Process for purifying clopidogrel bisulfate

Abstract

The application discloses a purification method of clopidogrel hydrogen sulfate, which comprises the following steps: (1) dissolving salt of crude clopidogrel hydrogen sulfate, then performing solvent extraction and separation to obtain organic phase one; (2) mixing the organic phase one with a hydroxyl protecting agent and a base two, and performing reaction; (3) quenching the reaction with a base three, and separating to obtain organic phase two, and then concentrating to dryness; (4) mixing the concentrate with solvent two and water, dissolving, performing salting, crystallization, separation and drying to obtain high-purity clopidogrel hydrogen sulfate. The method can efficiently remove various stubborn impurities and other impurities, significantly improves product quality safety, is convenient and efficient to operate, safe and environmentally friendly, and is suitable for large-scale preparation.

Description

Technical Field

[0001] This invention relates to a purification method for clopidogrel bisulfate, and more particularly to a purification method for clopidogrel bisulfate that is highly efficient and produces a high-quality product. Background Technology

[0002] Clopidogrel bisulfate is a common antiplatelet aggregation drug that inhibits the binding of adenosine diphosphate to platelet receptors, effectively preventing thrombosis.

[0003]

[0004] The established synthetic route for clopidogrel bisulfate is as follows:

[0005]

[0006] The above-mentioned synthesis process of clopidogrel bisulfate usually introduces a variety of impurities, especially the hydroxymethyl impurity of clopidogrel (Formula 1), the nitrogen methyl impurity of clopidogrel (Formula 2), and the disubstituted impurity (Formula 3), which are difficult to remove and affect the quality and safety of clopidogrel bisulfate drugs.

[0007]

[0008] CN106478657 discloses a purification method for clopidogrel bisulfate. This method can only remove specific impurities and cannot comprehensively remove multiple impurities. Furthermore, the removal effect on specific impurities is generally poor, while the removal effect on other impurities is also poor. The purification effect on clopidogrel bisulfate of different qualities is limited and it lacks universality. Additionally, this patented purification method uses a simple solvent heating and cooling crystallization process, which involves relatively high operating temperatures. The sulfuric acid contained in clopidogrel bisulfate can damage the product, causing it to turn yellow and exhibiting poor long-term stability. Summary of the Invention

[0009] Purpose of the invention: The present invention aims to provide a purification method for clopidogrel bisulfate that is efficient and of controllable quality.

[0010] Technical solution: The purification method for clopidogrel bisulfate according to the present invention includes the following steps:

[0011] (1) The crude clopidogrel bisulfate was desalted, and then extracted and separated by solvent to obtain organic phase one;

[0012] (2) Mix organic phase I with hydroxyl protectant and base I to carry out the reaction;

[0013] (3) After quenching with alkali and separation, organic phase II is obtained, and then concentrated to dryness;

[0014] (4) The concentrate is mixed with solvent II and water to dissolve it. After salt formation, crystallization, separation and drying, clopidogrel bisulfate is obtained.

[0015] The purification principle of the method of this invention is as follows:

[0016] 1. Salt and water-soluble organic impurities were removed by extraction and separation in step (1);

[0017] 2. The hydroxyl protection process in step (2) and the purification process in step (4) are used to remove the clopidogrel hydroxymethyl impurity (Formula 1);

[0018] 3. Other impurities such as clopidogrel nitrogen methyl impurity (Formula 2) and disubstituted impurity (Formula 3) are removed through the refining process in step (4).

[0019] The specific steps of the purification method are as follows:

[0020] (1) The crude clopidogrel bisulfate was mixed with water and solvent one, and the salt was dissolved by adding alkali. The organic phase containing clopidogrel was then separated.

[0021] (2) Under controlled temperature, organic phase I is mixed with base I and hydroxyl protectant and reacted;

[0022] (3) Add alkali to the reactants to quench the reaction, separate to obtain organic phase II, concentrate organic phase II to dryness, and obtain clopidogrel;

[0023] (4) Add solvent II and water to clopidogrel, stir to dissolve, add concentrated sulfuric acid under cooling to form salt, crystallize under controlled temperature, separate the crystals, and dry to obtain clopidogrel bisulfate.

[0024] Preferably, the pH value of the desalination adjustment in step (1) is 6 to 8, and a sodium carbonate solution with a mass concentration of 5% to 25% is used, more preferably a sodium carbonate solution with a mass concentration of 10%.

[0025] Preferably, the solvent in step (1) is selected from ethyl acetate, isopropyl acetate, toluene, chlorobenzene, n-butanol, dichloromethane, methyl isobutyl ketone, and methyl tert-butyl ether, more preferably dichloromethane or ethyl acetate, and even more preferably dichloromethane. The mass ratio of solvent to crude clopidogrel bisulfate is 3:1, and the mass ratio of water to crude clopidogrel bisulfate is 2:1.

