KR20110030116A - Preparation method of high purity n,n'-substituted 3,3'-dithiopropioneamide - Google Patents

Abstract

PURPOSE: A method for preparing high purity N,N'-disubstituted-3,3' dithiopropion amide is provided to improve the yield by suppressing N,N'-disubstituted-3,3' polythiodipropion amide or 3,3' polythiodipropionate dimethyl ester. CONSTITUTION: A method for preparing high purity N,N'-disubstituted-3,3' dithiopropion amide includes the following: methyl acrylate, sulfur, and water or organic solvent are agitated. Hydrogen sulfide is added to the agitated mixture to obtain an ester layer. The ester layer is separated to obtain the ester solution of mercapto propion methyl ester, 3,3'-dithiopropionate methyl ester, and 3,3'-trithiopropionate methyl ester. One or two compounds selected from sulphate and thiosulfate are added to the ester solution and are reacted at temperature between 5 and 70 degrees Celsius.

Description

Process for producing N, N'-disubstituted-3,3`-dithiodipropionamide of high purity {PREPARATION METHOD OF HIGH PURITY N, N'-SUBSTITUTED 3,3'-DITHIOPROPIONEAMIDE}

The present invention relates to a method for preparing substituted 3-isothiazolone, and more particularly, N, N'-disubstituted-3, which is an intermediate compound in the process of preparing substituted 3-isothiazolones, It relates to a method for producing 3'-dithiodipropionamide (N, N'-disubstituted-3,3'-dithiodipropionamides).

3-Isothiazolone was developed by Crow et al in 1965 and is now used throughout the industry as an antimicrobial and antimicrobial agent added to disinfectants, paints, cosmetics, textiles or plastics.

As a method for preparing 3-isothiazolone, U.S. Patent No. 3,849,430 discloses N, N'-disubstituted-3,3'-dithiodipropionamide or N-substituted-3-mercaptopropionamide by reacting with a halogenating agent. Methods of cyclization are disclosed.

The N, N'-disubstituted-3,3'-dithiodipropionamide reacts and hydrolyzes 2 or 3 mono- or di-substituted acrylate esters with thiol acetic acid to obtain 3-mercaptopropionic acid which is oxidized To obtain 3,3'-dithiodipropionic acid, and then react the 3,3'-dithiodipropionic acid with a gaseous amine compound as in Scheme 1 below.

Wherein X and Z are each independently hydrogen or a lower alkyl group, R is selected from the group consisting of hydrogen, an alkyl group, a phenyl group, a cyano group, a sulfone group and an aminocarbonyl group, Y is hydrogen, an alkyl group having 1 to 18 carbon atoms, A cycloalkyl group of up to 10 carbon atoms, an alalkyl group of up to 10 carbon atoms, an aryl group of up to 10 carbon atoms, an aryl group substituted by halogen, an aryl group substituted by lower alkyl, an aryl group substituted by lower alkoxy, cyano alkyl group, carbo Alkoxyalkyl group, haloalkyl group, alkoxyalkyl group, aryloxyalkyl group of up to 12 carbon atoms, alkoxyalkyl group of up to 12 carbon atoms, dialkylaminoalkyl group, alkylacyl group of up to 8 carbon atoms, lower alkylsulphone group, arylsulphone group of up to 10 carbon atoms , Cyano group, or carbamoyl group.

Using this method, stable N, N'-disubstituted-3,3'-dithiodipropionamide can be produced in high yield, but the purity is low, the reaction takes a long time of 48 hours or more, and by using gaseous amine There are problems in terms of safety and environment.

Meanwhile, the N-substituted-3-mercaptopropionamide is prepared by reacting the 3-mercaptopropionic acid prepared by the above method with an alcohol to obtain a 3-mercaptopropionic ester and reacting with a gaseous amine compound as shown in Scheme 2 below. .

Wherein X, Y, Z and R are the same as defined above.

Using this method, N-substituted-3-mercaptopropionamide can be produced in high yield and the reaction takes a relatively short time of less than 24 hours, but is low in purity and in terms of safety and environment due to the use of gaseous amines. Not only still there is a problem, but water is generated by oxidation, which, even in small amounts, lowers the yield of the next halogenation process, which is a problem that must be removed.

