A process for the preparation of 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 2-methyl-4-isothiazolin-3-one. The method comprises the following steps: taking an organic solvent as a solvent, adding an auxiliary agent A, adding N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas in stages, and alternately adding the N,N'-dimethyl-3,3'-dithiodipropionamide and the chlorine gas, so as to obtain a liquid reaction material containing MIT hydrochloride; the generation of by-products is reduced by adding the N,N'-dimethyl-3,3'-dithiodipropionamide in batches, and the auxiliary agent A is directly mixed with the N,N'-dimethyl-3,3'-dithiodipropionamide, so that the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is inhibited from the initial stage of the reaction. The method can improve the purity and the yield of 2-methyl-4-isothiazolin-3-one.

Description

TECHNICAL FIELD

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

[0002] 2-methyl-4-isothiazolin-3-one has a molecular formula of C4H5NOS, a CAS number of 2682-20-4, an English name of 2-Methyl-4-isothiazolin-3-one, and an English abbreviation of MIT, and a structural formula as shown in Figure 1 2-methyl-4-isothiazolin-3-one is a broad-spectrum bactericidal preservative, and can effectively kill algae, bacteria and fungi, and has advantages of broad spectrum and low toxicity. 2-methyl-4-isothiazolin-3-one is also one of raw materials for preparing daily chemical products, such as a pre-gelatinized starch and a preparation method thereof disclosed in Chinese patent CN103739721B, a liquorice whitening and moisturizing cream and a preparation method thereof disclosed in CN101543468B, and a leather waterproofing and preserving agent and a preparation method thereof disclosed in CN103695578B.

[0003] The prior art has a new process for the preparation of 2-methyl-4-isothiazolin-3-one. In the early years, Chinese patent CN102786491B prepared N,N'-dimethyl-3,3'-dithiodipropionamide or N-methyl-3-mercapto propionamide with an organic solvent, an alkali metal iodide catalyst, and then added a halogenated agent to obtain 2-methyl-4-isothiazolin-3-one hydrochloride, which was neutralized with a base to obtain the product 2-methyl-4-isothiazolin-3-one. By adding a catalyst, the formation of 5-chloro-2-methyl-4-isothiazolin-3-one is effectively inhibited, thereby obtaining high-purity 2-methyl-4-isothiazolin-3-one with a purity of more than 99.9%, the content of 5-chloro-2-methyl-4-isothiazolin-3-one is controlled to be less than 0.01%, and the yield of 2-methyl-4-isothiazolin-3-one can reach about 81%. Since high-purity 2-methyl-4-isothiazolin-3-one product is a general demand in the field, with the continuous deepening of research, Chinese patent CN112110870B discloses a preparation method of 2-methyl-4-isothiazolin-3-one aqueous solution, which comprises the following steps: uniformly mixing N,N'-dimethyl-3,3'-dithiodipropionamide or N-methyl-3-mercapto propionamide with a solvent; adding a halogenated agent to the mixed solution to perform halogenation and ring closure reaction; filtering out the product, washing the filter cake with ethyl acetate, and then drying to obtain 2-methyl-4-isothiazolin-3-one hydrochloride solid; dissolving the 2-methyl-4-isothiazolin-3-one hydrochloride solid with a sodium carbonate aqueous solution to obtain an aqueous solution with a pH of 5.0-7.0 and a 2-methyl-4-isothiazolin-3-one mass fraction of 50%. The 2-methyl-4-isothiazolin-3-one obtained by this method has a purity of more than 99.9%, and the content of 5-chloro-2-methyl-4-isothiazolin-3-one can be controlled to be less than 100 ppm, which can improve the purity of the product while the yield can reach 85%.

[0004] However, the preparation of 2-methyl-4-isothiazolin-3-one not only requires high-purity products, but also generally requires high yield, and the yield of the prior art method is still not high. SUMMARY

[0005] In order to improve the purity and yield of 2-methyl-4-isothiazolin-3-one, the present application provides a preparation method of 2-methyl-4-isothiazolin-3-one.

[0006] The application aims to provide a preparation method of 2-methyl-4-isothiazolin-3-one, comprising: taking an organic solvent as a solvent, adding an auxiliary A, adding N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas in stages, and alternately adding the N,N'-dimethyl-3,3'-dithiodipropionamide and the chlorine gas, and reacting to obtain a liquid reaction material containing MIT hydrochloride; wherein the auxiliary A is potassium iodide or sodium chloride; the by-product generation is reduced by adding the N,N'-dimethyl-3,3'-dithiodipropionamide in batches, the auxiliary A is directly mixed with the N,N'-dimethyl-3,3'-dithiodipropionamide, and the generation of 5-chloro-2-methyl-4-isothiazolin-3-one is inhibited from the initial stage of the reaction, which is different from the prior art in the reaction process and reaction principle.

