CN110461817A - Stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride and method for producing the same - Google Patents

Abstract

The present invention provides a method for producing stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride, comprising step (A), step ( A): use 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride with the aqueous solution of strong acid mineral acid salt or strong acid organic acid A process of cleaning with an aqueous solution.

Description

Stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane salt Acid and method for producing the same

technical field

The present patent application claims priority and benefits based on the Paris Convention of Japanese Patent Application No. 2017-67358 (filed on March 30, 2017 ), and the entire contents of the above-mentioned application are incorporated herein by reference.

The present invention relates to stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride and a method for producing the same.

Background technique

1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride is known to be useful as an insecticide. As a method for producing 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride, the methods described in Patent Documents 1 to 4 are known. Here, in any production method, a crystal of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride was obtained by filtering the reaction product. The washing method of the crystal after filtration is a method of washing the crystal with methanol as described in Example 6 and Comparative Example 2 of Patent Document 1.

prior art literature

Patent Literature

Patent Document 1: Chinese Patent No. 101519371

Patent Document 2: Chinese Patent Application Publication No. 101103725

Patent Document 3: Japanese Patent Publication No. 42-10969

Patent Document 4: Japanese Patent Publication No. 49-27857

SUMMARY OF THE INVENTION

The problem to be solved by the invention

The stability of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained by the conventional production method is insufficient, for example, in the case of long-term storage , quality degradation due to decomposition is sometimes observed. Therefore, an object of the present invention is to provide 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride having storage stability and a method for producing the same.

methods for solving problems

The inventors of the present invention have conducted studies in order to solve the above-mentioned problems, and as a result, have found that stable 1,3-bis(carbamoylthio)-2-(N,N-dimethyl group can be produced by the following method) amino)-propane hydrochloride.

Specifically, it was found that: by mixing 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride with an aqueous solution of a strongly acidic inorganic acid salt or a strongly acidic 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride can be produced by washing with an aqueous solution of the organic acid obtained by In addition, it was also found that the stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride contains a strongly acidic inorganic acid salt or a strongly acidic The organic acid is the strong acid inorganic acid salt of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride or the strong acid organic acid The form of the adduct is based on the weight of the adduct of the above-mentioned 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride. The content of the inorganic acid salt or strongly acidic organic acid is in the range of 0.05 to 10% by weight.

The present invention is described below, but is not limited thereto.

(Manufacturing method)

[1] A method for producing stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride, comprising step (A),

Step (A): 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride is treated with an aqueous solution of a strongly acidic inorganic acid salt or a strongly acidic organic A process of washing with an aqueous acid solution.

[2] The production method according to the above item [1], wherein the 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)- Propane hydrochloride is 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained in the following manner, and the manner is:

reacting 2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride with hydrogen chloride gas in methanol and an organic solvent that forms a bilayer system with methanol; or

2-(N,N-Dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride is reacted with hydrochloric acid in water and an organic solvent that forms a bilayer system with water.

[3] The production method according to the above item [2], wherein the organic solvent forming a double-layer system with methanol is selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, dichloromethane and chlorine One or more mixtures of benzene,

The organic solvent that forms a double-layer system with water is one or a mixture of two or more selected from toluene, xylene, 1,2-dichloroethane, chloroform, dichloromethane and chlorobenzene.

[4] The production method according to any one of the above items [1] to [3], wherein the 1,3-bis(carbamoylthio)-2-(N, N-Dimethylamino)-propane hydrochloride is 1,3-hydrochloride obtained by reacting 2-N,N-dimethylamino-1,3-propanedithiol and cyanate in the presence of hydrochloric acid Di(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride.

[5] The production method according to any one of the above items [1] to [4], wherein the strongly acidic inorganic acid salt is ammonium hydrogensulfate, sodium hydrogensulfate, potassium hydrogensulfate, or ammonium hydrogensulfate, and the strong acid is The organic acid is oxalic acid or citric acid.

(Compound (I) as an acid adduct)

[6] Addition of a strongly acidic inorganic acid salt or a strongly acidic organic acid of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride A product that satisfies the following (a) and (b):

(a) Addition of strongly acidic inorganic acid salt or strongly acidic organic acid to 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride The weight of the finished product, the content of the strong acid inorganic acid salt or the strong acid organic acid is in the range of 0.05 to 10% by weight,

(b) The pH of an aqueous solution of an inorganic acid salt of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride or an adduct of an organic acid is 3.7 the following.

[7] The inorganic acid salt or organic acid of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride according to the above item [6] Adducts, wherein, with respect to 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride, a strongly acidic inorganic acid salt or a strongly acidic organic acid salt The weight of the acid adduct, the content of the strongly acidic inorganic acid salt or the strongly acidic organic acid is in the range of 0.1 to 2% by weight.

[8] The 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride according to any one of the preceding items [6] or [7] The inorganic acid salt or organic acid adduct, wherein the strong acid inorganic acid salt or the strong acid organic acid is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, oxalic acid or citric acid.

According to the present invention, stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride can be produced by an industrially implementable method. This hydrochloride is excellent in thermal stability.

Detailed ways

(Manufacturing method)

The present invention is to produce stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) by a method comprising the following step (A) Methods.

The 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) used in the present invention can be produced by, for example, the following production methods (1) to ( 3) The method described in Manufacture.

Here, 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (hereinafter sometimes referred to as "compound (I)") is also referred to as It is called carbamazepine hydrochloride and refers to the compound represented by the following formula.

[hua 1]

In addition, this compound is described in, for example, pages 170-171 of The Pesticide Manual 17th edition.

Production method (1)

2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (hereinafter sometimes referred to as " Compound (II)") is reacted with hydrogen chloride gas, whereby 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) can be obtained.

Examples of the organic solvent that forms a double-layer system with methanol include one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, dichloromethane, and chlorobenzene. .

The reaction can be carried out according to the method described in Patent Document 1 or Patent Document 3.

Manufacturing method (2)

2-(N,N-Dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (II) is reacted with hydrochloric acid in water and organic solvents that form a bilayer system with water , 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) can be obtained thereby.

