KR20030008660A - Method for the preparation and purification of 1,2-benzisothiazoline-3-one derivatives - Google Patents

Abstract

PURPOSE: Methods for producing and purifying a 1,2-benzisothiazol-3(2H)-one derivative are provided, thereby cheaply producing the 1,2-benzisothiazol-3(2H)-one derivative in higher yield. CONSTITUTION: The method for producing a 1,2-benzisothiazol-3(2H)-one derivative comprises the steps of: (a)reaction of 2,2'-dithiosalicyclic acid dialkyl ester represented by formula(2) with aceteamide or urea in an organic solvent using a base; and (b) reaction of the resulted compound of the step (a) with a hydrogen peroxide solution, wherein R is methyl or ethyl; the organic solvent is selected from the group consisting of toluene, benzene, xylene, chlorobenzene and tetrahydrofuran; and the base is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium-t-butoxide, sodium hydride. The method for purifying a 1,2-benzisothiazol-3(2H)-one derivative comprises the steps of: (a) dissolving the 1,2-benzisothiazol-3(2H)-one derivative in sodium hydroxide, adding aluminium oxide and active carbon into the mixture, and heating the mixture; (b) hot filtering the mixture and washing the filtered material with hot water; and (c) cooling the washed material at room temperature, and acidifying it with a strong hydrochloric acid solution.

Description

Method for the preparation and purification of 1,2-benzisothiazoline-3-one derivatives {1] -benzisothiazoline-3 (2H) -one derivative

The present invention relates to a method for preparing and separating 1,2-benzisothiazolin-3 (2H) -one derivatives widely used as an industrial preservative or an antimicrobial agent, and more particularly, to a derivative having the structure of Formula 1 It relates to a preparation and purification method.

Such isothiazoline derivatives are industrial preservatives to remove or prevent fungi in the manufacture of fungicides, especially latex (latex) and papermaking, as well as intermediates, such as drugs for treating mental disorders among various medicines, especially diseases of the central nervous system Useful as Among them, the 1,2-benzisothiazolin-3 (2H) -one derivative having the structure of Chemical Formula 1 has a broad spectrum of antibacterial activity against bacteria and fungi, and thus, emulsions, latex paints, sludges and papermaking. It can be applied in various fields, adhesives, aqueous fluids, and the like. In addition, because of its relatively high heat stability and lack of volatility, it can be applied to high temperature fluids, is compatible with nonionic and anionic surfactants, and has a relatively wide application range of 3 to 11 depending on pH. There is this. However, it may cause skin irritation and the like, and there may be a problem in the use of industrial products in contact with the body, and it is known to be less effective in black molds and pseudomonas.

Japanese Patent No. 2000-7667 (Shin Nippon Ewha Co., Ltd.) has esterified using thiosalicylic acid as a starting material, and then synthesized a hydroxamic acid derivative using hydroxylamine, etc., and then using hydrogen peroxide. A method for preparing a 2-benzisothiazol-3 (2H) -one derivative is disclosed, but since thiosalicylic acid, which is a starting material, is an expensive compound, there is a problem in that the economic efficiency is low due to the increase in manufacturing price. Not suitable for production According to US Pat. No. 4,736,040, 2,2'-dithiosalicylamide (2,2'-dithiosalicylic acid) was used in 2 to 3 steps using 2,2'-dithiosalicylic acid, which is the same raw material as the present invention. After obtaining 2'-dithiosalicylamide), a method of obtaining 1,2-benzisothiazolin-3 (2H) -one derivative is disclosed by reacting an aqueous sodium hydroxide solution as a base in an alcohol solvent and adding hydrogen peroxide. The reaction production step is long, and also has a problem in that the yield is low due to the generation of side reactions in the reaction using hydrogen peroxide. U.S. Patent No. 5,633,384 discloses an oxime intermediate by reacting with hydroxylamine using thiobenzaldehyde as a starting material, and then using 1,2-benzisothiazolin-3 (2H) -one derivatives using chlorine gas. To obtain, it takes two to three steps to prepare the starting material thiobenzaldehyde, and also has the disadvantage of causing environmental pollution due to the use of chlorine gas, thereby causing a rise in the manufacturing price is an uneconomical method for mass production. Bull. Chem. Soc., Jpn., 1982, 55, 1183 to 1187, amidated by introducing various kinds of amine derivatives using alkyl thiosalicyl chloride as a starting material, from which 1,2, In order to obtain a benzisothiazolin-3 (2H) -one derivative, two to three steps are required to prepare alkylthio salicylic acid chloride as a starting material, and chlorine gas must be used to cause environmental pollution. There is a disadvantage that it is not suitable for mass production.

