A method for detecting impurities and intermediates in taurine production

Abstract

The invention discloses a method for detecting impurities and intermediates in taurine production, belonging to the technical field of analysis and detection. Taurine intermediates, impurity 1-urea, and impurity 2-acylurea are all highly polar organic sulfonates, which are difficult to retain and separate using conventional chromatographic columns, and the addition of ion pairs will lead to a decrease in detection sensitivity. The invention adopts a high-performance liquid chromatography method, uses a buffer to eliminate strong alkalinity in a sample, protects the chromatographic column, uses an ADME chromatographic column to separate various components in a sample solution to be tested, and calculates the content of each component using an external standard method. The method has a short analysis time and high accuracy, and the spiked recovery rates of the impurity 1-urea, impurity 2-acylurea, and taurine intermediate are 96.41% to 104.12%, 97.36% to 102.45%, and 98.78% to 101.78%, respectively. The method can be applied to in-process control analysis of a taurine synthesis process and can be used to track the reaction progress of a taurine synthesis process using acrylonitrile, thus having important significance for the quality control of taurine.

Description

Technical Field

[0001] The invention belongs to the technical field of analysis and detection, and specifically relates to a method for detecting impurities and intermediates in taurine production. Background Art

[0002] Taurine, also known as 2-aminoethanesulfonic acid, is one of the aminosulfonic acids found in many animal tissues. It is present in all vital organs of the human body (such as the brain, heart, liver, kidneys, pancreas, and retina), and is also found in breast milk and plasma. It not only participates in maintaining environmental homeostasis within the body but also plays a crucial regulatory role in the normal functioning of the central nervous system, digestive system, reproductive system, cardiovascular system, immune system, and endocrine system. Due to its unique properties, taurine is currently widely used in the fields of medicine, food, feed, and organic synthesis. It can also be used as a fluorescent brightener, biochemical reagent, wetting agent, and pH buffer, and has broad market prospects.

[0003] Taurine is typically synthesized through biological extraction and chemical methods. Biological extraction involves extracting taurine from seafood and other mollusks. This method results in difficult-to-remove impurities in the extracted taurine, making the subsequent taurine purification process very complex. Chemical methods are currently the primary route for synthesizing taurine. Chemical taurine synthesis primarily uses ethanolamine as a raw material, employing either esterification or chlorination. Ethanolamine is first reacted with sulfuric acid or hydrochloric acid to form 2-aminoethylsulfate or 2-chloroethylamine hydrochloride intermediates, which are then sulfonated to produce taurine. Both esterification and sulfonation reactions in this route are reversible, resulting in low overall yields, a long reaction cycle, and high energy consumption.

[0004] Patent CN114671784A reports a method for preparing taurine from acrylonitrile. After sulfonation, acrylonitrile is hydrolyzed using a biohydrolysis method to form an intermediate (sodium 3-amino-3-keto-propanesulfonate), which is then subjected to Hofmann degradation and acidification to obtain taurine. Compared with the traditional route, this route has mild reaction conditions, a safe preparation process, low energy consumption, and good application prospects. During the Hofmann degradation process, the intermediate isocyanate reacts with the product amine and the raw material amide during the hydrolysis process to generate urea (impurity 1) and acylurea (impurity 2) impurities, which affect the product yield and quality. Currently, no analytical method for monitoring urea and acylurea impurities in the taurine production process has been found. The generation mechanism of impurity 1-urea and impurity 2-acylurea is as follows:

[0005]

[0006] Common detection methods are volumetric methods, namely, the Kjeldahl nitrogen determination distillation method (GB / T 2440 urea) and the acid-base titration method (GB / T 20200 sodium α-olefin sulfonate). The Kjeldahl nitrogen determination method is suitable for determining the total nitrogen content in the sample, and the acid-base titration method is used for determining the total acidity of organic sulfonic acids. These two methods cannot completely distinguish between taurine and taurine intermediates, and are particularly unsuitable for the trace determination of impurities 1 and 2. Patent CN103728404B reports a method for determining organic sulfonates using ion chromatography; however, for determinations of complex components, similar polarity, and at least five organic sulfonates, the chromatographic column separation pressure is high, and the chromatographic peaks of high-concentration taurine sodium salt and taurine intermediates are tailing, affecting the peaks of impurities 1-urea and impurity 2-acylurea, thereby affecting the accuracy of the content determination of each component. Patent CN 109115926 reports a method for detecting sulfosuccinic acid compounds containing sulfonates using high performance liquid chromatography, but the chromatographic method cannot effectively separate the impurity 1-urea and the impurity 2-acylurea impurity components.