[0007] The liquid reaction material is removed of HCl, neutralized, washed, and distilled, and finally 2-methyl-4-isothiazolin-3-one concentrate is obtained.

[0008] Preferably, in the preparation method of 2-methyl-4-isothiazolin-3-one, the organic solvent is chloroform, dichloromethane or ethyl acetate.

[0009] Preferably, in the preparation method of 2-methyl-4-isothiazolin-3-one, the mass ratio of the N,N'-dimethyl-3,3'-dithiodipropionamide, the organic solvent, the chlorine gas and the auxiliary A is 1:3-5:0.7-0.9:0.01-0.1.

[0010] Preferably, in the preparation method of 2-methyl-4-isothiazolin-3-one, the N,N'-dimethyl-3,3'-dithiodipropionamide is added in at least two stages, and the amount of the first addition is 80-85% of the total mass of the N,N'-dimethyl-3,3'-dithiodipropionamide. Preferably, the N,N'-dimethyl-3,3'-dithiodipropionamide is added in two stages, and the amount of the first addition is 80% of the total mass of the N,N'-dimethyl-3,3'-dithiodipropionamide.

[0011] Preferably, in the preparation method of 2-methyl-4-isothiazolin-3-one, in the reaction container, the formula amount of 80% of the N,N'-dimethyl-3,3'-dithiodipropionamide, the formula amount of all of the chloroform and the auxiliary A are added, the reaction temperature is controlled at 10-15°C, the formula amount of 80% of the chlorine gas is introduced at this temperature, then the remaining formula amount of the N,N'-dimethyl-3,3'-dithiodipropionamide is added, the remaining formula amount of the chlorine gas is continuously introduced, and after the chlorine gas is introduced, the reaction is continuously incubated at 10-15°C for 20-40 min to obtain the liquid reaction material.

[0012] Preferably, in the preparation method of 2-methyl-4-isothiazolin-3-one,

[0013] The liquid reactant is removed of HCl, so that the total acidity of the liquid is less than or equal to 7%, and then the solvent is removed, neutralized, and the neutralization is performed as follows:

[0014] The chloroform and the MIT hydrochloride after the removal of the solvent are added into a reaction container, mixed, and then a sodium carbonate solution is added to neutralize the mixture to a pH of 5-7.

[0015] The principle of the neutralization is as follows:

[0016]

[0017] Preferably, in the above method for preparing 2-methyl-4-isothiazolin-3-one, the chloroform, the MIT hydrochloride filter cake, and the auxiliary agent B are added into a reaction container, mixed, and then a sodium carbonate solution with a concentration of 10 g / 100 mL is added to neutralize the mixture to a pH of 5-7, so as to obtain the neutralized material.

[0018] Preferably, in the above method for preparing 2-methyl-4-isothiazolin-3-one, the mass ratio of the chloroform, the MIT hydrochloride filter cake, and the auxiliary agent B is 3-5:1:0.01-0.1. Preferably, the auxiliary agent B is ethanol or methanol. When the auxiliary agent B is added, the removal of sodium chloride is more complete in the step of neutralization and removal of sodium chloride, and when the water washing step is performed, the water, the ethanol, and the chloroform meet, a part of the ethanol is dispersed in the chloroform, and a part of the ethanol is dispersed in the water, which is beneficial to the removal of impurities and can improve the purity and yield of MIT.

[0019] Preferably, in the above method for preparing 2-methyl-4-isothiazolin-3-one, the neutralized material is centrifuged by a sodium chloride centrifuge to remove sodium chloride, and the MIT-containing oil layer solution is collected and then washed, distilled, and dried to obtain 2-methyl-4-isothiazolin-3-one solid. When the auxiliary agent A is sodium chloride, the auxiliary agent A can not only catalyze the reaction, but also be recovered in the step of removing sodium chloride, which is convenient for reuse.

[0020] Preferably, in the above method for preparing 2-methyl-4-isothiazolin-3-one, the distillation is performed at a temperature of 65-70°C and a vacuum degree of -0.09 Mpa.

[0021] Compared with the prior art, the method has the following beneficial effects:

[0022] The method can reduce the generation of by-products by adding the auxiliary agent in batches, and finally produce high-purity MIT.

