JP3368542B2 - Isothiazolone aqueous preparation - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention relates to stabilized isothiazolone aqueous formulations. More specifically, the present invention relates to an aqueous preparation containing an isothiazolin-3-one compound useful as a non-medicinal bactericide, and particularly useful for preserving / antifungal treatment of various synthetic polymer emulsions.

[0002]

2. Description of the Related Art Isothiazolone compounds such as 5-chloro-2-methyl-isothiazolin-3-one and 2-methyl-isothiazolin-3-one have hitherto been known as non-medical fungicides. Known as antiseptic / antifungal agent, especially NBR latex, SB
It is useful as an antiseptic / antifungal agent for synthetic polymer emulsions such as R latex and acrylic resin emulsions.

Since this isothiazolone compound can be easily added to a preservative / antifungal system, it is usually made into a liquid preparation. However, the isothiazolone compound is very unstable to water and easily decomposes, and is decomposed even when the formulation contains a few% of water (especially, the water content in the formulation is 5% or less).
This tendency becomes remarkable when the content is more than 10%), so that it is usually dissolved and stored in an organic solvent containing no water.

As such an organic solvent, a hydrophilic glycol solvent is used, but such a product is
Since it contains a large amount of organic solvent, it is flammable. Inflammable products cannot be used safely and easily because they are subject to regulations regarding storage and transportation, for example, according to the Fire Defense Law and fire prevention regulations of public municipalities, and special care must be taken in their handling. .

Therefore, when the product is diluted with water to prevent flammability, when it is diluted with water to an appropriate concentration at the time of use, or when the isothiazolone compound is dissolved in water in consideration of flammability and economy, Is a water-labile isothiazolone compound that decomposes in a few hours to a few days,
There is a problem that the object cannot be achieved because the compound becomes a chain compound having no microbiocidal activity.

Conventionally, an isothiazolone compound is dissolved in water or an aqueous solvent as a complex with a metal salt such as a calcium salt or a magnesium salt to give stability, or an isothiazolone compound is dissolved in a large amount of an organic solvent. As a result, organic solvent preparations having a significantly reduced water content have been proposed (JP-A-61-156174 and JP-A-61-2125).
No. 76).

However, when an effective amount of the above conventional aqueous preparation is added as it is to a synthetic polymer emulsion as an antiseptic / antifungal agent, the emulsion is formed by the action of polyvalent metal ions such as calcium and magnesium contained in the preparation. There was a problem that the phase was destroyed and phase separation and solidification occurred (so-called emulsion shock). Therefore, when such an aqueous preparation is used, it is necessary to add it after sufficiently diluting it, but this causes a disadvantage such as a change in latex concentration of the synthetic polymer emulsion to be added, which causes quality deterioration. In addition, coagulation may occur even when diluted and used. There is also a proposal to use this aqueous preparation in a synthetic polymer emulsion without diluting it, but in this case, it was necessary to add a specific anionic surfactant together (JP-A-60-65042, JP-A-60-65042). 60-9665
No. 2).

On the other hand, when the above-mentioned organic solvent preparation was added to the synthetic polymer emulsion, there was a case where the organic solvent was partially brought into the system at a high concentration and a shock was generated. It has been suggested that a part of the component (A) and a part of the component (C) used in the present invention be combined in a non-aqueous preparation (Japanese Patent Publication No. 60-54281 and Japanese Patent Publication No. 63-316702). Nothing is known about the combination in aqueous formulations and the effects thereby.

Recently, a method for stabilizing an isothiazolone solution by adding triazoles and nitroalcohols has been proposed (JP-A-4-182474). According to this method, tentative stability is obtained, but long-term stability is not obtained. Moreover, in this method, the stability is further shortened in the presence of water, which has been found by the additional experiment of the present invention.

The present inventors have previously proposed an aqueous preparation comprising the component (A) used in the present invention, water or an aqueous solvent (B) and a stabilizing component (C) (JP-A-4-930).
No. 5). Although this formulation had some stability (40 ° C., 60 days: equivalent to 6 months or longer at room temperature), further studies were conducted for further long-term stabilization. That is, it was found that the stability of the preparation was further improved by adding the second stabilizing component (D) [50 ° C., 40 days or more (4
0 ° C, 4 months or more): Equivalent to 10 months or more at room temperature].

The present invention has been made under such circumstances, and in particular, it has excellent formulation stability over a long period of time, has no problem of flammability, is economically inexpensive, and is a synthetic polymer emulsion. It is intended to provide an isothiazolone compound-based aqueous preparation which does not cause shock even when directly added to.

