JPH09309807A - Production of mixture of 3-isothiazolone and composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition containing a less amount of impurities harmful to human bodies, safe and useful for various products as a microbe- killing agent by formulating a specific component. SOLUTION: This mixture of 3-isothiazolone is obtained by mixing a biologically effective dose of a component A which is a mixture of 2-methyl-4- isothiazoline-3-one expressed by formula I with 5-chloro-2-methyl-4-isothiazoline-3- one expressed by formula II, a component B which is an effective dose of a metal nitrate stabilizer and a sufficient amount of water to dissolve the components A and B. In this case, 4, 5-dichloro-2-methyl-4-isothiazoline-3-one, which is an impurity, is preferably contaminated in <20ppm based on 15,000ppm of the component A. A chromaticity of the obtained composition is preferably <=50.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to impurities as 4,
5-dichloro-2-methyl-4-isothiazoline-3-
The present invention relates to a method for producing a stabilized 3-isothiazolone mixture containing no on and nitrosamine or a derivative thereof, and a stabilized isothiazolone composition containing such a mixture as an active ingredient.

[0002]

2. Description of the Related Art A 2-methyl-4-isothiazolin-3-one of the following structural formula (J) and a 5-chloro-2-methyl-4-isothiazolin-3-one of the following structural formula (K) Mixtures are well known as stable and persistent microbicides.

[0003]

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Therefore, a composition containing such an isothiazolone mixture as an active ingredient is widely used as a preservative in various products such as paints, cosmetics, surfactants, agricultural chemicals and foods.

When the isothiazolone compounds are used together, they exhibit stronger activity due to the synergistic effect between them, but the activity of the mixture varies depending on the mixing ratio of the constituent compounds. It is known that the physiological activity is increased when the compound of the structural formula (K) is contained at a higher ratio than the compound of the structural formula (J). Therefore, much work has been done to develop improved processes for making effective compound (J) and compound (K) mixtures.
Most conventional manufacturing methods focus on effectively controlling or eliminating the formation of the nitrosamine precursor that is inevitably formed when using disulfide as a starting material in the manufacturing process of said mixture. There is.

However, a mixture of the compound (J) and the compound (K) produced by the conventional method is used as an inactive component and has the following structural formula (L) of 4,5-dichloro-2-methyl-4-.
Contains isothiazolin-3-one.

[0007]

[Chemical 6]

The following reaction scheme 1 is described in European Patent No. 9
A method for producing a mixture of the compound (J) and the compound (K) disclosed in 5,907 is shown.

[0009]

[Chemical 7]

In Reaction Scheme 1, the disulfide of structural formula (C) is amidated with methylamine of structural formula (D) to form N, N'-dimethyl-3,3 of structural formula (A-2). ′ -Dithiodipropionamide is obtained, which is a chlorinating agent, eg
A mixture of the target compound (J) and compound (K) is produced by performing a chlorination / cyclization reaction using chlorine.

However, the reaction process shown in the reaction scheme 1 is the structural formula (L
The dichloro compound of 1) is produced in a considerable amount. Furthermore, according to the results of animal experiments, animals temporarily stimulated by the compound (L) have the structural formula (K
It has been reported that the 5-chloro compound also causes skin irritation (Reference [Bruze et al., D
ermatosen 5,165-168 (198
7)])).

On the other hand, US Pat. No. 5,068,338 is a process for producing a mixture of a compound (J) and a compound (K), and the following structural formula ( It was reported that F) of N-methyl-3- (N-methylamino) aminopropionamide was produced.

[0013]

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In the above reaction scheme, the N-methylacrylamide of the structural formula (E) formed by decomposing the compound of the structural formula (A-2) is the 1,4-addition reaction with the methylamine of the structural formula (D). To produce N-methyl-3- (N-methylamino) aminopropionamide of structural formula (F). The compound of structural formula (F) is a nitrosamine precursor and can be further reacted with N-methylacrylamide of structural formula (E) to produce other nitrosamine precursors.

The above-mentioned US Pat. No. 5,068,338 also discloses that the nitrosamine precursor of the structural formula (F) is a compound (J).
And the compound (K 2) which remains in the mixture and is added as a stabilizer as shown in the following reaction scheme 3.
x) and undergoes a nitrosation reaction to produce N of the following structural formula (B).
It states that -methyl-3- (N-nitroso) aminopropionamide can be formed.

[0016]

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According to the embodiment of the above-mentioned US patent, after the amidation step, N, N'-dimethyl- of the above structural formula (A-2) is used.
0.5% in 3,3'-dithiodipropion (5,000
ppm) to 1.1% (11,000 ppm) range of nitrosamine precursors have been detected and 750 in the final product, a 15% aqueous solution, which has undergone chlorination, filtration, neutralization and nitrate addition steps. ˜1650 ppm nitrosamine has been detected.

