KR20230027520A - Method for producing high purity N-hydroxy succinimide using succinic anhydride - Google Patents

Abstract

The present invention relates to a method for producing and purifying n-hydroxysuccinimide (NHS). More specifically, the method comprises: a) a step of reacting succinic acid and hydroxylamine in the presence of a solvent to prepare N-hydroxysuccinamic acid; b) a step of reacting the N-hydroxysuccinamic acid in the presence of an acid catalyst and a reducing agent to prepare N-hydroxysuccinimide; and c) a purification step of purifying the N-hydroxysuccinimide with an organic base. According to the present invention, the method significantly increases purity, yield, and quality, and the overall process is simple and industrially useful, thereby being applicable to mass production and various industrial fields.

Description

Method for producing high purity N-hydroxy succinimide using succinic anhydride {Method for producing high purity N-hydroxy succinimide using succinic anhydride}

The present invention relates to the preparation and purification of N-hydroxy succinimide using succinic anhydride, and more particularly, to the preparation and purification of N-hydroxy succinimide using succinic anhydride and hydroxy amine in high yield in the presence of an acid catalyst and a reducing agent. It relates to a method for preparing high-purity N-hydroxy succinimide through a step of synthesizing and a step of purification using an organic base.

N-Hydroxysuccinimide is a useful compound that is used as a raw material for cosmetics and fine chemical products, or products applied with it are used as raw materials for pharmaceutical synthesis and functional cosmetics. In particular, it is used as an active substance for obtaining amide and carbamate substances in the field of pharmaceutical synthesis, and is recently used to develop cosmetic raw materials with excellent skin improvement ability.

N-hydroxy succinimide is prepared by generating N-hydroxy succinic acid from succinic anhydride and hydroxyamine and dehydrating it to obtain imidation, or by generating succinic acid/hydroxy salt from succinic acid and hydroxyamine and using a catalyst Many methods are known, such as a method obtained by imidization through a ring closure reaction of succinic acid monoester at a high temperature.

Among several conventional methods, the method through the dehydration reaction of succinic acid and hydroxyamine reacts at a high temperature under a catalyst, so a high rate of reaction by-products are generated, resulting in a very low yield and difficult mass production due to complicated production and purification processes. there is a problem. In addition, in the method obtained from succinic anhydride, succinic anhydride is decomposed into succinic acid due to the use of water as a reaction solvent, and the quality of the final product is greatly deteriorated due to problems such as remaining or mixed in the product and color change due to reaction temperature. unsuitable

Therefore, a method for preparing N-hydroxy succinamic acid produced from succinic anhydride and hydroxyamine at a low temperature using a dehydrating agent that accelerates the dehydration reaction has been developed commercially. Accordingly, various techniques have been proposed to improve the yield and purity of N-hydroxy succinimide prepared through the above method.

For example, in Chinese Laid-Open Patent Publication No. 103145601, N-hydroxysuccinamic acid is heated using a strong acid such as sulfuric acid, phosphoric acid, or acetic acid under a polar solvent capable of dissolving a hydroxyl amine salt as a catalyst, A method for preparing N-hydroxy succinimide by removing water produced during dehydration by azeotropic distillation together with a solvent is proposed. This method has the advantage of obtaining a high reaction yield by using an effective dehydration catalyst, but an excessive amount of succinic acid is generated and an excessive amount of reaction by-products such as product color change are generated due to the high temperature reaction process, so the purification process is complicated and expensive reaction solvent There is a reuse problem.

In addition, in US Patent Publication No. 5426190, N-hydroxy succinamic acid is prepared by reacting succinic anhydride with hydroxy sulfate, and then the N-hydroxy succinamic acid is heated and dehydrated at a high temperature under a sulfuric acid catalyst to perform imidation. A method of increasing the purity and yield of N-hydroxy succinimide by proceeding is proposed. This method has a problem in that a side reaction may be caused due to a large amount of water used as a reaction solvent and a high reaction temperature.

