Method for producing 4-bromoisothiazolinone derivatives, and 4-bromoisothiazolinone derivatives

Abstract

To provide a method for selectively producing a high-purity 4-bromoisothiazolinone derivative at a good yield.SOLUTION: Provided is a method for producing a 4-bromoisothiazolinone derivative represented by formula (1) (in which R is a hydrogen atom or a C1-12 alkyl group). The method involves using a brominating agent to brominate an isothiazolinone compound represented by formula (2) (in which R is the same as in formula (1)) or a chemically acceptable salt thereof in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a 4-bromoisothiazolinone derivative, and a 4-bromoisothiazolinone derivative obtained by the method. [Background technology]

[0002] Antibacterial agents (preservatives) are used in a variety of applications, including industrial preservatives, building materials, paints, adhesives, leather, pulp and paper, cooling towers, industrial oils, fibers, 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 have 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 to 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 practical application difficult.

[0003] For example, Patent Document 1 describes that the bromination reaction of 2-methyl-4-isothiazolin-3-one with bromine (1 equivalent) in dichloroethane solvent results in a yield of only 14% to obtain the target 4-bromo-2-methyl-4-isothiazolin-3-one. It also describes that the bromination of 2-(1,1,3,3-tetramethylbutyl)-4-isothiazolin-3-one with N-bromosuccinimide (2 equivalents) in chloroform solvent results in a yield of 54%.

[0004] Non-Patent Document 1 describes that the bromination reaction of 2-cyclohexyl-4-isothiazolin-3-one with bromine (1 equivalent) and the bromination reaction of 2-(2-phenylethyl)-4-isothiazolin-3-one with bromine (3 equivalents) give the target 2-alkyl-4-bromo-4-isothiazolin-3-one derivative in yields of 75% and 63%, respectively. However, it has been reported that the addition of an excess amount of bromine in the 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 isothiazoline ring is also brominated.

[0005] Patent Document 2 describes that a bromination reaction of 2-octyl-4-isothiazolin-3-one using 3 equivalents of bromine in N,N-dimethylformamide solvent is carried out to obtain the target 4-bromo-2-octyl-4-isothiazolin-3-one in a high yield of 93%, but does not describe at all the by-product 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 treat the highly reactive excess bromine after the reaction is completed, and this production method cannot be said to be economically efficient.

[0006] Non-Patent Document 2 describes the reaction of N,N-di-α-methylbenzyl-3,3-dithiodipropionamide with sulfuryl chloride, followed by bromination 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 therefore the method is not necessarily highly selective. Furthermore, a step for separating the by-product is required, making the method economically inefficient. The synthesis of 2-ethyl-4-bromo-4-isothiazolin-3-one is also described, but the yield was only 56%, which is unsatisfactory.

[0007] 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 and highly lipophilic substituent containing an aromatic group, such as a 1-(3-chlorophenyl)-1-methylethyl group, on the nitrogen atom at the 2-position.

[0008] 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 there is no description of an example in which the reaction is carried out in the presence of an aqueous solvent. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 4,105,431 [Patent Document 2] Chinese Patent No. 101412698 [Patent Document 3] DE 19620135 [Non-patent literature]

[0010] [Non-Patent Document 1] Journal of Heterocyclic Chemistry, 1977, vol. 14, pp. 627-630 [Non-patent document 2] Tetrahedron Letters, 1994, vol. 35, pp. 6551-6554 Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a method for producing a highly pure 4-bromoisothiazolinone derivative with high selectivity and yield, and to provide a 4-bromoisothiazolinone derivative obtained by the production method. [Means for solving the problem]

[0012] The present invention relates to a compound represented by formula (1) [ka] (wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms), Formula (2) [ka] (wherein R is the same as in formula (1)) or a chemically acceptable salt thereof is reacted with a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent. as bromine This is a method for producing a 4-bromoisothiazolinone derivative, in which the compound is brominated using

[0013] The method for producing a 4-bromoisothiazolinone derivative preferably comprises 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 in 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).

[0014] In the method for producing a 4-bromoisothiazolinone derivative, the purification method in the step b) is preferably a method by recrystallization or slurry washing.

