A process for the preparation of 5-chloro-2-methyl-4-isothiazolin-3-one

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-chloro-2-methyl-4-isothiazoline-3-ketone. N,N'-dimethyl-3,3'-dithiodipropionamide is mixed with ethyl acetate, cooled to 8-10 DEG C, and chlorine is added in stages, and the reaction is continued after the chlorine is passed; the adding mode of the chlorine is as follows: in the first stage, 25-30% of the chlorine is passed in 0.5h while maintaining the temperature of the reaction system at 10-12 DEG C; in the second stage, 25-30% of the chlorine is passed in 1h while maintaining the temperature of the reaction system at 13-14 DEG C; and in the third stage, the remaining chlorine is passed in 1.5h while maintaining the temperature of the reaction system at 15-18 DEG C. The application controls the generation of 5-chloro-2-methyl-4-isothiazoline-3-ketone by controlling the adding amount of the chlorine and the reaction temperature, and improves the yield of 5-chloro-2-methyl-4-isothiazoline-3-ketone.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one. BACKGROUND

[0002] 5-chloro-2-methyl-4-isothiazolin-3-one has a molecular formula of C4H4ClNOS, and a structural formula as shown in Figure 1 5-chloro-2-methyl-4-isothiazolin-3-one can be mixed with chlorine and most anions, cations and non-ionic surfactants. 5-chloro-2-methyl-4-isothiazolin-3-one is a raw material for the preparation of preservatives, and is often used in combination with 2-methyl-4-isothiazolin-3-one. 5-chloro-2-methyl-4-isothiazolin-3-one has a broad-spectrum bactericidal and preservative effect, and can effectively kill algae, bacteria and fungi. The combination of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one is also often used to prepare pregelatinized starch and biological slime inhibitor, etc. For example, CN103739721B discloses a kind of pregelatinized starch and a preparation method thereof, and CN103535369B discloses a kind of biological slime inhibitor and a preparation method thereof.

[0003] Although 5-chloro-2-methyl-4-isothiazolin-3-one is often used in combination with 2-methyl-4-isothiazolin-3-one, current preparations of the two are mostly focused on the preparation of 2-methyl-4-isothiazolin-3-one, and the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is inhibited. For example, CN102786491B and CN112110870B.

[0004] CN110066256B discloses a purification method of 5-chloro-2-methyl-4-isothiazolin-3-one, which comprises the following steps: a sample containing 5-chloro-2-methyl-4-isothiazolin-3-one is eluted in a chromatographic column using an eluent, and 5-chloro-2-methyl-4-isothiazolin-3-one is obtained. The eluent is a mixed solvent of a first solvent and a second solvent, the first solvent is petroleum ether, and the second solvent is at least one of dichloromethane and ethyl acetate. The purity of 5-chloro-2-methyl-4-isothiazolin-3-one obtained by the purification method is high, and can reach 99.9%. However, the purification operation is performed on a mixed sample containing 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, and the generation of 2-methyl-4-isothiazolin-3-one is not inhibited in the reaction stage of N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine, resulting in a low yield of 5-chloro-2-methyl-4-isothiazolin-3-one. SUMMARY

[0005] In order to improve the yield of 5-chloro-2-methyl-4-isothiazolin-3-one, the application provides a preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, which controls the generation of 5-chloro-2-methyl-4-isothiazolin-3-one by controlling the addition amount and reaction temperature of chlorine, thereby improving the yield of 5-chloro-2-methyl-4-isothiazolin-3-one.

[0006] The application aims to provide a preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, which comprises the following steps: mixing N,N'-dimethyl-3,3'-dithiodipropionamide and ethyl acetate, cooling to 8-10℃, and adding chlorine in stages; and continuing to react for 20-40min after the chlorine is completely added.

[0007] The reaction principle is as follows:

[0008]

[0009] The addition mode of chlorine is as follows:

[0010] The first stage: maintaining the temperature of the reaction system at 10-12℃, and adding 25-30% of chlorine within 0.5h;

[0011] The second stage: maintaining the temperature of the reaction system at 13-14℃, and adding 25-30% of chlorine within 1h;

[0012] The third stage: maintaining the temperature of the reaction system at 15-18℃, and adding the remaining chlorine within 1.5h.