On the other hand, US Patent Publication No. 5493031 proposes a method for preparing N-hydroxy succinimide using succinic anhydride and hydroxyamine under low pressure in order to solve the problems that occur under high temperature conditions under a conventional catalyst. there is. This method provides a relatively high reaction temperature and short reaction time, but additionally requires a reduced pressure facility and is difficult to apply to mass production because the production cost is high because the separation and purification process of the final product after the reaction is complicated.

Chinese Laid-Open Patent Publication No. 103145601 US Patent Publication No. 5426190 US Patent Publication No. 5493031

Conventional methods for producing N-hydroxy succinimide have low yields and complex processes, making them unsuitable for industrial use in terms of productivity, process efficiency, and economic feasibility. In addition, a lot of time and money are required because a specific reactant is used in excess or the reaction proceeds under severe conditions of high temperature. In addition, there are problems in that side reactions easily occur, resulting in lower yields, and low economic feasibility due to complicated and inefficient product separation and purification processes.

As a result of research to solve the above conventional problems, the applicant of the present invention has inevitably generated during the manufacturing process even under low temperature conditions by using an acid catalyst and a reducing agent that acts as an antioxidant in the production of N-hydroxy succinimide. The production of succinic acid and unreacted N-hydroxysuccinamic acid, which are reaction by-products, were minimized. In addition, the present invention was completed by confirming that the yield, purity, and quality of N-hydroxysuccinimide prepared through the purification process using an organic base were improved compared to conventional products.

Ultimately, an object of the present invention is to provide a method for producing N-hydroxy succinimide capable of achieving higher yield, purity and quality than conventional methods.

The present invention relates to a method for producing high purity and high yield N-hydroxy succinimide.

In the present invention, "high yield" means having a yield of 80% or more, preferably 90% or more, unless otherwise specified.

In the present invention, "high purity" means having a purity of 95% or more, preferably 98% or more, unless otherwise specified.

The method for preparing N-hydroxy succinimide according to the present invention

a) preparing N-hydroxy succinamic acid by reacting succinic anhydride with hydroxyamine in the presence of a solvent;

b) preparing N-hydroxy succinimide by reacting the N-hydroxy succinimide in the presence of an acid catalyst and a reducing agent; and

c) a purification step of purifying the N-hydroxy succinimide with an organic base;

A method for preparing N-hydroxy succinimide according to an embodiment of the present invention is shown in Reaction Scheme 1 below.

[Scheme 1]

Specifically, the preparation method includes a) preparing N-hydroxy succinamic acid by reacting succinic anhydride with hydroxyamine in the presence of a solvent; b) preparing N-hydroxy succinimide by reacting the N-hydroxy succinimide in the presence of an acid catalyst and a reducing agent; and c) a purification step of purifying the N-hydroxy succinimide with an organic base.

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

First, in step a), N-hydroxysuccinamic acid is prepared by reacting succinic anhydride with hydroxyamine in the presence of a solvent.

Succinic anhydride used in the present invention is a compound having a structure shown in Chemical Formula 3 of Reaction Scheme 1, and is one of the starting materials for preparing N-hydroxy succinimide.

The succinic anhydride may be directly synthesized through a method commonly performed in the art or purchased and used as a commercially available product.

The succinic anhydride may be used in an amount of 0.5 to 1.5 moles, preferably 0.8 to 1.2 moles, based on 1 mole of hydroxyamine described below. When the succinic anhydride is used in a molar ratio less than the above molar ratio, there is a problem that the reaction does not proceed smoothly, and on the other hand, when the molar ratio is exceeded, the yield is lowered and an excessive amount of unreacted material remains after the reaction is completed, so that a separate purification process is required. because it is uneconomical

The hydroxyamine used in the present invention reacts with the above-mentioned succinic anhydride to produce N-hydroxyamine succinamic acid as an intermediate product.

The organic solvent used in the present invention is a non-polar solvent that serves as an azeotropic distillation of water, which is a reaction by-product, and should be insoluble or immiscible with water, inert, and not participate in the reaction. In addition, a solvent having a boiling point of 50 to 170° C. may be used so that the reaction proceeds smoothly and can be easily removed after the reaction is completed.

The organic solvent used in the present invention may include at least one selected from the group consisting of toluene, xylene, ethylbenzene, isopropylbenzene, chlorobenzene, t-butylbenzene, trimethylbenzene, trimethylhexane and cyclohexylbenzene. . Preferably, it may be at least one selected from the group consisting of toluene and xylene.

