A preparation method of N-hydroxysuccinimide

Abstract

The present invention discloses a method for preparing N-hydroxysuccinimide. The method uses a weakly acidic cation exchange resin as a catalyst. By reducing the acidity of the reaction system, product decomposition can be avoided, thereby improving product yield and quality. The method also reduces the reaction temperature, lowers equipment anti-corrosion requirements, extends equipment service life, reduces energy consumption, and is more conducive to industrial implementation. Furthermore, the catalyst is recyclable and does not require the addition of a stabilizer, making it more environmentally friendly.

Description

Technical Field

[0001] The present invention relates to a method for preparing N-hydroxysuccinimide, and in particular to a method for preparing N-hydroxysuccinimide with high efficiency and convenience in reaction. Background Art

[0002] N-Hydroxysuccinimide (HOSU) is an important class of fine chemicals and chemical raw materials. Due to the active N-hydroxyl group in its structure, it can covalently bind to amino, carboxyl, and sugar groups in antigens, antibodies, enzymes, and nucleic acid molecules without affecting the activity of the molecules. Therefore, it is often used as a precursor for the preparation of peptides, antibiotics, amino acids, proteins, etc., and is used in affinity chromatography, tumor diagnosis, imaging, and treatment.

[0003]

[0004] N-Hydroxysuccinimide (HOSU)

[0005] CN110698381, CN110818607, CN111056984 and KR2023027520 all disclose methods for preparing N-hydroxysuccinimide. Different types of acid catalysts, such as sulfuric acid, phosphoric acid, etc., are used in each method, and stabilizers such as phosphorous acid need to be added to avoid oxidative side reactions caused by high-temperature reactions. At the same time, the temperature of the dehydration reaction is mostly above 100°C. Since the product is prone to decomposition, polymerization and other complex side reactions under excessive acid and high temperature conditions, the product yield and purity are greatly reduced. In addition, the acidic and high-temperature reaction environment aggravates equipment corrosion and reduces the durability of production equipment.

[0006]

[0007] CN103664732 discloses a method for acylation and cyclization of succinic anhydride with aniline using a strongly acidic cation exchange resin. However, actual studies have found that the strong acidity of the strongly acidic cation exchange resin still causes product decomposition. Therefore, there is currently no industrial method for preparing N-hydroxysuccinimide that can effectively avoid side reactions and improve product yield and quality. Summary of the Invention

[0008] Purpose of the invention: The present invention aims to provide a method for preparing N-hydroxysuccinimide which improves reaction yield and product quality and is conducive to industrialization.

[0009] Technical solution: The method for preparing N-hydroxysuccinimide of the present invention is characterized in that 4-(hydroxyamino)-4-oxobutyric acid is dehydrated by a weakly acidic cation exchange resin to generate N-hydroxysuccinimide:

[0010]

[0011] The present invention adopts a weakly acidic catalyst to enable the dehydration ring-closure reaction to proceed efficiently.

[0012] Preferably, the weakly acidic cation exchange resin is selected from carboxyl-type weakly acidic cation exchange resin and phosphonic acid-type weakly acidic cation exchange resin.

[0013] Preferably, the reaction temperature of the dehydration reaction is 50-70°C.

[0014] Preferably, the reaction pressure of the dehydration reaction is ≤0.98 MPa.

[0015] Preferably, the reaction time of the dehydration reaction is 2 to 6 hours.

[0016] Preferably, after the dehydration reaction is completed, isopropanol is added to the reaction system for extraction and heat preservation to remove insoluble matter, and n-heptane is added to the extract for low-temperature crystallization, and the crystals are separated and dried to obtain N-hydroxysuccinimide.

[0017] More preferably, the mass ratio of isopropyl alcohol to n-heptane is 1:2.

[0018] More preferably, the extraction temperature of the isopropyl alcohol heat preservation extraction is 60-70°C.

[0019] More preferably, the crystallization temperature of the extract is 0-10°C.

[0020] Preferably, N-hydroxysuccinimide is obtained by reacting hydroxylamine with succinic anhydride:

[0021]

[0022] More preferably, the mass ratio of the weakly acidic cation exchange resin to succinic anhydride is (0.01-0.5):1.

[0023] More preferably, the mass ratio of the weakly acidic cation exchange resin to succinic anhydride is 0.1:1.

[0024] More preferably, after the reaction of hydroxylamine and succinic anhydride is completed, no post-treatment is required and the next reaction is directly carried out.