Therefore, much research has been carried out to produce a mixture of compound (J) and compound (K) which is almost free of nitrosamine precursor. For example, in U.S. Pat. Nos. 4,939,266, 5,068,338 and 5,312,827, the following reaction scheme 4 is shown during the preparation of a mixture of compounds (J) and (K). By using separation techniques such as ion exchange, recrystallization and solvent extraction, or by using N-methylacrylamide (E) nucleophilic scavengers, such as nitrosamine or its precursor produced as a process by-product. A method of suppressing the amount at a level of 100 ppm or less is disclosed.

[0019]

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However, the above method has various disadvantages. That is, the recrystallization method, the solvent extraction method and the ion exchange method have problems of low product yield and long process time. Also,
In the scavenger method, N-methyl-3-mercaptopropionamide represented by the structural formula (A-1) is reacted with chlorine gas in an organic solvent to produce N-methyl-3 represented by the structural formula (B).
The formation of-(N-nitroso) aminopropionamide is suppressed, and at this time, the compound of the structural formula (A-1) is a compound of the structural formula (A-2) of N, N'-dimethyl-3,3 '. −
Since it is more reactive than dithiodipropionamide, it reacts violently with chlorine gas to generate a large amount of heat of reaction, and therefore, as a by-product of the reaction, 4,5-dichloro-2-methyl- 4-isothiazoline-
A large amount of 3-one is produced.

Therefore, there are many limitations to the commercial application of the manufacturing method of said US patent. That is, it is not economical in terms of production time and yield, and a large amount of 4,5-dichloro-2-methyl-4-isothiazolin-3-one of the above structural formula (L) is produced and produced. Also, the application of isothiazolone compounds is limited in the fields of cosmetics, medicine, etc., which are closely related to the human body, because they are harmful to the human body.

[0022]

Therefore, the main object of the present invention is not only nitrosamine or its precursor but also 4,5-dichloro-2-methyl-4 of structural formula (L).
-Isothiazolin-3-one 2-Methyl-4-isothiazolin-3-one of structural formula (J) and 5-chloro-2-methyl-4-isothiazolin- of structural formula (K) as active ingredients with few impurities. It is intended to provide a stabilized isothiazolone composition comprising a mixture of 3-ones.

It is also an object of the present invention to provide an improved method of making such a mixture.

[0024]

The present invention employs a mixed solvent system that internally burns out the heat of reaction, optionally with external cooling means to maintain the temperature of the reaction system constant in the range 5 to 20 ° C. By effectively inhibiting the compound of structural formula (L) present in the mixture. The thus-prepared isothiazolone mixture contains 4,5-dichloro while containing the components of structural formulas (J) and (K) in a biologically effective molar ratio (hereinafter referred to as "biologically effective amount"). -2-Methyl-4-isothiazoline-
It contains substantially little 3-one.

According to one embodiment of the present invention, a) a biologically effective amount of 2-methyl-4-isothiazolin-3-one of the following structural formula (J) and 5- of the following structural formula (K) A mixture with chloro-2-methyl-4-isothiazolin-3-one; (b) an effective amount of a metal nitrate stabilizer; and (c) a sufficient amount of water to dissolve the components (a) and (b). And a stabilized isothiazolone composition characterized by being substantially depleted of 4,5-dichloro-2-methyl-4-isothiazolin-3-one.

[0026]

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According to another aspect of the present invention,
Water and a) a mixture organism of the compound of the structural formula (J) and the compound of the structural formula (K) containing less than 100 ppm of 4,5-dichloro-2-methyl-4-isothiazolin-3-one A stabilized aqueous solution of isothiazolone is provided which comprises a biologically effective amount; and b) an effective amount of a water-soluble metal nitrate stabilizer.

According to another aspect of the present invention,
N-methyl-3-mercaptopropionamide of the following structural formula (A-1) or N, N ′ of the following structural formula (A-2)
-Dimethyl-3,3'-dithiodipropionamide or a mixture thereof and a chlorinating agent are reacted while maintaining a reaction temperature of 5 to 20 ° C to give 4,5-dichloro-
Provided is a method for producing a mixture of a compound (J) and a compound (K) which is almost free of 2-methyl-4-isothiazolin-3-one.

[0029]

[Chemical 12]

According to still another embodiment of the present invention, the compound of structural formula (A-1) or the compound of structural formula (A-2) or a mixture thereof and the chlorinating agent are dissolved in different organic solvents. To react, 4,5-dichloro-2
Provided is a method for producing a mixture of a compound (J) and a compound (K) which is almost free of -methyl-4-isothiazolin-3-one.

According to another embodiment of the present invention, the mixture of compound (J) and compound (K) obtained after the reaction is centrifuged to adjust the content of nitrosamine or its precursor in the mixture to less than 5 ppm. There is provided a method for producing the mixture, further comprising the step of:

The present invention will be described in more detail.

In addition to the active ingredients of the above structural formulas (J) and (K), in the commercially available isothiazolone composition or aqueous solution of isothiazolone, nitrosamine or a nitrosamine precursor is of course formed as a reaction by-product. Structural formula (L) of 4,5-dichloro-2-methyl-4
It was found that -isothiazolin-3-one was detected. The content of compound (L) is extremely small, but in consideration of the effects on the human body, it must be removed or must not be fundamentally generated.