The organic solvent of the present invention may be used in a volume ratio of 1 to 20, preferably 2 to 10, based on 1 volume of the aforementioned hydroxyamine.

In step b), N-hydroxy succinimide of Chemical Formula 1 is prepared by subjecting the N-hydroxy succinimide of Chemical Formula 2 prepared in step a) to a dehydration reaction under an acid catalyst.

The catalyst used in the present invention serves to prepare N-hydroxy succinimide of Formula 1 by imidizing N-hydroxy succinimide of Formula 2 by accelerating the dehydration reaction.

The acid catalyst of the present invention may include at least one selected from the group consisting of sulfuric acid, phosphoric acid, boric acid, trichloroacetic acid, trifluoroacetic acid and toluenesulfonic acid.

The acid catalyst of the present invention may be used in an amount of 0.01 to 1.0 mole, preferably 0.1 to 1.0 mole, based on 1 mole of the hydroxyamine used in step a). When the acid catalyst is used in a molar ratio less than the molar ratio, there is a problem in that the reaction does not proceed smoothly, and on the contrary, if the molar ratio is exceeded, the reaction activity of the catalyst is reduced and succinic acid, a side reaction, is excessively produced, resulting in a decrease in yield. NMR results using an acid catalyst according to an embodiment of the present invention are shown in FIG. 2 . H NMR (400 MHz, D2O, ppm) δ 2.52 (S, 4H), 2.70 (s, 2H) values, and the content ratio of N-hydroxy succinimide to succinic acid is 94.3:5.67. Therefore, it can be seen that it is very important to use an appropriate amount of acid catalyst.

The reducing agent of the present invention serves as a reaction stabilizer to help the imidation reaction of the present invention proceed more easily by suppressing the oxidation of a reactant in a high temperature state.

The reducing agent of the present invention may be at least one selected from the group consisting of formic acid, oxalic acid, diborane, hydrazine, trimethyl phosphate, triethyl phosphate, hypophosphoric acid, potassium hypophosphate, and sodium hypophosphate. More preferably, it may be at least one selected from the group consisting of trimethyl phosphate, potassium hypophosphate, and sodium hypophosphate.

The reducing agent of the present invention may be used in an amount of 0.01 to 1.0 mole, preferably 0.05 to 0.1 mole, based on 1 mole of the hydroxyamine used in step a). When the reducing agent is used in a molar ratio less than the above, a sufficient stabilizing effect cannot be obtained, and on the contrary, when the molar ratio is exceeded, the activity of the acid catalyst used together may be adversely affected. (FIG. 5)

The molar ratio of the acid catalyst and the reducing agent used in step b) of the present invention may be 1.4:1 to 2:1. When the molar ratio of the catalyst and the reducing agent is within the above range, the reaction rate is improved, so that N-hydroxy succinimide can be prepared in high yield and purity.

In the production method of the present invention, the reaction temperature for each step may vary depending on conditions. For example, step a) may be performed at 15 to 95°C, step b) may be performed at 50 to 200°C, and step c) may be performed at 20 to 80°C.

The reaction pressure of the present invention may also vary depending on the reaction conditions in each step. The reaction pressure is not particularly limited, but may be selected from a wide range of reduced pressure, normal pressure and increased pressure.

The reaction time for each step of the present invention also varies depending on conditions such as the type of solvent, the input amount of starting materials, the amount of catalyst used, and the reaction temperature, but may generally range from 0.5 to 15 hours.

The purification step of step c) of the present invention includes i) heating and refluxing the N-hydroxysuccinimide mixture;

ii) cooling to 20-30 °C; and iii) filtering the resulting solid by adding an organic base and stirring at 0 to 10° C. for 2 hours; It is characterized in that it includes.

Step c) of the present invention effectively forms an organic salt by reacting succinic acid and N-hydroxysuccinamic acid, which are reaction by-products mixed with the N-hydroxy imide of formula 1 obtained in step b), with an organic base. The purity and quality of N-hydroxy succinimide of Formula 1 is improved by playing a role in removing.