[0007] Therefore, developing an analytical method for quickly and accurately determining the content of impurity 1-urea, impurity 2-acylurea and taurine intermediates in the reaction solution during taurine synthesis can effectively monitor the reaction and promote taurine production. Summary of the Invention

[0008] To solve the above problems, the purpose of the present invention is to provide a method for detecting impurities and intermediates in taurine production.

[0009] To achieve the above-mentioned purpose, the present invention is implemented through the following technical solutions:

[0010] A method for detecting impurities and intermediates in taurine production comprises the following steps: dissolving a sample in a mixed solution of a buffered saline solution with a pH of 2.0 to 4.8 and acetonitrile, performing high performance liquid chromatography (HPLC) determination using a mobile phase of a phosphate solution with a pH of 2.0 to 3.0 and acetonitrile, separating the sample in an ADME chromatographic column using isocratic elution, and calculating the content of the impurities and intermediates in taurine production using a single-point external standard method using an ultraviolet detector or a diode array detector.

[0011] The impurities are 1-urea and 2-acylurea; and the intermediate is sodium 3-amino-3-keto-propanesulfonate.

[0012] The method for detecting impurities and intermediates in taurine production specifically comprises the following steps:

[0013] 1) Preparation of a mixed standard solution: dissolving a standard of impurity 1-urea, a standard of impurity 2-acylurea, and a standard of a taurine intermediate in a solvent, and filtering through a 0.45 μm filter membrane to obtain a mixed standard solution containing impurity 1-urea, impurity 2-acylurea, and a taurine intermediate;

[0014] The concentration of the taurine intermediate in the mixed standard solution is 0.1 mg / mL to 1.01 mg / mL, the concentration of the impurity 1-urea is 0.1 mg / mL to 0.51 mg / mL, and the concentration of the impurity 2-acylurea is 0.1 mg / mL to 0.51 mg / mL;

[0015] 2) Preparation of sample solution: Weigh 0.5-2.05 g of the taurine synthesis reaction solution into a 100 mL volumetric flask, dissolve with solvent, dilute to volume, and filter through a 0.45 μm filter to obtain a sample solution.

[0016] 3) Setting chromatographic conditions;

[0017] 4) Determination: The mixed standard solution prepared in step 1) and the sample solution prepared in step 2) were subjected to high performance liquid chromatography, the peak areas were recorded, and the contents of impurities and intermediates in taurine production were calculated using an external standard method;

[0018] The calculation formula is as follows:

[0019]

[0020] Wherein: wi-mass fraction of impurity 1-urea, impurity 2-acylurea or taurine intermediate in taurine synthesis reaction solution, unit is %; Ai-peak area of ​​impurity 1-urea, impurity 2-acylurea or taurine intermediate in sample solution; As-peak area of ​​impurity 1-urea, impurity 2-acylurea or taurine intermediate in mixed standard solution; mi-mass of taurine synthesis reaction solution, unit is g; m s -Impurity 1-urea standard, impurity 2-acylurea standard or taurine intermediate standard mass, in g; Ps-standard purity, in %.

[0021] The solvent in step 1) and step 2) is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a phosphate solution with a pH of 2.0 to 4.8 and a concentration of 50 to 100 mmol / L.

[0022] The phosphate is sodium dihydrogen phosphate, diammonium hydrogen phosphate or dipotassium hydrogen phosphate.

[0023] The preparation method of the impurity 1-urea standard or the impurity 2-acylurea standard in step 1) is:

[0024] Under nitrogen protection, sodium 3-amino-3-keto-propanesulfonate is added to a polar aprotic solvent, N-bromosuccinimide and a base are added at -10 to 10°C, and the mixture is fully stirred for 30 minutes. The temperature is then raised to 60 to 90°C, and the raw materials are added thereto. After the addition is completed, the mixture is kept warm for reaction for 2 to 6 hours. After the reaction is completed, the solvent is removed by vacuum concentration, and the mixture is developed using water and methanol in a volume ratio of 1:1 to 2. The mixture is separated on a C18 reverse phase column to obtain an impurity 1-urea standard or an impurity 2-acylurea standard. When the raw material is sodium 3-amino-3-ketopropanesulfonate, the impurity 1-urea standard is obtained; when the raw material is sodium taurine salt, the impurity 2-acylurea standard is obtained.