[0023] The present application uses an auxiliary agent A, which is potassium iodide or sodium chloride. The auxiliary agent A is directly mixed with N,N'-dimethyl-3,3'-dithiodipropionamide, which inhibits the generation of 5-chloro-2-methyl-4-isothiazolin-3-one from the initial stage of the reaction, and the reaction process and reaction principle are different from the prior art.

[0024] The present application uses an auxiliary agent B, which is ethanol. When the auxiliary agent B is added, the removal of sodium chloride is more sufficient during the neutralization and sodium chloride removal steps, and when the water washing step is performed, water, ethanol and chloroform meet, and a part of the ethanol is dispersed in chloroform and a part of the ethanol is dispersed in water, which is beneficial to impurity removal and can improve the purity and yield of MIT. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The structural formula of 2-methyl-4-isothiazolin-3-one.

[0026] Figure 2 The preparation route of Example 1 of the present application.

[0027] Figure 3 The HPLC spectrum of MIT of Example 1.

[0028] Figure 4 The HPLC spectrum of MIT of Example 3.

[0029] Figure 5 The HPLC spectrum of MIT of Example 5.

[0030] Figure 6 The HPLC spectrum of MIT of Control 1. DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to better understand the technical solutions of the present application and to implement them, the present application will be further described below in conjunction with specific examples and drawings.

[0032] In the description of the present application, unless otherwise specified, the reagents used are commercially available, and the methods used are conventional techniques in the art.

[0033] In the description of the present application, N,N'-dimethyl-3,3'-dithiodipropionamide has a purity of ≥97% and a molecular weight of 236.35.

[0034] In the description of the present application, chloroform has a purity of ≥99%, chlorine has a purity of ≥99%, the auxiliary agent A has a purity of ≥99%, and the auxiliary agent B has a purity of ≥99%.

[0035] Example 1

[0036] A preparation method of 2-methyl-4-isothiazolin-3-one, the technical route diagram is referred toFigure 2 , comprising:

[0037] (1) cyclization

[0038] N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine, and auxiliary agent M are used as raw materials, chloroform is used as a solvent, auxiliary agent M is added, and MIT hydrochloride is generated by reaction. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine, and auxiliary agent M is 1:2:0.7:0.01, and auxiliary agent M is potassium iodide.

[0039] The reaction principle is as follows:

[0040]

[0041] The operation steps are as follows:

[0042] In a reaction kettle equipped with mechanical stirring, a thermometer, a gas inlet pipe, and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 80 g, chloroform 200 g, and potassium iodide 0.01 g are added. Cool to 10°C, and then pass chlorine 56 g at this temperature for 2 h, then add N,N'-dimethyl-3,3'-dithiodipropionamide 20 g, and pass chlorine 14 g in 0.5 h. After passing chlorine, continue to react at 10°C for 20 min, and obtain liquid reaction material.

[0043] (2) Deacidification, remove excess HCl gas

[0044] Principle: Liquid HCl will volatilize to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0045] The operation steps are as follows: heat the liquid reaction material obtained in (1) to 55°C, and remove gaseous HCl. When the total acidity of the liquid is 7%, stop.

[0046] (3) Remove the solvent to obtain MIT hydrochloride

[0047] Use suction filtration to remove the solvent after deacidification in (2) to obtain MIT hydrochloride filter cake.

[0048] (4) Neutralization

[0049] MIT hydrochloride filter cake is reacted with sodium carbonate to generate free MIT, and the principle is as follows:

[0050]

[0051] The operation steps are as follows:

[0052] The chloroform and MIT hydrochloride filter cake are added into a reaction kettle and mixed under stirring. The MIT hydrochloride filter cake is broken up, and then a 10 g / 100 mL sodium carbonate solution is added to neutralize the mixture to a pH of 5 to obtain a neutralized material. In this step, the mass ratio of chloroform to MIT hydrochloride filter cake is 3:1.

[0053] (5) Centrifugation to remove sodium chloride

[0054] The neutralized material is centrifuged using a sodium chloride centrifuge to remove the sodium chloride solution and collect the MIT-containing oil phase layer solution.

