Detection method of maleic acid in pharmaceutical grade fumaric acid

Abstract

The invention discloses a detection method for maleic acid in pharmaceutical grade fumaric acid, belongs to the technical field of drug analysis and detection, and adopts high performance liquid chromatography to analyze maleic acid in fumaric acid, and the chromatographic column used contains a cation exchange material, and the cation exchange material adopts a copolymerization reaction of a matching material I and a matching material II; the matching material I is a polymer having a DL-2-amino-4-pentenoic acid group; the matching material II is a hydroxyl-containing polymer, a block copolymer or a hydroxy compound. The present invention can realize the separation and detection of maleic acid in fumaric acid, helps to improve the separation effect of maleic acid in fumaric acid, has high accuracy, good reproducibility, and low cost and simple process.

Description

Technical Field

[0001] The invention belongs to the technical field of drug analysis and detection, and particularly relates to a method for detecting maleic acid in pharmaceutical-grade fumaric acid. Background Art

[0002] Fumaric acid, also known as fumaric acid, fumaric acid, and trans-1,2-dicarboxyethylene, is an important organic basic chemical raw material and fine chemical product. Fumaric acid is included in the Chinese Pharmacopoeia as a pharmaceutical excipient, mainly used in pH regulators and effervescent agents.

[0003] Maleic acid, also known as maleic acid, is the cis-trans isomer of fumaric acid. It is mainly introduced in the production process, and its content directly reflects the production technology control level and product quality. Therefore, establishing a method for detecting maleic acid content in pharmaceutical-grade fumaric acid has a positive significance for controlling the quality of fumaric acid products.

[0004] The 2010 edition of the Chinese Pharmacopoeia uses a sulfonic acid cation exchange resin column to detect maleic acid as an impurity in fumaric acid. However, the use and storage methods of this chromatographic column are relatively complicated, and the measurement cost is high. Therefore, it is necessary to develop an exchange material with low cost, simple process and excellent separation effect to achieve the separation and detection of maleic acid in fumaric acid. Summary of the invention

[0005] The purpose of the present invention is to provide a method for detecting maleic acid in pharmaceutical-grade fumaric acid, which can realize the separation and detection of maleic acid in fumaric acid, help to improve the separation effect of maleic acid in fumaric acid, have high accuracy, good reproducibility, low cost and simple process.

[0006] The technical solution adopted by the present invention to achieve the above-mentioned purpose is:

[0007] Detection method of maleic acid in pharmaceutical grade fumaric acid,

[0008] The maleic acid in fumaric acid was analyzed by high performance liquid chromatography, the mobile phase was phosphoric acid solution and acetonitrile, the volume ratio of phosphoric acid solution to acetonitrile was 70-90:30-10; the pH of phosphoric acid solution was 2.5-4.0;

[0009] The chromatographic column used contains a cation exchange material, which is obtained by copolymerization of coordination material I and coordination material II;

[0010] The compounding material I is a polymer having DL-2-amino-4-pentenoic acid groups;

[0011] The compounding material II is a hydroxyl-containing polymer, block copolymer or other hydroxyl compound.

[0012] Furthermore, the complex material I is obtained by reacting DL-2-amino-4-pentenoic acid and a silane coupling agent.

[0013] The cation exchange material prepared by using the coordination material I and the coordination material II can be used to separate maleic acid from fumaric acid and realize the detection of maleic acid.

[0014] Furthermore, the compounding material II includes at least one of polyvinyl alcohol, a block copolymer containing hydroxyethyl acrylate, 3,4-dihydroxyphenylpropionic acid, catechol, tyrosine and the like.

[0015] Preferably, the compounding material II comprises a block copolymer containing hydroxyethyl acrylate and 3,4-dihydroxyphenylpropionic acid, and the mass ratio of the block copolymer of hydroxyethyl acrylate to 3,4-dihydroxyphenylpropionic acid is 1:0.5-2.

[0016] Preferably, the compounding material II comprises a block copolymer containing hydroxyethyl acrylate and tyrosine, and the mass ratio of the block copolymer of hydroxyethyl acrylate to tyrosine is 1:0.5-2.