[0025] The polar aprotic solvent is dimethylformamide or dimethyl sulfoxide.

[0026] The base is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium tert-butoxide.

[0027] The molar ratio of the sodium 3-amino-3-keto-propanesulfonate, N-bromosuccinimide, base and raw materials is 1:1 to 2.5:1 to 10:1.

[0028] Preferably, the polar aprotic solvent is dimethyl sulfoxide; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene; and the molar ratio of sodium 3-amino-3-ketopropanesulfonate, N-bromosuccinimide, base and raw materials is 1:1.5:3:1.

[0029] In the taurine synthesis reaction solution in step 2), the mass fraction of the impurity 1-urea is 0.1% to 3%, the mass fraction of the impurity 2-acylurea is 0.1% to 3%, and the mass fraction of the taurine intermediate is 0.1% to 5%.

[0030] The chromatographic conditions in step 3) are:

[0031] Chromatographic column: CAPCELL PAK ADME or column with equivalent column efficiency;

[0032] Mobile phase A: acetonitrile;

[0033] Mobile phase B: phosphate solution with a pH of 2.0-3.0 and a concentration of 5-50 mmol / L;

[0034] Flow rate: 0.8-1.2 mL / min;

[0035] Elution conditions: isocratic elution; mobile phase A: mobile phase B = 0-15: 100-85;

[0036] Detector: UV detector or diode array detector;

[0037] Detection wavelength: 210-230nm;

[0038] Column temperature: 20-40°C;

[0039] Detection time: 10 minutes;

[0040] Injection volume: 5-30 μL.

[0041] Preferably, the elution condition in the chromatography conditions in step 3) is isocratic elution; mobile phase A:mobile phase B=5:95; and the phosphate is potassium dihydrogen phosphate, sodium dihydrogen phosphate or ammonium dihydrogen phosphate.

[0042] Compared with the prior art, the present invention has the following advantages:

[0043] The method for detecting impurities and intermediates in taurine production of the present invention uses a CAPCELL PAK ADME chromatographic column, which can effectively retain highly polar compounds; the mobile phase effectively maintains the stability of the pH value after injection, increases the retention capacity of each component and improves the peak shape of the chromatographic peak; the pH value of excess sodium hydroxide in the sample is neutralized, reducing irreversible damage to the chromatographic column caused by excessively high pH while simplifying the operation; and when using a single-point external standard method, the content of the analyte in the standard solution and the sample solution is effectively controlled to be consistent, reducing errors caused by integration, and the method has high accuracy.

[0044] The synthesis of impurity 1-urea and impurity 2-acylurea standards adopts a polar aprotic solvent, effectively avoiding the occurrence of a hydrolysis side reaction. The use of a strong base with large steric hindrance not only shortens the reaction time but also avoids an amino ester side reaction, and the post-processing method is simple. Compared with the traditional phosgene method and the selenium-catalyzed carbon monoxide method for preparing urea, the method of the present invention has a milder reaction and is safer to operate.

[0045] The taurine intermediate, impurity 1-urea, and impurity 2-acylurea of ​​the present invention are all highly polar organic sulfonates, which are difficult to retain and separate using conventional chromatographic columns, and the addition of ion pairs can lead to a decrease in detection sensitivity. The present invention adopts high-performance liquid chromatography, uses a buffer to eliminate strong alkalinity in the sample, protects the chromatographic column, uses an ADME chromatographic column to separate the components in the test sample solution, and calculates the content of each component using an external standard method. The analysis time is short and the accuracy is high. The spiked recovery rates of the impurity 1-urea, impurity 2-acylurea, and taurine intermediate are 96.41% to 104.12%, 97.36% to 102.45%, and 98.78% to 101.78%, respectively. The present invention can be applied to in-process control analysis of the taurine synthesis process and can be used to track the reaction progress of the taurine synthesis process from acrylonitrile, which is of great significance to the quality control of taurine. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is a chromatogram of the mixed standard solution prepared in Example 3 of the present invention;