On the other hand, nitrosamine or a nitrosamine precursor present as an impurity is produced by using the disulfide represented by the structural formula (A-2) as a starting material. In the case of 4,5-dichloro-2-methyl-4-isothiazolin-3-one of the above structural formula (L), it is produced depending on temperature conditions, amount of chlorinating agent and organic solvent used in the process of producing the isothiazolone mixture. It is a by-product. That is, the compound (L) forms a mixture of the compounds (J) and (K) during the chlorination process and the cyclization process, and the excess internal energy or internal heat, the excess amount of the chlorinating agent, etc. It is produced by excessive reaction.

The inventors of the present invention produced the aforementioned compound (L) known as a skin irritant during the process of producing the isothiazolone mixture, and the formation of such harmful substances depends on the temperature in the reaction system, the amount of the chlorinating agent and It has been found that this can be suppressed by maintaining the composition of the solvent in a specific range. In the method for producing an isothiazolone mixture according to the present invention, N-methyl-3-mercaptopropionamide of the structural formula (A-1) and N, N'- of the structural formula (A-2) are used as starting materials.
Dimethyl-3,3'-dithiodipropionamide or mixtures thereof are used.

The chlorination reaction of the compound of the above structural formula (A-1) or (A-2) is an intense exothermic reaction, and a large amount of heat of reaction is generated during the reaction, which induces an excess reaction. In addition to the target active compounds of the compounds (J) and (K), the compound (K) can be produced as a reaction by-product.
In the present invention, the temperature in the reaction system is maintained at 5 to 20 ° C., and the object of the present invention can be achieved by maximally inhibiting the production of the compound (L) due to the excess reaction.

Generally, the heat generated by the exothermic reaction is removed by the external cooling means. However, in this method, the internal heat generated during the reaction stays in the reaction mixture for a certain period of time before being transferred to the outside. Therefore,
In order to effectively prevent the excessive reaction, it is preferable to remove the heat of reaction directly in the reaction system. That is, it is preferable to design the reaction system so that the temperature is controlled by the internal means in the reaction system.

The present invention, as one preferred example for this, is preferably accomplished by selecting a complex solvent system to control the reaction temperature. One embodiment of the composite solvent system of the present invention is to dissolve the starting material represented by the structural formula (A-1) or (A-2) and the chlorinating agent in different organic solvents to obtain the reactivity of each reactant. Is stabilized and the heat of reaction of the chlorination reaction is adjusted appropriately so that the desired reaction of the starting material is carried out properly while preventing excessive reaction. Preferably, the complex solvent system is used with cooling means such as a water jacket, an ice water bath and an acetone-dry ice bath.

Further, according to the present invention, the temperature in the reaction system can be controlled by an external cooling means even under a normal single solvent instead of the composite solvent. When the temperature in the reaction system is maintained at 5 to 20 ° C. by the above-mentioned complex solvent system or external cooling means, the 4,5-dichloro-2-methyl-4-isothiazoline-containing structure represented by the structural formula (L) is used.
The production of 3-one can be efficiently inhibited and the chlorination reaction of the reaction product can proceed well.

When the temperature in the reaction system is lower than 5 ° C., the reaction rate is excessively slow, and therefore 2-methyl-of the above structural formula (J) is used.
4-isothiazolin-3-one is 5 in the structural formula (K).
A significantly more biologically inert mixture is obtained than -chloro-2-methyl-4-isothiazolin-3-one. When the temperature in the reaction system exceeds 20 ° C., a large amount of 4,5-dichloro-2-methyl-4-isothiazolin-3-one represented by the structural formula (L) is produced due to excess reaction. That is, when the temperature of the reaction system is maintained in the range of 5 ° C to 20 ° C, the biologically effective mixture of the compound (J) and the compound (K), which does not form a harmful reaction product, has a high concentration of 95 mol% or more. Obtained in yield.

According to the present invention, the product mixture obtained by the chlorination reaction under the controlled reaction temperature as described above is centrifuged to remove impurities such as nitrosamine and its precursor remaining in the reaction mixture. It is preferable to completely remove it. After the reaction, a very small amount of other impurities contained in the reaction mixture can be removed by centrifugation.

As described above, according to the present invention, the formation of the 4,5-dichloro-2-methyl-4-isothiazolin-3-one by-product of the above structural formula (L) can be effectively performed using a complex solvent system. Can be suppressed. The use of the complex solvent system is based on the fact that a higher heat of reaction and a higher heat of formation are required when producing a compound of structural formula (L) than a mixture of compounds (J) and (K). .

The complex solvent system of the present invention is used as shown in Reaction Scheme 5 below.

[0044]

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In the formula, X ₂ is Cl ₂ or SO ₂ Cl ₂ , and S1 and S2 represent a first organic solvent and a second organic solvent, respectively.

