JP7783779B2 - Method for producing 4-bromoisothiazolinone derivatives, and 4-bromoisothiazolinone derivatives - Google Patents

Description

The present invention relates to a method for producing a 4-bromoisothiazolinone derivative and a 4-bromoisothiazolinone derivative obtained by the method.

Antibacterial agents (preservatives) are used in a variety of applications, including industrial preservatives, building materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, textiles, cleaning aids, cosmetics, and household products. There is a strong demand for the development of safer antibacterial agents that are less likely to cause health hazards such as allergic contact dermatitis. 4-Bromoisothiazolinone derivatives belong to the isothiazolinone antibacterial agent family and have been reported to possess bactericidal and antibacterial activity (see, for example, Patent Document 1). 4-Bromoisothiazolinone derivatives can be produced by brominating an isothiazolinone compound unsubstituted at the 4-position, as described in, for example, Patent Documents 1-3 and Non-Patent Documents 1 and 2. However, none of these methods are necessarily satisfactory in terms of reaction yield or product purity, making their practical application difficult.

For example, Patent Document 1 describes that in the bromination reaction of 2-methyl-4-isothiazolin-3-one using bromine (1 equivalent) in dichloroethane solvent, the yield of the desired 4-bromo-2-methyl-4-isothiazolin-3-one is only 14%. It also describes that when 2-(1,1,3,3-tetramethylbutyl)-4-isothiazolin-3-one is brominated in chloroform solvent using N-bromosuccinimide (2 equivalents), the yield of the desired product is 54%.

Non-Patent Document 1 describes that the bromination reaction of 2-cyclohexyl-4-isothiazolin-3-one using bromine (1 equivalent) and the bromination reaction of 2-(2-phenylethyl)-4-isothiazolin-3-one using bromine (3 equivalents) produce the desired 2-alkyl-4-bromo-4-isothiazolin-3-one derivative in yields of 75% and 63%, respectively. However, it has been reported that adding an excess amount of bromine in this reaction results in the by-product of a 2-alkyl-4,5-dibromo-4-isothiazolin-3-one derivative in which the 5-position of the isothiazolin ring is also brominated.

Patent Document 2 describes how a bromination reaction is carried out in N,N-dimethylformamide using 3 equivalents of bromine with 2-octyl-4-isothiazolin-3-one, resulting in the desired 4-bromo-2-octyl-4-isothiazolin-3-one in a high yield of 93%. However, it makes no mention of the by-production of 4,5-dibromo-4-isothiazolin-3-one derivatives that are produced when an excess amount of bromine is used. When an excess amount of bromine is used, a step is required to dispose of the highly reactive excess bromine after the reaction is complete, making this an economically inefficient production method.

Non-Patent Document 2 describes the reaction of N,N-di-α-methylbenzyl-3,3-dithiodipropionamide with sulfuryl chloride, followed by a bromination reaction using bromine in dichloromethane solvent, resulting in the production of the desired 2-(S)-α-methylbenzyl-4-bromo-4-isothiazolin-3-one in 72% yield. However, it also reports the by-product 2-(S)-α-methylbenzyl-4-bromo-5-chloro-4-isothiazolin-3-one, in which the 5-position of the isothiazoline ring is chlorinated, and this method is not necessarily highly selective. Furthermore, a step for separating the by-product is required, making this method economically inefficient. The synthesis of 2-ethyl-4-bromo-4-isothiazolin-3-one is also described, but the yield is only 56%, which is unsatisfactory.

Patent Document 3 describes that 4-bromo-2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one, a production intermediate for herbicidal compounds, can be synthesized in 88% yield by brominating the corresponding 4-unsubstituted 2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one with one equivalent of bromine in acetic acid; however, the raw material used has a bulky, highly lipophilic substituent containing an aromatic group, such as a 1-(3-chlorophenyl)-1-methylethyl group, on the nitrogen atom at the 2-position.

In addition, in the bromination methods described in Patent Documents 1 to 3 and Non-Patent Documents 1 and 2, the reaction is carried out in an organic solvent, and no examples of the reaction being carried out in the presence of an aqueous solvent are described.