[0047] Figure 2 This is a chromatogram of the sample solution prepared in Example 3 of the present invention;

[0048] Figure 3 is the chromatogram of the comparative sample solution;

[0049] In the figure, 1-taurine intermediate, 2-impurity 1-urea, 3-impurity 2-acylurea. DETAILED DESCRIPTION

[0050] In order to better understand the technical solutions of the present invention, the following is a further detailed description of the above content of the present invention through specific implementation methods in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0051] The taurine intermediate standard product in the present invention is prepared according to the preparation method of 3-amino-3-keto-sodium propanesulfonate intermediate in patent CN114671784A; the taurine synthesis reaction solution is the reaction solution obtained in step (d) in patent CN114671784A.

[0052] Example 1 Preparation of impurity 1-urea standard:

[0053] Under nitrogen atmosphere, 17.5 g of sodium 3-amino-3-keto-propanesulfonate was added to 300 mL of dimethyl sulfoxide, and 26.7 g of N-bromosuccinimide and 46 g of 1,8-diazabicyclo[5.4.0]undec-7-ene were added at 10 ° C. After stirring for 30 minutes, the temperature was raised to 60 ° C. Then, 14.7 g of sodium taurine was added thereto. After the addition was completed, the reaction was continued for 2 hours. After the reaction was completed, the solvent was removed by vacuum concentration to obtain a brown-red oily solid, which was separated by C18 reverse phase column to obtain the impurity 1-urea standard (developing solvent: H2O / MeOH=1 / 2). ( 1 HNMR) 1 H NMR (400MHz, D2O, 293K): δ8.91 (s, 2H, RNH), 3.87 (t, J = 7.6Hz, 4H, CHS), 3.32 (t, J = 7.6Hz, 4H, CHN).

[0054] Example 2 Preparation of impurity 2-acylurea standard:

[0055] Under nitrogen atmosphere, 17.5 g of sodium 3-amino-3-keto-propanesulfonate was added to 300 mL of dimethylformamide, and 35.4 g of N-bromosuccinimide and 56 g of potassium tert-butoxide were added at -5 ° C. After sufficient stirring for 30 minutes, the temperature was raised to 90 ° C. 17.5 g of sodium 3-amino-3-keto-propanesulfonate was added thereto. After the addition was completed, the reaction was continued for 6 hours. After the reaction was completed, the solvent was removed by vacuum concentration to obtain a dark reddish brown oily solid, which was separated by C18 reverse phase column to obtain the impurity 2-acylurea standard (developing solvent: H2O / MeOH=1 / 1). ( 1 HNMR) 1 H NMR (400MHz, D2O, 293K): δ11.52(s,H,CONHCO),8.91(s,H,RNHCO),3.90(t,J=7.4Hz,2H,NCH2 CHS), 3.50 (t, J = 7.2Hz, 2H, COCH2CHS), 3.38 (t, J = 7.4Hz, 2H, CHN), 3.24 (t, J = 7.2Hz, 2H, CHN).

[0056] The solvent in Example 3 is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a sodium dihydrogen phosphate solution with a pH of 2.0 and a concentration of 50 mmol / L.

[0057] Preparation of mixed standard solution: Weigh 100.24 mg of taurine intermediate standard, 50.23 mg of impurity 1-urea standard, and 50.02 mg of impurity 2-acylurea standard, dilute to 100 mL with solvent, shake well, and filter through a 0.45 μm filter to prepare a mixed standard solution of 1.0024 mg / mL taurine intermediate, 0.5023 mg / mL impurity 1-urea, and 0.5002 mg / mL impurity 2-acylurea.

[0058] Preparation of sample solution: Weigh 2.0135 g of taurine synthesis reaction solution and place it in a 100 mL volumetric flask. Dissolve it in solvent and dilute to the mark. Filter it through a 0.45 μm filter membrane to obtain a sample solution.