[0017] A block copolymer containing hydroxyethyl acrylate and tyrosine are used as the coordination material II to carry out copolymerization reaction with the coordination material I, and the obtained cation exchange material can greatly improve the separation effect of maleic acid from fumaric acid.

[0018] A block copolymer containing hydroxyethyl acrylate and tyrosine are used as the coordination material II to react with the coordination material I. The resulting cation exchange material contains a large number of hydroxyl groups and amino groups, forming a large number of branches and cross-linked structures. The presence of these branches and cross-linked structures increases the differential binding ability of the cation exchange material for fumaric acid and maleic acid, thereby improving the separation effect of fumaric acid and maleic acid when the chromatographic column prepared using the cation exchange material is used for high-performance liquid chromatography analysis and detection of fumaric acid samples. In addition, after the carboxylic acid group and silane group in the coordination material I react with the hydroxyl group in the coordination material II, the carboxyl group copolymer chain grows, and the large number of hydroxyl groups in the coordination material II can strengthen the OH through hydrogen bonds. - The combination of silane group and complex material II reduces Si-OC bonds. The continuous arrangement of fixed groups on the carbon chain in the obtained copolymer is beneficial to the transfer of cations, the ion permeability is improved, and it also helps to improve the separation effect of fumaric acid and maleic acid.

[0019] According to one aspect of the present invention, the preparation method of the compound material I comprises the following steps:

[0020] S1-1. Add toluene to DL-2-amino-4-pentenoic acid, heat to 55-80°C, then add initiator, and stir at 55-80°C at 120-200 r / min for 4-8 hours.

[0021] S1-2. Add silane coupling agent and initiator to the mixture obtained in S1-1, continue stirring at 55-80°C and 120-200 r / min for 4-8 hours; then purify by rotary evaporation at 70-85°C for 1-2 hours to obtain complex material I.

[0022] Preferably, in step S1-1 and step S1-2, the initiator is azobisisobutyronitrile (AIBN).

[0023] Preferably, in step S1-1, the usage ratio of DL-2-amino-4-pentenoic acid to toluene is 0.1 mol:300-500 mL, and the molar ratio of DL-2-amino-4-pentenoic acid to initiator is 50:0.1-0.5.

[0024] Preferably, in step S1-2, the silane coupling agent is at least one of 3-(methacryloyloxy)propyltrimethoxysilane, diethylaminomethyltriethoxysilane, and 3-(2,3-epoxypropyloxy)propyltriethoxysilane.

[0025] Preferably, in step S1-2, the molar ratio of DL-2-amino-4-pentenoic acid to the silane coupling agent is 1:0.5-3, and the molar ratio of the silane coupling agent to the initiator is 50:0.1-0.5.

[0026] According to one aspect of the present invention, a method for preparing a block copolymer containing hydroxyethyl acrylate comprises the following steps:

[0027] S2-1. Add the initiator, nitrogen-containing ligand, deactivator and glycidyl acrylate (GA) into dimethyl sulfoxide (DMSO) and mix them evenly by ultrasonic treatment for 15-30 min to obtain mixed solution I.

[0028] S2-2. Under nitrogen atmosphere, add a magnet wrapped with clean copper wire to the mixed solution I obtained in S2-1, stir at 20-30°C and 120-200 r / min for 16-36 hours to obtain poly(GA).

[0029] S2-3. Under nitrogen atmosphere, add hydroxyethyl acrylate (HEA) and DMSO to the poly(GA) obtained in S2-2; seal the mixture and stir at 20-30°C and 120-200 r / min for 16-36 h.

[0030] After the reaction, the obtained polymer solution was exposed to the air, diluted with water according to a volume ratio of 1:1-5, and then dialyzed with deionized water for 16-36 hours using a 1000Da dialysis bag, with the water changed every 4-6 hours on average, and then freeze-dried to obtain a block copolymer poly(GA)- b -(HEA).

[0031] Preferably, in step S2-1, the initiator is ethyl 2-bromoisobutyrate (EBiB) or 2-bromoisobutyryl bromide; the nitrogen-containing ligand is a tertiary amine compound, and further, the nitrogen-containing ligand is at least one of tris(2-(dimethylamino)ethyl)amine, tris(N,N-dimethylaminopropyl)amine, and N,N-dimethylethylamine; and the deactivator is CuBr2.