[0025] More preferably, the mass ratio of isopropyl alcohol to succinic anhydride added to the reaction system is 2:1.

[0026] More preferably, the mass ratio of n-heptane to succinic anhydride added to the extract is 4:1.

[0027] More preferably, hydroxylamine is obtained by dissociating hydroxylamine sulfate with sodium hydroxide:

[0028]

[0029] More preferably, the mass ratio of succinic anhydride to hydroxylamine sulfate is (1.1-1.2):1.

[0030] More preferably, the mass ratio of hydroxylamine sulfate to sodium hydroxide is 1:(0.45-0.55).

[0031] More preferably, the reaction solvent of the dissociation reaction is water, and the reaction temperature is 25-35°C.

[0032] More preferably, after the dissociation reaction of hydroxylamine sulfate with sodium hydroxide is completed, no post-treatment is required and the next reaction is directly carried out.

[0033] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0034] The present invention uses a weakly acidic cation exchange resin as a catalyst, which reduces the acidity of the reaction system, thereby preventing product decomposition and improving product yield and quality. This also lowers the reaction temperature, reduces corrosion requirements for equipment, extends equipment life, and reduces energy consumption, making it more conducive to industrial production. Furthermore, the catalyst is recyclable and does not require the addition of stabilizers, making it more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the H NMR spectrum of the target product in Example 1;

[0036] Figure 2 This is the H NMR spectrum of the target product in Comparative Example 1. DETAILED DESCRIPTION

[0037] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0038] Example 1

[0039] (1) Hydroxylamine sulfate is freed under the action of sodium hydroxide to obtain hydroxylamine

[0040]

[0041] Add 250 kg of hydroxylamine sulfate and 100 kg of water into a reactor at 25-35 ° C. In another reactor, add 1000 kg of water and 125 kg of sodium hydroxide in sequence. Then, slowly add the reserved feed liquid dropwise to the reactor. No post-treatment is required after the dropwise addition. Proceed to the next step with a yield of 100%.

[0042] (2) Hydroxylamine reacts with succinic anhydride to form 4-(hydroxyamino)-4-oxobutanoic acid

[0043]

[0044] 290 kg of succinic anhydride was added to the reactor in batches at room temperature, and the reaction temperature was maintained below 40°C. After the addition, the temperature was raised to 60°C and kept for 1 hour. The obtained reaction solution did not require post-treatment and was carried out to the next step with a yield of 100%.

[0045] (3) 4-(Hydroxyamino)-4-oxobutyric acid is dehydrated in a vacuum at 50-70°C under the catalysis of weakly acidic cationic resin to generate N-hydroxysuccinimide

[0046]

[0047] Add 29 kg of weakly acidic cationic resin (carboxylic acid type, model D113) to the reactor and distill water under reduced pressure at 50-70°C with stirring until no fraction is distilled off. Add 580 kg of isopropyl alcohol and stir at 60-70°C for 1 hour to extract the product. Filter while hot to remove solid insolubles. Add 1160 kg of heptane to the filtrate, stir, cool to 0-10°C for crystallization, filter, and dry in a vacuum oven at 50°C to obtain 326.8 kg of the product as a white solid with a yield of 98.0%, a content of 99.8%, and a melting point of 96.7°C.

[0048] Example 2

[0049] (1) Hydroxylamine sulfate is freed under the action of sodium hydroxide to obtain hydroxylamine

[0050]

[0051] Add 250 kg of hydroxylamine sulfate and 100 kg of water into a reactor at 25-35 ° C. In another reactor, add 1000 kg of water and 125 kg of sodium hydroxide in sequence. Then, slowly add the reserved feed liquid dropwise to the reactor. No post-treatment is required after the dropwise addition. Proceed to the next step with a yield of 100%.

[0052] (2) Hydroxylamine reacts with succinic anhydride to form 4-(hydroxyamino)-4-oxobutanoic acid

[0053]

[0054] 290 kg of succinic anhydride was added to the reactor in batches at room temperature, and the reaction temperature was maintained below 40°C. After the addition, the temperature was raised to 60°C and kept for 1 hour. The obtained reaction solution did not require post-treatment and was carried out to the next step with a yield of 100%.