US Patent No. 4,868,310 discloses a process for preparing N-substituted-3-mercaptopropionamide by simultaneously supplying a mixture of unsaturated nitrile and alcohol and a strong inorganic acid in a suitable organic solvent to form acrylamide and treating it with a thiolating agent. Although disclosed, there is still a problem in that water generated by oxidation must be removed.

U.S. Patent No. 4,052,440 mentions a method for obtaining mercaptopropionate methyl ester or polythiodipropionate methyl ester produced after reacting acrylic acid with hydrogen sulfide in a weakly basic amine catalyst to obtain 3,3'-dithiodipropionate methyl ester. Doing. Here, a method for separating mercaptopropionate methyl ester, dithiodipropionate methyl ester, and polythiodipropionate methyl ester using a difference in boiling point is proposed, but there is still a problem of remaining polythiodipropionate methyl ester.

US Pat. No. 4,067,901 describes a method of continuously separating methyl dithiodipropionate by reacting methyl acrylate and hydrogen sulfide by using polythiodipropionate methyl ester as an active reaction solvent, but the reaction yield is low.

The present invention has been made to solve the problems of the prior art as described above, the present invention is an intermediate of the manufacturing process of 3-isothiazolone N, N'-disubstituted-3,3'-dithiodipropionamide N, N'-disubstituted-3,3'-polythiodipropionamide or 3,3'-polythiodipropionate dimethyl ester is a material that causes yield decrease and impurities during production. The present invention is intended to provide a method for producing a high yield of N, N'-disubstituted-3,3'-dithiodipropionamide.

The present invention is a step of producing an ester layer by adding hydrogen sulfide while stirring methyl acrylate, sulfur and water and / or organic solvent, mercaptopropion methyl ester, 3,3'-dithio by separating the ester layer Step 2 to obtain an ester solution of propionate methyl ester and 3,3'-trithiopropionate methyl ester and to the ester solution were attached one or two compounds selected from sulfate and thiosulfate and an amine solution, followed by 5 to 70 ° C. It relates to a method for producing N, N'-disubstituted-3,3'-dithiodipropionamide comprising three steps of reacting at.

By using the method for preparing N, N'-disubstituted-3,3'-dithiodipropionamide according to the present invention, high purity stable N, N'-disubstituted-3,3'-dithiodipropionamide can be obtained in high yield. It can be prepared as.

The present invention is a step of producing an ester layer by adding hydrogen sulfide while stirring methyl acrylate, sulfur and water and / or organic solvent, mercaptopropion methyl ester, 3,3'-dithio by separating the ester layer Step 2 to obtain an ester solution of propionate methyl ester and 3,3'-trithiopropionate methyl ester and to the ester solution were attached one or two compounds selected from sulfate and thiosulfate and an amine solution, followed by 5 to 70 ° C. It relates to a method for producing N, N'-disubstituted-3,3'-dithiodipropionamide comprising three steps of reacting at.

In the above three steps, the reaction rate is less than 5 ℃ to have a disadvantageous effect in terms of production efficiency, and if it exceeds 70 ℃ has a side effect of reducing the yield by side reactions.

Preferably, the present invention relates to a method for producing N, N'-disubstituted-3,3'-dithiodipropionamide, wherein the sulfate is Na ₂ SO ₃ or K ₂ SO ₃ .

Preferably the thiosulfate is Na ₂ S ₂ O ₃ or K ₂ S ₂ O ₃ For the method for producing N, N'-disubstituted-3,3'-dithiodipropionamide will be.

More preferably, the amine solution is N, N, characterized in that one or two solutions selected from methylamine, octylamine, propylamine, isopropylamine, butylamine, isobutyl amine and hexylamine It relates to a process for preparing '-disubstituted-3,3'-dithiodipropionamide.

In the present invention, the organic solvent is N, N'-disubstituted-3, characterized in that one or two or more selected from toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane and benzene It relates to a process for preparing 3'-dithiodipropionamide.