U.S. Pat. No. 4,105,431 Chinese Patent No. 101412698 DE 19620135 A1

Journal of Heterocyclic Chemistry, 1977, vol. 14, pp. 627-630 Tetrahedron Letters, 1994, vol. 35, pp. 6551-6554

The object of the present invention is to provide a method for producing highly pure 4-bromoisothiazolinone derivatives with high selectivity and yield, and to provide 4-bromoisothiazolinone derivatives obtained by this production method.

The present invention relates to a compound represented by formula (1)
(wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms), the method for producing a 4-bromoisothiazolinone derivative represented by the formula:
Formula (2)
(wherein R is the same as in formula (1)), or a chemically acceptable salt thereof, is brominated with bromine as a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.

The method for producing the 4-bromoisothiazolinone derivative preferably includes the following steps: step a): brominating the isothiazolinone compound represented by formula (2) or a chemically acceptable salt thereof using the brominating agent in the aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent to synthesize the 4-bromoisothiazolinone derivative represented by formula (1); and step b): purifying the 4-bromoisothiazolinone derivative obtained in step a).

In the method for producing a 4-bromoisothiazolinone derivative, the purification method in step b) is preferably a recrystallization or slurry washing method.

In the method for producing a 4-bromoisothiazolinone derivative, it is preferable that the solvent used for the recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.

In the method for producing the 4-bromoisothiazolinone derivative, it is preferable that the amount of the aqueous solvent used be in a weight ratio relative to the raw materials in the range of 0.1 to 10.

In the method for producing the 4-bromoisothiazolinone derivative, the reaction temperature for the bromination is preferably in the range of 0°C to 80°C.

In the method for producing a 4-bromoisothiazolinone derivative, it is preferable that R is an alkyl group having 1 to 4 carbon atoms.

The present invention provides a method for producing highly pure 4-bromoisothiazolinone derivatives with high selectivity and yield, as well as the 4-bromoisothiazolinone derivatives obtained by this production method.

An embodiment of the present invention will be described below. This embodiment is an example of implementing the present invention, and the present invention is not limited to this embodiment.

After extensive research, the inventors discovered that brominating a specific isothiazolinone compound unsubstituted at the 4-position using a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent can produce a 4-bromoisothiazolinone derivative selectively brominated at the 4-position in good yield. Furthermore, they discovered a purification method that efficiently produces a highly pure target product by recrystallizing or slurry-washing the resulting 4-bromoisothiazolinone derivative under specific conditions.

The method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises the steps of:
Formula (1)
(wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms) (hereinafter, may be referred to as 4-bromoisothiazolinone derivative (1)), the method comprising:
Formula (2)
(wherein R is the same as in formula (1)) (hereinafter, this may be referred to as isothiazolinone compound (2)) or a chemically acceptable salt thereof is brominated using a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.

Further, the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises the steps of:
Step a): Formula (2)
(wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms) or a chemically acceptable salt thereof is brominated with a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent to obtain an isothiazolinone compound represented by the formula (1):
(wherein R is the same as in formula (2)),
Step b): a step of purifying the 4-bromoisothiazolinone derivative obtained in Step a).

The definition of the substituent R in the isothiazolinone compound (2) and the 4-bromoisothiazolinone derivative (1) is explained below.

Examples of alkyl groups having 1 to 12 carbon atoms represented by R include linear, branched, or cyclic alkyl groups having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, cyclononyl, n-decyl, cyclodecyl, n-undecyl, cycloundecyl, n-dodecyl, and cyclododecyl. From the perspective of good yield, alkyl groups having 1 to 4 carbon atoms are preferred, and methyl is more preferred.

Isothiazolinone compound (2) may form a chemically acceptable salt. The type of salt is not particularly limited, but examples include hydrochloride, hydrobromide, hydroiodide, nitrate, and sulfate. Hydrochloride is preferred because it is easily available.

This article describes a method for producing 4-bromoisothiazolinone derivatives.