Examples of the organic solvent that forms a double-layer system with water include one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, dichloromethane, and chlorobenzene. .

The reaction can be carried out according to the method described in Patent Document 2.

Manufacturing method (3)

1 can be obtained by reacting 2-(N,N-dimethylamino)-1,3-propanedithiol (hereinafter sometimes referred to as "compound (III)") with a cyanate salt in the presence of an acid , 3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I).

The reaction can be carried out according to the method described in Patent Document 4.

In the present specification, the cleaning treatment in the following step (A), step (B) and step (C) refers to: for 1,3-bis(carbamoylthio)-2-(N,N-dimethylformyl) 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) containing filtrate crystals of amino)-propane hydrochloride (I) ) crystals (e.g., wet crystals), the crystals are washed with an exemplified aqueous solution or alcohol (e.g., the crystals are immersed in the exemplified aqueous solution or alcohol, or the crystals are dispersed in the exemplified aqueous solution or alcohol), the result is , a part or all of the filtrate contained in the crystal is replaced by an aqueous solution or an alcohol.

1,3-bis(carbamoylthio)-2-(N,N-di) can be adjusted by further performing the following step (B) and/or step (C) after the step (A) is performed The amount of the strongly acidic inorganic acid salt or the strongly acidic organic acid contained in the methylamino)-propane hydrochloride (I). The step (B) and/or the step (C) means that only one of the step (B) or the step (C) may be performed, or both the step (B) and the step (C) may be performed.

First, the step (A) will be described.

In step (A), 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) is treated with an aqueous solution of a strongly acidic inorganic acid salt or Wash with an aqueous solution of a strongly acidic organic acid.

The 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) used in the step (A) may be prepared according to the above-mentioned production method (1). ) to the product prepared by the methods described in (3), or in the following step (B) (including the step (B) following the following step (C)) or the following step (C) (including the following step (B) any of the products prepared after the treatment in the subsequent step (C)). Preferably, it is a product prepared by the methods described in the above-mentioned production methods (1) to (3).

Examples of the strongly acidic inorganic acid salts include sulfates and nitrates, and specific examples of the sulfates include ammonium hydrogensulfate, sodium hydrogensulfate, potassium hydrogensulfate, and ammonium hydrogensulfate. For sodium bisulfate and potassium bisulfate, sodium bisulfate and potassium bisulfate produced by mixing sodium sulfate or potassium sulfate with concentrated hydrochloric acid can be used, respectively. In this case, sodium bisulfate and sodium chloride can be directly used, respectively. mixture, and a mixture of potassium bisulfate and potassium chloride. Ammonium bisulfate can be prepared by mixing ammonium sulfate with concentrated hydrochloric acid, or ammonium bisulfate containing ammonium chloride can be used.

Preferable specific examples of the strongly acidic inorganic acid salt include ammonium hydrogensulfate and sodium hydrogensulfate.

Examples of the strongly acidic organic acid include organic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, glycolic acid, lactic acid, glyceric acid, tartaric acid, and citric acid. Preferred specific examples of the strongly acidic organic acid include oxalic acid and citric acid.

As the strongly acidic inorganic acid salt or the strongly acidic organic acid, an acid with low volatility that can remain during long-term storage (eg, at high temperature) is preferable, and a strongly acidic inorganic acid salt is more preferable.

The aqueous solution containing a strongly acidic inorganic acid salt or a strongly acidic organic acid can be prepared by mixing the above-mentioned strongly acidic inorganic acid salt or strongly acidic organic acid, or the acid or salt used to prepare them, with water.

Typically, an aqueous solution of ammonium bisulfate is prepared by mixing concentrated sulfuric acid and ammonia. It can also be used in the form of an aqueous solution of a mixture of ammonium hydrogen sulfate and ammonium chloride.

Typically, aqueous solutions of sodium bisulfate are prepared by mixing concentrated sulfuric acid with sodium hydroxide, or by mixing concentrated sulfuric acid with aqueous sodium hydroxide. As the aqueous solution of sodium hydrogen sulfate, the aqueous solution of sodium hydrogen sulfate prepared as an aqueous solution of a mixture of sodium hydrogen sulfate and sodium chloride can also be used as it is.

Typically, an aqueous solution of potassium hydrogen sulfate is prepared by mixing concentrated sulfuric acid with potassium hydroxide, or by mixing concentrated sulfuric acid with an aqueous potassium hydroxide solution. As the aqueous solution of potassium hydrogen sulfate, an aqueous solution of potassium hydrogen sulfate prepared as an aqueous solution of a mixture of potassium hydrogen sulfate and potassium chloride can also be used.

The concentration of the inorganic acid salt or organic acid in the aqueous solution containing the strongly acidic inorganic acid salt or the strongly acidic organic acid is usually in the range of 0.5 to 30% by weight, preferably 1 to 15% by weight, based on the weight of the aqueous solution .

The temperature of the aqueous solution containing a strongly acidic inorganic acid salt or a strongly acidic organic acid used for washing is usually in the range of 0 to 30°C, preferably in the range of 0 to 10°C.

The usage-amount of the aqueous solution containing the strongly acidic inorganic acid salt or the strongly acidic organic acid used for washing|cleaning is the range of 5-70 weight% normally with respect to the weight of a wet crystal, Preferably it is the range of 30-50 weight%.

The crude composition containing 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (e.g. including reduced content and/or quality Substances that have been reduced) are slurried with water, hydrochloric acid, an aqueous solution of a strongly acidic inorganic acid salt, or an aqueous solution of a strongly acidic organic acid, and then filtered, and further added to an aqueous solution of water, hydrochloric acid, and a strongly acidic inorganic acid salt Or after heating and dissolving in an aqueous solution of a strongly acidic organic acid, cooling and crystallization, filtration, and subjecting the resultant to the production method of the present invention, stable 1,3-bis(carbamoylthio)-2 can be produced. -(N,N-Dimethylamino)-propane hydrochloride.

As required, the 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) obtained in the step (A) is further supplied to the following In the step (B) and/or (C), the content of the strongly acidic inorganic acid salt or strongly acidic organic acid to be contained can be adjusted.