The present invention relates to a method for preparing N, N'-disubstituted-3,3'-dithiodipropionamide, which is an intermediate of the production process of 3-isothiazolone, which is a substance that causes yield decrease and impurities to be produced during the manufacturing process. It was confirmed that it was, N'-disubstituted-3,3'-polythiodipropionamide or 3,3'-polythiodipropionate dimethyl ester. These substances are caused by various side reactions of sulfide ions, mainly disulfide (-S _2- ), trisulfide (-S _3- ), tetrasulfide (-S _4- ), and sulfide (-S _5- ). , In the form of hexasulfide (-S _6- ). These materials are present in proportions depending on the reaction conditions. Therefore, in the present invention, a method for removing 3,3'-polythiodipropionate dimethyl ester, N, N'-disubstituted-3,3'-polythiodipropionamide, which are impurities produced by the above-described causes, It was found that sulfates and thiosulfates (Na ₂ S ₂ O ₃ , Na ₂ SO ₃ , K ₂ S ₂ O ₃ , K ₂ SO ₃ ) can be used.

Polysulfide during synthesis by adding sulfate or thiosulfate to sulfide ions (S ₂ ^2- , S ₃ ^2- , S ₄ ^2- , S ₅ ^2- , S ₆ ^2- ) in the preparation of the material As the redox reaction occurs between molecules, sulfide ions can be reduced and finally reduced to sulfhydryl (SH-) compounds. In addition, the sulfate, thiosulfate and quickness of poly seolpayi de (S _{n, n>} 2) reacting the compound is converted by reaction of sulfhydryl (SH-) Compound speed ^{_{S 6 2 -> S 5 2}} -> S 4 ^{2 ->} S ₃ ^{2 -} has been found that the order of ^-> S _{² 2.}

When the temperature and concentration are controlled while reacting sulfate or thiosulfate with polysulfide (-S _n- , n> 2), the polysulfide (-S _n- , n> 2) compound is converted to dithio (-S _2). It was found that it could be converted completely into a compound. Thus, in the preparation of N, N'-disubstituted-3,3'-dithiodipropionamide, 3,3'-dithiodipropionate dimethyl ester, by adding sulfate or thiosulfate, 3,3'-polythio ( S _n , n> 2) propionate dimethyl ester and N, N'-disubstituted-3,3'-polythio (S _n n> 2) propionamide, the desired target N, N'-disubstituted-3 A method capable of converting to 3'-dithiodipropionamide, 3,3'-dithiodipropionate dimethyl ester was invented. This method can produce the target product with high purity and stable high yield within a short reaction time and control of the reaction is easy and safe.

In order to achieve the object of the present invention as described above, the present invention provides a mixture of 3-mercaptopropionic ester, 3,3'-dithiodipropionic acid ester, and 3,3'-polythiodipropionic acid ester represented by the following Scheme 3. Provided is a method for preparing a target product by reacting with an amine.

In the above formula, X and Z are each independently hydrogen or lower alkyl group, Y is hydrogen, alkyl group of 1 to 18 carbon atoms, cycloalkyl group of 10 or less carbon atoms, alalkyl group of 10 or less carbon atoms, aryl group of 10 or less carbon atoms, halogen-, Lower alkyl- or lower alkoxy-substituted aryl groups, cyano alkyl groups, carboalkoxyalkyl groups, haloalkyl groups, alkoxyalkyl groups, aryloxyalkyl groups having 12 or less carbon atoms, alkoxyalkyl groups having 12 or less carbon atoms, dialkylaminoalkyl groups, 8 carbon atoms It is selected from the group consisting of the following alkylacyl groups, lower alkyl sulfone groups, aryl sulfone groups having 10 or less carbon atoms, cyano groups and carbamoyl groups.

The step of preparing the N-substituted-3-mercaptopropionamide or N, N'-disubstituted-3,3'-dithiodipropionamide is substantially the same as the starting material of 3-mercaptopropionic acid ester or The ester which is an active reactor of 3,3'-dithiopropionic acid ester or 3,3'-polythiopropionic acid ester is converted into a reactor of amide. The 3-mercaptopropionic acid ester or the 3,3'-dithiopropionic acid ester or the 3,3'-polythiopropionic acid ester is preferably added and reacted with 1.0 to 1.1 equivalents of the amine. At this time, by reacting with an equivalent amount of 3,3′-polythiopropionic acid ester, Na ₂ SO ₃ , a sulfate, is reacted with 3,3′-polythiopropionic acid ester or N, N′-disubstituted-3,3 ′ as an impurity. Polythiodipropionamide is removed by reaction with sulfite to produce the desired product, N, N'-disubstituted-3,3'-dithiodipropionamide.