[0013] Preferably, in the above preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, the first stage: maintaining the temperature of the reaction system at 10℃, and adding 25% of chlorine at a uniform speed within 0.5h;

[0014] The second stage: maintaining the temperature of the reaction system at 13℃, and adding 25% of chlorine at a uniform speed within 1h;

[0015] The third stage: maintaining the temperature of the reaction system at 15℃, and adding the remaining chlorine at a uniform speed within 1.5h.

[0016] Preferably, in the above preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, the mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate and chlorine is 1:2-5:0.7-0.9.

[0017] Preferably, in the above preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, the material after the heat preservation reaction for 20-40min is subjected to deacidification, solvent removal, neutralization and purification, so as to obtain a purified 5-chloro-2-methyl-4-isothiazolin-3-one sample.

[0018] Preferably, the step of neutralization in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is as follows: mixing the aqueous magnesium nitrate solution, the solvent-removed material and the magnesium hydroxide, reacting, and adjusting the pH of the neutralized product to 1-2.

[0019] The principle is as follows:

[0020]

[0021] Preferably, the mass ratio of the aqueous magnesium nitrate solution, the solvent-removed material and the magnesium hydroxide in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is 1:3:0.1.

[0022] Preferably, the step of purification in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is as follows:

[0023] The neutralized material is extracted with an organic solvent, the organic phase is collected, dried, purified with a chromatographic column filled with thin-layer chromatography silica gel, and eluted with a mixed solvent of petroleum ether and ethanol.

[0024] Preferably, the organic solvent in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is ethyl acetate or a mixed solvent of ethyl acetate and ethanol.

[0025] Preferably, the volume ratio of ethyl acetate to ethanol in the mixed solvent in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is 5-10:1.

[0026] Preferably, the volume ratio of petroleum ether to ethanol in the mixed eluent in the above method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one is 3-5:1.

[0027] Compared with the prior art, the present application has the following beneficial effects:

[0028] In the present application, the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled by controlling the amount of chlorine gas added and the reaction temperature in the stage of reacting N,N'-dimethyl-3,3'-dithiodipropionamide with chlorine gas, thereby improving the yield of 5-chloro-2-methyl-4-isothiazolin-3-one.

[0029] In the present application, the neutralized product is purified in the first stage by extraction with an organic solvent, and purified in the second stage by using a chromatographic column filled with thin-layer chromatography silica gel. Compared with the existing purification technology, the yield and purity of 5-chloro-2-methyl-4-isothiazolin-3-one are higher. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1The structural formula of 5-chloro-2-methyl-4-isothiazolin-3-one of the present application.

[0031] Figure 2 HPLC chart of the mixed aqueous solution purchased. DETAILED DESCRIPTION

[0032] In order to make the skilled in the art better understand the technical solutions of the present application can be implemented, the following specific embodiments and the present application is further described with reference to the drawings.

[0033] In the description of the present application, if not special, the reagents used are commercially available, the methods used are conventional techniques in the art.

[0034] In the description of the present application, N,N'-dimethyl-3,3'-dithiodipropionamide, purity ≥97%, molecular weight 236.35.

[0035] In the description of the present application, ethyl acetate purity ≥99%, chlorine purity ≥99%.

[0036] In the description of the present application, the particle size of thin layer chromatography silica gel is 200 mesh, H level, chemical purity.

[0037] Example 1

[0038] A preparation method of 5-chloro-2-methyl-4-isothiazolin-3-one, comprising:

[0039] (1) cyclization

[0040] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine as raw materials, ethyl acetate as solvent, cyclization reaction. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate, chlorine is 1:5:0.9.

[0041] The reaction principle is as follows:

[0042]

[0043] The operation steps are as follows:

[0044] In the reaction kettle equipped with mechanical stirring, thermometer, air pipe, exhaust pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 100g, ethyl acetate 500g. Cool to 10℃, add chlorine in stages, continue to react at 15℃ for 20min after the chlorine is passed, get liquid reaction material.

[0045] Among them, the adding method of chlorine is as follows:

[0046] First stage: maintain the temperature of the reaction system at 10℃, 22.5g of chlorine is uniformly introduced in 0.5h;

[0047] Second stage: maintain the temperature of the reaction system at 13℃, and pass 22.5g chlorine at a constant speed for 1h;

[0048] Third stage: maintain the temperature of the reaction system at 15℃, and pass 45g chlorine at a constant speed for 1.5h.

[0049] By controlling the amount of chlorine added and the reaction temperature, the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled, and the yield of 5-chloro-2-methyl-4-isothiazolin-3-one is improved.