[0032] Preferably, in step S2-1, the mass volume ratio of GA to DMSO is 1-2 g:5-10 mL; the molar ratio of GA to nitrogen-containing ligand is 1000:3-10; the molar ratio of GA to initiator is 30:1-3; and the molar ratio of initiator to deactivator is 10:0.5-3.

[0033] Preferably, in step S2-1, GA can be replaced by glycidyl methacrylate.

[0034] Preferably, in step S2-3, the volume ratio of HEA to DMSO is 1:1-2; the molar ratio of HEA to GA in step S2-1 is 1:0.5-2.

[0035] A block copolymer containing hydroxyethyl acrylate and tyrosine is used as the compounding material II to carry out copolymerization with the compounding material I, especially poly(GA) -b- When a mixture of (HEA) and tyrosine is used as complex material II, the resulting cation exchange material can significantly improve the separation effect of maleic acid from fumaric acid.

[0036] Using poly(GA) -b- When a mixture of (HEA) and tyrosine is used as complex material II, the resulting cation exchange material can significantly improve the separation effect of maleic acid from fumaric acid.

[0037] After the carboxylic acid group and silane group in the complex material I react with the hydroxyl group in the complex material II, the carboxyl group copolymer chain grows, and the large amount of hydroxyl group in the complex material II can strengthen the OH group through hydrogen bonding. - The combination of silane group and complex material II reduces Si-OC bonds. The continuous arrangement of fixed groups on the carbon chain in the obtained copolymer is beneficial to the transfer of cations, the ion permeability is improved, and it also helps to improve the separation effect of fumaric acid and maleic acid.

[0038] Furthermore, the cation exchange material also includes a coordination material III, and the coordination material III is a polyhydroxy polymer.

[0039] Preferably, the compound material III is prepared by reacting 1,3-diamino-2-propanol (HD) with a glycidyl ester compound.

[0040] Preferably, when preparing the cation exchange material, the complexing material III and the complexing material II are added simultaneously.

[0041] Preferably, when preparing the cation exchange material, the mass ratio of the complexing material II to the complexing material III is 1:0.5-2.

[0042] Preferably, when preparing the cation exchange material, the block copolymer containing hydroxyethyl acrylate, tyrosine and the complex material III are used simultaneously, and the mass ratio of the block copolymer containing hydroxyethyl acrylate and tyrosine to the complex material III is 0.5:0.5:0.5-2.

[0043] In the process of preparing the cation exchange material, when the coordination material II and the coordination material I are copolymerized, the coordination material III prepared by the reaction of HD and glycidyl ester compounds is added, and the resulting cation exchange material can greatly improve the separation effect of maleic acid from fumaric acid. This may be because the coordination material III prepared by the reaction of HD and diglycidyl adipic acid contains not only a large number of hydroxyl groups, but also a large number of amine groups. After the coordination material III, the coordination material II and the coordination material I react, the branching and cross-linking structure of the resulting cation exchange material is further changed, and the difference in the binding ability of fumaric acid and maleic acid is further increased, thereby improving the separation effect of fumaric acid and maleic acid. In addition, after the addition of coordination material III, the hydroxyl groups and the like in it react with the carboxylic acid groups and silane groups in the coordination material I, the permeability of the resulting cation exchange material is further changed, which helps to improve the separation effect of fumaric acid and maleic acid.

[0044] According to one aspect of the present invention, the preparation method of the compound material III comprises the following steps:

[0045] S3-1. Under nitrogen atmosphere, dissolve HD in DMSO, then add glycidyl ester compounds; seal and react at 65-85°C for 2-6h.

[0046] S3-2. Add HD dissolved in DMSO to the reaction system of step S3-1 and continue the reaction for 0.5-2h. After the reaction is completed, cool to 20-30°C, and then use a 1000Da dialysis bag to dialyze with deionized water for 16-36h, changing the water every 4-6h on average, and then freeze-dry to obtain complex material III.

[0047] Preferably, in step S3-1, the mass volume ratio of HD to DMSO is 200-500 mg:5 mL; the molar ratio of HD to diglycidyl adipate is 2-5:1-3.