Therefore, in the production method of 1,2-benzisothiazol-3-one derivatives, there is an urgent need to solve the problems of low yield and long manufacturing steps as described above, the use of expensive raw materials and serious environmental pollution wastewater. Has been.

Accordingly, an object of the present invention is to provide a high-purity 1,2-benzisothiazolin-3 (2H) -one which uses low-cost raw materials, has a simple manufacturing process, and has a high yield and improves the problem of environmental pollution wastewater generation. It is to provide a method for producing a derivative.

Another object of the present invention is to provide a method for purifying the 1,2-benzisothiazol-3 (2H) -one derivative obtained in high purity.

In the present invention to achieve the above object,

(a) reacting a 2,2'-dithiosalicylic acid dialkyl ester having a structure of Formula 2 with acetamide or urea and a base under an organic solvent; And

(b) providing a method for preparing 1,2-benzisothiazol-3 (2H) -one derivative of Chemical Formula 1 including the step of reacting by adding an aqueous hydrogen peroxide solution.

(One)

(2)

Wherein R is methyl, ethyl.

The organic solvent is preferably any one selected from the group consisting of toluene, benzene, xylene, chlorobenzene, tetrahydrofuran.

The base is preferably any one selected from the group consisting of sodium methoxide, sodium ethoxide, potassium-t-butoxide, sodium hydride.

The 2,2'-dithiosalicylic acid dialkyl ester is prepared by reacting with 2,2'-dithiosalicylic acid having the following formula (3) with dialkyl sulfate using a sodium hydroxide aqueous solution as a base.

(3)

In addition, the present invention provides a method for recrystallizing the obtained 1,2-benzisothiazol-3 (2H) -one derivative using any one solvent selected from the group consisting of chlorobenzene, benzene and toluene.

In the present invention, the obtained 1,2-benzisothiazol-3 (2H) -one derivative

(a) dissolving in an aqueous sodium hydroxide solution and then adding aluminum oxide (Al ₂ O ₃ ) and activated carbon, followed by heating;

(b) filtering the solution (hot filtering) and washing with warm water; And

(c) It provides a method for purifying pure 1,2-benzisothiazolin-3 (2H) -one derivative of high purity comprising the step of cooling it to room temperature and acidifying with concentrated aqueous hydrochloric acid solution.

Hereinafter, the preparation method according to the present invention will be described in more detail step by step according to Scheme 1 below.

Examples of the base used in Scheme 1 include powdered sodium methoxide, sodium ethoxide, 5-30% sodium methoxide or sodium ethoxide alcohol solution, powdered potassium-t-butoxide, sodium dispersed in 60% oil. Preference is given to hydride (NaH) or 5-50% aqueous sodium hydroxide solution.