[0050] (2) Deacidification, remove excess HCl gas

[0051] Heat the liquid reaction material obtained in (1) to 55℃, and discharge gaseous HCl. Stop when the total acidity of the liquid is 7%.

[0052] (3) Solvent removal to obtain a solid filter cake

[0053] Remove the solvent after deacidification in (2) by suction filtration to obtain a solid filter cake.

[0054] (4) Neutralization

[0055] React the solid filter cake with magnesium nitrate aqueous solution with a mass fraction of 20% and magnesium hydroxide solid in a reaction kettle, and the principle is as follows:

[0056]

[0057] The operation steps are as follows:

[0058] Add magnesium nitrate aqueous solution with a mass fraction of 20%, solid filter cake, and magnesium hydroxide into the reaction kettle, stir and mix to obtain the neutralized material, and the pH of the neutralized product is 1-2. The mass ratio of magnesium nitrate aqueous solution, solid filter cake, and magnesium hydroxide is 1:3:0.1.

[0059] (5) Purification

[0060] The neutralized material contains 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, and the purification step is used to remove 2-methyl-4-isothiazolin-3-one and some impurities, and the specific operation is as follows:

[0061] Extract 100g of the neutralized material with ethyl acetate twice, each time using 30mL of ethyl acetate, combine the two organic phases, dry the combined organic phase with anhydrous sodium sulfate, then filter, and collect the filtrate and precipitate respectively; wash the precipitate with ethyl acetate to obtain a washing liquid, mix the filtrate and the washing liquid, then add 5g of thin layer chromatography silica gel, and evaporate the solvent with a rotary evaporator to obtain a powder sample.

[0062] The product is prepared in a chromatographic column with a length of 305 mm and a diameter of 40 mm filled with thin-layer chromatography silica gel. The silica gel is wetted with petroleum ether, and then the powder sample is transferred to the chromatographic column. The eluent is a mixture of petroleum ether and ethanol with a volume ratio of 5:1. The eluate is collected in stages, and the composition of the eluate is analyzed by TLC thin-layer chromatography. The eluate containing the target product is collected, and the solvent is evaporated. The product is dried at 35°C.

[0063] The purification step is a prior art purification step. The obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99.9% and a yield of 85%, which is higher than the purity and yield of the prior art. This indicates that the stepwise addition of chlorine is beneficial to the formation of the target product 5-chloro-2-methyl-4-isothiazolin-3-one.

[0064] Example 2

[0065] A method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one, comprising:

[0066] (1) Cyclization

[0067] Cyclization is carried out using N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine as raw materials and ethyl acetate as solvent. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate, and chlorine is 1:5:0.9. The reaction principle of this step is the same as that of Example 1.

[0068] The operation steps are as follows:

[0069] In a reaction kettle equipped with mechanical stirring, a thermometer, an air inlet pipe, and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 100 g and ethyl acetate 500 g are added. The temperature is cooled to 10°C, and chlorine is added in stages. After the chlorine is completely added, the reaction is continued at 15°C for 20 min to obtain a liquid reaction material.

[0070] The addition of chlorine is as follows:

[0071] First stage: maintain the reaction system temperature at 10°C, and uniformly introduce 27 g of chlorine in 0.5 h;

[0072] Second stage: maintain the reaction system temperature at 13°C, and uniformly introduce 27 g of chlorine in 1 h;

[0073] Third stage: maintain the reaction system temperature at 15°C, and uniformly introduce 36 g of chlorine in 1.5 h.

[0074] The generation of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled by controlling the amount of chlorine added and the reaction temperature, thereby improving the yield of 5-chloro-2-methyl-4-isothiazolin-3-one.

[0075] (2) Deacidification, removing excess HCl gas

[0076] The liquid reaction material obtained in (1) is heated to 60°C to remove gaseous HCl, and the process is stopped when the total acidity of the liquid is 7%.

[0077] (3) Solvent removal, obtaining a solid filter cake

[0078] The solvent after deacidification in (2) is removed by suction filtration to obtain a solid filter cake.

[0079] (4) Neutralization

[0080] The solid filter cake is reacted with a 20% by mass aqueous magnesium nitrate solution and solid magnesium hydroxide, and the reaction principle of this step is the same as that of Example 1.