The base of the present invention is an organic base and may include at least one selected from the group consisting of trimethylamine, triethylamine, isopropylamine, tributylamine and trioctylamine.

The organic base of the present invention may be used in an amount of 0.01 to 1.0 mole, preferably 0.1 to 1.0 mole, based on 1 mole of the hydroxyamine used in step a). When the organic base is used in a molar ratio less than the above, there is a problem in that reaction by-products are not removed, and on the other hand, when the molar ratio is exceeded, the yield may decrease due to reaction with N-hydroxy succinimide. Since it is an acid-base reaction, excessive use affects yield reduction.

Figure 3 is an NMR graph showing before the addition of an organic base, that is, before purification, and H NMR (400 MHz, D ₂ O, ppm) δ 2.64 (S, 4H), 2.75 (s, 2H), and N-hydroxy The content ratio of succinimide and succinic acid was found to be 94.38:5.62.

4 is an NMR graph showing after the addition of an organic base, that is, after purification, and H NMR (400 MHz, D ₂ O, ppm) δ 2.64 (S, 4H), 2.75 (s, 2H), N-hydroxy The content ratio of succinimide and succinic acid was found to be 99.90:0.01. As a result, it can be seen that succinic acid, a by-product, was removed through the purification process using an organic base, and the content of N-hydroxy succinimide was increased.

The method for preparing N-hydroxy succinimide of the present invention has the following advantages compared to conventional methods.

First, a method for preparing N-hydroxy succinimide having excellent productivity by showing high yield and high purity by maximizing the reaction activity of the catalyst by using a mixture of an acid catalyst and a reducing agent for imidation of N-hydroxy succinic acid is provided. .

Second, high-quality N-hydroxy succinimide is obtained by treating the N-hydroxy succinimide mixture with an organic base to effectively remove succinic acid and N-hydroxy succinamic acid, which are reaction by-products generated in the manufacturing process, through organic salt formation. A method for purifying the imide is provided.

Figure 1 shows the production steps of N-hydroxy succinimide.
2 is a result of analyzing the experimental results according to Example 1 of the present invention.
3 is a result of analysis before purification according to Example 1 of the present invention.
4 is an analysis result after purification through the addition of an organic base according to Example 1 of the present invention.
5 shows the reducing agent effect.

Hereinafter, the present invention will be described in detail with Examples and Comparative Examples.

However, the following Examples and Comparative Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Comparative Examples.

1. Preparation of N-hydroxy succinimide

<Example 1>

164 g (1.0 mol) of hydroxyamine sulfate, 40 g (1.0 mol) of sodium hydroxide, and 400 ml of purified water were added to a 1.0L reactor, and stirred for 20 to 30 minutes to completely dissolve hydroxyamine sulfate, followed by 100 g of succinic anhydride ( 1.0 mol) and 400 ml of toluene were added and reacted at room temperature for 1 hour to prepare N-hydroxysuccinamic acid.

Subsequently, 13.8 g (0.1 mol) of 85% phosphoric acid and 5.3 g (0.05 mol) of sodium hypophosphate hydrate were added to the reactor, and the reaction was performed at 120° C. for 6 hours. At this time, the input water and the produced water were removed through azeotropic distillation.

After completion of the reaction, toluene was distilled off under reduced pressure at 50 to 60° C., and 200 ml of acetone was added thereto, followed by stirring at 20 to 30° C. for 1 hour. After removing sodium sulfate as an insoluble solid by filtration, the filtered acetone solution was concentrated under reduced pressure to obtain an N-hydroxysuccinimide mixture.

After adding 500mL of ethyl acetate to the N-hydroxysuccinimide mixture, heating to reflux for 10 minutes, cooling to 20~30℃, adding 10g (0.1 mol) of triethylamine, and then adding 10g (0.1 mol) of triethylamine at 0~10℃ for 2 hours. The solid produced by stirring was filtered to obtain N-hydroxy succinimide.

<Example 2>

N-hydroxy succinimide was obtained in the same manner as in Example 1, except that 12.4 g (0.12 mol) of 95% sulfuric acid was used instead of 85% phosphoric acid.