[0059] Set up the chromatographic conditions:

[0060] Instrument: Thermo Fisher U3000 High Performance Liquid Chromatograph

[0061] Chromatographic column: CAPCELL PAK ADME (250 mm × 4.6 mm × 5 μm);

[0062] Mobile phase A: acetonitrile;

[0063] Mobile phase B: potassium dihydrogen phosphate solution with a pH of 2.5 and a concentration of 50 mmol / L;

[0064] Flow rate: 1.0 mL / min;

[0065] Elution conditions: isocratic elution; mobile phase A: mobile phase B = 5:95;

[0066] Detector: UV detector;

[0067] Detection wavelength: 215nm;

[0068] Column temperature: 30°C;

[0069] Detection time: 10 minutes;

[0070] Injection volume: 10 μL.

[0071] The mixed standard solution and sample solution were subjected to HPLC determination according to the above chromatographic conditions, and the chromatograms were recorded. The chromatogram of the standard solution was as follows: Figure 1 shown. Figure 1 In the analysis, the retention times of taurine intermediate, impurity 1-urea and impurity 2-acylurea were 4.04 min, 7.25 min and 7.87 min, respectively. The peak areas were 14.879, 5.321 and 4.925, respectively. The resolutions were 6.7 and 3.2, which met the baseline separation requirements.

[0072] The chromatogram of the sample solution is as follows Figure 2 The content of taurine intermediate in the taurine synthesis reaction solution was calculated by external standard method to be 4.93%, the content of impurity 1-urea was 0.48%, and the content of impurity 2-acylurea was 0.43%.

[0073] Example 4 Durability Evaluation:

[0074] The solvent is a buffer salt-acetonitrile solution with a volume ratio of 80:20; the buffer salt is a diammonium hydrogen phosphate solution with a pH of 2.0 and a concentration of 100 mmol / L.

[0075] Preparation of mixed standard solution: Weigh 20.35 mg of taurine intermediate, 10.75 mg of impurity 1-urea standard, and 10.23 mg of impurity 2-acylurea standard, dilute to 100 mL with solvent, shake well, and pass through a 0.45 μm filter to prepare a mixed standard solution of 0.2035 mg / mL taurine intermediate, 0.1075 mg / mL impurity 1-urea, and 0.1023 mg / mL impurity 2-acylurea.

[0076] Preparation of sample solution: Weigh 0.5034 g of taurine synthesis reaction solution and place it in a 100 mL volumetric flask. Dissolve it in solvent and dilute it to the mark. Filter it through a 0.45 μm filter membrane to obtain a sample solution.

[0077] The chromatographic conditions were set as shown in Table 1, and the other chromatographic conditions were the same as those in Example 3.

[0078] Table 1 Chromatographic conditions

[0079]

[0080] The mixed standard solution and sample solution were subjected to high performance liquid chromatography (HPLC) and the contents of the taurine intermediate, impurity 1-urea, and impurity 2-acylurea in the taurine synthesis reaction solution were calculated using the external standard method. The test results are shown in Table 2.

[0081] Table 2 Detection results under different chromatographic conditions

[0082] Serial number Taurine intermediate / % Impurity 1-urea / % Impurity 2-acylurea / % Chromatographic conditions 1 4.93 0.47 0.42 Chromatographic condition 2 4.93 0.43 0.42 Chromatographic conditions 3 4.97 0.47 0.41 Chromatographic conditions 4 4.98 0.46 0.42 Chromatographic conditions 5 4.93 0.48 0.46 Chromatographic conditions 6 4.94 0.46 0.42 Chromatographic conditions 7 4.92 0.47 0.41

[0083] As can be seen from the results in Table 2, under various chromatographic conditions, there was no significant difference in the test results of the taurine intermediate, the impurity 1-urea and the impurity 2-acylurea, indicating that the method of the present invention has good durability.

[0084] The solvent described in Example 5 is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a dipotassium hydrogen phosphate solution with a pH of 4.8 and a concentration of 75 mmol / L.

[0085] Preparation of mixed standard solution: Weigh 10.31 mg of taurine intermediate, 50.23 mg of impurity 1-urea standard, and 50.38 mg of impurity 2-acylurea standard, dilute to 100 mL with solvent, shake well, and pass through a 0.45 μm filter to prepare a mixed standard solution of 0.1031 mg / mL taurine intermediate, 0.5023 mg / mL impurity 1-urea, and 0.5038 mg / mL impurity 2-acylurea.

[0086] Preparation of sample solution: Weigh 1.5025 g of taurine synthesis reaction solution and place it in a 100 mL volumetric flask. Dissolve it in solvent and dilute to the mark. Filter through a 0.45 μm filter membrane to obtain a sample solution.