First, sulfonyl chloride (S
A chlorinating agent such as O ₂ Cl ₂ ) or chlorine gas (Cl ₂ ) is dissolved and the solution is stirred for 10 to 60 minutes. Then, the compound of the structural formula (A-1) or the compound of the structural formula (A-2) is dissolved in a second organic solvent. On this occasion,
The temperature in the reaction system during the chlorination reaction can be changed depending on the kind of the first organic solvent or the second organic solvent selected, and the larger the heat capacity of the selected organic solvent, the easier the temperature in the reaction system is adjusted. Here, the organic solvent having a large heat capacity means a solvent having a large vaporization energy required for vaporizing a unit solvent molecule.

[0047] As the first organic solvent in the composite solvent system of the present invention, well dissolved chlorinating agent is used to choose what heat of mixing is not high when mixed with a second organic solvent, preferably, C ₂ -C ₁₀ alkyl ether, C ₂ -
C ₈ alkyl esters, C ₅ -C ₁₂ hydrocarbons, CH ₂ X
₂ , CHCX ₃ , CX ₄ , CH ₃ CX ₃ , CH ₂ XCH
₂ X (where X is a halogen atom) and C ₆ −
It is a C ₁₀ aromatic hydrocarbon. The first organic solvent and the chlorinating agent are mixed in a weight ratio of 1: 1 to 20: 1.
If the amount of the organic solvent used is less than the lower limit value, it is not sufficient to eliminate the impact due to the reaction heat that can disperse the chlorinating agent, and if it is used in excess of the upper limit value, it is not economical.

On the other hand, as the second organic solvent that can be used in the composite solvent system of the present invention, the compound of the structural formula (A-1) and / or the compound of the structural formula (A-2) is easily dissolved to obtain a heat capacity. Although but using choose to relatively large heat of reaction can significant amount distributed into the solvent, preferably, C ₄ -C ₁₂ alkyl esters, C ₇ -C _{14 hydrocarbons, XCH = CHX, CH 2 =} CX 2 , CX ₂ = C
_{X 2, CHX = CX 2,} C 8 -C 12 aromatic hydrocarbons and _{C 6 H (6-n)} X n ( this time, n is 1 to 5 integer, X is a halogen atom) with is there. The second organic solvent and the starting material of the structural formula (A-1) or (A-2) are generally mixed in a weight ratio of 0.2: 1 to 20: 1. When the amount of the second organic solvent used is less than the lower limit value,
If the amount of the second organic solvent used is not sufficient to dissolve the starting material and exceeds the upper limit, an excessively large amount of solvent is used, which is not economical.

The effect is enhanced when the second organic solvent and the organic solvent form a specific combination. According to the experimental results, the preferred composite solvent system is such that the first organic solvent and the second organic solvent are C ₄ -C ₆ alkyl ester and C ₆ H (
_6-n ) X _n , CH _n X ( _4-n ) and C ₂ H _n X
( _4-n ) (where n is an integer of 1 to 3 and X is a halogen atom), and C ₆ -C ₁₀ aromatic hydrocarbon and C ₄ -C ₆ alkyl ester. This is the case.

In the present invention, the starting materials of compound (J) and compound (K) and the chlorinating agent are used in a molar ratio of 1: 2 to 1:10. Since the organic solvent used in the chlorination reaction can be recycled to the reaction system and a costly separation step is not required, the present invention has an advantage that the manufacturing cost can be significantly reduced.

The compound (J) and compound (K) in the isothiazolone mixture prepared by the process of the present invention are preferably present in a molar ratio of 1: 3 to 1:10.

The amount of the mixture of the compounds (J) and (K) used as the active ingredient in the composition of the present invention is generally in the range of 1.5 to 15% by weight of the composition. Can vary depending on the end use of the composition.

As the metal nitrate stabilizer that can be used in the composition of the present invention, it is preferable to use a water-soluble salt. For example, sodium nitrate, potassium nitrate, calcium nitrate, magnesium nitrate, copper nitrate, iron nitrate ( J),
It is selected in the group consisting of iron nitrate (K), nickel nitrate, zinc nitrate, barium nitrate, manganese nitrate, cobalt nitrate and mixtures thereof. The metal nitrate stabilizer is
An amount sufficient to stabilize the isothiazolone mixture is added, but generally in an amount of 1 to 30% by weight of the composition, preferably 2 to 20%.

The present invention also comprises a biologically effective amount of a mixture of compounds (J) and (K) prepared by the process of the present invention as described above, an effective amount of a metal nitrate stabilizer and said isothiazolone mixture. Containing nitrosamine or a nitrosamine precursor, and 4,5-dichloro-2 of the structural formula (L) above, containing sufficient amount of water to dissolve the metal nitrate.
-Comprising a stabilized isothiazolone composition or solution that is substantially free of methyl-4-isothiazolin-3-one.

The present invention provides a biologically effective amount of the compound (J) produced by the above-mentioned production method of the present invention.
Containing less than 5 ppm of nitrosamine or a nitrosamine precursor and 4,5-dichloro-2-methyl-4-isothiazoline-of the structural formula (L) above.
Includes isothiazolone compositions or aqueous solutions containing less than 100 ppm of 3-one.

