KR19990025181A - Process for the preparation of N, N'-disubstituted-3,3'-dithiodipropionamide and preparation of substituted 3-isothiazolone therewith - Google Patents

Abstract

3-mercaptopropionamide is prepared by reacting 3-mercaptopropionate with an aqueous amine solution, and reacting the N-substituted-3-mercaptopropionamide with an aqueous hydrogen peroxide solution to obtain N, N'-disubstituted -3,3'-dithiodipropionamide can be produced at a high yield and can be easily controlled in reaction, in a high purity, stable N, N'-disubstituted-3,3'-dithiodipropionamide within a short reaction time In addition, it is possible to omit the dehydration process prior to the halogenation step in the production of the substituted 3-isothiazolone, and to produce the substituted 3-isothiazolone in a high yield .

Description

Process for the preparation of N, N'-disubstituted-3,3'-dithiodipropionamide and preparation of substituted 3-isothiazolone therewith

[Industrial Applications]

The present invention relates to a process for the preparation of substituted 3-isothiazolones, and more particularly to a process for the preparation of substituted 3-isothiazolones, which is an intermediate compound of N, N'-disubstituted- (N, N'-disubstituted-3,3'-dithiodipropi-onamides) and a process for preparing substituted 3-isothiazolones using the same.

BACKGROUND ART [0002]

The substituted 3-isothiazolone represented by the following general formula (1) was developed by Krau et al. In 1965 and has been used throughout the industry as an antibacterial and antimicrobial agent added to paints, cosmetics, fibers or plastics as well as fungicides.

[Chemical Formula 1]

Wherein Y is hydrogen, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 10 or less carbon atoms, an aralkyl group having 10 or less carbon atoms, an aryl group having 10 or less carbon atoms, a halogen-, a lower alkyl- or a lower alkoxy- An alkoxyalkyl group having 12 or less carbon atoms, an alkoxyalkyl group having 12 or less carbon atoms, a dialkylaminoalkyl group, an alkyl acyl group having 8 or less carbon atoms, a lower alkyl sulfone group, a carbonyl group having 10 or less carbon atoms will be selected from the following aryl sulfone group, a cyano group, and the group consisting of carbazole to the parent group, R ₁ and R ₂ is each independently selected from the group consisting of hydrogen, halogen and lower alkyl.

As a method for producing the substituted 3-isothiazolone, U.S. Patent No. 3,849,430 discloses a method for producing N, N'-disubstituted-3,3'-dithiodipropionamide or N-substituted-3-mercaptopropionamide, And then reacting the resulting mixture with cyclization.

The N, N'-disubstituted-3,3'-dithiodipropionamide is obtained by reacting a 2 or 3 mono- or di-substituted acrylate ester with thiolacetic acid and hydrolyzing to obtain 3-mercaptopropionic acid, To obtain 3,3'-dithiodipropionic acid, and then reacting the 3,3'-dithiodipropionic acid with a gaseous amine compound as shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

Wherein Y is the same as defined above, X and Z are each independently hydrogen or a lower alkyl group, and 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.

Using this method, stable N, N'-disubstituted-3,3'-dithiodipropionamide can be prepared in high yields, but it takes a long time of 48 hours or longer for the reaction to be low in purity and the use of gaseous amines Safety and environment.

On the other hand, the N-substituted-3-mercaptopropionamide is prepared by reacting 3-mercaptopropionic acid prepared by the above method with an alcohol to obtain 3-mercaptopropionate and reacting it with a gaseous amine compound as shown in Reaction Scheme 2 .

[Reaction Scheme 2]

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

Using this method, it is possible to prepare N-substituted-3-mercaptopropionamide in a high yield, and the reaction takes a relatively short period of time of less than 24 hours. However, since the purity is low and the gaseous amine is used, Not only does it still have a problem, but it also has the difficulty of removing water, since the yield of the next halogenation process is lowered even if a small amount of water is produced by oxidation.

U.S. Patent No. 4,868,310 discloses a method for preparing N-substituted-3-mercaptopropionamide by simultaneously supplying a mixture of unsaturated nitrile and alcohol and a strong inorganic acid in an appropriate organic solvent to form an acrylamide and treating it with a thiolating agent However, it still has a problem that water generated by oxidation must be removed.

DISCLOSURE OF THE INVENTION The present invention has been made in order to solve the problems of the prior art as described above, and it is an object of the present invention to provide an N, N'-disubstituted-3,3'-dithiodipropion Amide can be produced in a high yield in a high yield by a method of producing N, N'-disubstituted-3,3'-dithiodipropionamide with high purity within a short reaction time, excellent in safety and environment In addition, it is another object of the present invention to provide a method for producing a substituted 3-isothiazolone in which a dehydration process prior to the halogenation step can be omitted and a substituted 3-isothiazolone can be produced in high yield.

