KR100310165B1 - Process for purifying 5-chloro-2-methyl-3-isothiazolone - Google Patents

Abstract

PURPOSE: A process for purifying 5-chloro-2-methyl-3-isothiazolone is provided, thereby cheaply producing high purity of 5-chloro-2-methyl-3-isothiazolone with higher antimicrobial activity without producing waste materials. CONSTITUTION: The process for purifying 5-chloro-2-methyl-3-isothiazolone comprises the steps of: adding halogenated carbohydrate or nitrated carbohydrate into an isothiazolone solution containing 5-chloro-2-methyl-3-isothiazolone of formula(1) to extract an organic layer containing 5-chloro-2-methyl-3-isothiazolone; washing 5-chloro-2-methyl-3-isothiazolone with water; and removing halogenated carbohydrate or nitrated carbohydrate from the organic layer, in which the halogenated carbohydrate is selected from methylene chloride, chloroform, carbon tetrachloride, ethylene chloride and dichloroethane; and the nitrated carbohydrate is selected from nitromethane and nitroethane.

Description

5-Chloro-2-methyl-3-isothiazolone purification method

[Industrial use]

The present invention relates to a method for purifying 5-chloro-2-methyl-3-isothiazolone of formula (1) below, more particularly 5-chloro-2-methyl-3-iso which is excellent in antibacterial and antimicrobial activity. A method for purifying thiazolone with high purity and a method for producing high purity 5-chloro-2-methyl-3-isothiazolone hydrochloride using the same.

[Prior art]

The isothiazolone compound was developed by Crow et al in 1965 and has been used throughout the industry as an antimicrobial and antimicrobial agent in paints, cosmetics, textiles or plastics, as well as fungicides.

In 1993, W. Paulus et al., Especially for the most commonly used isothiazolone-based products consisting of a mixture of 2-methyl-3-isothiazolone and 5-chloro-2-methyl-3-isothiazolone, It was found that the antimicrobial and antimicrobial activity of 5-chloro-2-methyl-3-isothiazolone represented by the general formula (1) was 200 times or more than the 2-methyl-3-isothiazolone represented by the following general formula (2). Thus, efforts have been made to produce pure 5-chloro-2-methyl-3-isothiazolone, not a mixture.

However, high-purity 5-chloro-2-methyl-3-isothiazolone has low stability and is not easily transported and handled because it exists as a supercooled fluid at room temperature. Therefore, it is stabilized by adding an organic solvent immediately after purification. There is a need to manufacture a lot in the form of solid hydrochloride, which is more stable and easier to handle.

As part of an attempt to prepare isothiazolones with excellent antimicrobial and antimicrobial activity as described above, US Pat. No. 5,466,818 discloses chloromethylisothiazolones by slurrying isothiazolone salts in an organic solvent and then dissolving them in a heat-soluble manner. Or methyl isothiazolone, or a method for preparing a 3-isothiazolone solution in a desired ratio is proposed. However, this method is difficult to control due to the different yield and purity depending on the working time, and because of the release of hydrogen chloride gas separated by heating during manufacture, it is not safe to operate and heats isothiazolone which is not stable to heat. There is a high possibility of impairing the stability, which also leads to the cumbersome work of separating the isothiazolone salt and the non-isolated isothiazolone salt through a process called filtration.

An object of the present invention as to solve the above problems is to provide a 5-chloro-2-methyl-3-isothiazolone purification method that can improve the productivity and economic efficiency by improving the workability and good processing conditions For sake.

[Means for solving the problem]

One aspect of the present invention for achieving the object of the present invention is to extract an isothiazolone aqueous solution containing 5-chloro-2-methyl-3-isothiazolone represented by the general formula (1) as a halogenated hydrocarbon or nitrated hydrocarbon And a step of washing the organic layer obtained by the extraction step with water and a step of removing the halogenated hydrocarbon or the nitrated hydrocarbon from the organic layer, and a purification method of 5-chloro-2-methyl-3-isothiazolone.

[Formula 1]

The halogenated hydrocarbon is preferably selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, dichloroethane. The nitrated hydrocarbon is preferably selected from the group consisting of nitromethane, nitroethane.