The bromination reaction in the method for producing a 4-bromoisothiazolinone derivative according to this embodiment is carried out in the presence of an aqueous solvent. This bromination reaction may be carried out using only water as the solvent, or in a mixed solvent of water and an organic solvent that is substantially non-destructive to the reaction. Examples of organic solvents used in bromination include halogen-based solvents such as chloroform, dichloromethane, and carbon tetrachloride; amide-based solvents such as dimethylformamide and dimethylacetamide; and aromatic solvents such as toluene, xylene, mesitylene, chlorobenzene, and o-dichlorobenzene. From the perspective of good yield, aromatic solvents are preferred, and chlorobenzene or o-dichlorobenzene is even more preferred.

The amount of water may be, for example, in a weight ratio to the raw materials in the range of 0.1 to 10. When the bromination reaction is carried out in a mixed solvent of water and an organic solvent, the mixing ratio of water to organic solvent is not particularly limited, but may be, for example, a volume ratio of water:organic solvent selected appropriately from the range of 1:10 to 10:1.

Brominating agents used in bromination reactions include bromine, bromine-1,4-dioxane complex, N-bromosuccinimide (hereinafter sometimes referred to as NBS), 1,3-dibromo-5,5-dimethylhydantoin (hereinafter sometimes referred to as DBH), tribromoisocyanuric acid, dibromoisocyanuric acid (hereinafter sometimes referred to as DBI), monosodium bromoisocyanurate, tetrabutylammonium tribromide, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, carbon tetrabromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, tetrapropyl Examples include ammonium nonabromide, pyridinium bromide perbromide, pyridinium bromochromate, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene trihydrobromide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, boron tribromide, phosphorus tribromide, bromodimethylsulfonium bromide, 5,5-dibromoMeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)bromonium hexafluorophosphate, trimethylsilyl bromide, sulfuryl bromide, and hydrogen bromide. Bromine, N-bromosuccinimide, and 1,3-dibromo-5,5-dimethylhydantoin are preferred due to their availability and good yield, with bromine being more preferred.

The amount of brominating agent used is preferably 0.5 to 2 molar equivalents relative to the amount of the starting isothiazolinone compound (2) or its chemically acceptable salt, and more preferably 0.8 to 1.5 molar equivalents in terms of good selectivity and yield.

There are no particular limitations on the method for contacting isothiazolinone compound (2) or its chemically acceptable salt with a brominating agent. For example, the brominating agent may be added to isothiazolinone compound (2) or its chemically acceptable salt in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent, and the mixture may be mixed using a stirring device such as a mechanical stirrer.

The bromination reaction can be carried out at a reaction temperature selected appropriately from the range of 0°C to the solvent reflux temperature, but from the viewpoint of good selectivity and yield, it is preferable to carry out the reaction at a reaction temperature selected from the range of 0°C to 80°C. The reaction time may be, for example, 1 to 48 hours.

After the bromination reaction is complete, the 4-bromoisothiazolinone derivative (1) obtained through typical post-treatment procedures such as extraction and concentration may contain impurities. These impurities include the unreacted starting isothiazolinone compound (2) or its chemically acceptable salts, which have similar chemical properties to the desired 4-bromoisothiazolinone derivative (1), as well as compounds brominated at the 5-position of the isothiazolinone ring and compounds brominated at both the 4- and 5-positions. Furthermore, when NBS or DBH is used as the brominating agent, succinimide or 5,5-dimethylhydantoin may remain. Therefore, it is difficult to remove these impurities and obtain a high-purity target product with a high recovery rate using typical purification methods.

Step b) is a step in which the 4-bromoisothiazolinone derivative (1) obtained by the bromination reaction is purified by recrystallization or slurry washing in a specific solvent, resulting in a high recovery rate of highly pure 4-bromoisothiazolinone derivative (1).

The solvent used in step b) is preferably a halogen-based solvent, an ester-based solvent, or an aromatic solvent.

Examples of halogen-based solvents include chloroform, dichloromethane, dichloroethane, and carbon tetrachloride. Examples of ester-based solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and tert-butyl acetate. Examples of aromatic solvents include toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, and nitrobenzene. Among these solvents, chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, toluene, chlorobenzene, and o-dichlorobenzene are preferred due to their high yield (recovery rate), with ethyl acetate, chlorobenzene, and o-dichlorobenzene being more preferred.