[0055] (6) Washing and distillation

[0056] The MIT-containing oil phase layer solution is washed with water, and some salt dissolves in the water to purify the MIT. The oil phase layer is separated, and then distilled at 60°C under a vacuum of -0.09 MPa. The MIT solid is dried at 40°C to obtain MIT solid. The 5-chloro-2-methyl-4-isothiazolin-3-one content in the MIT solid is 10 ppm, the synthesis yield is 93%, and the purity of the dried MIT solid material is more than 99.9%. The HPLC spectrum of the MIT solid material prepared in this example after dissolution is shown in FIG. 1. As shown in FIG. 1, there is a clear MIT peak and almost no impurity peak. Figure 3

[0057] Example 2

[0058] A method for preparing 2-methyl-4-isothiazolin-3-one, comprising:

[0059] (1) Cyclization

[0060] MIT hydrochloride is prepared by using N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine as raw materials and adding an auxiliary agent M to chloroform. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine, and auxiliary agent M is 1:5:0.9:0.1, and the auxiliary agent M is potassium iodide.

[0061] The reaction principle is as follows:

[0062]

[0063] The operation steps are as follows:

[0064] ​In a reaction kettle equipped with mechanical stirring, thermometer, air vent, waste pipe, add N, N'-dimethyl-3, 3'-dithiodipropionamide 80 g, chloroform 500 g, potassium iodide 0.1 g. Cool to 15°C, at this temperature, 72 g of chlorine is passed in for 2 h, then add N, N'-dimethyl-3, 3'-dithiodipropionamide 20 g, pass in chlorine 18 g in 0.5 h, after passing in chlorine, continue to react at 15°C for 40 min, to obtain liquid reaction material.

[0065] (2) Deacidification, remove excess HCl gas

[0066] Principle: Liquid HCl will volatilize to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0067] The operation steps are as follows: heat the liquid reaction material obtained in (1) to 60°C, discharge gaseous HCl, and stop when the total acidity of the liquid is 7%.

[0068] (3) Remove the solvent to obtain MIT hydrochloride

[0069] Remove the solvent after deacidification in (2) by suction filtration to obtain MIT hydrochloride filter cake.

[0070] (4) Neutralization

[0071] MIT hydrochloride filter cake reacts with sodium carbonate to form free MIT, the principle is as follows:

[0072]

[0073] The operation steps are as follows:

[0074] Add chloroform and MIT hydrochloride filter cake to the reaction kettle, stir and mix, the MIT hydrochloride filter cake is dispersed, then add sodium carbonate solution with a concentration of 10 g / 100 mL, neutralize to pH 7 to obtain the neutralized material. In this step, the mass ratio of chloroform to MIT hydrochloride filter cake is 5:1.

[0075] (5) Centrifugation to remove sodium chloride

[0076] Centrifuge the neutralized material with a sodium chloride centrifuge to remove the sodium chloride solution layer, and collect the oil phase layer solution containing MIT.

[0077] (6) Washing, distillation

[0078] The MIT-containing oil phase layer solution is washed with water, some salt dissolves in the water, MIT is purified, the layers are separated, and the oil phase layer is distilled at 70°C and a vacuum degree of -0.09 MPa, and dried at 35°C to obtain MIT solid. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in the MIT solid is 8 ppm, the synthesis yield is 94%, and the purity of the dried MIT solid is more than 99.9%.

[0079] Example 3

[0080] A method for preparing 2-methyl-4-isothiazolin-3-one, comprising:

[0081] (1) cyclization

[0082] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, chloroform is used as a solvent, and an additive M is added to react to generate MIT hydrochloride. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine gas, and additive M is 1:2:0.7:0.01, and the additive M is sodium chloride.

[0083] The reaction principle is as follows:

[0084]

[0085] The operation steps are as follows:

[0086] In a reaction kettle equipped with mechanical stirring, a thermometer, a gas inlet pipe, and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 80 g, chloroform 200 g, and sodium chloride 0.01 g are added. Cooling is performed to 10°C, chlorine gas 56 g is introduced at this temperature for 2 h, then N,N'-dimethyl-3,3'-dithiodipropionamide 20 g is added, chlorine gas 14 g is introduced within 0.5 h, and after the chlorine gas is introduced, 10°C incubation is continued for 20 min to obtain a liquid reaction material.

[0087] (2) deacidification and removal of excess HCl gas

[0088] Principle: Liquid HCl volatilizes to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0089] The operation steps are as follows: The liquid reaction material obtained in (1) is heated to 55°C, gaseous HCl is discharged, and when the total acidity of the liquid is 7%, the heating is stopped.

[0090] (3) removal of the solvent to obtain MIT hydrochloride

[0091] The solvent after deacidification in (2) is removed by suction filtration to obtain MIT hydrochloride filter cake.