A second aspect of the present invention is 5-chloro-2-methyl-3-isothiazolone free, which is stabilized by adding an organic solvent to pure 5-chloro-2-methyl-3-isothiazolone obtained by the above purification method. Aqueous solution. The organic solvent is preferably selected from the group consisting of glycols, alcohols, glycol ethers.

A third aspect of the present invention is to extract the aqueous solution of isothiazolone containing 5-chloro-2-methyl-3-isothiazolone of the formula (1) with halogenated hydrocarbon or nitrated hydrocarbon and obtained by the extraction process 5-chloro-2-methyl-3-isothiazolone hydrochloride comprising the step of washing the organic layer with water, and adding a hydrogen chloride gas to the organic layer washed with water and filtering the solid produced by adding the hydrogen chloride gas. It is a manufacturing method. The halogenated hydrocarbon is preferably selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, dichloroethane. The nitrated hydrocarbon is preferably selected from the group consisting of nitromethane, nitroethane. The 5-chloro-2-methyl-3-isothiazolone hydrochloride is preferably substantially pure.

[Action]

The present invention has resulted from a more economical and waste-free method of separating substantially pure 5-chloro-2-methyl-3-isothiazolones from which halogenated and nitrated hydrocarbons can be combined with other organic solvents. Is based on the discovery that large amounts of isothiazolone are distributed in aqueous solution. In more detail, isothiazolones, 5-chloro-2-methyl-3-isothiazolone and 2-methyl-3-isothiazolone, are both well dissolved in an acidic aqueous solution, but these two substances have a difference in basicity. In addition, since the basicity is very low and there are many opportunities to exist in the form of a free base, there is a possibility that it can be selectively extracted by using an organic solvent that has a suitable unshared electron pair capacity and does not mix with water. In 1975, V. Gutmann et al. Studied the capacity of lone pairs in many organic solvents, and found that the large organic solvents tend to mix well in water and have high boiling points. However, it was found that halogenated hydrocarbons and nitrated hydrocarbons show high water soluble pairing capacity but low water solubility and low boiling point. Therefore, if isothiazolone salt is directly dissolved in water or isothiazolone already dissolved in water is extracted using halogenated hydrocarbon or nitrated hydrocarbon, and then the organic layer is separated to remove halogenated hydrocarbon or nitrated hydrocarbon. Occurs. In this case, since the distribution of the water layer and the organic layer may vary according to the basicity of 5-chloro-2-methyl-3-isothiazolone and 2-methyl-3-isothiazolone, the organic solvent may be used as an organic solvent such as nitrated hydrocarbon or halogenated hydrocarbon. Extraction and washing with water to evaporate these organic solvents yields a substantially pure 5-chloro-2-methyl-3-isothiazolone freebase form. In addition, the solid produced by extraction with nitrated or halogenated hydrocarbons, washed with water and blown with hydrogen chloride gas in a solution in which the nitrated or halogenated hydrocarbons are not removed is filtered. Isothiazolone hydrochloride can be obtained.

The pure 5-chloro-2-methyl-3-isothiazolone obtained in the present invention is dissolved in 5-chloro-2-methyl-3-isothiazolone and added with an organic solvent capable of stabilizing high purity of 5-chloro- 2-methyl-3-isothiazolone anhydrous solution can be prepared. Hydroxyl solvents such as glycols, alcohols, glycol ethers can be used as this organic solvent, and aliphatic or aromatic hydrocarbons can be useful solvents in a series of compositions. Preferred solvents are those selected from the group consisting of ethylene glycol, propylene glycol, dipropylene glycol, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.

In addition, 5-chloro-2, which is used to purify the 5-chloro-2-methyl-3-isothiazolone of the present invention or to prepare high-purity 5-chloro-2-methyl-3-isothiazolone anhydrous solution or hydrochloride. Aqueous solutions containing -methyl-3-isothiazolone are typically mixtures of 5-chloro-2-methyl-3-isothiazolone and 2-methyl-3-isothiazolone, their weights in this aqueous solution The% ratio is preferably 50:50 to 99.99: 0.01.

(Example)

The following presents a preferred embodiment to aid the understanding of the present invention. However, the following examples are merely provided to more easily understand the present invention, and the present invention is not limited to the following examples.