[0055] (3) 4-(Hydroxyamino)-4-oxobutyric acid is dehydrated in a vacuum at 50-70°C under the catalysis of weakly acidic cationic resin to generate N-hydroxysuccinimide

[0056]

[0057] Add 29 kg of weakly acidic cationic resin (phosphonic acid type, model DLT-1) to the reactor and distill water under reduced pressure at 50-70°C with stirring until no fraction is distilled out. Add 580 kg of isopropyl alcohol and stir at 60-70°C for 1 hour to extract the product. Filter while hot to remove solid insolubles. Add 1160 kg of heptane to the filtrate, stir, cool to 0-10°C for crystallization, filter, and dry in a vacuum oven at 50°C to obtain 326.1 kg of the product as a white solid with a yield of 97.8%, a content of 99.8%, and a melting point of 96.6°C.

[0058] Comparative Example 1: Strong acid resin as catalyst

[0059] (1) Hydroxylamine sulfate is freed under the action of sodium hydroxide to obtain hydroxylamine

[0060]

[0061] 125 g of hydroxylamine sulfate and 50 g of water were added to a reactor at 25-35 ° C. 500 g of water and 62.5 g of sodium hydroxide were added to another reactor in sequence. The reserved feed liquid was then slowly added dropwise to the reactor. No post-treatment was required after the addition was completed. The next step was carried out with a yield of 100%.

[0062] (2) Hydroxylamine and succinic anhydride react to form 4-(hydroxyamino)-4-oxobutanoic acid

[0063]

[0064] 145 g of succinic anhydride was added to the reactor in batches at room temperature, and the reaction temperature was maintained below 40°C. After the addition, the temperature was raised to 60°C and kept for 1 hour. The obtained reaction solution did not require post-treatment and was carried out to the next step with a yield of 100%.

[0065] (3) 4-(Hydroxyamino)-4-oxobutyric acid is dehydrated in a vacuum at 50-70°C under the catalysis of a strong acidic cationic resin to generate N-hydroxysuccinimide

[0066]

[0067] 14.5 g of strongly acidic cationic resin (sulfonic acid type, model 732) was added to a reaction kettle. Water was evaporated under reduced pressure at 50-70°C with stirring until no fraction was distilled off. 290 g of isopropyl alcohol was added and the product was extracted by stirring at 60-70°C for 1 hour. The solid insoluble matter was filtered while hot. 580 g of heptane was added to the filtrate, and the temperature was cooled by stirring at 0-10°C to crystallize. The mixture was filtered and dried under vacuum at 50°C to obtain 153.5 g of the product as a white solid with a yield of 92.0%, a content of 98.8%, and a melting point of 94.9°C.

[0068] Depend on Figures 1 and 2Comparison of the H NMR spectrum and the melting point of the target product shows that the impurity quantity and impurity content of the product prepared in Example 1 are significantly less than those of the product prepared in Comparative Example 1. Therefore, the weakly acidic catalyst selected in the present invention can effectively avoid side reactions and significantly improve the yield and purity of the product.

Claims

1. A N -The preparation method of hydroxysuccinimide is characterized in that, It is produced by dehydration of 4-(hydroxyamino)-4-oxobutanoic acid catalyzed by weakly acidic cation exchange resin. N -Hydroxysuccinimide: ； The weakly acidic cation exchange resin is selected from carboxyl-type weakly acidic cation exchange resin and phosphonic acid-type weakly acidic cation exchange resin.

2. The preparation method according to claim 1, characterized in that The reaction temperature of the dehydration reaction is 50~70℃.

3. The preparation method according to claim 1, characterized in that The reaction pressure of the dehydration reaction is ≤0.98Mpa.

4. The preparation method according to claim 1, characterized in that 4-(Hydroxyamino)-4-oxobutanoic acid is obtained by the reaction of hydroxylamine and succinic anhydride: 。 5. The preparation method according to claim 4, characterized in that The mass ratio of the weakly acidic cation exchange resin to succinic anhydride is (0.01-0.5):

1.

6. The preparation method according to claim 5, characterized in that The mass ratio of the weakly acidic cation exchange resin to succinic anhydride is 0.1:

1.

7. The preparation method according to claim 4, characterized in that Hydroxylamine is obtained by dissociation of hydroxylamine sulfate with sodium hydroxide: 。 8. The preparation method according to claim 7, characterized in that The mass ratio of succinic anhydride to hydroxylamine sulfate is (1.1~1.2):

1.

9. The preparation method according to claim 7, characterized in that The mass ratio of hydroxylamine sulfate to sodium hydroxide is 1:(0.45~0.55).

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