[0048] Preferably, in step S3-1, the glycidyl ester compound is at least one of triglycidyl isocyanurate, diglycidyl adipate, glycidyl methacrylate, and the like.

[0049] Preferably, in step S3-2, the mass volume ratio of HD to DMSO is 1-2 g:0.5-2 mL.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] 1. The cation exchange material prepared by using the coordination material I and the coordination material II can be used to separate maleic acid from fumaric acid and detect maleic acid; the chromatographic column prepared by using the above cation exchange material and the high performance liquid chromatography method for separating fumaric acid and maleic acid has good separation degree and can be used for the determination of maleic acid content in pharmaceutical grade fumaric acid.

[0052] 2. Use block copolymers containing hydroxyethyl acrylate and tyrosine as the co-material II to carry out copolymerization with the co-material I, especially using poly(GA) -b- When a mixture of (HEA) and tyrosine is used as the complex material II, the resulting cation exchange material can greatly improve the separation effect of maleic acid from fumaric acid. This may be because the block copolymer of hydroxyethyl acrylate reacts with the hydroxyl groups in tyrosine and the carboxylic acid groups and silane groups in the complex material I, so that the resulting cation exchange material forms more branches and cross-linked structures. The presence of these branches and cross-linked structures increases the differential binding ability of the cation exchange material for fumaric acid and maleic acid, thereby improving the separation effect of fumaric acid and maleic acid when the chromatographic column prepared using the cation exchange material is subjected to high performance liquid chromatography analysis and detection of fumaric acid samples. It may also be because after the carboxylic acid groups and silane groups in the complex material I react with the hydroxyl groups in the complex material II, the carboxyl group copolymer chain grows, and the large number of hydroxyl groups in the complex material II can strengthen the OH through hydrogen bonds. - The combination of silane group and complex material II reduces Si-OC bonds. The continuous arrangement of fixed groups on the carbon chain in the obtained copolymer is beneficial to the transfer of cations, the ion permeability is improved, and it also helps to improve the separation effect of fumaric acid and maleic acid.

[0053] 3. When preparing cation exchange materials, adding complex material III prepared by reacting HD with diglycidyl adipic acid during the copolymerization reaction of complex material II and complex material I can further improve the separation effect of maleic acid from fumaric acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 In the test example of the present invention, the reference substance mixed solution is detected by the chromatographic column obtained in Example 1 to obtain the obtained spectrum. DETAILED DESCRIPTION

[0055] The technical solution of the present invention is further described in detail below in conjunction with specific implementation methods and drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0056] Example 1

[0057] Preparation of a cation exchange material

[0058] S1-1. Add toluene to DL-2-amino-4-pentenoic acid at a ratio of 0.1 mol:400 mL, heat to 70°C, then add azobisisobutyronitrile (AIBN) as an initiator, the molar ratio of DL-2-amino-4-pentenoic acid to AIBN is 50:0.225. Stir the mixture at 70°C at a speed of 150 r / min for 6 hours.

[0059] S1-2. Add 3-(methacryloyloxy)propyltrimethoxysilane and AIBN to the mixture obtained in S1-1, the molar ratio of DL-2-amino-4-pentenoic acid to 3-(methacryloyloxy)propyltrimethoxysilane is 1:1, and the molar ratio of 3-(methacryloyloxy)propyltrimethoxysilane to AIBN is 50:0.225; continue stirring at 70°C at a speed of 150 r / min for 6 hours; then, purify by rotary evaporation at 70°C for 2 hours to obtain complex material I.

[0060] S1-3. Add the compounding material II to the compounding material I obtained in S1-2. In this example, the compounding material II is a mixture of a block copolymer containing hydroxyethyl acrylate and tyrosine. The mass ratio of the compounding material I to the block copolymer containing hydroxyethyl acrylate and tyrosine is 1:0.5:0.5; wherein the block copolymer containing hydroxyethyl acrylate is prepared as a solution with a mass fraction of 5% when added, and the tyrosine is prepared as a solution with a mass fraction of 5% when added; then, stir at 60°C at a speed of 150r / min for 24h, and then purify by rotary evaporation at 70°C for 1.5h to obtain a cation exchange material. The above-obtained cation exchange material is washed with methanol 3 times and then vacuum dried at 50°C for 6h.