[0081] The operation steps are as follows:

[0082] The 20% by mass aqueous magnesium nitrate solution, solid filter cake, and magnesium hydroxide are added to a reaction kettle, stirred and mixed to obtain a neutralized material, and the pH of the neutralized product is 1-2. The mass ratio of the aqueous magnesium nitrate solution, solid filter cake, and magnesium hydroxide is 1:3:0.1.

[0083] (5) Purification

[0084] The neutralized material contains 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, and the purification step is used to remove 2-methyl-4-isothiazolin-3-one and some impurities, and the specific operation is as follows:

[0085] The 100 g of the neutralized material is extracted twice with 30 mL of ethyl acetate each time, the organic phases of the two times are combined, the combined organic phase is dried with anhydrous sodium sulfate, then filtered, and the filtrate and precipitate are collected respectively; the precipitate is washed with ethyl acetate to obtain a washing liquid, the filtrate and the washing liquid are mixed, then 5 g of thin layer chromatography silica gel is added, and the solvent is evaporated by a rotary evaporator to obtain a powder sample.

[0086] A chromatography column filled with thin layer chromatography silica gel with a length of 305 mm and a diameter of 40 mm is prepared, the silica gel is wetted with petroleum ether, and then the powder sample is transferred to the chromatography column, and elution is performed with a mixed solvent of petroleum ether and ethanol as the eluent, and the volume ratio of petroleum ether to ethanol is 5:1. The eluate is collected in stages, and the composition of the eluted eluate is analyzed by TLC thin layer chromatography, the eluate containing the target product is collected, and the solvent is evaporated and dried at 35°C.

[0087] The present purification step uses a purification step of the prior art, and the obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99.9% and a yield of 86%, which is higher than the purity and yield of the prior art, indicating that the stepwise addition of chlorine is beneficial to the generation of the target product 5-chloro-2-methyl-4-isothiazolin-3-one.

[0088] Example 3

[0089] A method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one, comprising:

[0090] (1) cyclization

[0091] Cyclization is performed with N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine as raw materials and ethyl acetate as a solvent. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate and chlorine is 1:2:0.7. The reaction principle of this step is the same as that of Example 1.

[0092] The operation steps are as follows:

[0093] In a reaction kettle equipped with mechanical stirring, a thermometer, a gas inlet pipe and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 100 g and ethyl acetate 200 g are added. Cooling is performed to 10°C, and chlorine is added in stages. After the chlorine is completely added, the reaction is continued at 15°C for 20 min to obtain a liquid reaction material.

[0094] The addition of chlorine is as follows:

[0095] First stage: maintain the reaction system temperature at 10°C, and uniformly add 21 g of chlorine in 0.5 h;

[0096] Second stage: maintain the reaction system temperature at 13°C, and uniformly add 21 g of chlorine in 1 h;

[0097] Third stage: maintain the reaction system temperature at 15°C, and uniformly add 28 g of chlorine in 1.5 h.

[0098] By controlling the addition amount of chlorine and the reaction temperature, the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled, and the yield of 5-chloro-2-methyl-4-isothiazolin-3-one is improved.

[0099] (2) deacidification and removal of excess HCl gas

[0100] The liquid reaction material obtained in (1) is heated to 55°C, and gaseous HCl is discharged. When the total acidity of the liquid is 7%, the reaction is stopped.

[0101] (3) solvent removal to obtain a solid filter cake

[0102] The solvent after deacidification in (2) is removed by suction filtration to obtain a solid filter cake.

[0103] (4) Neutralization

[0104] The solid filter cake is reacted with magnesium nitrate aqueous solution with a mass fraction of 20% and magnesium hydroxide solid, and the reaction principle of this step is the same as that of Example 1.

[0105] The operation steps are as follows:

[0106] The magnesium nitrate aqueous solution with a mass fraction of 20%, the solid filter cake, and the magnesium hydroxide are added to the reaction kettle, stirred and mixed to obtain the neutralized material, and the pH of the neutralized product is 1-2. The mass ratio of the magnesium nitrate aqueous solution, the solid filter cake, and the magnesium hydroxide is 1:3:0.1.

[0107] (5) Purification

[0108] The neutralized material contains 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, and the purification step is used to remove 2-methyl-4-isothiazolin-3-one and some impurities, and the specific operation is as follows:

[0109] The 100 g of the neutralized material is extracted with ethyl acetate twice, 30 mL of ethyl acetate is used each time, the organic phases of the two times are combined, the combined organic phase is dried with anhydrous sodium sulfate, then filtered, and the filtrate and the precipitate are collected respectively; the precipitate is washed with ethyl acetate to obtain a washing liquid, the filtrate and the washing liquid are mixed, then 5 g of thin layer chromatography silica gel is added, and the solvent is evaporated by a rotary evaporator to obtain a powder sample.