[0092] (4) neutralization

[0093] MIT hydrochloride filter cake is reacted with sodium carbonate to generate free MIT, according to the principle as follows:

[0094]

[0095] The operation steps are as follows:

[0096] Chloroform and MIT hydrochloride filter cake are added into a reaction kettle, stirred and mixed, the MIT hydrochloride filter cake is dispersed, then a sodium carbonate solution with a concentration of 10 g / 100 mL is added, neutralized to pH 5, to obtain a neutralized material. In this step, the mass ratio of chloroform and MIT hydrochloride filter cake is 3:1.

[0097] (5) Centrifugation to remove sodium chloride

[0098] The neutralized material is centrifuged by a sodium chloride centrifuge, the solution layer containing MIT is collected after the sodium chloride solution is separated.

[0099] (6) Washing and distillation

[0100] Water is added to the solution layer containing MIT for washing, some salt is dissolved in the water to purify MIT, the solution layer is separated, and the oil phase layer is distilled at 60°C under a vacuum degree of -0.09 MPa, and dried at 40°C to obtain MIT solid. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in the MIT solid is 7 ppm, the synthesis yield is 94%, and the purity of the dried MIT solid material is more than 99.99%. The HPLC spectrum of the MIT solid material prepared in this embodiment after dissolution is shown in Figure 4 It can be seen that there is an obvious MIT peak and no impurity peak.

[0101] Example 4

[0102] A preparation method of 2-methyl-4-isothiazolin-3-one, comprising:

[0103] (1) Cyclization

[0104] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, chloroform is used as a solvent, and an additive M is added, to generate MIT hydrochloride. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine gas, and additive M is 1:5:0.9:0.1, and the additive M is sodium chloride.

[0105] The reaction principle is as follows:

[0106]

[0107] The operation steps are as follows:

[0108] In a reaction kettle equipped with mechanical stirring, thermometer, air vent, waste pipe, add N, N'-dimethyl-3, 3'-dithiodipropionamide 80g, chloroform 500g, sodium chloride 0.1g. Cool to 15°C, at this temperature, 72g of chlorine is passed in for 2h, then add N, N'-dimethyl-3, 3'-dithiodipropionamide 20g, pass in 18g of chlorine in 0.5h, after passing in chlorine, continue to react at 15°C for 40min, to obtain liquid reaction material.

[0109] (2) Deacidification, remove excess HCl gas

[0110] Principle: Liquid HCl will volatilize to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0111] The operation steps are as follows: heat the liquid reaction material obtained in (1) to 60°C, discharge gaseous HCl, and stop when the total acidity of the liquid is 7%.

[0112] (3) Remove the solvent to obtain MIT hydrochloride

[0113] Remove the solvent after deacidification in (2) by suction filtration to obtain MIT hydrochloride filter cake.

[0114] (4) Neutralization

[0115] MIT hydrochloride filter cake reacts with sodium carbonate to form free MIT, the principle is as follows:

[0116]

[0117] The operation steps are as follows:

[0118] Add chloroform and MIT hydrochloride filter cake to the reaction kettle, stir and mix, the MIT hydrochloride filter cake is dispersed, then add sodium carbonate solution with a concentration of 10g / 100mL, neutralize to pH 7 to obtain the neutralized material. The mass ratio of chloroform to MIT hydrochloride filter cake is 5:1.

[0119] (5) Centrifugation to remove sodium chloride

[0120] Centrifuge the neutralized material with a sodium chloride centrifuge to remove the sodium chloride solution layer, and collect the oil phase layer solution containing MIT.

[0121] (6) Washing, distillation

[0122] The MIT-containing oil phase layer solution is washed with water, some salt dissolves in the water, MIT is purified, the layers are separated, and the oil phase layer is distilled at 70°C and a vacuum degree of -0.09 MPa, and dried at 35°C to obtain MIT solid. The 5-chloro-2-methyl-4-isothiazolin-3-one content in the MIT solid is 7 ppm, the synthesis yield is 95%, and the purity of the dried MIT solid is more than 99.99%.

[0123] Example 5

[0124] A method for preparing 2-methyl-4-isothiazolin-3-one, comprising:

[0125] (1) cyclization

[0126] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, chloroform is used as a solvent, and an additive M is added to react to generate MIT hydrochloride. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine gas, and additive M is 1:2:0.7:0.01, and the additive M is potassium iodide.

[0127] The reaction principle is as follows:

[0128]

[0129] The operation steps are as follows:

[0130] In a reaction kettle equipped with mechanical stirring, a thermometer, a gas inlet pipe, and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 80 g, chloroform 200 g, and potassium iodide 0.01 g are added. Cooling is performed to 10°C, chlorine gas 56 g is introduced at this temperature for 2 h, then N,N'-dimethyl-3,3'-dithiodipropionamide 20 g is added, chlorine gas 14 g is introduced within 0.5 h, and after the chlorine gas is introduced, the reaction is continued at 10°C for 20 min to obtain a liquid reaction material.