[0012]

[Means for Solving the Problems] From the above viewpoints, as a result of intensive studies and studies, the present inventors have found that a specific bromine compound and a carboxylic acid derivative are added to an aqueous solution of an unstable isothiazolone compound in a very small amount. The fact that the stability is remarkably improved without using an inorganic metal salt when prepared in accordance with I found a fact.

Thus, according to the present invention, (A) the general formula (I):

[0014]

[Chemical 7] (Wherein, X is the same or different and is a hydrogen atom or a halogen atom, and Y is an alkyl group), and an isothiazolone compound represented by the formula (B) is sufficient to dissolve at least the compound of the general formula (I). Water or aqueous solvent, (C)
The following formula (II) to be incorporated as a stabilizing component:

[0015]

[Chemical 8] [In the formula, X ¹ is a nitro group or a cyano group, Y ¹ and Y ² are the same or different and are a bromine atom, a nitro group, a cyano group,
Hydroxyl group, lower alkyl group substituted by bromine atom or cyano group, formula:

[0016]

[Chemical 9] (In the formula, R is a hydrogen atom or a lower alkyl group), a formula:

[0017]

[Chemical 10] (In the formula, R ¹ , R ² and R ³ are each a lower alkyl group or a hydrogen atom), or ^{one of} Y ^{1 and} Y ² has the formula:

[0018]

[Chemical 11] Or the other is a hydrogen atom or a bromine atom, or Y ¹ and Y ² are jointly represented by the formula:

[0019]

[Chemical 12] (Wherein Y ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group, m is an integer of 1 to 3), or Y ¹ and Y ² represents a dioxane residue which may be bonded to and substituted by a lower alkyl group], and at least one of the bromo compounds represented by the formula (III): R ⁴ (CO) _n (Z) _m (III) [wherein 1) n = 1, R ⁴ is a hydrogen atom, a C _1-3 alkyl group, or a formula: —R ⁵ —COOH (R ⁵ is C _{1- 5} alkylene, o-phenylene or vinylene group), Z is —NH ₂ group, m = 1, 2) n = 2, a) R ⁴ is C _1-5 alkylene, o-phenylene or vinylene group, and Z is m when the -NH ₂ group represents a 2, b) R ⁴ is C _2-5 alkylene, o- phenylene or vinylene group, Z is M when the NH group represents a 1, c) R ⁴ is o- phenylene group, Z is OM group (M represents a hydrogen atom or an alkali metal atom, provided that, M and m = 2 when are not hydrogen atoms at the same time) ] An isothiazolone aqueous preparation comprising at least one compound represented by

The aqueous preparation of the present invention is a solution preparation to which excellent preparation stability is imparted, without substantially containing the calcium and magnesium salts conventionally used for stabilization. And, in particular, it was made based on the surprising fact that a very small amount of the bromine compound (stabilizing component (C)) and carboxylic acid derivative (stabilizing component (D)) act as a stabilizer. is there.

When both the stabilizing component (C) and the stabilizing component (D) are contained, one stabilizing component (C)
The formulation can be kept at a higher temperature and stably for a longer period of time than the case of using only the (bromine compound). In addition, when the stabilizing component (D) (carboxylic acid derivative) alone is used as the stabilizer, it does not show any effect of imparting stability to the preparation. Therefore, this remarkable effect of imparting stability is due to the synergistic action of the stabilizing components (C) and (D).

Examples of the halogen atom of the substituent X of the isothiazolone compound of the formula (I) used in the present invention include chlorine atom, bromine atom and iodine atom.
A chlorine atom is preferred. On the other hand, as the lower alkyl group for the substituent Y, an alkyl group having 1 to 8 carbon atoms (for example, methyl,
Ethyl, butyl, octyl, etc.). Preferred is a methyl group.

A preferred representative example of these isothiazolone compounds of formula (I) is 2-methyl-5-chloro-
1,2-isothiazolin-3-one, 2-methyl-1,
2-isothiazolin-3-one and 2-octyl-4,
5-dichloro-1,2-isothiazolin-3-one may be mentioned. These isothiazolone compounds can be produced, for example, according to the synthetic method described in JP-B-46-12723, and are usually obtained as a mixture of the above compounds. These mixtures are also suitably used in the present invention.