[0087] Set up the chromatographic conditions:

[0088] Instrument: Thermo Fisher U3000 High Performance Liquid Chromatograph

[0089] Chromatographic column: CAPCELL PAK ADME (150 mm × 4.6 mm × 3 μm);

[0090] Mobile phase A: acetonitrile;

[0091] Mobile phase B: sodium dihydrogen phosphate solution with a pH of 2.0 and a concentration of 10 mmol / L;

[0092] Flow rate: 1.0 mL / min;

[0093] Elution conditions: isocratic elution; mobile phase A: mobile phase B = 5:95;

[0094] Detector: UV detector;

[0095] Detection wavelength: 215nm;

[0096] Column temperature: 35°C;

[0097] Detection time: 10 minutes;

[0098] Injection volume: 10 μL.

[0099] The mixed standard solution and sample solution were subjected to high performance liquid chromatography (HPLC) and the contents of the taurine intermediate, impurity 1-urea, and impurity 2-acylurea in the taurine synthesis reaction solution were calculated using the external standard method. The test results are shown in Table 3.

[0100] Table 3 Sample test results

[0101] serial number Taurine intermediate / % Impurity 1-urea / % Impurity 2-acylurea / % Taurine synthesis reaction solution 0.23 2.93 2.92

[0102] The solvent described in Example 6 is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a sodium dihydrogen phosphate solution with a pH of 2.0 and a concentration of 50 mmol / L.

[0103] Preparation of mixed standard solution: Weigh 50.05 mg of taurine intermediate, 50.17 mg of impurity 1-urea standard, and 50.32 mg of impurity 2-acylurea standard, dilute to 100 mL with solvent, shake well, and pass through a 0.45 μm filter to prepare a mixed standard solution of 0.5005 mg / mL taurine intermediate, 0.5017 mg / mL impurity 1-urea, and 0.5032 mg / mL impurity 2-acylurea.

[0104] Set up the chromatographic conditions:

[0105] Instrument: Thermo Fisher U3000 High Performance Liquid Chromatograph

[0106] Chromatographic column: CAPCELL PAK ADME (250 mm × 4.6 mm × 5 μm);

[0107] Mobile phase A: acetonitrile;

[0108] Mobile phase B: potassium dihydrogen phosphate solution with a pH of 2.5 and a concentration of 10 mmol / L;

[0109] Flow rate: 1.0 mL / min;

[0110] Elution conditions: isocratic elution; mobile phase A: mobile phase B = 5:95;

[0111] Detector: UV detector;

[0112] Detection wavelength: 215nm;

[0113] Column temperature: 35°C;

[0114] Detection time: 10 minutes;

[0115] Injection volume: 10 μL.

[0116] (1) Quantitation limit test

[0117] The detection limit and quantification limit of the method of the present invention were investigated by diluting with the mixed standard solution. The test results are shown in Table 4.

[0118] Table 4 Results of limit of quantification and limit of detection

[0119] name Limit of quantification (μg / mL) Detection limit (μg / mL) Taurine intermediates 2.71 1.2 Impurity 1-urea 1.03 0.53 Impurity 2-acylurea 1.04 0.49

[0120] (2) Precision test

[0121] 1.5351 g, 1.5347 g, 1.5124 g, 1.5254 g, 1.5147 g, and 1.5421 g of the taurine synthesis reaction solution were respectively weighed and placed in a 100 mL volumetric flask. The solution was dissolved with solvent and diluted to the mark. The solution was filtered through a 0.45 μm filter to obtain sample solutions 1 to 6. Sample solutions 1 to 6 were each subjected to high performance liquid chromatography (HPLC) to calculate the contents of the taurine intermediate, impurity 1-urea, and impurity 2-acylurea in the taurine synthesis reaction solution using the external standard method. The test results are shown in Table 5.