[0110] A chromatography column filled with thin layer chromatography silica gel with a length of 305 mm and a diameter of 40 mm is prepared, the silica gel is wetted with petroleum ether, then the powder sample is transferred to the chromatography column, and elution is performed with a mixed solvent of petroleum ether and ethanol as the eluent, and the volume ratio of petroleum ether to ethanol is 5:1. The eluate is collected in stages, the composition of the eluted eluate is analyzed by TLC thin layer chromatography, the eluate containing the target product is collected, and the solvent is evaporated and dried at 35°C.

[0111] The purification step used in this embodiment is the purification step of the prior art, and the obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99.9% and a yield of 86%, which is higher than the purity and yield of the prior art, indicating that the stepwise addition of chlorine is beneficial to the generation of the target product 5-chloro-2-methyl-4-isothiazolin-3-one.

[0112] Example 4

[0113] A method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one, comprising:

[0114] (1) Cyclization

[0115] Cyclization reaction was carried out with N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine as raw materials and ethyl acetate as solvent. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate and chlorine was 1:5:0.9. The reaction principle of this step was the same as that of Example 1.

[0116] The operation steps were as follows:

[0117] In a reaction kettle equipped with mechanical stirring, thermometer, air pipe and waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 100 g and ethyl acetate 500 g were added. Cooling to 10℃, chlorine was added in stages, and after the chlorine was passed, the reaction was continued at 15℃ for 20 min to obtain liquid reaction material.

[0118] The addition of chlorine was as follows:

[0119] First stage: maintain the reaction system temperature at 10℃, and uniformly pass 22.5 g of chlorine in 0.5 h;

[0120] Second stage: maintain the reaction system temperature at 13℃, and uniformly pass 22.5 g of chlorine in 1 h;

[0121] Third stage: maintain the reaction system temperature at 15℃, and uniformly pass 45 g of chlorine in 1.5 h.

[0122] By controlling the amount of chlorine added and the reaction temperature, the generation of 5-chloro-2-methyl-4-isothiazolin-3-one was controlled, and the yield of 5-chloro-2-methyl-4-isothiazolin-3-one was improved.

[0123] (2) Deacidification and removal of excess HCl gas

[0124] The liquid reaction material obtained in (1) was heated to 55℃, and gaseous HCl was discharged. When the total acidity of the liquid was 7%, the reaction was stopped.

[0125] (3) Solvent removal to obtain solid filter cake

[0126] The solvent after deacidification in (2) was removed by suction filtration to obtain a solid filter cake.

[0127] (4) Neutralization

[0128] The solid filter cake was reacted with magnesium nitrate aqueous solution with a mass fraction of 20% and magnesium hydroxide solid. The reaction principle of this step was the same as that of Example 1.

[0129] The operation steps were as follows:

[0130] The mass fraction of 20% magnesium nitrate aqueous solution, solid filter cake, magnesium hydroxide are added into the reaction kettle, stirred and mixed to obtain the neutralized material, and the pH of the neutralized product is 1-2. The mass ratio of magnesium nitrate aqueous solution, solid filter cake, magnesium hydroxide is 1:3:0.1.

[0131] (5) Purification

[0132] The neutralized material contains 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, and the purification step is used to remove 2-methyl-4-isothiazolin-3-one and some impurities, and the specific operation is as follows:

[0133] The 100g neutralized material is extracted twice with a mixed solvent of ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate to ethanol is 5:1, 30mL of mixed solvent is used each time, the organic phases of the two times are combined, the combined organic phase is dried with anhydrous sodium sulfate, then filtered, and the filtrate and precipitate are collected respectively; the precipitate is washed with mixed solvent to obtain a washing liquid, the filtrate and the washing liquid are mixed, then 5g of thin layer chromatography silica gel is added, and the solvent is evaporated by a rotary evaporator to obtain a powder sample.

[0134] A chromatography column filled with thin layer chromatography silica gel with a length of 305mm and a diameter of 40mm is prepared, the silica gel is wetted with petroleum ether, and then the powder sample is transferred to the chromatography column, and elution is performed with a mixed solvent of petroleum ether and ethanol as eluent, and the volume ratio of petroleum ether to ethanol is 5:1. The eluate is collected in stages, and the composition of the eluted eluate is analyzed by TLC thin layer chromatography, the eluate containing the target product is collected, and the solvent is evaporated and dried at 35°C.