The conditions for recrystallization in step b) are explained below. The 4-bromoisothiazolinone derivative (1) mixed with a solvent is heated to dissolve, and then cooled to precipitate a highly pure 4-bromoisothiazolinone derivative (1). The amount of solvent used is, for example, an amount appropriately selected from the range of 10% to 1000% by weight relative to the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). It is desirable to add the minimum amount of solvent necessary to completely dissolve the 4-bromoisothiazolinone derivative (1). The heating temperature can be selected from the range of 25°C to the solvent reflux temperature. There are no particular limitations on the cooling temperature; the mixture can be cooled in an ice bath or allowed to cool to room temperature (e.g., 18-28°C).

The conditions for performing the slurry washing in step b) are explained below. By suspending the 4-bromoisothiazolinone derivative (1) in a solvent, a highly pure 4-bromoisothiazolinone derivative (1) can be precipitated. The amount of solvent used can be appropriately selected, for example, from the range of 10% to 1000% by weight, based on the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). The suspension can be performed at a reaction temperature appropriately selected, for example, from the range of -20°C to the solvent reflux temperature.

After step b) is completed, the precipitated solid can be filtered off to isolate the highly pure 4-bromoisothiazolinone derivative (1). There are no particular restrictions on the filtration method; for example, natural filtration, vacuum filtration, centrifugal filtration, etc. can be selected appropriately depending on the reaction scale, etc. Vacuum filtration and centrifugal filtration are preferred because they are efficient and can shorten the reaction time.

The higher the purity of the 4-bromoisothiazolinone derivative (1) used in step b), the more efficiently it is possible to obtain a high-purity target product. When NBS or DBH is used as the brominating agent, it is preferable to remove as much of the succinimide and 5,5-dimethylhydantoin generated from NBS or DBH, respectively, as possible before recrystallization or slurry washing. One example of a method for removing these impurities is washing the reaction mixture with a basic aqueous solution after the bromination reaction is complete. Examples of basic aqueous solutions include aqueous sodium acetate, aqueous potassium acetate, aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, aqueous potassium carbonate, aqueous sodium bicarbonate, aqueous potassium bicarbonate, aqueous trisodium phosphate, and aqueous tripotassium phosphate.

The operation of step b) may be repeated until the 4-bromoisothiazolinone derivative (1) reaches the desired purity.

The method for producing 4-bromoisothiazolinone derivatives according to an embodiment of the present invention is useful as a method for producing 4-bromoisothiazolinone derivatives, which are useful as active ingredients in disinfectants and antibacterial agents, with good selectivity, yield, and purity.

The 4-bromoisothiazolinone derivatives that can be produced in high yield and with high purity by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention are useful as active ingredients in disinfectants and antibacterial agents, and can be used in a variety of applications, such as industrial preservatives, building materials, paints, adhesives, leather, pulp and paper, cooling towers, industrial oils, textiles, cleaning aids, cosmetics, and household products.

The 4-bromoisothiazolinone derivative represented by formula (1) above, produced by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention, contains less than 100 ppm of the isothiazolinone compound represented by formula (2) above or a chemically acceptable salt thereof.

The present specification includes the following embodiments.
[1] Formula (1)
(wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms), the method for producing a 4-bromoisothiazolinone derivative represented by the formula:
Formula (2)
(wherein R is the same as in formula (1)), or a chemically acceptable salt thereof, is brominated with a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.

[2] A method for producing the 4-bromoisothiazolinone derivative according to [1],
Step a): brominating the isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof using the brominating agent in the aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent, thereby synthesizing the 4-bromoisothiazolinone derivative represented by the formula (1);
Step b): Purifying the 4-bromoisothiazolinone derivative obtained in the step a);
A method for producing a 4-bromoisothiazolinone derivative, comprising:

[3] A method for producing the 4-bromoisothiazolinone derivative according to [2],
A method for producing a 4-bromoisothiazolinone derivative, wherein the purification method in the step b) is a method by recrystallization or slurry washing.

[4] A method for producing the 4-bromoisothiazolinone derivative according to [3],
The method for producing a 4-bromoisothiazolinone derivative, wherein the solvent used in the recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.