[0061] Wherein, the preparation method of the block copolymer containing hydroxyethyl acrylate is as follows:

[0062] S2-1. Add initiator EBiB, nitrogen-containing ligand tris(N,N-dimethylaminopropyl)amine, deactivator CuBr2, and glycidyl acrylate (GA) into dimethyl sulfoxide (DMSO) and mix evenly by ultrasonication for 20 min to obtain mixed solution I.

[0063] Among them, the mass volume ratio of GA to DMSO is 1.5 g:5 mL; the molar ratio of GA to tri(N,N-dimethylaminopropyl)amine is 1000:6; the molar ratio of GA to EBiB is 30:1; and the molar ratio of EBiB to CuBr2 is 10:1.

[0064] S2-2. Under nitrogen atmosphere, a magnet wrapped with clean copper wire was added to the mixed solution I obtained in S2-1, and the mixture was stirred at 25°C and 150 r / min for 24 h to obtain poly(GA).

[0065] S2-3. In a nitrogen atmosphere, hydroxyethyl acrylate (HEA) and DMSO were added to the poly (GA) obtained in S2-2; the mixture was sealed and stirred at 25°C for 24 hours at a speed of 150 r / min. The volume ratio of HEA to DMSO was 1:1; the molar ratio of HEA to GA in S1 was 1:1.

[0066] After the reaction, the obtained polymer solution was exposed to the air, diluted with water at a volume ratio of 1:1, and then dialyzed with deionized water for 24 hours using a 1000Da dialysis bag, with the water changed every 6 hours on average, and then freeze-dried to obtain a block copolymer containing hydroxyethyl acrylate, poly(GA)- b -(HEA).

[0067] Column preparation

[0068] The treated cation exchange material was put into a homogenization tank, and loaded into a stainless steel separation column with an inner diameter of 4.6 mm and a column length of 150 mm under high pressure to obtain a chromatographic column.

[0069] Example 2

[0070] The present embodiment is different from the embodiment 1 in that: in the preparation process of the cation exchange material, the material I in step S1-3 is combined with the block copolymer poly(GA)- b The mass ratio of -(HEA) to tyrosine is 1:0.75:0.75. The other steps and conditions are the same.

[0071] Example 3

[0072] The present embodiment is different from the embodiment 1 in that: in the preparation process of the cation exchange material, the material I in step S3 is combined with the block copolymer poly(GA) containing hydroxyethyl acrylate. -b- The mass ratio of (HEA) and tyrosine was 1:1:1. The other steps and conditions were the same.

[0073] Example 4

[0074] The present embodiment is different from the embodiment 1 in that: in the preparation process of the cation exchange material, in step S3, the block copolymer poly(GA) containing hydroxyethyl acrylate is added. -b- (HEA) and tyrosine are added simultaneously to the compounding material III, the block copolymer poly(GA) containing hydroxyethyl acrylate is used -b- The mass ratio of (HEA) and tyrosine to the complex material III is 0.5:0.5:0.5. The other steps and conditions are the same.

[0075] Wherein, the compounding material III is a polyhydroxy polymer, and its preparation method is as follows:

[0076] S3-1. Under nitrogen atmosphere, 1,3-diamino-2-propanol (HD) was dissolved in DMSO, and then diglycidyl adipate was added; the reaction was carried out at 80°C and sealed for 4 hours.

[0077] The mass volume ratio of HD to DMSO is 360 mg:5 mL; the molar ratio of HD to diglycidyl adipate is 2:1.

[0078] S3-2. Add HD dissolved in DMSO to the reaction system of step S3-1, wherein the mass volume ratio of HD to DMSO is 2g:1mL; continue the reaction for 1h. After the reaction is completed, cool to 25°C, and then use a 1000Da dialysis bag to dialyze with deionized water for 24h, changing the water every 6h on average, and then freeze-dry to obtain complex material III.