[0131] (2) deacidification and removal of excess HCl gas

[0132] Principle: Liquid HCl volatilizes to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0133] The operation steps are as follows: The liquid reaction material obtained in (1) is heated to 55°C, gaseous HCl is discharged, and when the total acidity of the liquid is 7%, the heating is stopped.

[0134] (3) removal of the solvent to obtain MIT hydrochloride

[0135] The solvent after deacidification in (2) is removed by suction filtration to obtain MIT hydrochloride filter cake.

[0136] (4) neutralization

[0137] MIT hydrochloride filter cake is reacted with sodium carbonate to generate free MIT, according to the principle as follows:

[0138]

[0139] The operation steps are as follows:

[0140] Chloroform, MIT hydrochloride filter cake and auxiliary agent B are added into a reaction kettle, and stirred and mixed. The MIT hydrochloride filter cake is broken up, and then a sodium carbonate solution with a concentration of 10 g / 100 mL is added to neutralize to a pH of 5, to obtain a neutralized material. The mass ratio of chloroform, MIT hydrochloride filter cake and auxiliary agent B is 3:1:0.01. The auxiliary agent B is ethanol.

[0141] (5) Centrifugation to remove sodium chloride

[0142] The neutralized material is centrifuged by a sodium chloride centrifuge, and the solution layer containing MIT is collected from the oil phase layer after the sodium chloride solution is separated.

[0143] (6) Washing and distillation

[0144] Water is added to the oil phase layer solution containing MIT to dissolve some salt into the water, so as to purify the MIT. The oil phase layer is separated, and then distilled at 60°C and a vacuum degree of -0.09 MPa. The MIT solid is obtained after drying at 40°C. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in the MIT solid is 6 ppm, the synthesis yield is 95%, and the purity of the dried MIT solid material is more than 99.99%. The HPLC spectrum of the MIT solid material prepared in this embodiment after dissolution is shown in FIG. 1. Figure 5 Only the MIT peak can be seen, and no impurity peak is present.

[0145] Example 5 has an additional processing step of auxiliary agent B compared to Example 1. By comparing the purity and yield of the MIT solid, it can be seen that the use of auxiliary agent B helps to improve the yield and purity.

[0146] Example 6

[0147] A preparation method of 2-methyl-4-isothiazolin-3-one, comprising:

[0148] (1) Cyclization

[0149] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, chloroform is used as a solvent, and auxiliary agent A is added to generate MIT hydrochloride. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine gas and auxiliary agent A is 1:2:0.7:0.01, and the auxiliary agent A is sodium chloride.

[0150] The reaction principle is as follows:

[0151]

[0152] The operation steps are as follows:

[0153] In a reaction kettle equipped with mechanical stirring, thermometer, air pipe, waste pipe, N, N'-dimethyl-3, 3'-dithiodipropionamide 80 g, chloroform 200 g, sodium chloride 0.01 g were added. Cool to 10°C, at this temperature, 56 g of chlorine was introduced for 2 h, then 20 g of N, N'-dimethyl-3, 3'-dithiodipropionamide was added, 14 g of chlorine was introduced within 0.5 h, after the chlorine was introduced, continue to keep the temperature at 10°C for 20 min, and the liquid reaction material is obtained.

[0154] (2) Deacidification, remove excess HCl gas

[0155] Principle: Liquid HCl will volatilize to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0156] The operation steps are as follows: 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%, stop.

[0157] (3) Remove the solvent to obtain MIT hydrochloride

[0158] The solvent after deacidification in (2) is removed by suction filtration to obtain MIT hydrochloride filter cake.

[0159] (4) Neutralization

[0160] MIT hydrochloride filter cake is reacted with sodium carbonate to form free MIT, and the principle is as follows:

[0161]

[0162] The operation steps are as follows:

[0163] Chloroform, MIT hydrochloride filter cake, and additive B are added to the reaction kettle, stirred and mixed, and the MIT hydrochloride filter cake is dispersed, then a 10 g / 100 mL sodium carbonate solution is added, and neutralized to pH 5 to obtain the neutralized material. The mass ratio of chloroform, MIT hydrochloride filter cake, and additive B is 3:1:0.01. Additive B is ethanol.

[0164] (5) Centrifugation to remove sodium chloride

[0165] The neutralized material is centrifuged with a sodium chloride centrifuge to remove the sodium chloride solution, and the oil phase layer solution containing MIT is collected.