[0122] Table 5 Test results of sample solutions 1 to 6

[0123] Serial number Taurine intermediate / % Impurity 1-urea / % Impurity 2-acylurea / % Sample solution 1 1.00 1.52 1.52 Sample solution 2 0.98 1.51 1.55 Sample solution 3 0.99 1.53 1.53 Sample solution 4 0.98 1.54 1.54 Sample solution 5 0.97 1.53 1.57 Sample solution 6 0.96 1.54 1.54 Mean / % 0.98 1.53 1.54 RSD / % 1.44 0.76 1.12

[0124] As shown in Table 5, the average content of the taurine intermediate in the taurine synthesis reaction solution was 0.98%, the impurity 1-urea was 1.53%, and the impurity 2-acylurea was 1.54%. The taurine synthesis reaction solution was weighed, and standard solutions of the taurine intermediate, impurity 1-urea, and impurity 2-acylurea were added to the weighed taurine synthesis reaction solution at 25%, 50%, and 100% of the content of the three components in the sample. The spiked recovery was determined, and the test results are shown in Table 6.

[0125] Table 6 Spike recovery test results

[0126]

[0127] As shown in Tables 5 and 6, the RSD of the precision test results of the three components is less than 2.0%. The spiked recoveries of the impurity 1-urea, impurity 2-acylurea and taurine intermediate are 96.41% to 104.12%, 97.36% to 102.45% and 98.78% to 101.78%, respectively. This shows that the precision and accuracy of the method of the present invention meet the requirements.

[0128] Comparative Example

[0129] The solvent is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a sodium dihydrogen phosphate solution with a pH of 2.0 and a concentration of 50 mmol / L.

[0130] Preparation of sample solution: Weigh 2.0135 g of taurine synthesis reaction solution and place it in a 100 mL volumetric flask. Dissolve it in solvent and dilute to the mark. Filter it through a 0.45 μm filter membrane to obtain a sample solution.

[0131] Set up the chromatographic conditions:

[0132] Instrument: Thermo Fisher U3000 High Performance Liquid Chromatograph

[0133] Chromatographic column: Shimpack GIST C18-AQ (250 mm × 4.6 mm × 5 μm);

[0134] Mobile phase A: acetonitrile;

[0135] Mobile phase B: potassium dihydrogen phosphate solution with a pH of 2.5 and a concentration of 50 mmol / L;

[0136] Flow rate: 0.8 mL / min;

[0137] Elution conditions: isocratic elution; mobile phase A: mobile phase B = 5:95;

[0138] Detector: UV detector;

[0139] Detection wavelength: 215nm;

[0140] Column temperature: 35°C;

[0141] Detection time: 10 minutes;

[0142] Injection volume: 5 μL.

[0143] The sample solution was subjected to high performance liquid chromatography according to the above chromatographic conditions, and the chromatogram was as follows Figure 3 As shown by Figure 3It can be seen that the taurine intermediate, impurity 1-urea and impurity 2-acylurea are all eluted together with the blank solvent, and the components are not completely separated. The chromatographic conditions are not suitable for the detection of taurine intermediates, impurity 1-urea and impurity 2-acylurea.

[0144] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

Claims

1. A method for detecting impurities and intermediates in taurine production, characterized by: The process is as follows: the sample was dissolved in a mixed solution of buffered saline solution with a pH of 2.0 to 4.8 and acetonitrile, and then determined by high-performance liquid chromatography. The chromatographic column was CAPCELLPAK ADME; mobile phase A was acetonitrile; mobile phase B was phosphate solution with a pH of 2.0 to 3.0 and a concentration of 5 to 50 mmol / L; the flow rate was 0.8 to 1.2 mL / min; the elution conditions were isocratic; mobile phase A: mobile phase B = 0 to 15: 100 to 85; Detector: UV detector or diode array detector; Detection Wavelength: 210-230 nm; column temperature: 20-40°C; detection time: 10 min; injection volume: 5-30 μL. Single-point external standard method is used to calculate the content of impurities and intermediates in taurine production. The impurities are 1-urea and 2-acylurea; the intermediate is sodium 3-amino-3-keto-propanesulfonate; The structural formula of the impurity 1-urea is: ； The structural formula of the impurity 2-acylurea is: 。 2. The method for detecting impurities and intermediates in taurine production according to claim 1, wherein: The specific steps include: 1) Preparation of mixed standard solution: Dissolve the impurity 1-urea standard, the impurity 2-acylurea standard, and the taurine intermediate standard in a solvent and filter through a 0.45 μm filter membrane to obtain a mixed standard solution containing the impurity 1-urea, the impurity 2-acylurea, and the taurine intermediate; The concentration of the taurine intermediate in the mixed standard solution is 0.1 mg / mL to 1.01 mg / mL, the concentration of the impurity 1-urea is 0.1 mg / mL to 0.51 mg / mL, and the concentration of the impurity 2-acylurea is 0.1 mg / mL to 0.51 mg / mL; 2) Sample solution preparation: Weigh 0.5-2.05 g of taurine synthesis reaction solution into a 100 mL volumetric flask, dissolve with solvent, dilute to volume, and filter through a 0.45 μm filter to obtain a sample solution. 3) Set chromatographic conditions; 4) Determination: The mixed standard solution prepared in step 1) and the sample solution prepared in step 2) were subjected to high performance liquid chromatography, and the peak areas were recorded. The content of impurities and intermediates in taurine production was calculated using the external standard method; The calculation formula is as follows: ; Among them: w i -The mass fraction of the impurity 1-urea, impurity 2-acylurea or taurine intermediate in the taurine synthesis reaction solution, unit is %; A i -The peak area of ​​impurity 1-urea, impurity 2-acylurea or taurine intermediate in the sample solution; A s - Peak area of ​​impurity 1-urea, impurity 2-acylurea or taurine intermediate in mixed standard solution; m i -Mass of taurine synthesis reaction solution, in g; m s -The mass of impurity 1-urea standard, impurity 2-acylurea standard or taurine intermediate standard, in g; P s -Purity of the standard product, in %.