The isothiazolone compositions or aqueous solutions currently commercially available or disclosed as patents are:
Despite efforts to maximally eliminate nitrosamine or nitrosamine precursors, nitrosamine or nitrosamine precursor 100p typically in 1.5% aqueous solution
It contains pm or more. On the contrary, the isothiazolone composition or solution produced by the production method of the present invention contains no nitrosamine or nitrosamine precursor or less than 5 ppm by simply centrifuging the mixture obtained after the chlorination reaction. To do.

Although the above-mentioned US patent does not mention the existence of the compound (L) known as a skin irritant, it is inevitable for the isothiazolone composition or solution prepared by the conventional manufacturing method. Therefore, the compound (L) is contained in a considerable amount. However, according to the manufacturing method of the present invention,
The isothiazolone composition or solution prepared by controlling the temperature in the reaction system completely excludes the compound (L 2) or contains less than 100 ppm.

The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto. All units, percentages, parts, etc. used in this application are by weight unless otherwise noted.

HPLC (High Performance Liquid Chromatography) analysis of the samples in the examples was carried out under the following conditions: Column: μ-Bondapak (3.
Mobile phase: Methanol / water = 2/3 Flow rate: 1.0 ml / min Temperature: 25 ° C.

Example 1 After adding 310 g of diethyl ether to a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 72 g of sulfuryl chloride (SO ₂ Cl ₂ ) was added at 0 ° C.
(0.53 mol) was added. To this, N-methyl-3-
Mercaptopropionamide (Purity 99%) 30g
(0.25 mol) is 1,2-dichloroethylene 120 g
The solution dissolved in was cooled to −5 ° C. and gradually added over 2 hours. At this time, the temperature inside the reaction system was 5 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 2-methyl-4-isothiazoline-formula of the formula (J). 42.2 g (83% yield) of the product mixture containing 3-one and 5-chloro-2-methyl-4-isothiazolin-3-one of formula (K) were obtained as white crystals, which were analyzed by HPLC. The results are shown in Table 1.

Example 2 After placing 360 g of n-hexane in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer,
At −5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. Then, 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide was added to 160 g of n-hexyl acetate.
The solution dissolved in g was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 11 ° C., and the mixture was stirred at this temperature for 2 hours, left standing for 1 hour, and centrifuged to give 47.4 g (yield 98%) of a white mixture as a white crystal. The result was analyzed by HPLC, and the results are shown in Table 1.
It was shown to.

Example 3 300 equipped with a thermometer, dropping funnel and stirrer
After putting 78 g of chloroform in a three-necked flask having a capacity of ml, 76 g (0.56 mol) of sulfuryl chloride was added at -5 ° C. To this, a solution of 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide dissolved in 6 g of tetrachloroethylene was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 14 ° C., and the mixture was stirred at this temperature for 2 hours, left standing for 1 hour, and then centrifuged to produce a product mixture as white crystals 43.6.
g (yield 89%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 4 1500 g of toluene was placed in a 3 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and then-
At 5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, a solution in which 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide was dissolved in 300 g of n-decane was gradually added at 10 ° C. over 2 hours.
At this time, the temperature inside the reaction system was 13 ° C., and the mixture was stirred at this temperature for 2 hours, left standing for 1 hour, and centrifuged to obtain 46.2 g of a product mixture as white crystals (yield 98
%), Which was analyzed by HPLC and the results are shown in Table 1.

Example 5 After placing 440 g of n-propyl acetate in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 82 g (0.61 mol) of sulfuryl chloride was added at -5 ° C. . To this, 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide was added to p-xylene 140.
The solution dissolved in g was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 12 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to yield 46.2 g of a product mixture as white crystals (yield 98%). ) Was obtained, and this was analyzed by HPLC, and the results are shown in Table 1.

Example 6 380 g of dichloromethane was placed in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and 70 g (0.52 mol) of sulfuryl chloride was added at -5 ° C. To this, a solution of 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide dissolved in 10 g of 1,1,2-trichloroethane was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system is 16
C. and stirring the mixture at this temperature for 2 hours, then
The mixture was left standing for a while and centrifuged to obtain 46.2 g (yield 98%) of the product mixture as white crystals, which was analyzed by HPLC and the results are shown in Table 1.

Example 7 1100 g of 1,2-dichloroethane in a 3 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer.
After the addition of 76 g of sulfuryl chloride at -5 ° C (0.56
Mol) was added. To this, a solution of 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide in 600 g of monochlorobenzene was gradually added over 2 hours at 10 ° C. At this time, the temperature inside the reaction system is 14
C. and stirring the mixture at this temperature for 2 hours, then
The mixture was left standing for a while and centrifuged to obtain 46.2 g (yield 98%) of the product mixture as white crystals, which was analyzed by HPLC and the results are shown in Table 1.