In order to accomplish the above object, the present invention provides a process for preparing N-substituted-3-mercaptopropionamide represented by the following Formula 3 by reacting 3-mercaptopropionate represented by the following Formula 4 with an amine aqueous solution And preparing an N, N'-disubstituted-3,3'-dithiodipropionamide by reacting the N-substituted-3-mercaptopropionamide with an aqueous hydrogen peroxide solution. Di-substituted < / RTI > 3,3'-dithiodipropionamide.

(2)

(3)

[Chemical Formula 4]

Wherein X and Z are each independently hydrogen or a lower alkyl group and Y is hydrogen, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 10 or less carbon atoms, an aralkyl group having 10 or less carbon atoms, an aryl group having 10 or less carbon atoms, A lower alkyl- or lower alkoxy-substituted aryl group, a cyanoalkyl group, a carboalkoxyalkyl group, a haloalkyl group, an alkoxyalkyl group, an aryloxyalkyl group having a carbon number of 12 or less, an alkoxyalkyl group having a carbon number of 12 or less, a dialkylaminoalkyl group, A lower alkylsulfone group, an arylsulfone group having 10 or less carbon atoms, a cyano group, and a carbamoyl group.

In the step of preparing the N-substituted-3-mercaptopropionamide, it is preferable to add about 1.0 to 1.5 equivalents of an aqueous 5 to 50% by weight amine solution to the 3-mercaptopropionate at room temperature for about 17 hours.

The step of preparing the N, N'-disubstituted-3,3'-dithiodipropionamide is preferably carried out by adding 0.5 to 5.5 equivalents of an aqueous hydrogen peroxide solution of 10% by weight or more in an organic solvent at room temperature or lower, for about 0.5 hour Do.

The organic solvent is preferably selected from the group consisting of toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane, benzene, and mixtures thereof.

In the above method, it is more preferable that X and Z are a hydrogen atom, and Y is a methyl group.

The present invention also provides a process for preparing N-substituted-3-mercaptopropionamide represented by Formula 3 by reacting 3-mercaptopropionate represented by Formula 4 with an amine aqueous solution, -Mercapto propionamide with an aqueous hydrogen peroxide solution to produce N, N'-disubstituted-3,3'-dithiodipropionamide; and reacting the N, N'-disubstituted-3,3'-dithiodi And reacting the propionamide with a halogenating agent.

The halogenating agent may be chlorine (Cl ₂ ), bromine (Br ₂ ), sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide and N-bromosuccinimide (N-bromosuccinimide).

Methyl-3-mercaptopropionamide by reacting 3-mercaptomethyl propionate with an aqueous methylamine solution, and reacting the N-methyl-3-mercaptopropionamide with an aqueous hydrogen peroxide solution to obtain N, N, N'-dimethyl-3,3'-dithiodipropionamide, and reacting said N, N'-dimethyl-3,3'-dithiodipropionamide with chlorine, sulfuryl chloride and N-chlorosuccinimide With a compound selected from the group consisting of < RTI ID = 0.0 > 5-chloro-2-methyl-3-isothiazolone. ≪ / RTI >

Hereinafter, the present invention will be described in detail.

The production process of the present invention can be represented by the following reaction formula (3).

[Reaction Scheme 3]

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

Mercapto propionate is added to the 3-mercaptopropionic ester in an amount of 5 to 50% by weight, more preferably about 40% by weight, based on 3-mercaptopropionate, in an amount of 1.0 to 1.5 equivalents, and reacted for about 17 hours with stirring . At this time, the reaction can be easily controlled by using an amine aqueous solution instead of the existing gaseous amine compound on the basis of water, and an excellent effect can be obtained in terms of safety and environment. When the amine aqueous solution is used in an amount of less than 5% by weight, the amount of the reactant increases to lower the reaction efficiency. If the amine aqueous solution is used in an amount of more than 50% by weight, the pressure may increase during the reaction. , The yield of N-substituted-3-mercaptopropionamide is lowered, and when it is used in excess of 1.5 equivalents, the amount of unreacted amine remaining after the reaction may increase.

Subsequently, the alcohol generated by heating is removed, an organic solvent is added, and an aqueous hydrogen peroxide solution of 10 wt% or more, more preferably about 35 to 50 wt%, at room temperature or lower is added to 0.5 To 5.5 equivalents, and the reaction is carried out for about 0.5 hour. At this time, the use of the aqueous solution of hydrogen peroxide also facilitates the control of the reaction and has an excellent safety and environmental effect. If the hydrogen peroxide solution is used in an amount less than 10% by weight, the amount of the reactant may be increased to lower the reaction efficiency.