[0015] In the method for producing a 4-bromoisothiazolinone derivative, the solvent used in the recrystallization or slurry washing is preferably at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.

[0016] In the method for producing a 4-bromoisothiazolinone derivative, the amount of the water solvent used is preferably in the range of 0.1 to 10 in terms of weight ratio to the raw material.

[0018] In the method for producing a 4-bromoisothiazolinone derivative, the reaction temperature in the bromination is preferably in the range of 0°C to 80°C.

[0019] In the method for producing a 4-bromoisothiazolinone derivative, R is preferably an alkyl group having 1 to 4 carbon atoms. [Effects of the Invention]

[0021] According to the present invention, it is possible to provide a method for producing a highly pure 4-bromoisothiazolinone derivative with high selectivity and yield, and a 4-bromoisothiazolinone derivative obtained by the production method. DETAILED DESCRIPTION OF THE INVENTION

[0022] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following describes an embodiment of the present invention. The embodiment is an example of implementing the present invention, and the present invention is not limited to the embodiment.

[0023] As a result of extensive research, the present inventors have found that a 4-bromoisothiazolinone derivative selectively brominated at the 4-position can be produced in good yield by brominating a specific isothiazolinone compound unsubstituted at the 4-position with a brominating agent in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent. Furthermore, they have found a purification method that allows the target product to be obtained efficiently with high purity by recrystallizing or slurry-washing the obtained 4-bromoisothiazolinone derivative under specific conditions.

[0024] The method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises the steps of: Formula (1) [ka] (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 the steps of: Formula (2) [ka] (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.

[0025] Furthermore, the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises the steps of: Process a): Formula (2) [ka] (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): [ka] (wherein R is the same as in formula (2)), Step b): a step of purifying the 4-bromoisothiazolinone derivative obtained in Step a).

[0026] The definition of the substituent R in the isothiazolinone compound (2) and the 4-bromoisothiazolinone derivative (1) will be explained below.

[0027] Examples of the alkyl group 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. In terms of high yield, alkyl groups having 1 to 4 carbon atoms are preferred, and methyl is more preferred.

[0028] The isothiazolinone compound (2) may form a chemically acceptable salt. The type of salt is not particularly limited, but examples thereof include hydrochloride, hydrobromide, hydroiodide, nitrate, and sulfate. Hydrochloride is preferred because it is easily available.

[0029] A method for producing a 4-bromoisothiazolinone derivative will be described.

[0030] 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 may be carried out in a mixed solvent of water and an organic solvent that is substantially harmless to the reaction. Examples of organic solvents used in the 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. In terms of good yield, aromatic solvents are preferred, and chlorobenzene or o-dichlorobenzene is more preferred.

[0031] 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 the organic solvent is not particularly limited, and may be, for example, a volume ratio of water:organic solvent appropriately selected from the range of 1:10 to 10:1.

[0032] Brominating agents used in the bromination reaction 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 of suitable bromine-containing compounds 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 in terms of availability and good yield, with bromine being more preferred.

[0033] The amount of the brominating agent used is preferably 0.5 to 2 molar equivalents relative to the amount of the starting isothiazolinone compound (2) or a chemically acceptable salt thereof, and more preferably 0.8 to 1.5 molar equivalents in terms of good selectivity and yield.

[0034] The method for contacting the isothiazolinone compound (2) or a chemically acceptable salt thereof with the brominating agent is not particularly limited. For example, the brominating agent may be added to the isothiazolinone compound (2) or a chemically acceptable salt thereof 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.

[0035] The bromination reaction can be carried out at a reaction temperature appropriately selected from the range of 0° C. to the reflux temperature of the solvent, but in terms of good selectivity and yield, it is preferably carried out 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.

[0036] After the bromination reaction, the 4-bromoisothiazolinone derivative (1) obtained by typical post-treatments such as extraction and concentration may contain impurities. These impurities include unreacted starting isothiazolinone compound (2) or its chemically acceptable salts, which have similar chemical properties to the target 4-bromoisothiazolinone derivative (1), as well as compounds brominated at the 5-position of the isothiazolinone ring or 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 the target product with a high recovery rate using typical purification methods.