Example 8 After putting 1000 g of toluene in a 3 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, −
At 5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, a solution in which 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide was dissolved in 180 g of ethyl acetate was gradually added at 10 ° C. over 2 hours.
At this time, the temperature inside the reaction system was 13 ° C., and the mixture was stirred at this temperature for 2 hours, left standing for 1 hour, and then centrifuged to obtain 45.9 g of a product mixture as white crystals (yield 98
%), Which was analyzed by HPLC and the results are shown in Table 1.

Example 9 1380 g of ethyl acetate was placed in a 3 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and
At −5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. A solution of 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide dissolved in 10 g of toluene was gradually added thereto at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 12 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to yield 46.2 g of a product mixture as white crystals (yield 98%). )
Was obtained and the result was shown in Table 1.

Example 10 1100 g of butyl acetate was placed in a 3 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer.
At -5 ° C, 76 g (0.56 mol) of sulfonyl chloride was added. To this, 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide was added as monochlorobenzene 15.
The solution dissolved in g was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 15 ° C., and the mixture was stirred at this temperature for 2 hours, left standing for 1 hour, and centrifuged to give 46.4 g of a product mixture as white crystals (yield 98%). ) Was obtained, and this was analyzed by HPLC, and the results are shown in Table 1.

Example 11 1000 g of butyl acetate was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer.
At -5 ° C, 76 g (0.56 mol) of sulfonyl chloride was added. To this, a solution of 30 g (0.25 mol) of N-methyl-3-mercaptopropionamide dissolved in 12 g of 1,2-dichlorobenzene was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 14 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to produce a product mixture as white crystals 46.3.
g (yield 98%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 12 300 equipped with a thermometer, dropping funnel and stirrer
72 g of diethyl ether was placed in a three-necked flask having a capacity of ml, and then 72 g (0.53 mol) of sulfuryl chloride was added at 0 ° C.
Was added. To this, 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide was added.
A solution of 5 g of 2-dichloroethylene was gradually added at -5 ° C over 2 hours. At this time, the temperature inside the reaction system was 6 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to obtain 42.2 g of a product mixture as white crystals (yield 83%). ) Is obtained and
The results of the analysis are shown in Table 1.

Example 13 300 g of n-hexane was put into a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer.
At −5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, a solution of 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide in 160 g of n-hexyl acetate was gradually added at 10 ° C over 2 hours. At this time, the temperature inside the reaction system was 8 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to form a mixture 47.
4 g (yield 98%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 14 500 equipped with a thermometer, dropping funnel and stirrer
After putting 200 g of chloroform into a three-necked flask having a capacity of ml, 76 g (0.56 mol) of sulfuryl chloride at -5 ° C.
Was added. A solution of 24 g (0.10 mol) of N, N′-dimethyl-3,3′-dithiodipropionamide dissolved in 60 g of tetrachloroethylene was added thereto at 2 ° C. at 2 ° C.
Gradually added over time. At this time, the temperature inside the reaction system was 19 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 43.6 g of a product mixture as white crystals (yield 89%). Was obtained and the result was shown in Table 1.

Example 15 980 g of toluene was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and then -5.
At 0 ° C. 76 g (0.56 mol) of sulfuryl chloride were added.
To this, 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide was added to n-decane 24.
The solution dissolved in g was gradually added at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 17 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 46.2 g of a product mixture as white crystals (yield 98%). Which was analyzed by HPLC and the results are shown in Table 1.
It was shown to.

Example 16 To a one-liter three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 380 g of n-propyl acetate was added, and then 76 g (0.56 mol) of sulfuryl chloride was added at -5 ° C. . To this, a solution of 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide dissolved in 150 g of p-xylene was gradually added at 10 ° C over 2 hours. At this time, the temperature inside the reaction system is 14 ° C.
Then, the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give the product mixture 4 as white crystals.
6.2 g (yield 98%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 17 1110 g of dichloromethane was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and 76 g (0.56 mol) of sulfuryl chloride was added at -5 ° C. To this, 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide was added.
1 solution of 15 g of 1,2-trichloroethane
It was added slowly at 0 ° C. over 2 hours. At this time, the temperature inside the reaction system was 15 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 46.2 g of a product mixture as white crystals (yield 98%). And get this H
PLC analysis was performed and the results are shown in Table 1.

Example 18 480 g of 1,2-dichloroethane was placed in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and 76 g (0.56 mol) of sulfuryl chloride was added at -5 ° C. It was In addition to this, N, N'-dimethyl-3,3 '
A solution of 24 g (0.10 mol) of dithiodipropionamide in 50 g of monochlorobenzene was added slowly at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 16 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 46.2 g of a product mixture as white crystals (yield 98%). Which is obtained by HPLC
The results of the analysis are shown in Table 1.

Example 19 980 g of dichloromethane was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and 76 g (0.56 mol) of sulfonyl chloride was added at -5 ° C. To this, a solution of 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide dissolved in 7 g of ethyl acetate was gradually added at 10 ° C over 2 hours. At this time, the temperature inside the reaction system was 14 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to produce white crystals.
(Yield 98%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 20 1000 g of ethyl acetate was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer,
At −5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide was added to toluene 3
A solution of 2 g was added slowly at 10 ° C. over 2 hours. At this time, the temperature inside the reaction system was 5 ° C., and the mixture was stirred at this temperature for 2 hours, then allowed to stand for 1 hour and centrifuged to give 47.4 g of a product mixture as white crystals (yield 98%). Which was analyzed by HPLC and the results are shown in Table 1.
It was shown to.