[0166] (6) Washing and distillation

[0167] The MIT-containing oil phase layer solution is washed with water, some salt dissolves in the water, MIT is purified, the layers are separated, and the oil phase layer is distilled at 60°C and a vacuum degree of -0.09 MPa, and dried at 40°C to obtain MIT solid. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in the MIT solid is 5 ppm, the synthesis yield is 96%, and the purity of the dried MIT solid is more than 99.99%.

[0168] Control 1

[0169] A method for preparing 2-methyl-4-isothiazolin-3-one, comprising:

[0170] (1) cyclization

[0171] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, chloroform is used as a solvent, and an additive M is added, and MIT hydrochloride is generated by reaction. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform, chlorine gas, and additive M is 1:2:0.7:0.01, and the additive M is potassium iodide.

[0172] The reaction principle is as follows:

[0173]

[0174] The operation steps are as follows:

[0175] In a reaction kettle equipped with mechanical stirring, a thermometer, a gas inlet pipe, and a waste pipe, N,N'-dimethyl-3,3'-dithiodipropionamide 1000 g, chloroform 200 g, and potassium iodide 0.01 g are added. Cool to 10°C, and pass in chlorine gas 70 g at this temperature for 2 h. After the chlorine gas is passed in, continue to incubate at 10°C for 20 min to obtain liquid reaction material.

[0176] (2) deacidification and removal of excess HCl gas

[0177] Principle: Liquid HCl will volatilize to gaseous HCl when heated and stirred, reducing the HCl content in the system.

[0178] The operation steps are as follows: 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%, stop.

[0179] (3) removal of solvent to obtain MIT hydrochloride

[0180] The solvent after deacidification in (2) is removed by suction filtration to obtain MIT hydrochloride filter cake.

[0181] (4) neutralization

[0182] MIT hydrochloride filter cake is reacted with sodium carbonate to generate free MIT, according to the principle as follows:

[0183]

[0184] The operation steps are as follows:

[0185] Chloroform and MIT hydrochloride filter cake are added into a reaction kettle, and stirred and mixed. The MIT hydrochloride filter cake is broken up, and then a sodium carbonate solution with a concentration of 10 g / 100 mL is added to neutralize to a pH of 5, to obtain a neutralized material. The mass ratio of chloroform to MIT hydrochloride filter cake is 3:1.

[0186] (5) Centrifugation to remove sodium chloride

[0187] The neutralized material is centrifuged by a sodium chloride centrifuge, and the solution layer containing MIT is collected from the oil phase layer.

[0188] (6) Washing and distillation

[0189] Water is added to the oil phase layer solution containing MIT to wash and purify the MIT, and the oil phase layer is separated. The oil phase layer is distilled at 60°C and a vacuum degree of -0.09 MPa, and dried at 40°C, to obtain MIT solid. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in the MIT solid is 23 ppm, the synthesis yield is 85%, and the purity of the dried MIT solid material is 99%.

[0190] Figure 6 HPLC spectrum of MIT of Control 1. Control 1 does not alternate the addition of N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas, so that the MIT solid material prepared has more impurity peaks in the HPLC spectrum.

[0191] Control 2

[0192] A method for preparing 2-methyl-4-isothiazolin-3-one, comprising:

[0193] (1) Cyclization

[0194] N,N'-dimethyl-3,3'-dithiodipropionamide and chlorine gas are used as raw materials, and chloroform is used as a solvent to generate MIT hydrochloride. The mass ratio of N,N'-dimethyl-3,3'-dithiodipropionamide, chloroform and chlorine gas is 1:2:0.7.

[0195] The operation steps are as follows:

[0196] In a reaction kettle equipped with mechanical stirring, thermometer, air vent, waste pipe, add N,N'-dimethyl-3,3'-dithiodipropionamide 1000g, chloroform 200g. Cool to 10°C, at this temperature, with 2h into the chlorine 70g, after the chlorine is finished, continue 10°C for 20min, get liquid reaction material.

[0197] (2) deacidification, remove excess HCl gas

[0198] Principle: liquid HCl will be volatile when heated and stirred into gaseous HCl, reduce the HCl content in the system.

[0199] The operation steps are as follows: the liquid reaction material obtained in (1) is heated to 55°C, and the gaseous HCl is discharged. When the total acidity of the liquid is 7%, stop.

[0200] (3) remove the solvent, get MIT hydrochloride

[0201] Remove the solvent after deacidification in (2) by suction filtration to get MIT hydrochloride filter cake.