The organic solvent is preferably selected from the group consisting of toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane, benzene, and mixtures thereof.

In the above, it is preferable that X and Z are a hydrogen atom and Y is a methyl group, that is, N-methyl-3-mercaptopropionamide is prepared by reacting 3-mercaptomethylpropionate with an aqueous methylamine solution, It is more preferable to prepare N, N'-dimethyl-3,3'-dithiodipropionamide by reacting the N-methyl-3-mercaptopropionamide with an aqueous hydrogen peroxide solution.

Further, the above N, N'-disubstituted-3,3'-dithiodipropionamide can be obtained from the group consisting of chlorine, bromine, sulfur chloride, bromide sulfuryl, N-chlorosuccinimide and N-bromosuccinimide Substituted 3-isothiazolones can be prepared by reacting with selected halogenating agents. At this time, since water is not produced in the step of producing the N, N'-disubstituted-3,3'-dithiodipropionamide, the dehydration process can be omitted.

In particular, N-methyl-3-mercaptopropionamide is prepared by reacting 3-mercaptomethyl propionate with an aqueous methylamine solution, and N-methyl-3-mercaptopropionamide is reacted with an aqueous hydrogen peroxide solution. '-Dimethyl-3,3'-dithiodipropionamide, and reacting the N, N'-dimethyl-3,3'-dithiodipropionamide with chlorine, sulfuryl chloride and N-chlorosuccinimide To produce 5-chloro-2-methyl-3-isothiazolone.

[Example]

Preferred embodiments and comparative examples of the present invention will be described. However, the following embodiments are only examples of the present invention showing the structure and effects of the present invention, and the present invention is not limited to the following embodiments.

Preparation of N, N'-dimethyl-3,3'-dithiodipropionamide

Example 1

100 g of a 40% by weight methylamine aqueous solution was added to 120 g of 3-mercaptomethyl propionate at room temperature and reacted for 17 hours with stirring to prepare N-methyl-3-mercaptopropionamide. The temperature was raised to 65 DEG C to remove the generated methanol, and 200 g of toluene was added. 25 g of 35% by weight aqueous hydrogen peroxide solution was gradually added at room temperature and reacted for 0.5 hour to prepare N, N'-dimethyl-3,3'-dithiodipropionamide, which was then filtered and dried.

Example 2

Except that 200 g of methylene chloride was used in place of the toluene in Example 1 above.

Example 3

Except that 200 g of cyclohexane was used in place of the toluene in Example 1 above.

Example 4

Except that 200 g of 1-butanol was used in place of the toluene in Example 1 above.

Comparative Example 1

At room temperature, 119 g of N, N'-dimethyl-3,3'-dithiodipropionate was introduced with 40 g of methylamine gas. The injection of the gas took 2 hours and the pressure rose to 4 atm. The reaction was carried out with stirring for 40 hours and the temperature was raised to 65 DEG C to remove methanol and excess methylamine to prepare N, N'-dimethyl-3,3'-dithiodipropionamide.

Preparation of N-methyl-3-mercaptopropionamide

Comparative Example 2

40 g of methylamine gas was introduced into 120 g of 3-mercaptomethyl propionate at room temperature. The injection of the gas took 2 hours and the pressure rose to 4 atm. The reaction was carried out with stirring for 17 hours and the temperature was raised to 65 ° C to remove methanol and excess methylamine to prepare N-methyl-3-mercaptopropionamide.

The results of the above Examples and Comparative Examples are shown in Table 1 below.

yield(%) water(%)* Reaction time (hours) Pressure (atmospheric pressure) Water content (%) Example 1 92 99 17 0 - Example 2 91 98 17 0 - Example 3 91 98 17 0 - Example 4 91 98 17 0 - Comparative Example 1 80 80 40 4 - Comparative Example 2 95 93 17 4 2.5

*: Measured by high performance liquid chromatography.

Preparation of 5-chloro-2-methyl-3-isothiazolone

N, N'-dimethyl-3,3'-dithio-dibropionamide produced in Examples 1 to 4 and Comparative Example 1 and 28.9 g of N-methyl-3-mercaptopropionamide produced from Comparative Example 2 Was added 200 g of ethanol, and 70 g of sulfuric chloride (SO ₂ Cl ₂ ) was added to prepare 5-chloro-2-methyl-3-isothiazolone. The yield of the compound is shown in Table 2 below.

Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 yield(%) 85 85 84 85 78 65

As shown in Table 1 and Table 2, the above Example can produce N, N'-disubstituted-3,3'-dithiodipropionamide of high purity with high yield within a shorter reaction time than the Comparative Example The reaction can be easily controlled, the safety and the environment can be improved, and the substituted 3-isothiazolone can be produced at a high yield.