Example 21 580 g of butyl acetate was placed in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and then-
At 5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, a solution of 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide dissolved in 10 g of monochlorobenzene was gradually added at 10 ° C over 2 hours. At this time, the temperature inside the reaction system was 11 ° C.
After stirring the mixture at this temperature for 2 hours, the mixture was left standing for 1 hour and centrifuged to produce white crystals.
6.2 g (yield 98%) was obtained, which was analyzed by HPLC and the results are shown in Table 1.

Example 22 800 g of butyl acetate was placed in a 2 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and then-
At 5 ° C., 76 g (0.56 mol) of sulfuryl chloride was added. To this, a solution of 24 g (0.10 mol) of N, N'-dimethyl-3,3'-dithiodipropionamide dissolved in 8 g of 1,2-dichlorobenzene was gradually added at 10 ° C over 2 hours. . At this time, the temperature inside the reaction system is 1
5 ° C. and after stirring the mixture at this temperature for 2 hours,
The mixture was left standing for 1 hour and centrifuged to obtain 45.9 g (yield 98%) of the product mixture as white crystals, which was analyzed by HPLC and the results are shown in Table 1.

Comparative Example 1 500 g of ethyl acetate was placed in a 1 L three-necked flask equipped with a thermometer, a dropping funnel and a stirrer, and then 1
21.3 g (0.3 mol) of chlorine gas was introduced at 5 ° C.
To this, 11.9 g (0.1 mol) of N-methyl-3-mercaptopropionamide was added in 10 fractions.
At this time, the temperature inside the reaction system was 35 ° C. The reaction solution was filtered through a Buchner funnel to collect a precipitate, which was washed with ethyl acetate and dried to obtain 13.5 g of white crystals (yield 62%), which was analyzed by HPLC.
Analysis was performed and the results are shown in Table 1.

Comparative Example 2 1280 g of butyl acetate was placed in a three-liter three-necked flask equipped with a thermometer, a dropping funnel and a stirrer.
At -35 ° C, 76 g (0.56 mol) of sulfonyl chloride was added. To this, a solution of 20 g (0.17 mol) of N-methyl-3-mercaptopropionamide in 10 g of butyl acetate was gradually added at 0 ° C. over 8 hours. At this time, the temperature inside the reaction system was 25 ° C. The mixture was stirred at this temperature for 8 hours, then allowed to stand for 1 hour and centrifuged to obtain 38.2 g of white crystals (yield 82%).
The results of LC analysis are shown in Table 1.

[0084]

[Table 1] Note) Compound (J): 2-methyl-4-isothiazoline-3-
On Compound (K): 5-chloro-2-methyl-4-isothiazolin-3-one Compound (L): 4,5-dichloro-2-methyl-4-isothiazolin-3-one

Example 23 In a 250 ml three-necked flask equipped with a stirrer and a pH meter, 59.7 g of water and Mg (NO3) 2.
6H2 O (38 g) was added and the mixture was stirred for 30 minutes. to this,
2.1 g of the crystal of the isothiazolone mixture prepared in the above Example or Comparative Example was added and stirred for 30 minutes, and then MgO was added.
The pH of the solution was adjusted to between 2 and 5 with. The resulting composition was analyzed by HPLC and the results are shown in Table 2 below.

The chromaticity (APHA Color) was measured by the colorimetric method described in ASTM D 1209 in order to quantitatively measure the content of color-forming organic and inorganic impurities in these compositions. The results are shown in Table 2 below.
It was shown to. The higher the chromaticity value, the more impurities were contained.

[0087]

[Table 2] Note) Compound (J): 2-methyl-4-isothiazoline-3-
On Compound (K): 5-chloro-2-methyl-4-isothiazolin-3-one Compound (L): 4,5-dichloro-2-methyl-4-isothiazolin-3-one

[0088]

The compound (J) produced by the present invention
The mixture of (K) and (K) contains the compound (J) and the compound (K) in a physiologically effective mixing ratio, that is, in a molar ratio of 1: 3 to 10 and thus can be effectively used as a microbicide in various products. Moreover, the content of 4,5-dichloro-2-methyl-4-isothiazolin-3-one and nitrosamine impurities, which are harmful to the human body, is very low and the chromaticity is 50 or less, so that it can be safely used.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Han Jun Sung, Republic of Korea, Seoul 151-050, Gwanak-dong, Gwanak-dong, Gwanggak-gu, 123 modern apartments No. 1402

Claims (18)

