aminoguanidine bicarbonate is most preferable from the viewpoint of good operability when the reaction is carried out on an industrial scale, easy availability, and the like.

In the first-stage reaction, when a compound having a thiocyanate 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 and ammonia and carbon dioxide are distilled off together with water to generate aminoguanidine thiocyanate can also be suitably employed.

The acid which can be used in the first-stage 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. The use of hydrochloric acid or sulfuric acid is preferred 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 viewpoint of easy availability and reactivity, for example, water;
Use of lower alcohols such as methyl alcohol, ethyl alcohol and i-propyl alcohol;
The use of water is particularly preferred.

It is considered that the first-stage reaction of the method of the present invention proceeds as in the following formula (1).

[0024]

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

As is clear from the above reaction formula, one equivalent of a thiocyanate group and one equivalent of an acid are required for one equivalent of an aminoguanidine group. However, from the viewpoint of good reactivity, one equivalent of an aminoguanidine group is required. Thiocyanic acid group is 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 it is preferable to drop it into the reaction system at an appropriate concentration with water or the like, if necessary.

The reaction can be carried out generally at a temperature of 50 ° C. or higher, but is preferably 80 ° C. to 120 ° C. from the viewpoints of the reaction rate, decomposition of raw materials and GTU produced and suppression of side reactions.

Although the reaction time is not particularly limited, it is generally from 5 minutes to 4 hours, preferably from 10 to 3 hours.

After completion of the reaction, the obtained reaction solution is concentrated if necessary and then cooled to crystallize a GTU salt which is an intermediate of the desired compound ASTA of the present invention, and the mixture is filtered off. GTU salt crystals can be obtained. Since GTU salts have some water solubility, a considerable amount of GTU is contained in the filtrate.
Although the salt is dissolved, the GTU salt yield can be improved by recycling the filtrate.

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

Second Step Reaction The target compound ASTA of the present invention was produced as described above.
GTU can be produced by dissolving a salt of GTU in the same polar solvent as described above, adding an alkaline compound to the obtained GTU solution or the like to make the solution alkaline, and then performing a heating reaction. After completion of the reaction, the reaction solution after the completion of the reaction can be used as a GTU solution without separating and collecting the salt of GTU.

The first stage reaction of the method of the present invention is represented by the following formula (2) and
It is thought to proceed as in (3).

[0034]

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[0035]

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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 the solution to an appropriate concentration with water or the like and to drop it into the reaction system. The pH of the reaction solution is generally about 7 to 14, preferably about 9 to 13.

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

Although the reaction time is not particularly limited, it is generally from 10 minutes to 6 hours, preferably from 1 to 2 hours.

After completion of the reaction, ASTA, which is the target compound of the present invention, can be obtained with high purity by adding the acid exemplified above such as hydrochloric acid to the obtained reaction solution to adjust the pH to about 1 to 2. . If a higher purity is desired, 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 form an aqueous solution of an alkali metal salt of ASTA, and insoluble components such as sulfur are removed by suction filtration. Filter off. And that
Add hydrochloric acid or the like to the aqueous solution of ASTA alkali metal salt and add pH 1-2.
Then, the precipitated ASTA is separated by suction filtration and dried to obtain 85 to 100% of ASTA crystals.

[0043]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 In a 100 ml eggplant type flask equipped with a thermometer and a stirrer, 27.2 g (about 0.2 mol) of aminoguanidine bicarbonate, 15.2 g (about 0.2 mol) of ammonium thiocyanate and 10 g of deionized water
And heated on an oil bath to raise the reaction liquid temperature to 108 ° C.
Water, carbon dioxide, and ammonia were distilled off until the temperature became.

Next, a reflux condenser was set in this apparatus, and the reaction solution was heated to 95 ° C. and stirred while stirring at 28.0 g of 35% by weight hydrochloric acid.
(Approximately 0.27 mol) was added dropwise over 2 hours, and the mixture was kept at the same temperature for 1 hour, cooled to room temperature, and the crystallized crystal was filtered. The obtained wet crystal was dried under reduced pressure at 50 ° C overnight under reduced pressure. ,purity
16.3 g (about 0.11 mol) of 91% by weight of GTU hydrochloride crystals were obtained.
The melting point of the obtained GTU hydrochloride is 195-197 ° C, and
The result of infrared spectroscopy (IR) was as shown in FIG.
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% based on aminoguanidine bicarbonate.