The reaction in Comparative Example 1 takes a long time and low yield in the amidation reaction at a low reaction rate due to the physical properties of the N, N'-disubstituted-3,3'-dithiodipropionamide. The use of gaseous amines also increases the pressure and requires additional equipment to control the gaseous amines, making it difficult to control the reaction.

In addition to the difficulty in controlling the reaction due to the use of the gaseous amine, the reaction in Comparative Example 2 continuously generates water, which is a by-product, by oxidation of the -SH group contained in the molecule in contact with air. This moisture affects the next process, the cyclization reaction, and the yield is significantly lowered.

Using the process for preparing N, N'-disubstituted-3,3'-dithiodipropionamide according to the present invention, stable N, N'-disubstituted-3,3'-dithiodipropion Amide can be produced at a high yield, the reaction can be easily controlled, the safety and environment are excellent, and further, the dehydration process before the step of reacting with the halogenating agent in the production of the substituted 3-isothiazolone is omitted Substituted 3-isothiazolones can be prepared in high yields.

Claims (8)

Reacting a 3-mercaptopropionate represented by the following formula (4) with an amine aqueous solution to prepare an N-substituted-3-mercaptopropionamide represented by the following formula (3); And Preparing a N, N'-disubstituted-3,3'-dithiodipropionamide by reacting the N-substituted-3-mercaptopropionamide with an aqueous hydrogen peroxide solution; N, N'-disubstituted-3,3'-dithiodipropionamide represented by the following formula (2). (2) (3) [Chemical Formula 4] X and Z are each independently hydrogen or a lower alkyl group, Y is hydrogen, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 10 or less carbon atoms, an aralkyl group having 10 or less carbon atoms, an aryl group having 10 or less carbon atoms, , A lower alkyl- or lower alkoxy-substituted aryl group, a cyanoalkyl group, a carboalkoxyalkyl group, a haloalkyl group, an alkoxyalkyl group, an aryloxyalkyl group having a carbon number of 12 or less, an alkoxyalkyl group having a carbon number of 12 or less, a dialkylaminoalkyl group, A lower alkyl sulfide group, an aryl sulfone group having a carbon number of 10 or less, a cyano group, and a carbamoyl group. The method for preparing N-substituted-3-mercaptopropionamide according to claim 1, wherein the N-substituted-3-mercaptopropionamide is prepared by adding 1.0 to 1.5 equivalents of an aqueous 5 to 50% by weight amine solution to the 3-mercaptopropionate at room temperature for about 17 hours ≪ RTI ID = 0.0 > N, N'-disubstituted-3,3'-dithiodipropionamide. ≪ / RTI > 2. The method according to claim 1, wherein the step of preparing the N, N'-disubstituted-3,3'-dithiodipropionamide comprises adding 0.5 to 5.5 equivalents of an aqueous hydrogen peroxide solution of 10 wt% ≪ / RTI > disubstituted-3,3'-dithiodipropionamide. 4. The process according to claim 3, wherein the organic solvent is selected from the group consisting of N, N'-disubstituted-3,3-dihydroxybenzene, which is selected from the group consisting of toluene, 1-butanol, methylene chloride, chloroform, hexane, cyclohexane, benzene, &Apos; -dithiodipropionamide. ≪ / RTI > The process for producing N, N'-disubstituted-3,3'-dithiodipropionamide according to any one of claims 1 to 4, wherein X and Z are a hydrogen atom and Y is a methyl group. Reacting the 3-mercaptopropionate represented by Formula 4 with an amine aqueous solution to prepare N-substituted-3-mercaptopropionamide represented by Formula 3; Preparing N, N'-disubstituted-3,3'-dithiodipropionamide by reacting the N-substituted-3-mercaptopropionamide with an aqueous hydrogen peroxide solution; And Reacting the N, N'-disubstituted-3,3'-dithiodipropionamide with a halogenating agent, Lt; RTI ID = 0.0 > 3-isothiazolone. ≪ / RTI > 7. The process of claim 6, wherein the halogenating agent is selected from the group consisting of chlorine, bromine, sulfur chloride, bromide sulfuryl, N-chlorosuccinimide, and N-bromosuccinimide. ≪ / RTI > Methyl-3-mercaptopropionamide by reacting a 3-mercaptomethyl propionate with an aqueous methylamine solution; Preparing N, N'-dimethyl-3,3'-dithiodipropionamide by reacting the N-methyl-3-mercaptopropionamide with an aqueous hydrogen peroxide solution; And Reacting said N, N'-dimethyl-3,3'-dithiodipropionamide with a compound selected from the group consisting of chlorine, sulfuryl chloride and N-chlorosuccinimide; Chloro-2-methyl-3-isothiazolone. ≪ / RTI >