Step (B) will be described.

In the step (B), 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) is washed with a weakly acidic inorganic salt aqueous solution.

Examples of weakly acidic inorganic salts include ammonium chloride, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, and preferably ammonium chloride.

The weakly acidic inorganic salt aqueous solution can be prepared by mixing the weakly acidic inorganic salt with water, and examples thereof include ammonium chloride aqueous solution.

The concentration of the weakly acidic inorganic salt aqueous solution is usually in the range of 0.5 to 30% by weight, preferably in the range of 1 to 20% by weight, based on the weight of the aqueous solution.

The temperature of the weakly acidic inorganic salt aqueous solution used for washing|cleaning is the range of 0-30 degreeC normally, Preferably it is the range of 0-10 degreeC.

The usage-amount of the weakly acidic inorganic salt aqueous solution used for washing|cleaning is the range of 5 to 60 weight% normally with respect to the weight of a wet crystal, Preferably it is the range of 10 to 30 weight%.

Step (C) will be described.

In step (C), 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride is washed with lower alcohol.

The step (C) is preferably applied to the product obtained by the treatment in the step (A) or the step (B), and more preferably applied to the product obtained by the treatment in the step (A).

The lower alcohol refers to an alcohol having 1 to 3 carbon atoms, and examples thereof include methanol, ethanol, and isopropanol, and methanol is preferable.

The temperature of the lower alcohol used for washing|cleaning is the range of 0-30 degreeC normally, Preferably it is the range of 0-10 degreeC.

The usage-amount of the lower alcohol used for washing|cleaning is the range of 5 to 60 weight% normally with respect to the weight of a wet crystal, Preferably it is the range of 10 to 30 weight%.

The target 1,3-bis(carbamoylthio)-2-(N) can be obtained through a drying step after the last step in the step (A), the step (B) or the step (C). , N-dimethylamino)-propane hydrochloride (I).

All operations of the production method of the present invention can be performed at room temperature. However, in order to suppress the amount of decrease due to mixing of the target product into the cleaning solution, it is preferable to perform cleaning using the cooled cleaning solution.

In the step (A) of the present invention, for 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) containing reduced content and/or reduced quality The composition of 1,3-bis(carbamoylthio)-2 can also be produced in a stable manner by using the salt of the formula (I) with reduced content and/or reduced quality in the production method of the present invention. -(N,N-Dimethylamino)-propane hydrochloride (I). After the salt of formula (I) with reduced content and/or quality is made into a slurry with water, hydrochloric acid, etc., and then filtered, and further heated and dissolved in water, hydrochloric acid, etc., and filtered after cooling and crystallization, the obtained The material is supplied to step (A).

(Compound (I) as an acid adduct)

Strongly acidic inorganic acid salt or strong acid of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride produced by the production method of the present invention In terms of the amount of strongly acidic inorganic acid salts or strongly acidic organic acids contained in the organic acid adduct, relative to 1,3-bis(carbamoylthio)-2-(N,N- The weight of the highly acidic inorganic acid salt or the highly acidic organic acid adduct of dimethylamino)-propane hydrochloride is usually in the range of 0.05 to 10% by weight, preferably in the range of 0.1 to 2% by weight, The range of 0.1 to 1.5 weight% is more preferable, and the range of 0.1 to 1.1 weight% is still more preferable. In addition, the pH of the aqueous solution of the 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride adduct is 4.5 or less, usually 3.0 or more to 4.5 or less , preferably 3.0 or more and 4.2 or less, more preferably 3.3 or more and 4.0 or less, still more preferably 3.7 or less, and still more preferably 3.3 or more and 3.7 or less. Here, the pH of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) means that 1 g of the dry hydrochloride was prepared by dissolving it. A solution obtained in 100 ml of water (hereinafter referred to as "1% aqueous solution") was pH obtained by measuring the pH of the aqueous solution. The pH of a 1% aqueous solution is usually 3.0 to 4.5, but when 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) is decomposed, the Ammonia is produced and the pH tends to rise. Therefore, the pH value is an important indicator for judging whether content reduction and decomposition have occurred. A pH greater than 4.5 (especially 3.7) is not preferred.

The stable 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) produced by the production method of the present invention is the same as that produced by the conventional method. The obtained 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) is more pure and stable (eg, thermally stable) improved, so long-term storage is possible.

The produced 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I), as described in Patent Document 3 and Patent Document 4, has It has strong insecticidal action and can be used as an agricultural insecticidal composition.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples (including Comparative Examples), but the present invention is not limited to these Examples.

The content analysis of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) was carried out by iodometry.

Inorganic acid contained in this inorganic acid salt of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) or an adduct of an organic acid _The content of salts (such as _NH4 ⁺ and ^SO42- plasma) or organic acids (such as oxalic acid) can be calculated from the results of the analysis of ions as follows by using high performance ion chromatography (HIC). ) using the absolute standard curve method. When the organic acid is citric acid, it can be determined by an absolute calibration curve method using liquid chromatography (LC) by UV wavelength detection.

1) Analysis method of sulfate ion (SO ₄ ^2- )

High performance ion chromatography (HIC) method

Main body: DX-120Ion Chromatograph

Detector: Conductivity detector

Suppressor: ASRS-ULTRA 4mm

P/N=061561

Column: IonPac AS4A-SC (4×250mm)

P/N=43174

Guard column: IonPac AG14A (4×50mm)

P/N=46134

Eluent: 1.8mmol/L-Na ₂ CO ₃

1.7mmon/L-NaHCO ₃ mixture

Sample injection volume: 25μL

Column temperature: 35℃

Automatic regeneration suppressor (SelfRegeneration Suppressor (SRS)) current value: 50mA

Flow: 1.0mL/min

Pressure: about 1500PSI

2) Analysis method of ammonium ion (NH ₄ ⁺ ) and sodium ion (Na ⁺ ) ion

Main body: ICS-1000 (DIONEX, Japan) Ion Chromatograph

Detector: Conductivity detector

Chromatographic column: CG16/CS16 (DIONEX, Japan)

Eluent: 30 mmol methanesulfonic acid

Sample injection volume: 25μL

The content of the sodium hydrogensulfate salt was determined by the following calculation formula from the analytical value of sulfate ion (SO ₄ ^2- ) and the analytical value of sodium ion (Na ⁺ ).