[0135] The purification step used in this embodiment is the purification step of the prior art, and the obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99.9% and a yield of 90%, which is higher than the purity and yield of the prior art, indicating that the stepwise addition of chlorine is beneficial to the formation of the target product 5-chloro-2-methyl-4-isothiazolin-3-one.

[0136] Example 5

[0137] A method for preparing 5-chloro-2-methyl-4-isothiazolin-3-one, comprising:

[0138] (1) Cyclization

[0139] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine are used as raw materials, and ethyl acetate is used as a solvent for cyclization reaction. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, ethyl acetate, chlorine is 1:5:0.9. The reaction principle of this step is the same as that of Example 1.

[0140] The operation steps are as follows:

[0141] Into a reaction kettle equipped with mechanical stirring, thermometer, air vent, waste pipe, add N,N'-dimethyl-3,3'-dithiodipropionamide 100 g, ethyl acetate 500 g. Cool to 10 °C, add chlorine in stages, continue to react at 15 °C for 20 min after the chlorine is passed, to obtain liquid reaction material.

[0142] The addition of chlorine is as follows:

[0143] First stage: maintain the reaction system temperature at 10 °C, and uniformly pass in 22.5 g of chlorine in 0.5 h;

[0144] Second stage: maintain the reaction system temperature at 13 °C, and uniformly pass in 22.5 g of chlorine in 1 h;

[0145] Third stage: maintain the reaction system temperature at 15 °C, and uniformly pass in 45 g of chlorine in 1.5 h.

[0146] The generation of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled by controlling the amount of chlorine added and the reaction temperature, and the yield of 5-chloro-2-methyl-4-isothiazolin-3-one is improved.

[0147] (2) Deacidification, remove excess HCl gas

[0148] Heat the liquid reaction material obtained in (1) to 55 °C, and discharge gaseous HCl. Stop when the total acidity of the liquid is 7%.

[0149] (3) Solvent removal, to obtain a solid filter cake

[0150] Remove the solvent after deacidification in (2) by suction filtration to obtain a solid filter cake.

[0151] (4) Neutralization

[0152] The solid filter cake is reacted with magnesium nitrate aqueous solution with a mass fraction of 20% and magnesium hydroxide solid. The reaction principle of this step is the same as that of Example 1.

[0153] The operation steps are as follows:

[0154] Add magnesium nitrate aqueous solution with a mass fraction of 20%, solid filter cake, and magnesium hydroxide into a reaction kettle, stir and mix to obtain the neutralized material, and the pH of the neutralized product is 1-2. The mass ratio of magnesium nitrate aqueous solution, solid filter cake, and magnesium hydroxide is 1:3:0.1.

[0155] (5) Purification

[0156] The neutralized material contains 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one. The purification step is used to remove 2-methyl-4-isothiazolin-3-one and some impurities. The specific operation is as follows:

[0157] The 100 g of the neutralized material is extracted twice with a mixed solvent of ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate to ethanol is 5:1, and 30 mL of the mixed solvent is used each time. The organic phases of the two times are combined, the combined organic phase is dried with anhydrous sodium sulfate, and then filtered to collect the filtrate and the precipitate respectively. The precipitate is washed with the mixed solvent to obtain a washing liquid. The filtrate and the washing liquid are mixed, and then 5 g of thin layer chromatography silica gel is added. The solvent is evaporated by a rotary evaporator to obtain a powder sample.

[0158] A chromatography column filled with thin layer chromatography silica gel with a length of 305 mm and a diameter of 40 mm is prepared. The silica gel is wetted with petroleum ether, and then the powder sample is transferred to the chromatography column. The mixed solvent of petroleum ether and ethanol is used as the eluent, and the volume ratio of petroleum ether to ethanol is 3:1. The eluate is collected in stages, and the composition of the eluate is analyzed by TLC thin layer chromatography. The eluate containing the target product is collected, and the solvent is evaporated. The product is dried at 35°C.

[0159] The purification step used in this embodiment is the purification step of the prior art. The obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99.99% and a yield of 92%, which is higher than the purity and yield of the prior art. This indicates that the stepwise addition of chlorine is beneficial to the formation of the target product 5-chloro-2-methyl-4-isothiazolin-3-one.