[0026] Preferably, the hydroxyl protecting agent in step (2) is selected from acetyl chloride, acetic anhydride, trimethylchlorosilane, tert-butyldimethylchlorosilane, benzyl bromide, and benzyl chloride, more preferably acetic anhydride and acetyl chloride, and even more preferably acetyl chloride. The molar ratio of the hydroxyl protecting agent to crude clopidogrel bisulfate is 0.1:1.

[0027] Preferably, the base in step (2) is selected from pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, dimethylisopropylamine, 1-methylpiperidine, and 4-methylmorpholine, more preferably triethylamine or pyridine, and even more preferably triethylamine. The molar ratio of the base to the hydroxyl protecting agent is 0.2:1.

[0028] Preferably, the reaction temperature in step (2) is 15–25°C, specifically selected from 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, and 25°C. Each specific temperature point can also fluctuate within the temperature control range of the equipment, that is, the temperature is controlled within the range of the target value ± control accuracy value. For example, when the temperature control accuracy is 0.5°C, it can also be selected from 15°C ± 0.5°C, 16°C ± 0.5°C, 17°C ± 0.5°C, 18°C ​​± 0.5°C, 19°C ± 0.5°C, 20°C ± 0.5°C, 21°C ± 0.5°C, 22°C ± 0.5°C, 23°C ± 0.5°C, 24°C ± 0.5°C, and 25°C ± 0.5°C.

[0029] Preferably, the alkali 2 mentioned in step (3) is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, and ammonia water, more preferably sodium carbonate and sodium hydroxide, and even more preferably sodium carbonate. Specifically, a sodium carbonate solution with a mass concentration of 5%-25% is used, more preferably a sodium carbonate solution with a mass concentration of 10%. The molar ratio of alkali 2 to hydroxyl protecting agent is 3:1.

[0030] Preferably, the concentration to dryness in step (3) is such that almost no fraction is distilled off.

[0031] Preferably, the solvent in step (4) is selected from ethyl acetate, isopropyl acetate, toluene, chlorobenzene, dichloromethane, acetone, methanol, ethanol, isopropanol, n-butanol, sec-butanol, tert-butanol, methyl isobutyl ketone, methyl tert-butyl ether, and more preferably from n-butanol, acetone, sec-butanol, and more preferably n-butanol.

[0032] Preferably, the mass ratio of the concentrate to water in step (4) is 10:1 to 50:1, more preferably 10:1 to 20:1, specifically selected from 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, and more preferably 20:1.

[0033] Preferably, the mass ratio of the concentrate to solvent II in step (4) is 1:10 to 1:5, specifically selected from 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, and more preferably 1:8.

[0034] Preferably, the crystallization temperature in step (4) is -5 to 35°C, more preferably 10 to 20°C, specifically selected from 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, and 20°C. Each specific temperature point can also fluctuate within the temperature control range of the equipment, that is, the temperature is controlled within the range of the target value ± control accuracy value. For example, when the temperature control accuracy is 0.5°C, it can also be selected from 10°C ± 0.5°C, 11°C ± 0.5°C, 12°C ± 0.5°C, 13°C ± 0.5°C, 14°C ± 0.5°C, 15°C ± 0.5°C, 16°C ± 0.5°C, 17°C ± 0.5°C, 18°C ​​± 0.5°C, 19°C ± 0.5°C, and 20°C ± 0.5°C.

[0035] Preferably, the salt formation temperature in step (4) is no more than 20°C, more preferably 15-20°C, specifically selected from 15°C, 16°C, 17°C, 18°C, 19°C, and 20°C. Each specific temperature point can also fluctuate within the temperature control range of the equipment, that is, the temperature is controlled within the range of the target value ± control accuracy value. For example, when the temperature control accuracy is 0.5°C, it can also be selected from 15°C ± 0.5°C, 16°C ± 0.5°C, 17°C ± 0.5°C, 18°C ​​± 0.5°C, 19°C ± 0.5°C, and 20°C ± 0.5°C.

[0036] The two-phase separation in the method includes static separation and dynamic separation. Static separation is, for example, static separation in a column kettle, while dynamic separation is dynamic separation in a coalescer. The drying in the method includes atmospheric pressure drying, vacuum drying, inert gas drying, fluidized bed drying, and freeze drying.

[0037] The purified clopidogrel bisulfate obtained by the above purification method can be further processed by washing, pulping, filtering, centrifugation, and drying. Drying includes atmospheric pressure drying, vacuum drying, inert gas drying, boiling drying, and freeze drying.