[0079] Example 5

[0080] The present embodiment is different from the embodiment 4 in that: in the preparation process of the cation exchange material, in step S3, the block copolymer poly(GA) containing hydroxyethyl acrylate is added. -b- Compounding material III, block copolymer poly(GA) containing hydroxyethyl acrylate, with simultaneous addition of (HEA) and tyrosine -b- The mass ratio of (HEA) and tyrosine to the complex material III is 0.5:0.5:1. The other steps and conditions are the same.

[0081] Comparative Example 1

[0082] The difference between this comparative example and Example 1 is that in the preparation process of the cation exchange material, in step S3, the tyrosine used is replaced by poly(GA) of equal mass. -b- (HEA). Other steps and conditions were the same.

[0083] Comparative Example 2

[0084] The difference between this comparative example and Example 1 is that in the preparation process of the cation exchange material, in step S3, the poly(GA) -b- (HEA) was replaced with an equal amount of tyrosine. Other steps and conditions were the same.

[0085] Comparative Example 3

[0086] The difference between this comparative example and Example 1 is that in the preparation process of the cation exchange material, in step S3, the poly(GA) -b- (HEA) and tyrosine were replaced by an equal amount of polyvinyl alcohol. Other steps and conditions were the same.

[0087] Test example

[0088] Detection of Maleic Acid in Pharmaceutical Grade Fumaric Acid

[0089] Instrument: High performance liquid chromatograph, Shimadzu LC-2030plus UV detector

[0090] Reagent: Fumaric acid reference substance (source: Aladdin, batch number D2122250, content 99.975%)

[0091] Maleic acid reference substance (source: Aladdin, batch number K2130456, content 99.056%)

[0092] Phosphoric acid (analytical grade, Sinopharm Chemical Reagent Co., Ltd.)

[0093] Acetonitrile (chromatographic grade, Honeywell)

[0094] Deionized water (self-made from a pure water machine)

[0095] Chromatographic conditions

[0096] Mobile phase: phosphoric acid solution and acetonitrile (V:V=85:15), where the pH of the phosphoric acid solution is 3.0

[0097] Chromatographic column: Chromatographic column prepared in Examples 1-5 and Comparative Examples 1-3

[0098] Flow rate: 1.0 mL / min

[0099] Column temperature: 30 °C

[0100] Detection wavelength: 210 nm

[0101] Injection volume: 20 μL

[0102] Analysis time: 20 min

[0103] Solution preparation

[0104] Reference solution: Weigh the fumaric acid reference substance and the maleic acid reference substance separately, add the mobile phase to dissolve and quantitatively dilute to make a mixed solution containing 1 μg of each in each mL as the reference solution.

[0105] Chromatographic analysis

[0106] Take 10 mL of the above-mentioned fumaric acid reference solution and maleic acid reference solution respectively, mix them evenly, inject them into the machine, and perform high performance liquid chromatography detection and analysis. During the detection process, the chromatographic columns prepared in Examples 1-5 and Comparative Examples 1-3 are used respectively.

[0107] The above-mentioned reference substance mixed solution was detected by the chromatographic column obtained in Example 1 to obtain the spectrum. Figure 1 , it can be seen that the separation degree of fumaric acid and maleic acid is good, and the above chromatographic conditions can meet the detection requirements. Under the above chromatographic conditions, the chromatographic columns obtained by using Examples 2-5 and Comparative Examples 1-3 have good separation degree for fumaric acid and maleic acid, and Example 1 is better than Comparative Example 1, better than Comparative Example 2, and better than Comparative Example 3; the separation effect of Examples 2-5 is better than that of Example 1. It can be seen that the cation exchange material prepared by using the coordination material I and the coordination material II can be used to separate maleic acid from fumaric acid and realize the detection of maleic acid. The block copolymer containing hydroxyethyl acrylate and tyrosine are used as coordination material II to carry out copolymerization reaction with coordination material I, especially using poly(GA) -b- When a mixture of (HEA) and tyrosine is used as complex material II, the resulting cation exchange material can significantly improve the separation effect of maleic acid from fumaric acid.

[0108] Spike recovery test

[0109] The chromatographic columns obtained in Examples 1-6 and Comparative Examples 1-2 were used to perform base spike recovery tests of maleic acid at three gradient levels of low, medium and high. Six parallel tests were performed at each concentration level, and the recovery rate and relative standard deviation (RSD) were calculated. The results are shown in Table 1.