[Claims] 1. A) A biologically effective amount of the following structural formula (J
) 2-Methyl-4-isothiazolin-3-one and 5-chloro-2-methyl-4-isothiazolin-3-one of the following structural formula (K); b) effective amount of metal nitrate stabilization Agent; and c) Water is contained in an amount sufficient to dissolve the above (a) component and (b) component, and 4,5-dichloro-2-methyl-4 is contained relative to 15,000 ppm of the above (a) component. -A stabilized isothiazolone composition characterized by being substantially free of isothiazolin-3-ones. Embedded image 2. The amount of 4,5-dichloro-2-methyl-4-isothiazolin-3-one contained in less than 20 ppm relative to 15,000 ppm of the component (a). The composition as described. 3. The chromaticity of the composition (APHA Colo
The composition according to claim 1, wherein r) is 50 or less. 4. A biologically effective amount of the following structural formula (J
) 2-Methyl-4-isothiazolin-3-one and 5-chloro-2-methyl-4-isothiazolin-3-one of the following structural formula (K); b) effective amount of metal nitrate stabilization An agent; and c) a sufficient amount of water to dissolve the components a) and b) is contained, and the component 1)
Stabilized, characterized in that it contains less than 100 ppm of 4,5-dichloro-2-methyl-4-isothiazolin-3-one and less than 5 ppm of nitrosamine or its precursor relative to 5,000 ppm. Isothiazolone composition. Embedded image 5. The 4,5-dichloro-2-methyl-4-isothiazolin-3-one is contained in an amount of less than 20 ppm with respect to 15,000 ppm of the component (a). The composition as described. 6. The composition according to claim 4, wherein the chromaticity of the composition is 50 or less. 7. N-methyl-3 having the following structural formula (A-1):
-Mercaptopropionamide or the following structural formula (A-
2) N, N′-dimethyl-3,3′-dithiodipropionamide or a mixture thereof and a chlorinating agent are reacted while maintaining a reaction temperature of 5 to 20 ° C.
5-dichloro-2-methyl-4-isothiazoline-3-
The following structural formula (J containing less than 100 ppm of on
) 2-Methyl-4-isothiazolin-3-one and a 5-chloro-2-methyl-4-isothiazolin-3-one of the following structural formula (K). Embedded image 8. The mixture containing less than 20 ppm of 4,5-
8. The method of claim 7, comprising dichloro-2-methyl-4-isothiazolin-3-one. 9. A process characterized in that the mixture comprises compound (J) and compound (K) in a molar ratio of 1: 3 to 1:10. 10. The method of centrifuging a mixture of the compound (J) and the compound (K) obtained after the reaction to adjust the content of nitrosamine or its precursor in the mixture to be less than 5 ppm. Method according to claim 7, 8 or 9, characterized in that it comprises: 11. N-methyl-in the following structural formula (A-1):
Mercaptopropionamide or the following structural formula (A-
2) N, N'-dimethyl-3,3'-dithiodipropionamide or a mixture thereof and a chlorinating agent are dissolved in different organic solvents and reacted to give 4,5-dichloro-2-methyl- 4-isothiazolin-3-one is 1
2-of the following structural formula (J) contained in less than 00 ppm
A process for preparing a mixture of methyl-4-isothiazolin-3-one with 5-chloro-2-methyl-4-isothiazolin-3-one of the following structural formula (K): 12. The mixture contains less than 20 ppm of 4,5
12. The method of claim 11, comprising -dichloro-2-methyl-4-isothiazolin-3-one. 13. The method according to claim 11, wherein the mixture contains the compound (J) and the compound (K) in a molar ratio of 1: 3 to 1:10. 14. The method further comprising centrifuging the mixture of the compound (J) and the compound (K) obtained after the reaction to adjust the content of nitrosamine or its precursor in the mixture to less than 5 ppm. 13. The method according to claim 11, characterized in that
Or the method described in 13 above. 15. The structural formula (A-1) or (A-
The organic solvent to dissolve the compound of 2), C ₄ -C ₁₂ alkyl esters, C ₇ -C ₁₄ hydrocarbons, XCH = CH
X, CH ₂ = CX ₂ , CX ₂ = CX ₂ , CHX = C
X _2, C ₈ -C ₁₂ aromatic hydrocarbons and C ₆ H _(6-n)
The method according to claim 11, wherein the method is selected from the group consisting of X _n (wherein n is an integer of 1 to 5 and X is a halogen atom). 16. The structural formula (A-1) or (A-
The compound of 2) and the organic solvent are 1: 0.2 to 1:20.
16. The method according to claim 11 or 15, characterized in that they are mixed in a weight ratio of. 17. Organic solvents are C ₂ -C ₁₀ alkyl ether for melting of the chlorinating agent, C ₂ -C ₈ alkyl esters, C ₅ -C ₁₂ hydrocarbons, CH ₂ X _2, CHC
_{X 3, CX 4, CH 3} CX 3, CH 2 XCH 2 X claims, characterized in that it is selected from the group consisting of (at this time, X is a halogen atom in a) and C ₆ -C ₁₀ aromatic hydrocarbon 11. The method according to 11. 18. The method according to claim 11, wherein the chlorinating agent and the organic solvent are mixed in a weight ratio of 1: 1 to 1:20.