In addition, the present reaction is preferably carried out in an organic solvent or an aqueous solution, and the organic solvent may be selected from the group consisting of toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane, benzene, and mixtures thereof. The equivalent amount of sulfite salt added to the reaction depends on the amount of 3,3′-polythiopropionic acid ester. 3,3`-polythiopropionic acid esters exist in the form of trisulfide (-S <sub>3-</sub> ) tetrasulfide (-S <sub>4-</sub> ), pentasulfide (-S <sub>5-</sub> ), hexasulfide (-S <sub>6-</sub> ) cargo trisulfide (-S <sub>3</sub> -) in the form, and sulfite salts are equivalent cargo trisulfide (-S <sub>3</sub> -) a disulfide (-S <sub>2</sub> -) in 3,3`- dithiocarbamic acid ester, or N, N'- 1.0 to 1.1 equivalents are used to reduce to di-substituted-3,3'-dithiodipropionamide. In this case, the 3,3′-polythiopropionic acid ester or N, N′-disubstituted-3,3′-polythiodipropionamide to be removed can be easily identified by liquid chromatography method.

Hereinafter, the present invention will be described in more detail.

The production method of the present invention can be represented by the following scheme.

Wherein X, Y, Z and R are the same as defined above.

Preferred examples and comparative examples of the present invention are described. However, the following examples are merely examples of the present invention showing the constitution and effects of the present invention, and the present invention is not limited to the following examples.

Example  One. Na ₂ SO ₄ Wow Octylamine  Used N, N ' - Dioctyl -3,3'- Dithiodipropion Amide manufacturers

In a 3 L flask, 190 g of hydrogen sulfide was added to the reactor for 3 hours while stirring with 500 g of methyl atryle, 130 g of sulfur, and 900 g of water at room temperature. The reaction solution was allowed to stand for at least 1 hour, and the aqueous solution layer and the ester layer on the lower layer oil were separated.

The weight of the separated ester layer is 350 g, and the components are separated and quantitated by liquid chromatography. Mercaptopropion methyl ester (5%), 3,3`-dithiopropionate methyl ester (90%), 3,3` Trithiopropionate methyl ester (5%).

350 g of the ester solution mixture was placed in a 2 L flask, and 380 g of octylamine was added thereto, followed by 8.7 g of sodium sulfite (Na ₂ SO ₄ ). 500 g of water was added as a reaction solvent. After the reaction was stirred for 24 hours or more at room temperature conditions around 20 ℃. 10 g of 50% hydrogen peroxide was added to the reaction solution and reacted for 1 hour. The solid formed in the reactor was then filtered in a filter flask and dried to prepare N, N'-dioctyl-3,3'-dithiodipropionamide to weigh it. After performing purity analysis by liquid chromatography it is shown in Table 1 below.

Purity (%) of N, N '-(dioctyl / methyl) -3,3'-dithiodipropion amide Example 1 99 Example 2 99 Example 3 99 Comparative Example 1 80 Comparative Example 2 85 Comparative Example 3 87

Example  2. Na ₂ SO ₄ And N using methylamine, N ' -Dimethyl-3,3'- Dithiodipropionamide  Produce

In a 3 L flask, 500 g of methyl atylate, 130 g of sulfur, and 900 g of water were added at room temperature, and 190 g of hydrogen sulfide was added to the reactor for 3 hours while stirring. The reaction solution was allowed to stand for at least 1 hour, and the aqueous solution layer and the lower oil phase ester layer were separated.

The weight of the separated ester layer is 350 g, and the components are separated and quantified by liquid chromatography. Mercaptopropion methyl ester (5%), 3,3`-dithiopropionate methyl ester (90%), 3,3`- It was trithiopropionic acid methyl ester (5%).

350 g of the above ester solution mixture was placed in a 2 L flask, and 230 g of methylamine aqueous solution (40%) was added thereto, followed by 8.7 g of sodium sulfite (Na ₂ SO ₄ ). 500 g of water was added as a reaction solvent. After the reaction was stirred for 24 hours or more at room temperature conditions around 20 ℃. 10 g of 50% hydrogen peroxide was added to the reaction solution and reacted for 1 hour. The solid formed in the reactor was then filtered in a filter flask and dried to prepare N, N'-dimethyl-3,3'-dithiodipropionamide. Purity analysis was then performed by liquid chromatography.