[5] A method for producing the 4-bromoisothiazolinone derivative according to any one of [1] to [4],
A method for producing a 4-bromoisothiazolinone derivative, wherein the amount of the water solvent used is in the range of 0.1 to 10 in weight ratio to the raw material.

[6] A method for producing the 4-bromoisothiazolinone derivative according to any one of [1] to [5],
The method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.

[7] A method for producing the 4-bromoisothiazolinone derivative according to any one of [1] to [6],
The method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C.

[8] A method for producing the 4-bromoisothiazolinone derivative according to any one of [1] to [7],
A method for producing a 4-bromoisothiazolinone derivative, wherein R is an alkyl group having 1 to 4 carbon atoms.

[9] A 4-bromoisothiazolinone derivative represented by formula (1), wherein the content of an isothiazolinone compound represented by formula (2) or a chemically acceptable salt thereof contained in the 4-bromoisothiazolinone derivative is less than 100 ppm.
(In the formula, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.)
(In the formula, R is the same as in formula (1).)

The present invention will be explained in more detail below using examples and comparative examples, but the present invention is not limited to the following examples.

[ ¹ H-NMR measurement]
A Bruker ASCEND HD (400 MHz; manufactured by BRUKER) was used for ¹ H-NMR measurements. ¹ H-NMR measurements were performed using deuterated chloroform (CDCl ₃ ) as the measurement solvent and tetramethylsilane (TMS) as the internal standard. The purity of the compound was calculated from the integral ratio of the measured ¹ H-NMR. Commercially available reagents were used.

In Examples 20 and 21 and Comparative Examples 1 and 2, the composition and yield of the crude product were determined by ^{the 1} H-NMR internal standard method. In ^{the 1} H-NMR internal standard method, a predetermined amount of 1,4-di-tert-butylbenzene was added to the crude product as an internal standard substance, and chloroform or a mixed solution of chloroform and dimethylformamide was added to prepare a substantially homogeneous solution. A portion of this solution was sampled and diluted with deuterated chloroform, and ¹ H-NMR measurement was performed. From the integral value in the obtained ¹ H-NMR spectrum, the ratio of the amount of substance of the target product and raw material relative to the internal standard substance was calculated, and the composition and yield were determined.

Example 1
Water (4.40 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 2.00 g, 8.68 mmol), and then bromine (0.530 mL, 10.4 mmol) was added dropwise over 10 minutes. This mixed solution was stirred at room temperature (18-28°C) for 1.5 hours. The reaction solution was neutralized with a 20 wt % aqueous sodium carbonate solution, and then extracted with ethyl acetate (10 mL x 3), and each organic layer was washed with saturated brine (1 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.68 g).

Ethyl acetate (approximately 2 mL) was added to the obtained crude product, and the mixture was heated to dissolve it. After cooling to room temperature, the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.44 g, yield: 86%, purity: 99.9%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.07 (s, 1H), 3.42 (s, 3H). The results are shown in Table 1.

Example 2
Water (26.4 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 12.0 g, 52.1 mmol), and then bromine (3.20 mL, 62.5 mmol) was added dropwise over 45 minutes while cooling in a water bath at 25°C or below. This mixed solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, followed by extraction with ethyl acetate (40 mL x 3), and each organic layer was washed with a 1:1 mixture (2 mL each) of 20 wt% aqueous sodium carbonate solution and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (9.50 g).

Ethyl acetate (approximately 11 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (8.09 g, yield: 80%, purity: 99.9%). The results are shown in Table 1.

Example 3
Water (4.40 g) was added to 2-methyl-4-isothiazolin-3-one (50% aqueous solution by weight, 2.00 g, 8.68 mmol), and then bromine (0.53 mL, 10.4 mmol) was added dropwise over 10 minutes. This mixed solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (9 mL) was added, followed by extraction with ethyl acetate (10 mL x 4). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).

Ethyl acetate (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.28 g, yield: 76%, purity: 99.9%). The results are shown in Table 1.