In the present invention, the compound of the formula (II) is used as a stabilizer (C) for the preparation. In this compound (II), the lower alkyl group represented by Y ¹ , Y ² , Y ³ , R ¹ , R ² and R ³ has 1 carbon atom as described above.
~ 8 alkyl groups, such as methyl, ethyl,
Examples include propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like. A methyl group is particularly preferable.

Specific examples of the compound of the above formula (II) include tribromonitromethane, 2,2-dibromo-3-nitrilopropionamide, N-methyl-2,2 - dibromo-3-nitrilopropionamide, 2 , 2-dibromo-2-nitroethanol, 1,1-dibromo-1-nitro-2-propanol, 1,1-dibromo-1-nitro-2-acetoxyethane, 1,1-dibromo-1-nitro-2 -Acetoxypropane, 2-bromo-2-nitro-1,3-diacetoxypropane, 2-bromo-2-nitro-1,3-diformyloxypropane, 2-nitro-2-bromo-1,3-propane Diol, 1,2-dibromo-2,4-dicyanobutane, 2,3-dibromo-
Propionnitrile, (1,2-dibromo-2-nitroethyl) benzene, β-bromo-β-nitrostyrene,
1- (1,2-dibromo-2-nitroethyl) -4-chlorobenzene, β-bromo-4-chloro-β-nitrostyrene, β-bromo-β, p-dinitrostyrene, β-
Bromo-4-methyl-β-nitrostyrene, 5-bromo-5-nitro-1,3-dioxane, 5-bromo-2-
Methyl-5-nitro-1,3-dioxane and the like can be mentioned. These may be used alone or in combination of two or more. Of these, 2-nitro-2-bromo-1, in terms of the synergistic stability imparting effect with the stabilizing component (D),
3-propanediol, 2-bromo-2-nitro-1,
3-diacetoxypropane, 2,2-dibromo-2-nitroethanol, 2-bromo-2-nitro-1,3-diformyloxypropane, 1,1-dibromo-1-nitro-2-propanol, 2, 2-dibromo-3-nitrilopropionamide, tribromonitromethane, 1,2
-Dibromo-2,4-dicyanobutene, β-bromo-β
-Nitrostyrene, 5-bromo-5-nitro-1,3-
Dioxane or 5-bromo-2-methyl-5-nitro-
Preference is given to using 1,3-dioxane.

Further, in the present invention, one or more of the following compounds (III) are used as the stabilizing component (D). That is, (1) the compound of the formula (III) is represented by the formula: R ⁴ CONH ₂ when 1) n = 1, Z = -NH ₂ , and m = 1. When R ⁴ is a hydrogen atom or a C _1-3 alkyl group, specifically, a first amide compound of a carboxylic acid such as formamide, acetamide, propionamide, butyramide, R ⁴ is represented by the formula: —R ⁵ —COOH. Examples of the compound to be used include alkylenedicarboxylic acid monoamide compounds such as malonic acid monoamide, succinic acid monoamide, glutaric acid monoamide, adipic acid monoamide and pimelic acid monoamide, phenylenedicarboxylic acid monoamide compounds such as phthalic acid monoamide, maleic acid monoamide and fumaric acid monoamide. vinyl dicarboxylic acid monoamide compounds such, 2) n = 2, Z = -NH 2, R 4 = C 1-5 alkylene, o
-Phenylene or vinylene, when m = 2, the formula:

[0027]

[Chemical 13] Indicated by. Specifically, alkylenedicarboxylic acid diamide compounds such as malonic acid amide, succinic acid amide, glutaric acid amide, adipic acid amide and pimelic acid amide,
Phenylene dicarboxylic acid diamide compounds such phthalamide, maleic amide, vinyl dicarboxylic acid diamide compounds such fumaramide, 3) n = 2, Z = NH, R 4 = C 2-5 alkylene, o-
Phenylene or vinylene, when m = 1, formula:

[0028]

[Chemical 14] Indicated by. Specifically, succinimide, glutarimide, adipine imide, pimeline imide, phthalimide,
Dicarboximide compounds such as maleimide, and 4) n = 2, Z = OM, R 4 = o- phenylene, m = 2
Then the expression:

[0029]

[Chemical 15] Indicated by. Specific examples thereof include alkali metal phthalate compounds such as sodium hydrogen phthalate, potassium hydrogen phthalate, sodium phthalate and potassium phthalate. Among these compounds, 1) acetamide, formamide, propionamide, 2) succinamide, phthalamide, maleamide, 3) maleimide, which have particularly excellent stability when used together with the stabilizing component (C), And 4) potassium hydrogen phthalate.