In Scheme 1, 1.0 equivalent of 2,2'-dithiosalicylic acid and 3.0 to 5.0 equivalents of dimethylsulfate (dimethylsulfate; DMS) or diethylsulfate (DES) were used, and 5 to 50% aqueous sodium hydroxide solution was used. It is used in a volume ratio of 300 to 800 relative to '-dithiosalicylic acid. While adjusting the pH of the reaction mixture to 9.0 to 12.0, the reaction is carried out for 5 to 18 hours in the temperature range of 30 to 60 ℃ to obtain the compound of formula 2 in 95-98% yield. Preferably, the reaction mixture is prepared by using 1.0 equivalent of 2,2'-dithiosalicylic acid and 4.0 equivalents of dimethyl sulfate or diethyl sulfate and using a 5% aqueous sodium hydroxide solution in a volume ratio of 500 with respect to the 2,2'-dithiosalicylic acid. The pH of the reaction was adjusted to 10.0 to 11.0 for 4 hours at a temperature in the range of 45 to 50 ° C. to obtain dialkyl-dithiosalicylate (Formula 2) in a yield of 98%. After completion of the reaction, the compound of formula 2 can be isolated by filtration and dried completely for the next reaction. The compound of formula 2 is 2.0 to 4.0 equivalents of acetamide (CH ₃ CONH ₂ ) or urea and powdered sodium methoxide or sodium ethoxide or 5-28% sodium methoxide or sodium ethoxide alcohol solution or powder 10 to 20 volume ratios of toluene based on dialkyl-dithiosalicylate (Formula 2) using 2.0-6.0 equivalents of potassium-t-butoxide or sodium hydride (NaH) dispersed in 60% oil Under a solvent such as benzene, xylene, chlorobenzene, tetrahydrofuran or the like at a temperature of 100 to 140 ° C for 1 to 4 hours, and cooled to 25 ° C or less. Next, the reaction was terminated using 10-20 times volume ratio of water based on dialkyl-dithiosalicylate (Formula 2), followed by layer separation, and then 1.0-2.5 equivalents of aqueous hydrogen peroxide solution (10) To 28% aqueous solution) and reacted at a temperature of 30 to 60 ° C. for 1 to 2 hours to produce 1,2-benzisothiazolin-3 (2H) -one derivative (Formula 1) in a yield of 90 to 95%. Get Preferably, the compound of the formula (II) is used in an amount of 110 to 110 to about 3.0 equivalents of acetamide or urea and 4.0 equivalents of powdered sodium methoxide under a 20-volume ratio of chlorobenzene based on dialkyl-dithiosalicylate (Formula 2). After the reaction at a temperature of 120 ℃ for 2 hours, and cooled (up to 25 ℃), the reaction was terminated using 20 times the volume ratio of water based on the dialkyl-dithiosalicylate (Formula 2) to separate the layers The 1,2-benzisothiazol-3 (2H) -one derivative (Formula 1) was added 98% by adding 2.2 equivalents of 10% aqueous hydrogen peroxide solution to the aqueous solution and reacting at a temperature of 30 to 35 ° C for 1 hour. Get in yield. The obtained compound of formula 1 is recrystallized in a solvent such as chlorobenzene, benzene, toluene or dissolved in 5 to 10% aqueous sodium hydroxide solution in 10 to 20 volume ratios based on dialkyl-dithiosalicylate (Formula 2) To 30% by weight of aluminum oxide (aluminum oxide, Al ₂ O ₃ ) and 10 to 30% by weight of activated carbon is added, followed by stirring at 80 to 90 ℃. Next, the heated solution was filtered, washed with hot water of 50 ° C. or higher, cooled to room temperature, acidified with concentrated aqueous hydrochloric acid solution, and purified with high purity pure 1,2-benzisothiazoline-3 ( 2H) -one derivative (Formula 1) is obtained in a yield of 95%.

Hereinafter, the present invention will be described in more detail with reference to preferred examples, but the present invention is not limited thereto.

Example 1

Example 1- (1): Preparation of 2,2'-dithiosalicylic acid dimethyl ester (Formula 2)

60 g of 2,2'-dithiosalicylic acid (Formula 3) was dissolved in 400 ml of 5% aqueous NaOH solution. After adjusting the reaction temperature to 30 ° C., 57 g of dimethyl sulfate was temporarily added at one time. In order to maintain the pH of the reaction solution to 10 or more, an appropriate amount of 5% NaOH aqueous solution was added during the reaction. When dimethyl sulfate was added, the reaction mixture was exothermic so that the temperature of the reaction mixture did not exceed 50 ° C. The reaction mixture was stirred at room temperature for 24 hours, filtered, washed with water and dried under reduced pressure to give 63.5 g (95% yield) of the target compound as a white solid.

m.p. 131-133 degreeC

NMR (CDCl ₃ ) δ 3.85 (s, 6H, OCH ₃ ), 7.0-7.3 (m, 4H, aromatic H),

7.74 (d, 2H, aromatic H), 8.01 (d, 2H, aromatic H)

Mass (EI) 335 (M ⁺ +1), 334 (M ⁺ ), 304 (-2CH ₃ ), 216 (-2CO ₂ )