The method of obtaining the content of NaHSO ₄ and NaCl

NaHSO ₄ (wt%)=SO ₄ ^2- (%)/96.07×120.06

NaCl (wt%)=(Na ⁺ (%)/22.99-SO ₄ ^2- (%)/96.07)×58.44

In the formula, the symbols have the following meanings.

SO ₄ ^2- (%): Analysis result of SO ₄ ^2- by ion chromatography

Na ⁺ (%): Analysis result of Na ⁺ by ion chromatography

In the case of potassium, instead of Na ⁺ , K ⁺ was analyzed based on ion chromatography.

Calculation method of NH ₄ HSO ₄ and NH ₄ Cl content

NH ₄ HSO ₄ (wt%)=SO ₄ ^2- (%)/96.07×115.11

NH ₄ Cl (wt%)=(NH ₄ ⁺ (%)/18.04-SO ₄ ^2- (%)/96.07)×53.49

In the formula, the symbols have the following meanings.

SO ₄ ^2- (%): Analysis result of SO ₄ ^2- by ion chromatography

NH ₄ ⁺ (%): Analysis results of NH ₄ ⁺ by ion chromatography

3) Analysis method of oxalic acid and citric acid

3-1) Analysis conditions of oxalic acid

The same conditions as for SO ₄ ^2- analysis based on ion chromatography (HIC).

Retention time (RT) for detection of oxalic acid = about 15.2 minutes

3-2) The analysis conditions of citric acid by liquid chromatography (LC) are as follows.

Use LC-20A equivalent

LC column: Mightysil RP-8GP (5μm×4.6mm×250mm)

Flow: 1.0mL/min

Detector: UV wavelength 210nm

Temperature: 40℃

Injection volume: 2 μL

Mobile phase (3L): acetonitrile/water=350mL/2650mL

Sodium 1-pentanesulfonate 2.64g/3L

40% phosphoric acid 0.80g/3L (adjusted to pH=3.0)

Quantitative method: absolute standard curve method (3 points)

Retention time (RT) for citric acid detection = about 5.9 minutes

In the following examples, the pH of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) refers to the preparation of the dry hydrochloric acid pH obtained by measuring the pH of a 1% aqueous solution of the salt.

In the examples, the stability test of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) was performed at constant temperature of 55°C and 60°C implemented in the slot.

Example 1

A solution of 2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (II) 29.6g (0.147mol) in 1,2-dichloroethane 138.0 53.3 g of methanol was added to g (21.4% in compound II concentration), and 55 g (1.496 mol) of hydrogen chloride gas was blown in under cooling at 0 to 5°C over 6 hours. Then, it stirred at 0-5 degreeC for 12 hours. The reaction solution was gradually heated to an internal temperature of 65°C, and after the hydrogen chloride gas and methanol were distilled off, 55 g of water was added. After heating to an internal temperature of 75°C, 1,2-dichloroethane was distilled off by azeotroping with water. After 1,2-dichloroethane was distilled off, the mixture was slowly cooled to 5°C or lower, and the precipitated crystals were filtered, washed with 12.4 g of a separately prepared 10% NH ₄ HSO ₄ aqueous solution, and then washed with 6.2 g of methanol. Under reduced pressure, it was dried at 60° C. for 2 hours to obtain 34.6 g (purity) of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I). 97.8%, yield 83.8%). Appearance is white crystal, pH of 1% aqueous solution is 3.30.

As a result of measurement by ion chromatography of the product, the content of NH ₄ HSO ₄ was 0.61%, and the content of NH ₄ Cl was 0%.

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 3.46, Week 6 3.46, Week 9 3.63, Week 12 4.31

Content determination results after acceleration at 60°C:

Week 3 97.1%, Week 6 98.0%, Week 9 98.1%, Week 12 97.9%

Appearance observation results after acceleration at 60°C:

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the 6th week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the ninth week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

At the 12th week, there was no odor of ammonia, and it was in a powdery and non-sticky state.

Until the 12th week, the pH was 4.5 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 2

A solution of 2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (II) 29.6g (0.147mol) in 1,2-dichloroethane 137.6 53.3 g of methanol was added to g (21.5% in compound (II) concentration), and 47 g (1.358 mol) of hydrogen chloride gas was blown in under cooling at 0 to 5°C over 7 hours. Then, it stirred at 0-5 degreeC for 12 hours. The reaction solution was gradually heated to an internal temperature of 65°C, and after the hydrogen chloride gas and methanol were distilled off, 55 g of water was added. After heating to an internal temperature of 75°C, 1,2-dichloroethane was distilled off by azeotroping with water. After the 1,2-dichloroethane was distilled off, it was slowly cooled to below 5°C, and the precipitated crystals were filtered and washed with 12.4 g of a separately prepared mixture aqueous solution of 10.7% NH ₄ HSO ₄ and 5.0% NH ₄ Cl. It wash|cleaned with methanol 8.0g. Here, a mixture aqueous solution of 10.7% NH ₄ HSO ₄ and 5.0% NH ₄ Cl was prepared by dissolving 5 g of (NH ₄ ) ₂ SO ₄ in 30.7 g of water, and then adding 3.8 g of 35% hydrochloric acid for cleaning purposes. , using 12.4 g of this mixture aqueous solution. Under reduced pressure, it was dried at 60°C for 2 hours to obtain 35.9 g (purity) of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I). 97.5%, yield 86.4%). Appearance is white crystal, pH of 1% aqueous solution is 3.01.

As a result of measurement by ion chromatography analysis of the product, it was found that 1.12% of NH ₄ HSO ₄ and 0.28% of NH ₄ Cl were contained.

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 3.41, Week 6 3.28, Week 9 3.34, Week 12 4.07

Content determination results after acceleration at 60°C:

Week 3 97.1%, Week 6 98.0%, Week 9 98.1%, Week 12 97.5%

Appearance observation results after acceleration at 60°C:

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the 6th week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the ninth week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

At the 12th week, there was no odor of ammonia, and it was in a powdery and non-sticky state.