5-chloro-2-methyl-3-isothiazolone tablet

Example 1

165 g of a mixture of a hydrochloride of 5-chloro-2-methyl-3-isothiazolone (CMI) with a hydrochloride of 2-methyl-3-isothiazolone (MI) (CMI: MI = 73: 27; unit by weight) Was dissolved completely in water to make 1000 g, and then 1000 g of chloroform was added to separate layers. The organic layer obtained here was washed with 1000 g of water. The lower layer was then separated and chloroform was evaporated to give 72 g of a mixture with CMI: MI = 98.6: 1.4 (unit: wt%).

Example 2

Except for performing layer separation using methylene chloride instead of chloroform in Example 1 was carried out in the same manner as in Example 1 to obtain 69g of a mixture of CMI: MI = 98.3: 1.7 (unit: wt%).

Example 3

Except for using 1,2-dichloroethane instead of chloroform in Example 1 was carried out in the same manner as in Example 1 to obtain a mixture 65g CMI: MI = 98.1: 1.9 (unit: wt%).

Example 4

Except for using nitromethane instead of chloroform in Example 1 was carried out in the same manner as in Example 1 to obtain a mixture 65g CMI: MI = 98.2: 1.8 (unit: wt%).

Example 5

1000 g of chloroform was added to 1000 g of a commercially available 14% isothiazolone aqueous solution composition to perform layer separation. The organic layer obtained here was washed with 1000 g of water. The lower layer was then separated and chloroform was evaporated to give 72 g of a mixture with CMI: MI = 98.6: 1.4 (unit: wt%).

Preparation of high purity 5-chloro-2-methyl-3-isothiazolone hydrochloride

Example 6

Hydrochloric acid salt of 5-chloro-2-methyl-3-isothiazolone (CMI) and hydrochloride salt of 2-methyl-3-isothiazolone (MI) are mixed at about 3: 1 weight ratio to 165 g of isothiazolone hydrochloride. After completely dissolved in water to make 1000g to 1000g of chloroform was added to separate the layers. The organic layer obtained here was washed with 1000 g of water. Subsequently, the lower layer was separated, dried over anhydrous magnesium sulfate, the drying agent was filtered, hydrogen chloride gas was added, and the resulting solid was filtered to obtain 90 g of a hydrochloride mixture having CMI: MI = 98.2: 1.8 (unit: wt%).

Preparation of high purity 5-chloro-2-methyl-3-isothiazolone anhydrous solution

Example 7

Ethylene glycol was added to the mixture of CMI: MI = 98.6: 1.4 (unit: wt%) obtained in Example 1, and the concentration was adjusted to 10%. At this time, the moisture content was about 500 ppm (moisture content of ethylene glycol: 450 ppm). After the solution was placed in a 65 ° C. thermostat, the thermal stability was measured by measuring the degree of thermal decomposition using high performance liquid chromatography. As a result, the residual content (%) was maintained at 100% for 10 days.

Preparation of high purity 5-chloro-2-methyl-3-isothiazolone hydrochloride aqueous solution

Example 8

130 g of the hydrochloride mixture obtained in Example 6 and 300 g of magnesium nitrate hexahydrate were completely dissolved in water to make 1000 g, and then neutralized with anhydrous magnesium oxide to obtain a pH of 1.5 to 3.0. After leaving this solution in a 65 degreeC thermostat, thermal stability was measured. The degree of degradation by thermal stability measurement was determined by high performance liquid chromatography, and the residual content (%) was measured to maintain at least 90% of the active ingredient for 28 days.

The composition ratio (weight% ratio) of the isothiazolone obtained in Examples 1-6 is shown in Table 1 below.

CMI MI Example 1 98.6% 1.4% Example 2 98.3% 1.7% Example 3 98.1% 1.9% Example 4 98.2% 1.8% Example 5 98.6% 1.4% Example 6 98.2% 1.8%

CMI = 5-chloro-2-methyl-3-isothiazolone

MI = 2-methyl-3-isothiazolone

It can be seen that 5-chloro-2-methyl-3-isothiazolone was obtained as substantially as shown in Table 1 above. In addition, as shown in the results of Examples 7 and 8, the high purity 5-chloro-2-methyl-3-isothiazolone anhydrous solution of Example 7 and the high purity 5-chloro-2-methyl-3 of Example 8 It can be seen that the isothiazolone hydrochloride aqueous solution has excellent stability over time.