The aqueous preparation of the present invention is prepared by preparing an aqueous solution of the compound of the formula (I) and adding a predetermined amount of the stabilizing component (C) and the stabilizing component (D) to the solution. You can However, it can also be manufactured in any order.

The water used as the solvent here is
Ordinary water, for example, tap water, soft water, pure water and the like,
Industrial water and the like can also be used. Instead of water, a hydrophilic organic solvent (for example, ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, 1,4-butanediol, 1,5-pentanediol, ethylene Known various polyols such as glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether and tripropylene glycol monomethyl ether, or liquid compounds of polyol ether type, N, N-dimethylformamide, N, N-diethylformamide, N, N-
It is also possible to use an aqueous solvent in which dimethylacetamide, N-methyl-2-pyrrolidone, etc.) and water are mixed. However, considering the flammability of the formulation, the content of water in the formulation is preferably 5% by weight or more, and the content of water in the formulation is 10% by weight in order to prevent shock of the synthetic polymer emulsion. % Or more is preferable, 50% by weight
The above is particularly preferable.

When the above-mentioned organic solvent is used in the aqueous preparation of the present invention, it is also possible to prepare a preparation by adding a predetermined amount of the stabilizing component to a solution of the organic solvent of the formula (I) and dilute it with water before use. It is possible. In this case, there are economic advantages in transportation.

The organic solvent used in the above organic solvent preparation includes N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide and N-.
From the viewpoint of storage stability of the preparation, it is preferable to use an amide compound such as methyl-2-pyrrolidone alone or a mixed solvent of these amide compounds and the glycol solvent. The compounding amount of the compound of the formula (I) in the aqueous preparation of the present invention is 0.
1 to 30% by weight is preferable from the viewpoint of storage stability,
It is particularly preferable that the amount is 0.5 to 30% by weight.

The amount of the nitrobrom compound or cyanobrom compound as the stabilizing component (C) is preferably 0.001 to 10 parts by weight per 1 part by weight of the compound of the formula (I) in view of storage stability. It is usually sufficient to use 0.004 to 1.0 parts by weight. Compound (III) as stabilizing component (D)
The amount of the compound is 0.1 part with respect to 1 part by weight of the compound of the formula (I).
003 to 10 parts by weight is preferable from the viewpoint of storage stability, and normally 0.01 to 5 parts by weight is sufficient.

Since the aqueous preparation of the present invention does not use a polyvalent metal, and does not use an organic solvent at all or is used in a significantly reduced amount, a shock upon addition of a synthetic polymer emulsion is prevented or suppressed. Will be done. In addition, there is no inconvenience in handling such as flammability, it is economically inexpensive, and it exhibits excellent stability as an aqueous preparation.

[0036]

【Example】

Example 1 As an isothiazolone compound, a mixture of 2-methyl-5-chloro-isothiazolin-3-one and 2-methyl-isothiazolin-3-one (weight ratio 9: 1), (hereinafter M
(Abbreviated as IT), this is dissolved in the solvent (water and ethylene glycol) described in Table 1, the stabilizing components (C) and (D) are further added, and the mixture is stirred to give the preparation of Example. In the comparative example, only the stabilizing component (C) was added to obtain a pharmaceutical product (note that all component numbers in the table indicate parts by weight). The following tests were conducted on these various preparations.

"Storage stability test" Test method: Each preparation was placed in a glass container and left at 50 ° C. As a result of observing the condition over time and measuring by HPLC (High Performance Liquid Chromatography), there is no change in appearance.
A sample having a MIT decomposition rate of less than 5% by C measurement was evaluated as Δ, and a sample having a large amount of crystals precipitated and clouding and having a decomposition rate of 5% or more was evaluated as x.

However, it is estimated from long-term test results that the 50 ° C. stability of 2 months in this test corresponds to 1 year or more at room temperature. The results are shown in Table 1.

[0039]

[Table 1]

[0040]

[Table 2]

[0041]

[Table 3]

[0042]

[Table 4] From this result, the aqueous preparation of the present invention has excellent stability,
In addition, it can be seen that it is an excellent one that does not adversely affect the polymer emulsion. The abbreviations in the above table mean the following compounds.

[0043]

[Table 5]

[0044]

[Table 6]

Example 2 Similar to Example 1, except that EG and water (about 2.7: 1) were used as a solvent, MAC was used as a stabilizing component (C), and various stabilizing components (D) were further added. The test was conducted. Further, the same test as above was carried out using only the component (C) or only the component (D) as a stabilizer, and made a comparative example.
The results are shown in Table 2.