IR (CHCl ₃ ) 1710 cm ^-1

Example 1-(2): Preparation of 1,2-benzisothiazol-3 (2H) -one (Formula 1)

80.1 g of powdered sodium methoxide and 44.5 g of acetamide (CH ₃ CONH ₂ ) were added to 400 g of toluene, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a solution of 85 g of the compound of formula 2 in 850 ml of toluene and heated to reflux for 24 hours. The reaction mixture was cooled, toluene was concentrated and recovered, and then 450 ml of methanol and 50 g of water were added to the residue. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure to recover MeOH, and cooled to 5 ° C. After acidification (pH = 5 to 6) with 1N aqueous hydrochloric acid, the mixture was left at the same temperature for 24 hours, and then the resulting solid was filtered, washed with a small amount of cooling water and dried to give 73 g of the target compound as a yellow solid (yield). 95%). The obtained solid was recrystallized in toluene to give 69 g (yield 90%) of the target compound as an off-white solid.

m.p. 155-157 ℃

NMR (CDCl ₃ ) δ 7.43 (m, 1H, aromatic H), 7.62 (m, 2H, aromatic H),

8.04 (m, 1H, aromatic H), 10,47 (bs, 1H, NH)

Mass (EI) 151 (M ⁺ ), 123 (M ⁺ ), 96 (M ⁺ ), 77 (M ⁺ )

Example 2

Preparation of 2,2'-dithiosalicylic acid dimethyl ester (Formula 2)

17.2 g (1.05 mole) of isatoic anhydride were mixed in 130 ml of methanol and heated to reflux at 80 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, methanol was recovered by distillation under reduced pressure, 50 ml of water and 50 ml of ethyl acetate (EtOAc) were added thereto, the mixture was stirred for 1 hour, the layers were separated, and the organic layer was dried over anhydrous manganese and concentrated under reduced pressure. To 15.1 g (yield 95%) of methyl anthranilate.

Next, the methyl anthranilate obtained above was used directly in the next reaction without purification. 15.1 g of methyl anthranilate was added to 180 ml of 6N aqueous hydrochloric acid solution, and the mixture was cooled to 5 ° C or lower with stirring. 50 g of 10% aqueous sodium sulfite (Na ₂ SO ₃ ) solution was slowly added thereto, and stirred at room temperature for 1 hour to obtain a clear solution (solution 1).

Separately from the above, 80 g of water was mixed with 39 g (0.15 mole) of sodium sulfide (Na ₂ S) and 4.8 g (0.15 mole) of sulfur (Sulfur, S ₈ ) and heated at 100 ° C. for 1 hour. 40 ml of 5N aqueous sodium hydroxide solution was added to the mixture, followed by cooling to 5 ° C to prepare Solution 2.

To Solution 1, Solution 2 was slowly added at room temperature and stirred for 3 hours. 40 ml of 6N aqueous hydrochloric acid solution was added to the mixture, and the resulting solid was filtered, washed with water and dried to obtain 31.7 g (95% yield) of 2,2'-dithiosalicylic acid dimethyl ester.

m.p. 131-133 degreeC

NMR (CDCl ₃ ) δ 3.85 (s, 6H, OCH ₃ ), 7.0-7.3 (m, 4H, aromatic H),

7.74 (d, 2H, aromatic H), 8.01 (d, 2H, aromatic H)

Mass (EI) 335 (M ⁺ +1), 334 (M ⁺ ), 304 (-2CH ₃ ), 216 (-2CO ₂ )

IR (CHCl ₃ ) 1710 cm ^-1

Example 3

Except that 45.2 g of urea was used, 70 g (91% yield) of 1,2-benzisothiazol-3 (2H) -one (Formula 1) was obtained in the same manner as in Example 1- (2).