<Example 3>

N-hydroxy succinimide was obtained in the same manner as in Example 1, except that 7.4 g (0.12 mol) of boric acid was used instead of sulfuric acid.

<Comparative Example 1>

N-hydroxy succinimide was obtained in the same manner as in Example 1, except that the reaction was performed without sodium hypophosphate hydrate in the same manner as in Example 1.

<Comparative Example 2>

N-hydroxy succinimide was obtained in the same manner as in Example 1, except that the reaction was performed without an organic base purification process in the same manner as in Example 1.

2. End product analysis

The yield of N-hydroxy succinimide prepared in the above Examples and Comparative Examples was calculated based on the hydroxy sulfate used. In addition, in order to analyze the purity of N-hydroxy succinimide obtained from the above Examples and Comparative Examples, 1.0 g of solid N-hydroxy succinimide was dissolved in 10.0 ml of purified water and then analyzed using acid-base titration. At this time, The obtained results are shown in Table 1 below.

Succinic acid production rate (main unreacted material) NHS Purity (%) NHS yield (%) NHS color Example 1 0 % 99.8 85 White Example 2 0 % 99.5 83 Off-White Example 3 0 % 99.7 80 White Comparative Example 1 0.5% 100.5 85 Yellow Comparative Example 2 3.5% 102.5 83 Off-White

In the case of Examples according to the present invention, comparing Example 1 using an acid catalyst and a reducing agent and Comparative Example 1 synthesized without using a reducing agent, the acid catalyst and the reducing agent improved the reaction conversion rate and purity of N-hydroxysuccinamic acid, It can be confirmed that the yield, purity and quality of N-hydroxy succinimide are improved.

In addition, when comparing Examples 1, 2, and 3 in which an organic base was added and Comparative Example 2 in which no organic base was added, Examples 1, 2, and 3 had a succinic acid production rate of 0%, whereas Comparative Example 2 had a succinic acid production rate of 3.5%. was found to be created. That is, it can be confirmed that the organic base reacts with succinic acid and N-hydroxysuccinamic acid, which are reaction by-products, to form an organic salt and effectively remove them.

Claims (9)

a) preparing N-hydroxy succinamic acid by reacting succinic anhydride with hydroxyamine in the presence of a solvent;
b) preparing N-hydroxy succinimide by reacting the N-hydroxy succinimide in the presence of an acid catalyst and a reducing agent; and
c) a purification step of purifying the N-hydroxy succinimide with an organic base; The method of claim 1, wherein the purification step of c)
i) heating the N-hydroxy succinimide mixture to reflux;
ii) cooling to 20-30 °C; and
iii) adding an organic base and stirring at 0 to 10° C. for 2 hours and filtering the resulting solid; A method for producing N-hydroxy succinimide, characterized in that it comprises a. According to claim 1,
The acid catalyst is a method for producing N-hydroxy succinimide comprising at least one selected from the group consisting of sulfuric acid, phosphoric acid, boric acid, trichloroacetic acid, trifluoroacetic acid and toluenesulfonic acid. According to claim 1,
The reducing agent is a method for producing N-hydroxy succinimide comprising at least one selected from the group consisting of formic acid, oxalic acid, diborane, hydrazine, trimethyl phosphate, triethyl phosphate, hypophosphoric acid, potassium hypophosphate, and sodium hypophosphate. . According to claim 1,
The organic base comprises at least one selected from the group consisting of trimethylamine, triethylamine, isopropylamine, tributylamine and trioctylamine. According to claim 1,
The method for producing N-hydroxy succinimide, characterized in that the acid catalyst is used in an amount of 0.1 to 1.0 mol relative to 1 mol of the hydroxyamine in step a). According to claim 1,
The method for producing N-hydroxy succinimide, characterized in that the reducing agent is used in an amount of 0.05 to 0.1 mol relative to 1 mol of the hydroxyamine in step a). According to claim 1,
A method for producing N-hydroxy succinimide, characterized in that the molar ratio of the acid catalyst and the reducing agent is 1.4: 1 to 2: 1. According to claim 1,
The method for producing N-hydroxy succinimide, characterized in that the organic base is used in an amount of 0.1 to 1.0 mol relative to 1 mol of the hydroxyamine in step a).

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