Example 4
Water (2.30 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), and then bromine (0.53 mL, 10.4 mmol) was added dropwise over 10 minutes. This mixed solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, followed by extraction with ethyl acetate (15 mL x 3), and each organic layer was washed with a 1:1 mixture (2 mL each) of 20 wt% aqueous sodium carbonate solution and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.60 g).

Ethyl acetate (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.32 g, yield: 79%, purity: 99.9%). The results are shown in Table 1.

Example 5
Water (1.50 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 2.00 g, 8.68 mmol), and then bromine (0.53 mL, 10.4 mmol) was added dropwise over 10 minutes. This mixed solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt % aqueous sodium carbonate solution, followed by extraction with ethyl acetate (15 mL x 3), and each organic layer was washed with a 1:1 mixture (2 mL each) of 20 wt % aqueous sodium carbonate solution and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).

Ethyl acetate (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.35 g, yield: 80%, purity: 99.9%). The results are shown in Table 1.

Example 6
Water (75.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 100.23 g, 435 mmol), and then bromine (27.0 mL, 524 mmol) was added dropwise over 2.5 hours. This mixed solution was stirred at room temperature for 1 hour. The reaction solution was neutralized with a 20 wt % aqueous sodium carbonate solution, and then saturated brine (200 mL) was added, followed by extraction with ethyl acetate (350 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.45 g).

Ethyl acetate (approximately 70 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (67.04 g, yield: 79%, purity: 99.9%). The results are shown in Table 1.

Example 7
Water (75.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 100.19 g, 435 mmol), and then bromine (27.0 mL, 524 mmol) was added dropwise over 2.5 hours. This mixed solution was stirred at room temperature for 1 hour. The reaction solution was neutralized with a 20 wt % aqueous sodium carbonate solution, and then saturated brine (200 mL) was added, followed by extraction with ethyl acetate (350 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.57 g).

Ethyl acetate (50 mL) was added to the resulting crude product, followed by slurry washing under ice cooling for 1 hour. The precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (71.60 g, yield: 85%, purity: 99.9%). The results are shown in Table 1.

Example 8
Water (150.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 200.09 g, 869 mmol), and then bromine (54.0 mL, 1.05 mol) was added dropwise over 5 hours. This mixed solution was stirred at room temperature for 1 hour. The reaction solution was neutralized with a 20 wt % aqueous sodium carbonate solution, and then saturated brine (400 mL) was added, followed by extraction with ethyl acetate (500 mL x 4). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (159.33 g).

Ethyl acetate (100 mL) was added to the resulting crude product, followed by slurry washing under ice cooling for 30 minutes. The precipitated solid was filtered off to obtain a white solid of 4-bromo-2-methyl-4-isothiazolin-3-one (146.67 g, yield: 87%, purity: 99.8%). The results are shown in Table 1.

Example 9
Water (3.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), and then bromine (1.07 mL, 20.9 mmol) was added dropwise at 40°C over 10 minutes. This mixed solution was stirred at 40°C for 2 hours. A saturated aqueous solution of sodium carbonate was added to the reaction solution to neutralize it, and then saturated brine (8 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.14 g).

Ethyl acetate (approximately 3 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (2.67 g, yield: 79%, purity: 99.9%). The results are shown in Table 1.

Example 10
Water (2.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), and then bromine (1.07 mL, 20.9 mmol) was added dropwise at 40°C over 10 minutes. This mixed solution was stirred at 40°C for 5 hours. A saturated aqueous solution of sodium carbonate was added to the reaction solution to neutralize it, and then saturated brine (8 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.04 g).

Ethyl acetate (approximately 4 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (2.69 g, yield: 80%, purity: 99.9%). The results are shown in Table 1.

Example 11
Water (7.50 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), and then bromine (2.70 mL, 52.4 mmol) was added dropwise over 45 minutes. This mixed solution was stirred overnight (12 hours) at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (20 mL) was added, followed by extraction with methyl isobutyl ketone (35 mL x 3 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.85 g).

Methyl isobutyl ketone (approximately 8 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (6.70 g, yield: 79%, purity: 99.9%). The results are shown in Table 1.