[0038] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0039] 1. It can effectively remove a variety of stubborn impurities and other impurities, with the product purity reaching 99.9% at its best, and specific single impurities less than 0.05% at its best, significantly improving product quality and safety;

[0040] 2. It is easy and efficient to operate, requiring no special equipment, reagents and conditions. It is safe and environmentally friendly, and suitable for large-scale preparation. Attached Figure Description

[0041] Figure 1 The high-performance liquid chromatography (HPLC) spectrum of the clopidogrel bisulfate concentrate prepared in Example 1 is shown. Detailed Implementation

[0042] The technical solution of the present invention will be further described below with reference to the embodiments.

[0043] Example 1

[0044] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand and separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of n-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 47g of clopidogrel bisulfate, with a yield of 94%, purity of 99.88%, and a maximum single impurity of 0.04%.

[0045] Example 2

[0046] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of ethyl acetate to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand and separate the ethyl acetate layer. Control the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5h. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 39g of clopidogrel. Add 320g of n-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, control the temperature at 15°C and stir to allow crystallization for 2h. Filter and dry at room temperature to obtain 45g of clopidogrel bisulfate, with a yield of 90%, purity of 99.86%, and a maximum single impurity of 0.05%.

[0047] Example 3

[0048] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 1.22g of acetic anhydride dropwise, stirring for 0.5h. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 36g of clopidogrel. Add 288g of n-butanol and 1.8g of water, stir to dissolve, cool to below 20°C, and add 10.0g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 43g of clopidogrel bisulfate, with a yield of 86%, purity of 99.89%, and a maximum single impurity of 0.04%.

[0049] Example 4

[0050] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 1.9g of pyridine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5h. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of n-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2h. Filter and dry at room temperature to obtain 46g of clopidogrel bisulfate, with a yield of 92%, purity of 99.87%, and a maximum single impurity of 0.04%.

[0051] Example 5

[0052] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of n-butanol and 4g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 44g of clopidogrel bisulfate, with a yield of 88%, purity of 99.90%, and a maximum single impurity of 0.03%.

[0053] Example 6

[0054] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of n-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 30°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 45g of clopidogrel bisulfate, with a yield of 90%, purity of 99.86%, and a maximum single impurity of 0.04%.

[0055] Example 7

[0056] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 200g of n-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 47g of clopidogrel bisulfate, with a yield of 94%, purity of 99.80%, and a maximum single impurity of 0.06%.

[0057] Example 8

[0058] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of acetone and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 47g of clopidogrel bisulfate, with a yield of 94%, purity of 99.83%, and a maximum single impurity of 0.05%.

[0059] Example 9

[0060] Add 50g of crude clopidogrel bisulfate, 100g of water, and 150g of dichloromethane to a flask. Adjust the pH to 6.0–8.0 by adding 151g of 10% sodium carbonate solution dropwise. Allow the mixture to stand to separate the dichloromethane layer. Maintain the temperature at 15–25°C, add 2.4g of triethylamine, and add 0.94g of acetyl chloride dropwise, stirring for 0.5 hours. Add 40g of 10% sodium carbonate aqueous solution, stir, allow to stand and separate the layers. Concentrate the organic layer to dryness under reduced pressure to obtain 40g of clopidogrel. Add 320g of sec-butanol and 2g of water, stir to dissolve, cool to below 20°C, and add 11.1g of 98% concentrated sulfuric acid dropwise. After the addition is complete, maintain the temperature at 15°C and stir to allow crystallization for 2 hours. Filter and dry at room temperature to obtain 46g of clopidogrel bisulfate, with a yield of 92%, purity of 99.83%, and a maximum single impurity of 0.05%.

[0061] Comparative Example 1

[0062] 50 g of crude clopidogrel bisulfate, 5 mL of water, and 250 mL of acetone were added to a reaction flask. The mixture was heated to 65 °C and stirred until dissolved. The solution was then slowly cooled to 10 °C, and crystallization was carried out with stirring for 1 hour. After filtration and drying, 47 g of clopidogrel bisulfate was obtained, with a yield of 94%, a purity of 99.85%, and a maximum single impurity of 0.06%.

[0063] Comparative Example 2

[0064] 50 g of crude clopidogrel bisulfate, 25 mL of water, and 250 mL of acetonitrile were added to a reaction flask. The mixture was heated to 65 °C and stirred until dissolved. The solution was then slowly cooled to 5 °C, and crystallization was carried out with stirring for 1 hour. After filtration and drying, 47 g of clopidogrel bisulfate was obtained, with a yield of 94%, a purity of 99.65%, and a maximum single impurity of 0.15%.