[0037] Step b) is a step of purifying the 4-bromoisothiazolinone derivative (1) obtained by the bromination reaction, in which high-purity 4-bromoisothiazolinone derivative (1) is obtained with a high recovery rate by recrystallization or slurry washing in a specific solvent.

[0038] The solvent used in step b) is preferably a halogen-based solvent, an ester-based solvent, an aromatic solvent, or the like.

[0039] 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 in terms of high yield (recovery rate), and ethyl acetate, chlorobenzene, and o-dichlorobenzene are more preferred.

[0040] The conditions for recrystallization in step b) are explained below. The 4-bromoisothiazolinone derivative (1) mixed with a solvent is heated to dissolve it, 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 that completely dissolves the 4-bromoisothiazolinone derivative (1). The heating temperature can be selected appropriately from the range of 25°C to the solvent reflux temperature. The cooling temperature is not particularly limited; the mixture may be cooled in an ice bath or allowed to cool to room temperature (e.g., 18 to 28°C).

[0041] 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% by weight to 1000% by weight, based on the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). The temperature during suspension can be appropriately selected, for example, from the range of -20°C to the solvent reflux temperature.

[0042] After completion of step b), the precipitated solid can be filtered off to isolate a highly pure 4-bromoisothiazolinone derivative (1). The filtration method is not particularly limited, and may be appropriately selected from, for example, gravity filtration, vacuum filtration, centrifugal filtration, etc., depending on the reaction scale, etc. Vacuum filtration and centrifugal filtration are preferred because they are efficient and can shorten the reaction time.

[0043] The higher the purity of the 4-bromoisothiazolinone derivative (1) used in step b), the more efficiently a high-purity target product can be obtained. When NBS or DBH is used as the brominating agent, it is preferable to remove as much succinimide or 5,5-dimethylhydantoin as possible from NBS or DBH before recrystallization or slurry washing. Examples of methods for removing these impurities include 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.

[0044] The operation of step b) may be carried out repeatedly until the 4-bromoisothiazolinone derivative (1) reaches a desired purity.

[0045] The method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is useful as a method for producing a 4-bromoisothiazolinone derivative useful as an active ingredient of a disinfectant or antibacterial agent with good selectivity, yield and purity.

[0046] 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 of disinfectants and antibacterial agents, and can be used in a variety of applications, such as industrial preservatives, building materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, fibers, cleaning aids, cosmetics, and household products.

[0047] The 4-bromoisothiazolinone derivative represented by the above formula (1) produced by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention has a content of the isothiazolinone compound represented by the above formula (2) or a chemically acceptable salt thereof of less than 100 ppm.

[0048] The present specification includes the following embodiments. [1] Formula (1) [ka] (wherein R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms), Formula (2) [ka] (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.

[0049] [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 to synthesize 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:

[0050] [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.

[0051] [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.

[0052] [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.

[0053] [6] A method for producing the 4-bromoisothiazolinone derivative according to any one of [1] to [5], A method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.

[0054] [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.

[0055] [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 the R is an alkyl group having 1 to 4 carbon atoms.

[0056] [9] A 4-bromoisothiazolinone derivative represented by formula (1), wherein the content of the isothiazolinone compound represented by formula (2) or a chemically acceptable salt thereof contained in the 4-bromoisothiazolinone derivative is less than 100 ppm. [ka] (In the formula, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.) [ka] (wherein R is the same as in formula (1)). [Example]

[0057] EXAMPLES The present invention will be explained in more detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0058] [ 1 H-NMR measurement] 1 For the H-NMR measurement, a Bruker ASCEND HD (400 MHz; manufactured by BRUKER) was used. 1 H-NMR was measured using deuterated chloroform (CDCl3) as the measurement solvent and tetramethylsilane (TMS) as the internal standard. 1 The values ​​were calculated from the integral ratio of H-NMR. Commercially available reagents were used.