3. The method for detecting impurities and intermediates in taurine production according to claim 2, wherein: The solvent in step 1) and step 2) is a buffer salt-acetonitrile solution with a volume ratio of 80:20; wherein the buffer salt is a phosphate solution with a pH of 2.0-4.8 and a concentration of 50-100 mmol / L.

4. The method for detecting impurities and intermediates in taurine production according to claim 3, wherein: The phosphate is sodium dihydrogen phosphate, diammonium hydrogen phosphate or dipotassium hydrogen phosphate.

5. The method for detecting impurities and intermediates in taurine production according to claim 2, wherein: The preparation method of the impurity 1-urea standard or the impurity 2-acylurea standard in step 1) is as follows: Under nitrogen protection, sodium 3-amino-3-keto-propanesulfonate is added to a polar aprotic solvent, N-bromosuccinimide and a base are added at -10~10°C, and the mixture is fully stirred for 30 minutes. The temperature is then raised to 60~90°C, and the raw materials are added thereto. After the addition is completed, the mixture is kept warm for reaction for 2~6 hours. After the reaction is completed, the solvent is removed by vacuum concentration, and the mixture is developed using water and methanol in a volume ratio of 1:1~2. The mixture is separated on a C18 reverse phase column to obtain an impurity 1-urea standard or an impurity 2-acylurea standard. When the raw material is sodium 3-amino-3-ketopropanesulfonate, the impurity 1-urea standard is obtained; when the raw material is sodium taurine salt, the impurity 2-acylurea standard is obtained.

6. The method for detecting impurities and intermediates in taurine production according to claim 5, wherein: The polar aprotic solvent is dimethylformamide or dimethyl sulfoxide; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium tert-butoxide; and the molar ratio of sodium 3-amino-3-ketopropanesulfonate, N-bromosuccinimide, the base and the raw materials is 1:1 to 2.5:1 to 10:

1.

7. The method for detecting impurities and intermediates in taurine production according to claim 5, wherein: The polar aprotic solvent is dimethyl sulfoxide; the base is 1,8-diazabicyclo[5.4.0]undec-7-ene; and the molar ratio of sodium 3-amino-3-ketopropanesulfonate, N-bromosuccinimide, the base and the raw material is 1:1.5:3:

1.

8. The method for detecting impurities and intermediates in taurine production according to claim 2, wherein: In the taurine synthesis reaction solution in step 2), the mass fraction of the impurity 1-urea is 0.1% to 3%, the mass fraction of the impurity 2-acylurea is 0.1% to 3%, and the mass fraction of the taurine intermediate is 0.1% to 5%.

9. The method for detecting impurities and intermediates in taurine production according to claim 2, wherein: The elution condition in the chromatographic conditions in step 3) is isocratic elution; mobile phase A:mobile phase B=5:95; and the phosphate is potassium dihydrogen phosphate, sodium dihydrogen phosphate or ammonium dihydrogen phosphate.

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