[0065] Comparative Example 3

[0066] 50 g of crude clopidogrel bisulfate, 75 mL of isopropyl ether, and 225 mL of acetone were added to a reaction flask. The mixture was heated to 65 °C and stirred until dissolved. The solution was then slowly cooled to 10 °C, and crystallization was carried out with stirring for 1 hour. After filtration and drying, 47.5 g of clopidogrel bisulfate was obtained, with a yield of 95%, a purity of 99.70%, and a maximum single impurity of 0.10%.

[0067] Example 10

[0068] 1. Comparative study of the zero-time quality of products prepared by different purification methods

[0069] The purity of crude clopidogrel bisulfate before and after purification was determined by HPLC.

[0070] (1) Sample preparation

[0071] Weigh approximately 65 mg of the sample into a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and mix well.

[0072] (2) Detection conditions

[0073] Chromatographic column: Waters Symmetry C18, 150*3.9mm, 5μm;

[0074] Mobile phase: A: (0.96 g / L sodium pentanesulfonate solution, pH adjusted to 2.5 with phosphoric acid) : methanol = 95 : 5; B: acetonitrile : methanol = 95 : 5;

[0075] Gradient procedure:

[0076] 0 89.5 10.5 3 89.5 10.5 48 31.5 68.5 68 31.5 68.5 70 89.5 10.5 75 89.5 10.5

[0077] Detection wavelength: 220 nm, column temperature: 30 ℃, flow rate: 1.0 ml / min, injection volume: 10 μl;

[0078] Diluent: Mobile phase A: Acetonitrile = 40:60;

[0079] Blank solution: diluent.

[0080] (3) Test results

[0081] The following table compares the impurities in the product before and after refining:

[0082] Clopidogrel hydrogen sulfate crude product 97.50 0.11 0.70 0.26 0.70 Example 1 99.88 0.01 0.04 ND 0.04 Example 2 99.86 0.01 0.05 0.01 0.05 Example 3 99.89 0.01 0.04 0.01 0.04 Example 4 99.87 0.02 0.04 0.01 0.04 Example 5 99.90 0.01 0.03 ND 0.03 Example 6 99.86 0.01 0.04 0.01 0.04 Example 7 99.80 0.02 0.06 0.01 0.06 Example 8 99.83 0.01 0.05 0.02 0.05 Example 9 99.83 0.02 0.05 0.03 0.05 Comparative Example 1 99.85 0.06 0.05 0.03 0.06 Comparative Example 2 99.65 0.07 0.15 0.08 0.15 Comparative Example 3 99.70 0.05 0.10 0.07 0.10

[0083] 2. Comparative study on the long-term stability of products prepared by different purification methods

[0084] To further illustrate the superiority of the clopidogrel bisulfate product prepared by this invention, a comparison was made under long-term stability test conditions, using physical properties, purity, and content as representative indicators. The specific comparison results are shown in the table below:

[0085]

[0086] Therefore, the purification method of the present invention can obtain clopidogrel bisulfate with a purity of ≥99.8% and a single impurity of ≤0.06%, and with more stable quality. It can effectively remove a variety of stubborn impurities and other impurities, which is beneficial to improving product quality and safety.

Claims

1. A method for purifying clopidogrel bisulfate, characterized in that, Includes the following steps: (1) The crude clopidogrel bisulfate was mixed with water and solvent one, and the salt was dissolved by adding alkali and separated to obtain organic phase one; (2) Mix organic phase I with hydroxyl protectant and base I, and react them; (3) After quenching with alkali and separation, organic phase II is obtained and then concentrated to dryness; (4) The concentrate is mixed with solvent II and water to dissolve it, and after salt formation, crystallization, separation and drying, clopidogrel bisulfate is obtained; The solvent mentioned in step (1) is selected from ethyl acetate and dichloromethane, and the pH value adjusted by desalting is 6~8; The hydroxyl protectant mentioned in step (2) is selected from acetyl chloride and acetic anhydride, and the molar ratio of the hydroxyl protectant to crude clopidogrel bisulfate is 0.1:1; the base is selected from pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, dimethylisopropylamine, 1-methylpiperidine, and 4-methylmorpholine, and the molar ratio of the base to the hydroxyl protectant is 0.2:1; The solvent in step (4) is selected from n-butanol, acetone, and sec-butanol, and the salt formation temperature is no more than 20°C.

2. The purification method according to claim 1, characterized in that, The alkali mentioned in step (3) is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, and ammonia.

3. The purification method according to claim 1, characterized in that, The mass ratio of the concentrate to water in step (4) is 10:1 to 50:

1.

4. The purification method according to claim 1, characterized in that, The mass ratio of the concentrate to solvent II in step (4) is 1:10 to 1:

5.

5. The purification method according to claim 1, characterized in that, The crystallization temperature in step (4) is -5~35℃.

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