Comparative Example 1

In accordance with US Pat. No. 5,466,818 was performed as follows.

A 500 ml flask was equipped with a condenser equipped with a stirrer, a thermometer, and a drying tube. 50.6 g of a mixture of CMI-HCl and MI-HCl in a ratio of 73:27 was added to the flask, and 349.4 g of ethyl acetate anhydride was added thereto to slurry. This slurry (10% solids) was heated to reflux and the solvent was partially distilled off (rate 20 mL / min). At this time, it was supplemented with clean ethyl acetate. A small amount was taken from the mother liquor over time, and the filtered and filtered solid was washed with ethyl acetate, and then the content of isothiazolone was analyzed and the filtered liquid content was analyzed. The reaction was stopped after refluxing for 7 hours. The results of analyzing the content of the filtered solid and the filtered solution are shown in Table 2 below.

Filtered liquid (wt%) Filtered solid (% by weight) Response time (hr) CMI MI CMI: MI CMIHCl MIHCl CMIHCl: MIHCl - - - - 53.9 18.0 73:27 0 86.9 1.2 98.6: 1.4 37.2 32.4 53.4: 46.6 One 90.0 2.8 97.0: 3.0 0.31 64.7 0.5: 99.5 2 82.0 10.8 88.4: 11.6 0.29 65.1 0.4: 99.6 3 77.2 14.6 83.9: 16.1 0.42 65.2 0.6: 99.4 4 76.5 18.2 80.5: 19.5 - - - 5 72.8 20.0 78.4: 21.6 - - - 6 73.6 20.8 78.0: 22.0 - - - 7 69.4 25.7 73.0: 27.0 - - -

As a result of comparing Table 2, which is the result of the Comparative Example, and Table 1, which is the result of the Example, it can be seen that the Example is superior in the purification of 5-chloro-2-methyl-3-isothiazolone.

As described above, the present invention can reuse the halogenated hydrocarbon or nitrated hydrocarbon used as the extraction solvent in the purification of 5-chloro-2-methyl-3-isothiazolone without separate separation and filtration process, extraction and washing Since isothiazolone contained in the aqueous solution generated in the process can be re-separated and reused, almost no waste is generated, and the process conditions are good. It is advantageous in that there is no separate filtration process, etc. can improve productivity and economy by improving workability.

Claims (7)

To the isothiazolone aqueous solution containing 5-chloro-2-methyl-3-isothiazolone represented by the following formula (1), a halogenated hydrocarbon or a nitrated hydrocarbon is added to the 5-chloro-2-methyl-3-isothiazolone Extracting an organic layer comprising a; Washing the organic layer obtained by the extraction process with water; Removing halogenated hydrocarbons or nitrated hydrocarbons from the organic layer; 5-Chloro-2-methyl-3-isothiazolone purification method comprising. [Formula 1]

The method of claim 1, wherein the halogenated hydrocarbon is selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, dichloroethane. The method of claim 1, wherein the nitrated hydrocarbon is selected from the group consisting of nitromethane and nitroethane. A 5-chloro-2-methyl-3-isothiazolone anhydrous solution in which an organic solvent is added to 5-chloro-2-methyl-3-isothiazolone obtained by the method of claim 1. Extracting an aqueous isothiazolone solution containing 5-chloro-2-methyl-3-isothiazolone of formula 1 as a halogenated hydrocarbon or a nitrated hydrocarbon; Washing the organic layer obtained by the extraction process with water; Adding hydrogen chloride gas to the organic layer washed with water; Filtering the solid produced by the step of adding the hydrogen chloride gas; 5-Chloro-2-methyl-3-isothiazolone hydrochloride manufacturing method containing. [Formula 1]

The method of claim 5, wherein the halogenated hydrocarbon is selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, ethylene chloride and dichloroethane. The method for preparing 5-chloro-2-methyl-3-isothiazolone hydrochloride according to claim 5, wherein the nitrated hydrocarbon is selected from the group consisting of nitromethane and nitroethane.