Until the twelfth week, the pH was 4.1 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 3

A solution of 2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (II) 29.6g (0.147mol) in 1,2-dichloroethane 137.6 53.3 g of methanol was added to g (21.5% in compound (II) concentration), and 47 g (1.358 mol) of hydrogen chloride gas was blown in under cooling at 0 to 5°C over 7 hours. Then, it stirred at 0-5 degreeC for 12 hours. The reaction solution was gradually heated to an internal temperature of 65°C, and after the hydrogen chloride gas and methanol were distilled off, 46 g of water was added. After heating to an internal temperature of 75°C, 1,2-dichloroethane was distilled off by azeotroping with water. After the 1,2-dichloroethane was distilled off, it was slowly cooled to below 5°C, and the precipitated crystals were filtered and washed with 8.9 g of a separately prepared aqueous mixture of 5.2% NH ₄ HSO ₄ and 2.4% NH ₄ Cl. It wash|cleaned with methanol 12.4g. An aqueous solution of 5.2% NH ₄ HSO ₄ and 2.4% NH ₄ Cl was prepared by dissolving 4.5 g of (NH ₄ ) ₂ SO ₄ in 73.1 g of water and then adding 3.8 g of 35% hydrochloric acid. 8.9 g of this mixture aqueous solution. Under reduced pressure, it was dried at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 35.2 g (purity 98.9%, yield 87.2%). Appearance is white crystal, pH of 1% aqueous solution is 3.88.

As a result of the measurement by ion chromatography of the product, it was found that it contained 0.11% of _NH4HSO4 and 0.07% of _{NH4Cl .}

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 4.23, Week 6 4.10, Week 9 4.13, Week 12 4.21

Content determination results after acceleration at 60°C:

Week 3 97.9%, Week 6 98.5%, Week 9 99.0%, Week 12 99.0%

Appearance observation results after acceleration at 60°C:

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the 6th week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the ninth week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

At the 12th week, there was no odor of ammonia, and it was in a powdery and non-sticky state.

Until the twelfth week, the pH was 4.3 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 4

The same reaction and treatment as in Example 1 were carried out, and 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) before filtration was carried out. After 542.26 g of slurry liquids were cooled to around 5°C, they were centrifuged with a tabletop small centrifuge. The obtained wet crystals were washed with 37.28 g of a mixture aqueous solution of 10.7% NH ₄ HSO ₄ and 5.0% NH ₄ Cl prepared from (NH ₄ ) ₂ SO ₄ and 36% hydrochloric acid, and then with methanol 84.00 g.

226.74 g of the obtained wet crystals were dried at 75° C. under reduced pressure for 2 hours to obtain 168.11 g of a dried product (purity 97.5%). Appearance is white crystal, pH of 1% aqueous solution is 3.51. As a result of measurement by ion chromatography analysis of the product, it was found that it contained 0.35% of NH ₄ HSO ₄ and 0.19% of NH ₄ Cl.

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 3.59, Week 6 3.81

Content determination results after acceleration at 60°C:

97.5% in week 3, 97.7% in week 6

Appearance observation results after acceleration at 60°C:

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the 6th week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

Until the sixth week, the pH was 4.0 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 5

The same reaction and treatment as in Example 1 were carried out, and 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) before filtration was carried out. After 532.68 g of slurry liquids were cooled to around 5°C, they were centrifuged with a tabletop small centrifuge. The resulting wet crystals were washed with 51.31 g of a mixture aqueous solution of 10.7% NH ₄ HSO ₄ and 5.0% NH ₄ Cl prepared from (NH ₄ ) ₂ SO ₄ and 36% hydrochloric acid, followed by washing with 20% NH ₄ Cl 69.32 g.

289.67 g of the obtained wet crystals were dried at 75° C. under reduced pressure for 2 hours to obtain 183.13 g of a dried product (purity 92.0%). Appearance is white crystal, pH of 1% aqueous solution is 3.11. In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 3.28, Week 6 3.84

Content determination results after acceleration at 60°C:

93.1% in week 3, 93.5% in week 6

Appearance observation results after acceleration at 60°C:

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the 6th week, there was no odor of ammonia, and it was in a powdery and non-sticking state.

Until the sixth week, the pH was 4.0 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 6

40 g (0.146 mol) of degraded 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (content: 95.8%, pH 5.20) ) in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 13.1 g of concentrated hydrochloric acid to 28.0 g of water), slurried at 5°C or less, stirred for 1 hour, and then filtered the precipitated crystals with After washing with 7.5 g of methanol, washing was performed with 9.4 g of a mixture aqueous solution of 7.1% NH ₄ HSO ₄ and 3.3% NH ₄ Cl. Here, a mixture aqueous solution of 7.1% NH ₄ HSO ₄ and 2.4% NH ₄ Cl was prepared by dissolving 0.79 g of (NH ₄ ) ₂ SO ₄ in 78.0 g of water, and then adding 0.61 g of 35% hydrochloric acid. After drying at 60°C for 2 hours under reduced pressure, 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 37.8 g (purity 99.2 g) was obtained %, recovery rate 94.4%). Appearance is white crystal, pH of 1% aqueous solution is 3.38.

As a result of measurement based on ion chromatography analysis of the product, it was found that it contained 0.92% of _NH4HSO4 and 0.47% of _{NH4Cl .}

pH measurement results after acceleration at 60°C:

Week 2 3.50, Week 3 3.56, Week 5 3.67

Content determination results after acceleration at 60°C:

Week 2 98.9%, Week 3 98.7%, Week 5 98.5%

Appearance observation results after acceleration at 60°C:

In the second week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

In the third week, there was no smell of ammonia, and it was in a powdery and non-sticky state.

Until the 5th week, the pH was 4.0 or less, and neither the decrease in the content of the product nor the change in appearance was observed.