Example 2 The same apparatus as in Example 1 was used, and the same amounts of aminoguanidine bicarbonate, ammonium thiocyanate and deionized water as in Example 1 were added thereto, and heated in an oil bath in the same manner. , Carbon dioxide and ammonia were distilled off. Next, a reflux condenser was set in this apparatus, and the reaction solution was heated to 95 ° C. and stirred while stirring, as in Example 1.
(About 0.27 mol) was added dropwise over 2 hours, and further kept at the same temperature for 1 hour to obtain a reaction solution containing GTU hydrochloride.

Next, 18.3 g (about 0.23 mol) of a 50% by weight aqueous sodium hydroxide solution was added to the reaction solution to make the reaction solution alkaline, and the mixture was heated under reflux (about 110 ° C.) on an oil bath for 1.5 hours.
Allowed to react for hours. After the reaction is completed, cool the reaction solution to room temperature.
9.5 g of 35% by weight hydrochloric acid was added to adjust the pH to 1-2, and it was formed.
The ASTA precipitate was separated by filtration to obtain 24.5 g of water-containing ASTA. This hydrous A
STA was dried under reduced pressure at 50 ° C. overnight, and ASTA having a purity of 97.1% by weight was obtained.
19.2 g of crystals (about 0.161 mol; about 80.3% yield based on aminoguanidine bicarbonate) were obtained. The decomposition temperature of the obtained ASTA is
298-301 ° C, and the results of infrared spectroscopy (IR) are as shown in FIG.

Example 3 13.2 g (about 0.13 mol) of 98% by weight concentrated sulfuric acid instead of using 28.0 g (about 0.27 mol) of 35% by weight hydrochloric acid in the step of producing a reaction solution containing GTU hydrochloride of Example 2 16.8 g (0.138 mol; ratio to aminoguanidine bicarbonate 70.5%) of ASTA crystals was obtained in the same manner except for using. The decomposition temperature of the obtained ASTA was 295 to 299 ° C, which almost coincided with the standard.

EXAMPLE 4 1382 g (about 10 mol) of aminoguanidine bicarbonate, 767 g (about 10 mol) of ammonium thiocyanate and 500 g of deionized water were placed in a 5-liter separable flask equipped with a thermometer and a stirrer.
And heated on an oil bath to raise the reaction liquid temperature to 108 ° C.
Water, carbon dioxide, and ammonia were distilled off until the temperature became.

Next, a reflux condenser was set in this apparatus, and 1247 g of 35% by weight hydrochloric acid was heated and stirred at 95 ° C.
(About 12 mol) was added dropwise over 2 hours.
After holding for a time, a reaction solution containing GTU hydrochloride was obtained.

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

[0052]

According to the method of the present invention, a compound having both a thiocyanic acid group and an aminoguanidine group, such as aminoguanidine thiocyanate, which is a raw material never used in the conventional method, or a raw material not used in the conventional method is used. A combination of a compound having an aminoguanidine group such as aminoguanidine bicarbonate and a compound having a thiocyanate group such as ammonium thiocyanate, which is subjected to a heat reaction in a polar solvent in the presence of an acid in the presence of an acid. -Pertaining 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 heated and reacted in a polar solvent in the presence of an acid. The present invention further relates to the production of 3-amino-5-mercapto-1,2,4-triazole, wherein the resulting reaction solution is heated and reacted under alkaline conditions.

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

[Brief description of the drawings]

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

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

Continuation of the front page (56) References JP-A-5-247004 (JP, A) JP-A-58-193541 (JP, A) Journal of Heterocyclic Chemistry; vol. 26 (No. 2) p355-360 (1989) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 249/14 C07C 337/06 BEILSTEIN (STN) CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] Claims 1. A compound having both a thiocyanic acid group and an aminoguanidine group, or a compound having a thiocyanic acid group and a compound having an aminoguanidine group are heated and reacted 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 thiocyanic acid group and an aminoguanidine group, or a compound having a thiocyanic acid group and a compound having an aminoguanidine group are heated and reacted in a polar solvent in the presence of an acid. A method for producing 3-amino-5-mercapto-1,2,4-triazole, wherein the obtained reaction solution is heated and reacted under alkaline conditions.