Example 12
Water (7.50 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), and then bromine (2.70 mL, 52.4 mmol) was added dropwise over 45 minutes. This mixed solution was stirred overnight at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (20 mL) was added, followed by extraction with chlorobenzene (35 mL x 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.57 g).

Chlorobenzene (approximately 7 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (6.29 g, yield: 75%, purity: 99.9%). The results are shown in Table 1.

Example 13
Water (7.50 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.03 g, 43.5 mmol), and then bromine (2.70 mL, 52.4 mmol) was added dropwise over 45 minutes. This mixed solution was stirred overnight at room temperature. The reaction solution was neutralized with a saturated aqueous sodium carbonate solution, and then saturated brine (20 mL) was added, followed by extraction with o-dichlorobenzene (35 mL x 3 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.53 g).

o-Dichlorobenzene (approximately 7 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (6.49 g, yield: 77%, purity: 99.8%). The results are shown in Table 1.

Example 14
Water (4.00 g) was added to 2-methyl-4-isothiazolin-3-one hydrochloride (1.01 g, 6.64 mmol), and then bromine (0.38 mL, 7.37 mmol) was added dropwise over 15 minutes. This mixture was stirred at room temperature for 1 hour. Saturated brine (5 mL) was added to the reaction solution, which was then neutralized with a 20 wt % aqueous sodium carbonate solution and extracted with ethyl acetate (10 mL x 4). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.21 g).

Ethyl acetate (approximately 1 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.04 g, yield: 80%, purity: 99.9%). The results are shown in Table 1.

Example 15
Water (3.00 g) was added to 2-methyl-4-isothiazolin-3-one hydrochloride (1.00 g, 6.62 mmol), and then bromine (0.395 mL, 7.66 mmol) was added dropwise over 15 minutes. This mixture was stirred at room temperature for 3 hours. Saturated brine (5 mL) was added to the reaction solution, which was then neutralized with a 20 wt % aqueous sodium carbonate solution and extracted with ethyl acetate (10 mL x 4). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.18 g).

Ethyl acetate (approximately 1 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (0.99 g, yield: 77%, purity: 99.9%). The results are shown in Table 1.

Example 16
To 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.07 g, 8.99 mmol) was added water (2.00 g), and then a solution of bromine (0.56 mL, 10.9 mmol) in chlorobenzene (4.0 mL) was added dropwise over 30 minutes. This mixture was stirred overnight at room temperature. Saturated brine (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate and extracted with chlorobenzene (10 mL x 4 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.79 g).

Chlorobenzene (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.54 g, yield: 88%, purity: 99.9%). The results are shown in Table 1.

Example 17
Water (10.0 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.11 g, 43.9 mmol), and then a solution of bromine (2.75 mL, 53.3 mmol) in chlorobenzene (20.0 mL) was added dropwise over 30 minutes. This mixture was stirred overnight at room temperature. Saturated brine (50 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate and extracted with chlorobenzene (50 mL x 4). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (8.06 g).

Chlorobenzene (approximately 8 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (6.87 g, yield: 81%, purity: 99.9%). The results are shown in Table 1.

Example 18
Water (1.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), and then a solution of bromine (0.54 mL, 10.5 mmol) in chlorobenzene (4.0 mL) was added dropwise over 30 minutes. This mixture was stirred overnight at room temperature. Saturated brine (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate and extracted with chlorobenzene (10 mL x 4 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.61 g).

Chlorobenzene (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.34 g, yield: 79%, purity: 99.9%). The results are shown in Table 1.

Example 19
To 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.03 g, 8.81 mmol) was added water (2.00 g), and then a solution of bromine (0.55 mL, 10.7 mmol) in o-dichlorobenzene (4.0 mL) was added dropwise over 30 minutes. This mixture was stirred at room temperature for 6 hours. Saturated brine (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate solution and extracted with o-dichlorobenzene (10 mL x 4 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.86 g).

o-Dichlorobenzene (approximately 2 mL) was added to the resulting crude product, which was then heated to dissolve. The mixture was then cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (1.46 g, yield: 85%, purity: 99.8%). The results are shown in Table 1.