Example 7

The same reaction and treatment as in Example 1 were carried out, and the unwashed 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained by filtration was (1) After 45.0 g of wet crystals (content: 84.1%, 0.138 mol) were slurried in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 13.1 g of concentrated hydrochloric acid to 28.0 g of water), the temperature was 5°C or lower. After cooling and stirring for 1 hour, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% oxalic acid aqueous solution (0.68 g of oxalic acid was dissolved in 12.94 g of water). It was dried under reduced pressure at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 33.97 g (purity 97.6 g) %, recovery rate 87.6%). As a result of measurement by ion chromatography analysis of the product, it was found that 0.24% of oxalic acid was contained. Appearance is white crystal, pH of 1% aqueous solution is 3.18.

pH measurement results after acceleration at 55°C:

Week 2 3.25, Week 2 3.38, Week 6 3.53, Week 8 4.02

Content determination results after acceleration at 55°C:

Week 8 97.3%

Appearance observation results after acceleration at 55°C:

Until the 8th week, the pH was 4.0 or less, there was no odor of ammonia, and it was in a powdery and non-sticky state. The content residual ratio was 99.7%, and no increase in impurities or change in appearance was observed.

Example 8

The same reaction and treatment as in Example 1 were carried out, and the unwashed 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained by filtration was (1) After 45.0 g of wet crystals (content: 84.1%, 0.138 mol) were slurried in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 13.1 g of concentrated hydrochloric acid to 28.0 g of water), the temperature was 5°C or lower. After cooling and stirring for 1 hour, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% citric acid aqueous solution (0.68 g of citric acid was dissolved in 12.94 g of water). It was dried under reduced pressure at 60° C. for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 35.24 g (purity 98.2 g) %, recovery rate 91.4%). As a result of analysis and measurement of the product, it was found that 0.32% of citric acid was contained. Appearance is white crystal, pH of 1% aqueous solution is 3.50.

pH measurement results after acceleration at 55°C:

Week 2 3.51, Week 2 3.61, Week 6 3.66, Week 8 3.80

Content determination results after acceleration at 55°C:

Week 8 98.1%

Appearance observation results after acceleration at 55°C:

Until the 8th week, the pH was 4.0 or less, there was no odor of ammonia, and it was in a powdery and non-sticky state. Neither an increase in impurities nor a change in appearance was observed.

Example 9

30 g (0.102 mol) of degraded 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (content: 93.1%, pH 5.00) ) was slurried in 2.0% dilute hydrochloric acid (diluted hydrochloric acid obtained by adding 1.9 g of concentrated hydrochloric acid to 33.0 g of water), and then heated to 70° C. to dissolve completely. After adding 9.0 g of 36% hydrochloric acid at the same temperature, it was cooled to 55°C, and methanol 12.0 was added. After slowly cooling to 10° C. or lower, and stirring for 1 hour, the precipitated crystals were filtered, washed with 7.5 g of methanol, and then washed with a 3.0% NH ₄ HSO ₄ water/methanol mixed solution. Here, a 3.0% NH ₄ HSO ₄ water/methanol mixed solution was prepared by dissolving 0.30 g of NH ₄ HSO ₄ in 5.1 g of water, and then adding 4.50 g of methanol. It was dried under reduced pressure at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 25.3 g (purity 98.6 g) %, recovery rate 90.7%). As a result of measurement based on ion chromatography analysis of the product, it was found that NH ₄ HSO ₄ was 0.54% and the content of NH ₄ Cl was 0%. Appearance is white crystal, pH of 1% aqueous solution is 3.33.

pH measurement results after acceleration at 60°C:

Week 2 3.38, Week 3 3.37, Week 5 3.28, Week 7 3.46,

Week 10 3.60

Appearance observation results after acceleration at 60°C:

Until the 10th week, the pH was 3.6 or less, there was no odor of ammonia, and it was in a powdery and non-sticky state. Compared with Comparative Example 6, the pH did not rise, and the stability improved. The content survival rate at week 10 was 99.5%.

Example 10

The slurry liquid obtained by carrying out the same reaction and treatment as in Example 1 was placed in a centrifuge, and the 1,3-bis(carbamoylthio)-2-(N,N-dimethyl group) collected by filtration Amino)-propane hydrochloride (I) about 35 parts by weight of wet crystals was sprayed and washed with about 7 parts by weight of methanol on a centrifugal separator, and further mixed with about 4% w/w of NH ₄ HSO ₄ -water-methanol About 8.5 parts by weight of the solution (0.35 parts by weight of NH ₄ HSO ₄ , 2.8 parts by weight of water, and 5.3 parts by weight of methanol) were sprayed and washed. This operation was carried out a dozen times using a basket, and the obtained wet crystals were air-dried to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane salt Acid (I) (purity 98.1%). As a result of the measurement based on the ion chromatography analysis of the product, the content of NH ₄ HSO ₄ was 0.31%, and the content of NH ₄ Cl was 0%. Appearance is white crystal, pH of 1% aqueous solution is 3.50.

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 1 3.51, Week 2 3.48, Week 4 3.50, Week 7 3.57,

Week 8 3.54

Content determination results after acceleration at 60°C:

Week 8 98.0% (content residual rate 99.8%)

Appearance observation results after acceleration at 60°C:

Until the 8th week, there was no odor of ammonia, a powdery and non-sticky state, and no change in appearance was observed.

Compared with Comparative Example 7 in which only methanol was used for washing, the stability was greatly improved.

Example 11

The same reaction and treatment as in Example 1 were carried out, and the unwashed 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained by filtration was (1) After 45.0 g of wet crystals (content: 84.1%, 0.138 mol) were slurried in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 13.1 g of concentrated hydrochloric acid to 28.0 g of water), the temperature was 5°C or lower. After cooling and stirring for 1 hour, the precipitated crystals were filtered and prepared using a 10.0% NaHSO ₄ aqueous solution (1.28 g of 98% sulfuric acid was diluted with 12.2 g of water and then neutralized with 1.90 g of 27% NaOH, pH 0.52) 15.42 g After spray cleaning, spray cleaning was performed using 10% NaH ₂ PO ₄ 7.7 g (pH 4.13). It was dried at 60°C under reduced pressure for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 38.07 g (purity 98.3 g) %, recovery rate 98.9%). As a result of measurement based on ion chromatography analysis of the product, the content of NH ₄ HSO ₄ was 0.41%, and the content of NH ₄ Cl was 0%. Appearance is white crystal, pH of 1% aqueous solution is 3.20.

pH measurement results after acceleration at 55°C:

Week 2 3.28, Week 2 3.29, Week 6 3.44, Week 8 4.06

Content determination results after acceleration at 55°C:

Week 8 97.8%

Appearance observation results after acceleration at 55°C:

Until the 8th week, the pH was 4.0 or less, there was no odor of ammonia, and it was in a powdery and non-sticky state. The content residual ratio was 99.5%, and no increase in impurities or change in appearance was observed.