[0059] In Examples 20 and 21 and Comparative Examples 1 and 2, 1 The composition and yield of the crude product were determined by the H-NMR internal standard method. 1 For the H-NMR internal standard method, a predetermined amount of 1,4-di-tert-butylbenzene was added to the crude product as an internal standard, and chloroform or a mixture of chloroform and dimethylformamide was added to prepare a substantially homogeneous solution. A portion of this solution was taken and diluted with deuterated chloroform. 1 H-NMR measurement was carried out.1 The ratio of the amount of the target substance and the raw material to the internal standard substance was calculated from the integral value in the 1 H-NMR spectrum, and the composition and yield were determined.

[0060] 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. The mixture was stirred at room temperature (18-28°C) for 1.5 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, 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 crude product (1.68 g).

[0061] Ethyl acetate (approximately 2 mL) was added to the obtained crude product, and the mixture was heated to dissolve it. After that, the mixture was cooled to room temperature, and the precipitated solid was filtered off to obtain a white solid of 4-bromo-2-methyl-4-isothiazolin-3-one (1.44 g, yield: 86%, purity: 99.9%). 1 H-NMR (400 MHz, CDCl): δ 8.07 (s, 1H), 3.42 (s, 3H). The results are shown in Table 1.

[0062] <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 bromine (3.20 mL, 62.5 mmol) was added dropwise over 45 minutes while cooling in a water bath below 25°C. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, extracted 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 and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (9.50 g).

[0063] The crude product was dissolved in ethyl acetate (approximately 11 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (8.09 g, yield: 80%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0064] 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. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate, followed by the addition of saturated brine (9 mL) and 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 crude product (1.62 g).

[0065] The crude product was dissolved in ethyl acetate (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.28 g, yield: 76%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0066] 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. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, extracted 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 and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.60 g).

[0067] The crude product was dissolved in ethyl acetate (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.32 g, yield: 79%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0068] <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. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, extracted 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 and saturated brine. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.62 g).

[0069] The crude product was dissolved in ethyl acetate (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.35 g, yield: 80%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0070] 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. The mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, followed by the addition of saturated brine (200 mL) and 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 crude product (78.45 g).

[0071] The crude product was dissolved in ethyl acetate (approximately 70 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (67.04 g, yield: 79%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0072] 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. The mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, followed by the addition of saturated brine (200 mL) and 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 crude product (78.57 g).

[0073] Ethyl acetate (50 mL) was added to the obtained crude product, and the mixture was washed with slurry under ice cooling for 1 hour. The precipitated solid was filtered 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.

[0074] 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. The mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 20 wt% aqueous sodium carbonate solution, followed by the addition of saturated brine (400 mL) and 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).

[0075] The crude product was added with ethyl acetate (100 mL) and subjected to slurry washing under ice cooling for 30 minutes. The precipitated solid was filtered to obtain 4-bromo-2-methyl-4-isothiazolin-3-one as a white solid (146.67 g, yield: 87%, purity: 99.8%). The results are shown in Table 1.

[0076] 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 over 10 minutes at 40°C. The mixture was stirred at 40°C for 2 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (8 mL) was added and extracted 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).

[0077] The crude product was dissolved in ethyl acetate (approximately 3 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (2.67 g, yield: 79%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0078] 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 over 10 minutes at 40°C. The mixture was stirred at 40°C for 5 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (8 mL) was added and extracted 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).

[0079] The crude product was dissolved in ethyl acetate (approximately 4 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (2.69 g, yield: 80%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0080] 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. The mixture was stirred overnight (12 hours) at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, followed by the addition of saturated brine (20 mL) and 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 crude product (7.85 g).

[0081] The crude product was dissolved in methyl isobutyl ketone (approximately 8 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (6.70 g, yield: 79%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0082] 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. The mixture was stirred overnight at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, followed by the addition of saturated brine (20 mL) and 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 crude product (7.57 g).

[0083] The crude product was dissolved in chlorobenzene (approximately 7 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (6.29 g, yield: 75%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0084] 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. The mixture was stirred overnight at room temperature. The reaction solution was neutralized with saturated aqueous sodium carbonate, followed by the addition of saturated brine (20 mL) and extraction with o-dichlorobenzene (35 mL x 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (7.53 g).

[0085] The crude product was dissolved in o-dichlorobenzene (approximately 7 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (6.49 g, yield: 77%, purity: 99.8%) as a white solid. The results are shown in Table 1.