[0110] Table 1 Recovery rate and relative standard deviation of maleic acid spike recovery test

[0111]

[0112] Referring to the data in Table 1, the recovery rates of the technical solutions for detecting fumaric acid samples using the chromatographic columns prepared in Examples 1-5 and Comparative Examples 1-3 are all above 75%, which shows that the cation exchange material prepared by using the coordination material I and the coordination material II can be used to separate maleic acid from fumaric acid with high accuracy and good reproducibility. In other words, the cation exchange material prepared by using the coordination material I and the coordination material II can be used to separate maleic acid from fumaric acid, thereby facilitating the detection of maleic acid.

[0113] Compared with Comparative Example 3, the recovery rates of samples treated according to the technical solutions of Examples 1-5 and Comparative Examples 1-2 were improved. When the spiked amount was 10 μg / mL, the recovery rates of Examples 1-3 were increased by 15.8%, 18.8%, and 20.7% respectively compared with Comparative Example 3; the recovery rates of Examples 4-5 were increased by 22.7% and 23.6% respectively compared with Comparative Example 3; the recovery rates of Comparative Examples 1-2 were increased by 12.9% and 9.2% respectively compared with Comparative Example 3; when the spiked amount was 50 μg / mL, the recovery rates of Examples 1-3 were increased by 1 1.5%, 13.4%, 16.8%; the recoveries of Examples 4-5 were increased by 19.6% and 21.0% respectively relative to Comparative Example 3; the recoveries of Comparative Examples 1-2 were increased by 7.7% and 5.7% respectively relative to Comparative Example 3; when the spiked amount was 100 μg / mL, the recoveries of Examples 1-3 were increased by 11.5%, 13.2%, 16.5% respectively relative to Comparative Example 3; the recoveries of Examples 4-5 were increased by 19.9% ​​and 21.1% respectively relative to Comparative Example 3; the recoveries of Comparative Examples 1-2 were increased by 8.4% and 6.5% respectively relative to Comparative Example 3.

[0114] It can be seen that in the process of preparing cation exchange materials, poly(GA) -b- The mixture of (HEA) and tyrosine was used as the coordination material II to copolymerize with the coordination material I, and the obtained cation exchange material was used to separate maleic acid from fumaric acid. The accuracy and reproducibility of this technical solution were better than those of the cation exchange material obtained by copolymerizing polyvinyl alcohol as the coordination material II with the coordination material I. Moreover, within a certain range, as the poly(GA) -b- The more the amount of (HEA) and tyrosine is used, the better the recovery rate of the resulting cation exchange material for the separation scheme of maleic acid.

[0115] In the process of preparing cation exchange materials, poly(GA) -b-The mixture of (HEA) and tyrosine was used as the coordination material II to copolymerize with the coordination material I. The obtained cation exchange material was used to separate maleic acid from fumaric acid. The accuracy and reproducibility of this technical solution were better than those of using poly(GA) alone. -b- The cation exchange material obtained by using a mixture of (HEA) as complex material II and tyrosine alone as complex material II.

[0116] In the process of preparing the cation exchange material, during the copolymerization reaction of the complex material II and the complex material I, the complex material III prepared by reacting HD and diglycidyl adipic acid is added. The obtained cation exchange material is used for separating maleic acid from fumaric acid. The accuracy and reproducibility of this technical solution are better than those of the cation exchange material obtained without using the complex material III.

[0117] The conventional operations in the operating steps of the present invention are well known to those skilled in the art and will not be described in detail here.