Example 20
Water (4.40 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 2.02 g, 8.75 mmol), and then bromine (0.54 mL, 10.5 mmol) was added dropwise over 10 minutes. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, and then saturated brine (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 4). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.66 g). Analysis by ^{the 1} H-NMR internal standard method revealed the following composition and yield. The results are shown in Table 1.

Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 93.5%
2-methyl-4-isothiazolin-3-one: 0.0%
Yield: 91%

Example 21
Water (2.00 g) was added to 2-methyl-4-isothiazolin-3-one (50 wt % aqueous solution, 2.02 g, 8.78 mmol), and then a solution of bromine (0.54 mL, 10.5 mmol) in chlorobenzene (4.0 mL) was added dropwise over 30 minutes. This mixed solution was stirred overnight at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (10 mL) was added, followed by extraction with chlorobenzene (10 mL x 4 times). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g). Analysis by ¹ H-NMR internal standard method revealed the following composition and yield. The results are shown in Table 1.

Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 95.0%
2-methyl-4-isothiazolin-3-one: 0.0%
Yield: 90%

<Comparative Example 1>
Bromine (0.45 mL, 8.76 mmol) was slowly added dropwise to a solution of 2-methyl-4-isothiazolin-3-one (1.00 g, 8.68 mmol) in ethyl acetate (17.0 mL), and the mixture was then heated and stirred at 80°C for 8 hours. The reaction solution was concentrated under reduced pressure, and chloroform (25 mL) and water (10 mL) were added, followed by stirring for 30 minutes. This mixed solution was extracted with chloroform (10 mL x 3), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.49 g). Analysis by ¹ H-NMR internal standard method revealed the composition and yield as follows. The results are shown in Table 1.

Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 85.2%
2-methyl-4-isothiazolin-3-one: 6.7%
Yield: 76%

<Comparative Example 2>
To a solution of 2-methyl-4-isothiazolin-3-one (1.02 g, 8.86 mmol) in acetic acid (15.0 mL) was slowly added dropwise under ice-cooling, followed by stirring for 1 hour under ice-cooling (0-5°C) and then for an additional 17 hours at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution (14 mL), saturated aqueous sodium thiosulfate solution (14 mL), and water (5 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.31 g). Analysis by ¹ H-NMR internal standard method revealed the following composition and yield. The results are shown in Table 1.

Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 74.0%
2-methyl-4-isothiazolin-3-one: 4.7%
Yield: 56%

As such, the method of this example enabled the production of highly pure 4-bromoisothiazolinone derivatives with high selectivity and yield.

Claims (7)

Formula (1)
(wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms), the method for producing a 4-bromoisothiazolinone derivative represented by the formula:
Formula (2)
(wherein R is the same as in formula (1)), or a chemically acceptable salt thereof, is brominated with bromine as a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent. A method for producing the 4-bromoisothiazolinone derivative according to claim 1, comprising the steps of:
Step a): brominating the isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof using the brominating agent in the aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent, thereby synthesizing the 4-bromoisothiazolinone derivative represented by the formula (1);
Step b): Purifying the 4-bromoisothiazolinone derivative obtained in the step a);
A method for producing a 4-bromoisothiazolinone derivative, comprising: A method for producing the 4-bromoisothiazolinone derivative according to claim 2, comprising the steps of:
A method for producing a 4-bromoisothiazolinone derivative, wherein the purification method in the step b) is a method by recrystallization or slurry washing. A method for producing the 4-bromoisothiazolinone derivative according to claim 3, comprising the steps of:
The method for producing a 4-bromoisothiazolinone derivative is characterized in that the solvent used in the recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene. A method for producing the 4-bromoisothiazolinone derivative according to any one of claims 1 to 4, comprising the steps of:
A method for producing a 4-bromoisothiazolinone derivative, characterized in that the amount of the water solvent used is in the range of 0.1 to 10 in weight ratio to the raw material. A method for producing the 4-bromoisothiazolinone derivative according to claim 1 or 2, comprising the steps of:
The method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C. A method for producing the 4-bromoisothiazolinone derivative according to claim 1 or 2, comprising the steps of:
4. A method for producing a 4-bromoisothiazolinone derivative, wherein R is an alkyl group having 1 to 4 carbon atoms.