[0202] (4) neutralization

[0203] Add chloroform and MIT hydrochloride filter cake to the reaction kettle, stir and mix, the MIT hydrochloride filter cake is dispersed, then add sodium carbonate solution with a concentration of 10g / 100mL, neutralize to pH 5 to get the neutralized material. The mass ratio of chloroform and MIT hydrochloride filter cake is 3:1.

[0204] (5) centrifugation, remove sodium chloride

[0205] Centrifuge the neutralized material with a sodium chloride centrifuge to remove the sodium chloride solution layer, and collect the oil phase layer solution containing MIT.

[0206] (6) washing, distillation

[0207] Add water to the oil phase layer solution containing MIT to wash, some salt dissolves in water to purify MIT, separate the layers, and distill the oil phase layer at 60°C under a vacuum of-0.09Mpa, and dry at 40°C to get MIT solid. The content of 5-chloro-2-methyl-4-isothiazolin-3-one in MIT solid is 1642ppm, and the synthesis yield is 71%.

[0208] Summary: Example 1 and Example 2 are the MIT solid prepared with different raw material ratio and different parameters when the auxiliary agent A is potassium iodide, the results show that the MIT has high purity, high yield and less impurities. Example 1 and Example 3 are the MIT solid prepared with different auxiliary agent A (potassium iodide or sodium chloride), when the auxiliary agent A is sodium chloride, the MIT has better purity and yield. Example 5 and Example 6 are the MIT solid prepared with the addition of auxiliary agent B, the results show that the use of auxiliary agent B helps to improve the purity and yield of MIT and reduce the content of 5-chloro-2-methyl-4-isothiazoline-3-ketone. Control 1 is the result of adding raw materials without stages, and control 2 is the result of not adding auxiliary agent, the MIT yield of the two control groups is relatively low, and the content of 5-chloro-2-methyl-4-isothiazoline-3-ketone is also relatively high.

[0209] It should be noted that when the present application involves a numerical range, it should be understood that each numerical range has two endpoints 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.

[0210] 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 2-methyl-4-isothiazolin-3-one, characterized in that, The application relates to a method for preparing 2-methyl-4-isothiazolin-3-one. In a reaction container, 80% of the formula amount of N, N'-dimethyl-3, 3'-dithiodipropionamide, all of the formula amount of chloroform and an auxiliary agent A are added, the reaction temperature is controlled at 10-15 DEG C, 80% of the formula amount of chlorine is continuously introduced at the temperature, then the remaining N, N'-dimethyl-3, 3'-dithiodipropionamide is added, the remaining chlorine is continuously introduced, and the reaction is continuously carried out at 10-15 DEG C for 20-40 min after the chlorine is introduced, so that liquid reaction materials are obtained, wherein the auxiliary agent A is sodium chloride; The HCl in the liquid reaction materials is removed, then the solvent is removed, neutralization, washing, distillation, and finally 2-methyl-4-isothiazolin-3-one concentrate is obtained; The mass ratio of the N, N'-dimethyl-3, 3'-dithiodipropionamide, chloroform, chlorine and auxiliary agent A is 1:3-5:0.7-0.9:0.01-0.

1.

2. The process for the preparation of 2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, The operation steps of the neutralization are as follows: The chloroform and MIT hydrochloride after the solvent is removed are added into a reaction container, mixed, then sodium carbonate solution is added, and neutralization is carried out until the pH is 5-7.

3. The process for the preparation of 2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, The operation steps of the neutralization are as follows: The chloroform, MIT hydrochloride filter cake and auxiliary agent B are added into a reaction container, mixed, then 10g / 100mL sodium carbonate solution is added, and neutralization is carried out until the pH is 5-7, so that neutralized materials are obtained; the auxiliary agent B is ethanol.

4. The process for the preparation of 2-methyl-4-isothiazolin-3-one according to claim 3, characterized in that, The mass ratio of the chloroform, MIT hydrochloride filter cake and auxiliary agent B is 3-5:1:0.01-0.

1.

5. The process for the preparation of 2-methyl-4-isothiazolin-3-one according to claim 4, characterized in that, The neutralized materials are centrifuged by a sodium chloride centrifuge, sodium chloride is removed, MIT-containing oil layer solution is collected, and then washing, distillation and drying are carried out, so that 2-methyl-4-isothiazolin-3-one solid is obtained.

6. The process for the preparation of 2-methyl-4-isothiazolin-3-one according to claim 1, characterized in that, The distillation conditions are as follows: the temperature is 65-70 DEG C, and the vacuum degree is kept at -0.09 Mpa.

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