[0086] 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. The mixture was stirred at room temperature for 1 hour. Saturated brine (5 mL) was added to the reaction solution, which was then neutralized with 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 crude product (1.21 g).

[0087] The crude product was dissolved in ethyl acetate (approximately 1 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.04 g, yield: 80%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0088] Example 15 Water (3.00 g) was added to 2-methyl-4-isothiazolin-3-one hydrochloride (1.00 g, 6.62 mmol), followed by dropwise addition of bromine (0.395 mL, 7.66 mmol) over 15 minutes. The mixture was stirred at room temperature for 3 hours. Saturated brine (5 mL) was added to the reaction solution, which was then neutralized with 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 crude product (1.18 g).

[0089] The crude product was dissolved in ethyl acetate (approximately 1 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (0.99 g, yield: 77%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0090] Example 16 To 2-methyl-4-isothiazolin-3-one (50% by weight 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). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.79 g).

[0091] The crude product was dissolved in chlorobenzene (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.54 g, yield: 88%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0092] Example 17 To 2-methyl-4-isothiazolin-3-one (50% by weight aqueous solution, 10.11 g, 43.9 mmol) was added water (10.0 g), 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 crude product (8.06 g).

[0093] The crude product was dissolved in chlorobenzene (approximately 8 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (6.87 g, yield: 81%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0094] Example 18 To 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol) was added water (1.00 g), 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). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.61 g).

[0095] The crude product was dissolved in chlorobenzene (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.34 g, yield: 79%, purity: 99.9%) as a white solid. The results are shown in Table 1.

[0096] Example 19 To 2-methyl-4-isothiazolin-3-one (50% by weight 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. The 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 and extracted with o-dichlorobenzene (10 mL x 4). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.86 g).

[0097] The crude product was dissolved in o-dichlorobenzene (approximately 2 mL) and cooled to room temperature. The precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one (1.46 g, yield: 85%, purity: 99.8%) as a white solid. The results are shown in Table 1.

[0098] 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. The mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate, and then saturated brine (10 mL) was added and extracted 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 crude product (1.66 g). 1 Analysis by the H-NMR internal standard method revealed the following composition and yield, and the results are shown in Table 1.

[0099] Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 93.5% 2-Methyl-4-isothiazolin-3-one; 0.0% Yield: 91%

[0100] Example 21 To 2-methyl-4-isothiazolin-3-one (50% by weight aqueous solution, 2.02 g, 8.78 mmol) was added water (2.00 g), 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. The reaction solution was neutralized with saturated aqueous sodium carbonate, followed by the addition of saturated brine (10 mL) and extraction with chlorobenzene (10 mL x 4). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.62 g). 1 Analysis by the H-NMR internal standard method revealed the following composition and yield, and the results are shown in Table 1.

[0101] Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 95.0% 2-Methyl-4-isothiazolin-3-one; 0.0% Yield: 90%

[0102] <Comparative Example 1> To a solution of 2-methyl-4-isothiazolin-3-one (1.00 g, 8.68 mmol) in ethyl acetate (17.0 mL), bromine (0.45 mL, 8.76 mmol) was slowly added dropwise, followed by stirring 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 mixture was extracted with chloroform (10 mL x 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product (1.49 g). 1 Analysis by the H-NMR internal standard method revealed the following composition and yield, and the results are shown in Table 1.

[0103] Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 85.2% 2-methyl-4-isothiazolin-3-one; 6.7% Yield: 76%

[0104] <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 bromine (0.46 mL, 8.89 mmol) under ice-cooling, followed by stirring for 1 hour at 0-5°C and then at room temperature for an additional 17 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (14 mL), saturated aqueous sodium thiosulfate (14 mL), and water (5 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product (1.31 g). 1 Analysis by the H-NMR internal standard method revealed the following composition and yield, and the results are shown in Table 1.

[0105] Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 74.0% 2-methyl-4-isothiazolin-3-one; 4.7% Yield: 56%

[0106] [Table 1]

[0107] Thus, the method of the present example enabled the production of a highly pure 4-bromoisothiazolinone derivative with high selectivity and yield.

Claims

1. Formula (1) 【Chemistry 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) 【Chemistry 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.

2. 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:

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

Images