Comparative Example 1

A solution of 2-(N,N-dimethylamino)-1,3-bis(thiocyanoyl)-propane hydrochloride (II) 29.6g (0.147mol) in 1,2-dichloroethane 133.4 53.4 g of methanol was added to g (22.2% in compound II concentration), and 49.5 g (1.358 mol) of hydrogen chloride gas was blown in under cooling at 0 to 5°C over 8 hours. Then, it stirred at 0-5 degreeC for 12 hours. The reaction solution was gradually heated to an internal temperature of 65°C, and after the hydrogen chloride gas and methanol were distilled off, 55 g of water was added. After heating to an internal temperature of 75°C, 1,2-dichloroethane was distilled off by azeotroping with water. After 1,2-dichloroethane was distilled off, it cooled gradually to 5 degreeC or less, and the crystal|crystallization which precipitated was filtered, and it wash|cleaned with methanol 12.5g. Under reduced pressure, it was dried at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 33.6 g ( Purity 98.7%, yield 83.2%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance was white crystals, with a slight product specific odor, and the pH of a 1% aqueous solution was 4.03. In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 4.51, Week 6 4.71, Week 9 5.48, Week 12 5.86

Content determination results after acceleration at 60°C:

Week 3 98.0%, Week 6 98.5%, Week 9 98.4%, Week 12 94.5%

Appearance observation results after acceleration at 60°C:

Slight ammonia odor in week 3.

Slight ammonia odor at 6 weeks.

Slight ammonia odor at week 9.

Slight ammonia odor at week 12.

After the 3rd week, the pH slowly rose and an ammonia odor was emitted.

If the pH exceeds 4.5 after the 3rd week, an abnormal value is shown.

Comparative Example 2

80 g (0.292 mol) of degraded 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (content: 95.8%, pH 5.20) ) in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 26.3 g of concentrated hydrochloric acid to 56.0 g of water), then slurried at 5°C or less, stirred for 1 hour, and then filtered the precipitated crystals with 26.9 g of methanol was used for washing. It was dried at 60°C for 2 hours to obtain 74.3 g of 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (purity 99.2%, recovered rate 93.6%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 4.36. In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 3 5.28, Week 6 5.62

Content determination results after acceleration at 60°C:

99.0% in week 3, 98.4% in week 6

Appearance observation results after acceleration at 60°C:

Slight ammonia smell in 3rd week. No sticking.

Slight ammonia smell at 6th week. Slightly sticky, but easy to untangle.

For only 3 weeks, the pH exceeded 5.2, showing an abnormal value.

Comparative Example 3

1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I ) of 224.96 g of unwashed wet crystals were dried at 75° C. under reduced pressure for 2 hours to obtain 197.99 g of a dried product (purity 98.0%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 3.95.

pH measurement results after acceleration at 60°C:

Week 2 4.20, Week 3 4.45, Week 6 4.65, Week 9 5.02

Content determination results after acceleration at 60°C:

Week 2 98.0%, Week 3 98.1%, Week 6 97.4%, Week 9 96.3%

Appearance observation results after acceleration at 60°C:

Slight ammonia smell in the 2nd week. It is powdery and non-sticky.

Slight ammonia smell in 3rd week. It is powdery and non-sticky.

Ammonia smell in week 6. Sticking occurs slightly.

Ammonia smell in week 9. Sticking occurs.

The pH started to rise from only 2 weeks, an ammonia odor developed at the 3rd week, and a decrease was observed.

Comparative Example 4

1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I ) of 233.00 g of uncleaned wet crystals and 233.00 g of the filtrate were mixed, and the solution obtained by reslurrying was cooled to around 5° C., and then centrifuged with a small table-top centrifuge. Washing was performed while centrifuging the obtained wet crystals using 64.0 g of methanol. 217.20 g of the obtained wet crystals were dried at 75° C. under reduced pressure for 2 hours to obtain 190.00 g of a dried product (purity 98.0%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 4.27.

pH measurement results after acceleration at 60°C:

Week 3 4.46, Week 6 5.08, Week 9 5.12

Content determination results after acceleration at 60°C:

Week 3 98.1%, Week 6 96.2%, Week 9 96.0%

Appearance observation results after acceleration at 60°C:

Slight ammonia smell in 3rd week. It is powdery and not sticky.

Ammonia smell in week 6. Sticking occurs slightly.

Ammonia smell in week 9. Sticking occurs.

After only 3 weeks, the pH increased and an ammonia odor was generated, and at the 6th week, the pH was 5.0 or more and became an abnormal value.

Comparative Example 5

The same reaction and treatment as in Example 1 were carried out, and the unwashed 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride obtained by filtration was (1) After 45.0 g of wet crystals (content: 84.1%, 0.138 mol) were slurried in 11.5% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 13.1 g of concentrated hydrochloric acid to 28.0 g of water), the temperature was 5°C or lower. After cooling and stirring for 1 hour, the precipitated crystals were filtered and washed with 12.87 g of methanol. It was dried under reduced pressure at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 34.53 g (purity 99.2 g) %, recovery rate 91.3%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 4.14.

pH measurement results after acceleration at 55°C:

Week 2 4.24, Week 4 4.37, Week 6 4.51, Week 8 4.93

Appearance observation results after acceleration at 55°C:

The pH6 gradually increased from the second week, and after the sixth week, yellow-spotted foreign matter was observed and an odor was emitted. The odor intensified and decomposed at week 8.