[0118] The above-described embodiments provide a detailed description of the technical solution of the present invention. It should be understood that the above-described embodiments are only specific embodiments of the present invention and are not intended to limit the present invention. Any person skilled in the art who is familiar with the present technical field can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. Separation method of maleic acid from fumaric acid, The maleic acid in the fumaric acid is analyzed by high performance liquid chromatography, and the chromatographic column used contains a cation exchange material, and the cation exchange material is obtained by copolymerization of the coordination material I and the coordination material II; The coordination material I is a polymer having a DL-2-amino-4-pentenoic acid group, and the coordination material I is obtained by reacting DL-2-amino-4-pentenoic acid and a silane coupling agent; The compounding material II is a mixture of a block copolymer containing hydroxyethyl acrylate poly(GA)-b-(HEA) and tyrosine, a block copolymer containing hydroxyethyl acrylate poly(GA)-b-(HEA), tyrosine or polyvinyl alcohol; The mobile phase is phosphoric acid solution and acetonitrile, the volume ratio of phosphoric acid solution to acetonitrile is 70-90:30-10; the pH of the phosphoric acid solution is 2.5-4.0, and the detection wavelength is 210nm.

2. The method for separating maleic acid from fumaric acid according to claim 1, wherein The preparation method of the compound material I comprises the following steps: S1-1. Add toluene to DL-2-amino-4-pentenoic acid, heat to 55-80°C, then add the initiator, and stir at 55-80°C at 120-200 r / min for 4-8h; S1-2. Add silane coupling agent and initiator to the mixture obtained in S1-1, continue stirring at 55-80°C and 120-200 r / min for 4-8 hours; then purify by rotary evaporation at 70-85°C for 1-2 hours to obtain complex material I.

3. The method for separating maleic acid from fumaric acid according to claim 2, wherein In step S1-1 and step S1-2, the initiator is azobisisobutyronitrile; in step S1-1, the ratio of DL-2-amino-4-pentenoic acid to toluene is 0.1 mol:300-500 mL, and the molar ratio of DL-2-amino-4-pentenoic acid to the initiator is 50:0.1-0.5; In step S1-2, the silane coupling agent is at least one of 3-(methacryloyloxy)propyltrimethoxysilane, diethylaminomethyltriethoxysilane, and 3-(2,3-epoxypropoxy)propyltriethoxysilane; in step S1-2, the molar ratio of DL-2-amino-4-pentenoic acid to the silane coupling agent is 1:0.5-3, and the molar ratio of the silane coupling agent to the initiator is 50:0.1-0.

5.

4. The method for separating maleic acid from fumaric acid according to claim 1, wherein The preparation method of the block copolymer containing hydroxyethyl acrylate is as follows: S2-1. Add the initiator, nitrogen-containing ligand, deactivator and glycidyl acrylate to dimethyl sulfoxide and mix evenly by ultrasonication for 15-30 min to obtain a mixed solution Ⅰ; S2-2. Under a nitrogen atmosphere, a clean copper wire-wrapped magnet was added to the mixed solution obtained in S2-1, and the reaction was stirred at 20-30°C and 120-200 r / min for 16-36h to obtain poly(GA); S2-3. In a nitrogen atmosphere, hydroxyethyl acrylate and dimethyl sulfoxide were added to the poly (GA) obtained in S2-2; the mixture was sealed and stirred at 20-30°C and 120-200 r / min for 16-36 hours to obtain a block copolymer poly (GA) - b -(HEA).

5. The method for separating maleic acid from fumaric acid according to claim 4, characterized in that: The initiator is ethyl 2-bromoisobutyrate or 2-bromoisobutyryl bromide; the nitrogen-containing ligand is a tertiary amine compound, and the nitrogen-containing ligand is at least one of tris(2-(dimethylamino)ethyl)amine, tris(N,N-dimethylaminopropyl)amine, and N,N-dimethylethylamine; and the deactivator is CuBr2.

6. The method for separating maleic acid from fumaric acid according to claim 4, characterized in that: In step S2-1, the mass volume ratio of glycidyl acrylate to dimethyl sulfoxide is 1-2g:5-10mL; the molar ratio of glycidyl acrylate to nitrogen-containing ligand is 1000:3-10; the molar ratio of glycidyl acrylate to initiator is 30:1-3; and the molar ratio of initiator to deactivator is 10:0.5-3.

7. The method for separating maleic acid from fumaric acid according to claim 4, characterized in that: In step S2-3, the volume ratio of hydroxyethyl acrylate to dimethyl sulfoxide is 1:1-2; the molar ratio of hydroxyethyl acrylate to glycidyl acrylate in step S2-1 is 1:0.5-2.

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