[0046]

[Table 7]

[0047]

[Table 8]

Example 3 EG and water (1: about 2.7) or only water was used as a solvent, and a fixed amount (0.4) of MAC was used as a stabilizing component (C).
And various stabilizing components (D) were added, and the same test as in Example 1 was performed. The results are shown in Table 3.

[0049]

[Table 9]

[0050]

[Table 10]

Reference Example A preparation described in JP-A-4-182474 (Preparation Example 1-3) was prepared and the same test as in Example 1 was conducted. The results are shown in Table 4.

[0052]

[Table 11]

As shown in the above Examples and Comparative Examples,
The isothiazolone aqueous preparation of the present invention is excellent in stability and storage stability by adding the stabilizing component (C) and the stabilizing component (D). And, when added directly to the polymer emulsion, no adverse effect occurs. Therefore, not only is it convenient to handle, but it is also possible to expand the uses and usage of isothiazolone compounds.
It is also of the.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) A01N 43/80 102 A01N 25/04 101 A01N 25/22 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. (A) General formula (I): (Wherein, X is the same or different and is a hydrogen atom or a halogen atom, and Y is an alkyl group), and an isothiazolone compound represented by the formula (B) is sufficient to dissolve at least the compound of the general formula (I). Water or aqueous solvent, (C)
Formula (II) blended as a stabilizing component: [In the formula, X ¹ is a nitro group or a cyano group, Y ¹ and Y ² are the same or different and are a bromine atom, a nitro group, a cyano group,
A lower alkyl group substituted with a hydroxyl group, a bromine atom or a cyano group, the formula: (In the formula, R is a hydrogen atom or a lower alkyl group), a group represented by the formula: (Wherein R ¹ , R ² , and R ³ are each a lower alkyl group or a hydrogen atom), or either one of Y ¹ or Y ² is represented by the formula: In the group represented by, the other is a hydrogen atom or a bromine atom, or Y ¹ and Y ² are jointly represented by the formula: (Wherein Y ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group, m is an integer of 1 to 3), or Y ¹ and Y ² represents a dioxane residue which may be bonded to and substituted by a lower alkyl group], and at least one of the bromo compounds represented by the formula (III): R ⁴ (CO) _n (Z) _m (III) [wherein 1) n = 1, R ⁴ is a hydrogen atom, a C _1-3 alkyl group, or a formula: —R ⁵ —COOH (R ⁵ is C _{1- 5} alkylene, o-phenylene or vinylene group), Z is —NH ₂ group, m = 1, 2) n = 2, a) R ⁴ is C _1-5 alkylene, o-phenylene or vinylene group, and Z is m when the -NH ₂ group represents a 2, b) R ⁴ is C _2-5 alkylene, o- phenylene or vinylene group, Z is M when the NH group represents a 1, c) R ⁴ is o- phenylene group, Z is OM group (M represents a hydrogen atom or an alkali metal atom, provided that, M and m = 2 when are not hydrogen atoms at the same time) ] An isothiazolone aqueous preparation comprising at least one compound represented by: 2. The compound blended as the stabilizing component (C) is 2-nitro-2-bromo-1,3-propanediol, 2-bromo-2-nitro-1,3-diacetoxypropane, 2 , 2-dibromo-2-nitroethanol,
2-bromo-2-nitro-1,3-diformyloxypropane, 1,1-dibromo-1-nitro-2-propanol, 2,2-dibromo-3-nitrilopropionamide, tribromonitromethane, 1,2 -Dibromo-
2,4-dicyanobutene, β-bromo-β-nitrostyrene, 5-bromo-5-nitro-1,3-dioxane or 5-bromo-2-methyl-5-nitro-1,3-dioxane. The isothiazolone aqueous preparation according to 1. 3. The compound to be added as the stabilizing component (D) is acetamide, formamide, propionamide, succinamide, phthalamide, maleamide,
A maleimide or potassium hydrogen phthalate.
The isothiazolone aqueous preparation described. Wherein 0 compound is in the formulation of the general formula _(I).. 1 to
The aqueous preparation according to claim 1, which is an isothiazolone aqueous preparation containing 30% by weight. 5. The weight ratio of the stabilizing component (C) to the isothiazolone compound 1 represented by the general formula (I) is 0.0 _.
01 to 10, 0 stabilizing component (D) is in a weight ratio to said isothiazolone compound from 1.003 _to 10 Aqueous formulations according to claim 1 comprising blended.