Comparative Example 6

30 g (0.102 mol) of degraded 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) (content: 93.1%, pH 5.00) ) was slurried in 1.0% dilute hydrochloric acid (dilute hydrochloric acid obtained by adding 0.9 g of concentrated hydrochloric acid to 30.0 g of water), and then heated to 70° C. to dissolve completely. After adding 10.5 g of 36% hydrochloric acid at the same temperature, it was cooled to 55°C, and methanol 12.0 was added. After slowly cooling to 10° C. or lower and stirring for 1 hour, the precipitated crystals were filtered and washed with 7.5 g of methanol. It was dried under reduced pressure at 60°C for 2 hours to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) 26.9 g (purity 98.6 g) %, recovery rate 90.8%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 4.10.

pH measurement results after acceleration at 60°C:

Week 2 4.18, Week 3 4.30, Week 5 4.35, Week 7 4.40

Week 10 4.58

Appearance observation results after acceleration at 60°C:

An increase in pH was observed from about the third week, and the occurrence of odor was observed after the fifth week. The odor also became stronger at the 10th week, and the content residual rate was 97.5%. The degraded 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride (I) was purified by recrystallization to be the same as the usual product (Padan). (registered trademark)), the stability was improved, but compared with the product obtained by washing with NH ₄ HSO ₄ aqueous methanol solution as in Example 9, the stability was poor.

Comparative Example 7

The same reaction and treatment as in Example 1 were carried out, and the 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane hydrochloride ( 1) About 35 parts by weight of wet crystals are sprayed and washed with about 7 parts by weight of methanol on a centrifugal separator. This operation was carried out a dozen times using a basket, and the obtained wet crystals were air-dried to obtain 1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)-propane salt Acid (I) (purity 98.3%). As a result of measurement by ion chromatography of the product, NH ₄ HSO ₄ and NH ₄ Cl were not detected. Appearance is white crystal, pH of 1% aqueous solution is 3.94.

In order to confirm the stability, an accelerated test at 60°C was carried out to observe the progress. The results of the accelerated test at 60°C are shown below.

pH measurement results after acceleration at 60°C:

Week 1 4.08, Week 2 4.83, Week 4 5.50, Week 7 5.15,

Week 8 5.32

Content determination results after acceleration at 60°C:

Week 8 96.0% (content residual rate 97.7%)

Appearance observation results after acceleration at 60°C:

Strong ammonia odor from week 2, fully solidified by week 8.

Industrial Availability

According to the production method of the present invention, 1,3-bis(carbamoylthio)-2-(N,N having excellent insecticidal action can be produced as a substance with good purity and yield and good stability - Dimethylamino)-propane hydrochloride (I).

Claims (8)

1. a kind of manufacturing method of stable 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt, It includes process (A),

Process (A): by the nothing of 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt highly acid The process that the aqueous solution of the organic acid of the aqueous solution or highly acid of machine hydrochlorate is cleaned.

2. the manufacturing method according to claim 1, wherein 1,3- bis- (carbamyl sulfenyl) -2- for process (A) (N, N- dimethylamino)-propane hydrochloride salt is 1, the 3- bis- as obtained from following manner (carbamyl sulfenyl) -2- (N, N- Dimethylamino)-propane hydrochloride salt, the mode are as follows:

In methanol and the organic solvent for forming the double-deck system with methanol, keep 2- (N, N- dimethylamino) -1,3- bis- (thio Cyanato)-propane hydrochloride salt reacted with hydrogen chloride gas, or

In water and the organic solvent for forming the double-deck system with water, make 2- (N, N- dimethylamino) (thio cyanato- of -1,3- bis- Base)-propane hydrochloride salt reacted with hydrochloric acid.

3. manufacturing method according to claim 2, wherein the organic solvent for forming the double-deck system with methanol is selected from first The mixture of one or more of benzene, dimethylbenzene, 1,2- dichloroethanes, chloroform, methylene chloride and chlorobenzene,

With water formed the double-deck system organic solvent be selected from toluene, dimethylbenzene, 1,2- dichloroethanes, chloroform, methylene chloride and The mixture of one or more of chlorobenzene.

4. manufacturing method described in any one of claim 1 to 3, wherein 1,3-, the bis- (carbamyl for process (A) Base sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt be by making 2-N, N- dimethylamino -1,3- propanedithiol 1,3- bis- obtained from being reacted in the presence of hydrochloric acid with cyanate (carbamyl sulfenyl) -2- (N, N- dimethylamino)-the third Heptane hydrochloride salt.

5. manufacturing method according to any one of claims 1 to 4, wherein the inorganic acid salt of highly acid be ammonium hydrogen sulfate, Sodium bisulfate, potassium acid sulfate or ammonium hydrogen sulfate, the organic acid of highly acid are ethanedioic acid or citric acid.

6. one kind 1, the inorganic acid of the highly acid of 3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt The addition product of the organic acid of salt or highly acid meets following (a) and (b):

(a) relative to the inorganic of the highly acid of 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt The content of the weight of the addition product of the organic acid of hydrochlorate or highly acid, the organic acid of the inorganic acid salt or highly acid of highly acid is The range of 0.05 weight of weight %~10 %,

(b) inorganic acid salt of 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt or organic acid The pH of the aqueous solution of addition product is 3.7 or less.

7. 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino)-propane hydrochloride salt according to claim 6 The addition product of inorganic acid salt or organic acid, wherein relative to 1,3- bis- (carbamyl sulfenyl) -2- (N, N- dimethylamino) - The weight of the addition product of the organic acid of the inorganic acid salt or highly acid of the highly acid of propane hydrochloride salt, the inorganic acid salt of highly acid or The content of the organic acid of highly acid is the range of 0.1 weight of weight %~2 %.

1,3- bis- described in any one of according to claim 6 or 7 8. (carbamyl sulfenyl) -2- (N, N- dimethylamino) - The inorganic acid salt of propane hydrochloride salt or the addition product of organic acid, wherein the inorganic acid salt of highly acid or the organic acid of highly acid are Ammonium hydrogen sulfate, sodium bisulfate, potassium acid sulfate, ethanedioic acid or citric acid.