[0160] Control group

[0161] A commercially available mixed aqueous solution of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one is purchased from Aldrich, wherein the content of 5-chloro-2-methyl-4-isothiazolin-3-one is 2%. The HPLC spectrum of the mixed aqueous solution is shown in Figure 2 .

[0162] 100 g of the commercially available mixed aqueous solution of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one is extracted twice with ethyl acetate, 30 mL of ethyl acetate is used each time, the organic phases of the two times are combined, the combined organic phase is dried with anhydrous sodium sulfate, and then filtered to collect the filtrate and the precipitate respectively. The precipitate is washed with ethyl acetate to obtain a washing liquid. The filtrate and the washing liquid are mixed, and then 5 g of thin layer chromatography silica gel is added. The solvent is evaporated by a rotary evaporator to obtain a powder sample.

[0163] The powder sample was transferred to a chromatographic column filled with thin layer chromatography silica gel with a length of 305 mm and a diameter of 40 mm, the silica gel was wetted with petroleum ether, and then the powder sample was transferred to the chromatographic column, and eluted with a mixed solvent of petroleum ether and ethyl acetate as eluent, the volume ratio of petroleum ether and ethyl acetate was 5:1. The eluate was collected in stages, and the composition of the eluate was analyzed by TLC thin layer chromatography, and the eluate containing the target product was collected, and the solvent was evaporated, and dried at 35°C.

[0164] The present purification step uses a prior art purification step, and the obtained 5-chloro-2-methyl-4-isothiazolin-3-one white solid has a purity of 99% and a yield of 80%.

[0165] It should be noted that when the present application involves numerical ranges, both endpoints of each numerical range and any number between the two endpoints can be selected. Since the same steps and examples are used, the preferred embodiments of the present application are described to prevent redundancy. Although the preferred embodiments of the present application have been described, those skilled in the art can make additional changes and modifications to these embodiments once they understand the basic inventive concept. Therefore, the appended claims are intended to include the preferred embodiments and all changes and modifications falling within the scope of the present application.

[0166] Obviously, those skilled in the art can make various modifications and variations to the present application without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application fall within the scope of the claims of the present application and their equivalents, the present application also intends to include these modifications and variations.

Claims

1. A process for the preparation of 5-chloro-2-methyl-4-isothiazolin-3-one, characterized in that, First, N, N'-dimethyl-3, 3'-dithiodipropionamide is mixed with ethyl acetate, cooled to 8-10℃, and chlorine is added in stages. After the chlorine is added, the reaction is continued for 20-40 min. The chlorine is added as follows: First stage: maintain the reaction system temperature at 10-12℃, and add 25-30% of the chlorine in 0.5h; Second stage: maintain the reaction system temperature at 13-14℃, and add 25-30% of the chlorine in 1h; Third stage: maintain the reaction system temperature at 15-18℃, and add the remaining chlorine in 1.5h; After the reaction is completed, the material is deacidified, desolvated, neutralized, and purified to obtain the purified 5-chloro-2-methyl-4-isothiazolin-3-one sample. The purification steps are as follows: After neutralization, the material is extracted with a mixed solvent of ethyl acetate and ethanol, the organic phase is collected, dried, purified with a chromatographic column filled with thin layer chromatography silica gel, and eluted with a mixed solvent of petroleum ether and ethanol. In the mixed solvent, the volume ratio of ethyl acetate to ethanol is 5-10:

1. In the mixed eluent, the volume ratio of petroleum ether to ethanol is 3-5:

1. The mass ratio of N, N'-dimethyl-3, 3'-dithiodipropionamide, ethyl acetate, and chlorine is 1:2-5:0.7-0.

9.

2. The process for the preparation of 5-chloro-2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, First stage: maintain the reaction system temperature at 10℃, and add 25% of the chlorine at a uniform rate in 0.5h; Second stage: maintain the reaction system temperature at 13℃, and add 25% of the chlorine at a uniform rate in 1h; Third stage: maintain the reaction system temperature at 15℃, and add the remaining chlorine at a uniform rate in 1.5h.

3. The process for the preparation of 5-chloro-2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, The neutralization steps are as follows: mix the aqueous magnesium nitrate solution, the desolvated material, and magnesium hydroxide, react, and neutralize the product to a pH of 1-2.

4. The process for the preparation of 5-chloro-2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, The mass ratio of the aqueous magnesium nitrate solution, the desolvated material, and magnesium hydroxide is 1:3:0.1.

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