Example  3. Na ₂ S ₂ O ₃ And N using methylamine, N ' - Dioctyl -3,3'- Dithiodipropionamide  Produce

In a 3 L flask, 500 g of methyl atylate, 130 g of sulfur, and 900 g of water were added at room temperature, and 190 g of hydrogen sulfide was added to the reactor for 3 hours while stirring. The reaction solution was allowed to stand for at least 1 hour, and the aqueous solution layer and the lower oil phase ester layer were separated.

The weight of the separated ester layer is 350 g, and the components are separated and quantified by liquid chromatography. Mercaptopropion methyl ester (5%), 3,3`-dithiopropionate methyl ester (90%), 3,3`- It was trithiopropionic acid methyl ester (5%).

350 g of the ester solution mixture was placed in a 2 L flask, and 380 g of octylamine was added thereto, followed by 8.7 g of sodium thiosulfite (Na ₂ S ₂ O ₃ ). 500 g of water was added as a reaction solvent. After the reaction was stirred for 24 hours or more at room temperature conditions around 20 ℃. 10 g of 50% hydrogen peroxide was added to the reaction solution and reacted for 1 hour. Thereafter, the solid formed in the reactor was filtered and then dried in a filter flask to prepare N, N'-dioctyl-3,3'-dithiodipropionamide, the weight was measured, and then purity chromatography was performed by liquid chromatography.

Comparative example  One. Na ₂ SO ₄ N without using N ' - Dioctyl -3,3'- Dithiodipropiona Mead manufacturer

In Example 1, 8.7 g of sodium sulfite (Na ₂ SO ₄ ) was added thereto, followed by drying under the same reaction conditions as in Example 1 to obtain N, N'-dioctyl-3,3'-dithiodipropionamide. It was prepared and subjected to purity analysis in the same manner as the yield.

Comparative example  2. Na ₂ SO ₄ N without using N ' -Dimethyl-3,3'- Dithiodipropiona Mead manufacturer

In Example 2, the sodium sulfite (Na 2 SO 3) 8.7gr was added in the same reaction conditions as in Example 2 and dried to prepare N, N'-dimethyl-3,3'-dithiodipropionamide was prepared in the same manner Purity analysis was performed.

Comparative example  3. Na ₂ S ₂ O ₃ N without using N ' -Dimethyl-3,3'- Dithiodipropionamide  Produce

In Example 3, except that 8.7 g of sodium thiosulfite (Na ₂ S ₂ O ₃ ) was added thereto, the reaction mixture was dried under the same reaction conditions as in Example 3 and dried to form N, N'-dioctyl-3,3 '. -Dithiodipropionamide was prepared and subjected to purity analysis in the same manner as in yield.

As shown in Table 1, Example 1-3 is to prepare a high-purity stable N, N'-disubstituted-3,3'-dithiodipropionamide in high yield compared to Comparative Example 1-3 It is possible.

Claims (5)

1 step of generating an ester layer by adding hydrogen sulfide while stirring methyl acrylate, sulfur and water and / or an organic solvent; Separating the ester layer to obtain an ester solution of mercaptopropion methyl ester, 3,3'-dithiopropionic acid methyl ester and 3,3'-trithiopropionic acid methyl ester; And Attaching the amine solution with one or two compounds selected from sulfate and thiosulfate to the ester solution and reacting at 5 to 70 ° C .; Method for producing N, N'-disubstituted-3,3'-dithiodipropionamide comprising a. The method of claim 1, The sulfate is Na ₂ SO ₃ or K ₂ SO ₃ The process for producing N, N'-disubstituted-3,3'-dithiodipropionamide. The method of claim 1, The thiosulfate is Na ₂ S ₂ O ₃ or K ₂ S ₂ O _{3 The} method for producing N, N'-disubstituted-3,3'-dithiodipropionamide. The method of claim 1, The amine solution is N, N'-disubstituted-3, characterized in that one or two solutions selected from methylamine, octylamine, propylamine, isopropylamine, butylamine, isobutyl amine and hexylamine Process for the preparation of 3'-dithiodipropionamide. The method of claim 1, The organic solvent is one, or a mixture of two or more selected from toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane and benzene N, N'-disubstituted-3,3'-dithiodi Process for the preparation of propionamide.