Example 4

80.1 g of powdered sodium methoxide and 44.5 g of acetamide were added to 400 g of chlorobenzene, and the mixture was stirred at room temperature for 5 hours. 85 g of the compound of formula 2 was added to the reaction mixture and heated to reflux for 24 hours. The reaction mixture was cooled, the chlorobenzene was concentrated under reduced pressure to recover, and 250 g of water was added to the residue. A catalytic amount of 10% H ₂ O ₂ was added and the reaction mixture was stirred at room temperature for 24 hours. After cooling to −5 ° C., acidified with 1N aqueous hydrochloric acid solution (pH = 4 to 5) and left at the same temperature for 24 hours. The resulting solid was filtered, washed with a small amount of cooling water and dried to give 73 g (yield 95%) of 1,2-benzisothiazol-3 (2H) -one as a yellow solid. The obtained solid was recrystallized from chlorobenzene to give 71.3 g (yield 93%) of the target compound as an off-white solid.

Example 5

37 g (91% yield) of 1,2-benzisothiazol-3 (2H) -one was obtained in the same manner as in Example 3, except that 45.2 g of urea was used.

Example 6

Method for Purifying 1,2-benzisothiazol-3 (2H) -one

The obtained compound of formula 1 was dissolved in 5 to 10% aqueous sodium hydroxide solution at a volume ratio of 10 to 20 based on dialkyl-dithiosalicylate (formula 2), and then 10 to 30% by weight based on the compound of formula 1 After adding aluminum oxide of 10 to 30% by weight of activated carbon and stirred at 80 to 90 ℃. The heated solution was filtered (hot filtering), washed with warm water at 50 ° C. or higher, cooled to room temperature, acidified with concentrated aqueous hydrochloric acid solution, and then purified by pure 1,2-benzisothiazoline-3 (2H)-of high purity. -One derivative (Formula 1) was obtained in a yield of 95%.

The process according to the invention is much more effective and economical in terms of yield, purity and production cost than known methods, in particular 2,2'-dithiosalicylic acid dialkyl esters. An aqueous sodium hydroxide solution was used as the reaction solvent and base when preparing (Formula 2), and since the yield of the reaction was obtained in a higher yield than the known method, there is an effect of lowering the manufacturing price with increasing the overall yield. In addition, in the preparation of 1,2-benzisothiazol-3 (2H) -one (Formula 1) from Chemical Formula 2, the production cost was lowered by using acetamide or urea, which is an inexpensive raw material, and the reaction time using hydrogen peroxide. This has been shortened, and thus has an effect of improving the manufacturing yield, and thus has advantages such as process efficiency and high yield.

Claims (6)

(a) reacting a 2,2'-dithiosalicylic acid dialkyl ester having a structure of Formula 2 with acetamide or urea and a base under an organic solvent; And (b) A method for preparing the 1,2-benzisothiazol-3 (2H) -one derivative of Chemical Formula 1, comprising the step of reacting by adding an aqueous hydrogen peroxide solution. (One) (2) Wherein R is methyl, ethyl. The preparation of 1,2-benzisothiazol-3 (2H) -one derivative according to claim 1, wherein the organic solvent is selected from the group consisting of toluene, benzene, xylene, chlorobenzene, and tetrahydrofuran. Way. The 1,2-benzisothiazole- according to claim 1, wherein the base is any one selected from the group consisting of sodium methoxide, sodium ethoxide, potassium-t-butoxide and sodium hydride. Method for preparing 3 (2H) -one derivative. The method of claim 1, wherein the 2,2'-dithiosalicylic acid dialkyl ester is prepared by reacting 2,2'-dithiosalicylic acid having the formula (3) with dimethyl sulfate or diethyl sulfate using a sodium hydroxide aqueous solution as a base. Method for producing a 1,2-benzisothiazol-3 (2H) -one derivative, characterized in that. (3) Recrystallizing the 1,2-benzisothiazol-3 (2H) -one derivative obtained in any one of claims 1 to 4 using any one solvent selected from the group consisting of chlorobenzene, benzene and toluene. Method for purifying 1,2-benzisothiazol-3 (2H) -one derivative, characterized in that. The 1,2-benzisothiazol-3 (2H) -one derivative obtained in any one of claims 1 to 4 (a) dissolving in an aqueous sodium hydroxide solution and then adding aluminum oxide (Al ₂ O ₃ ) and activated carbon, followed by heating; (b) filtering the solution (hot filtering) and washing with warm water; And (c) a method of purifying a high-purity 1,2-benzisothiazolin-3 (2H) -one derivative comprising the step of cooling it to room temperature and then acidifying with concentrated aqueous hydrochloric acid solution.