Preparation method of trospium chloride

Abstract

The invention provides a preparation method of trospium chloride. The preparation method of trospium chloride comprises the following steps: dissolving a trospium chloride crude product in a mixed solution of methanol and ethanol, and filtering; and (2) adding methyl tert-butyl ether into the filtrate obtained in the step (1), fully and uniformly mixing, cooling, crystallizing, filtering and drying to obtain trospium chloride. The preparation method is simple and feasible, the target product yield is high, impurities such as the product impurity C can be effectively controlled, the solvent residue content is low, the purity is high, the clarity can meet the EP pharmacopoeia standard, and the industrial application prospect is good.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a method for preparing high-purity, high-yield, high-clarity, and low-solvent-residue trox chloride. Background Technology

[0002] Trax chloride is an orally administered quaternary ammonium compound with antagonistic effects against muscarinic drugs. Also known as tosbimuth subsalicylate, its chemical name is 3-diphenylethanolylnorhyoscyamine-8-spiro-1-pyrrolidine chloride. Developed by Madaus AG in Germany, it was first marketed in Germany in 1990 and is widely used clinically as an anti-urinary incontinence drug. Cobenfy (KarXT, trax chloride / trisbimethinazole), a novel combination oral muscarinic antipsychotic developed by Bristol-Myers Squibb (BMS), was approved by the US FDA in September 2024 for the treatment of schizophrenia in adults.

[0003] The publicly disclosed preparation methods for troxammonium chloride are as follows: The paper "Research on the Synthesis Process of Tris-Ammonium Chloride" published by Zhao Wenjing et al. (Zhao Wenjing, Gao Lihu, Zhu Nianqing. Research on the Synthesis Process of Tris-Ammonium Chloride [J]. Guangdong Chemical Industry, 2009, 036(012):65-66) reported a preparation scheme of the finished product using isopropanol as the refining solvent. In this scheme, crude tris-ammonium chloride is dissolved in isopropanol under reflux, and insoluble matter is removed by hot filtration. The product is then obtained by cooling and crystallization. The specific process is as follows: The obtained tris-ammonium chloride (estimated to be about 18g based on the yield) is heated to reflux for 30 min with 120 mL of isopropanol, the insoluble matter is filtered off, and the mixture is allowed to stand and cool to precipitate white crystals. After filtration and drying, 15.3 g of refined tris-ammonium chloride is obtained, with a yield of 85%.

[0004] However, upon repetition of this scheme (see Comparative Example 1 of this invention), it was found that this scheme used isopropanol as the solvent for the final product. The recrystallization reaction system required reflux at a weight ratio of 63 times that of isopropanol to achieve complete dissolution, resulting in a product yield of only 67.2%. Furthermore, the purified product contained a high level of isopropanol (0.37% residue), which was difficult to remove by drying. This purification process also showed poor removal of impurity C, with a detection rate of 0.32% in the product, failing to meet the limits set by USP NF2025. The clarity of the product obtained using this process also did not meet the requirements of EP11.8.

[0005] The paper "Synthesis of Tris-Chronic Acid" published by Liu Suyun et al. (Liu Suyun. Synthesis of Tris-Chronic Acid [J]. China Pharmaceutical Industry Magazine, 2010, 41(3):2) reported an experimental scheme for purification using a mixed solvent of ethanol / ether. The specific description is as follows: crude tris-chronic acid was recrystallized with ethanol-ether (3:2), filtered, and dried under reduced pressure at 40 °C for 10 h to obtain white solid tris-chronic acid (0.66 kg, 43%).

[0006] However, when the scheme was repeated, using the reported ethanol: ether = 3:2 volume ratio mixed solvent, the crude product could not be dissolved even when 80 times its weight of the mixed solvent tresamine chloride was added under high temperature reflux conditions. Furthermore, ether is a flammable solvent with a low flash point, posing a safety hazard in production. It is difficult to achieve large-scale industrial production using this scheme.

[0007] The paper "Study on the Synthesis Process of Tris-Cl" published by Song Weiguo et al. (Song Weiguo, Yang Dawei, Gao Dongsheng, et al. Study on the Synthesis Process of Tris-Cl [J]. Chinese Journal of Medicinal Chemistry, 2016) reported an experimental scheme using ethanol as the purification solvent, which is described as follows: crude tris-cleanserium chloride (estimated to be about 5 g based on the yield) was recrystallized with anhydrous ethanol (40 mL), filtered, and dried to obtain 4.0 g of white solid (tris-cleanserium chloride), with a yield of 80%.

[0008] However, upon repetition of the proposed method, crude trexammonium chloride could be dissolved using the reported purified solvent ethanol under high-temperature reflux conditions. After filtration and cooling crystallization, trexammonium chloride could be obtained (see Comparative Example 2 of this invention for details). This method had a low yield of only 56.0%; a high ethanol content of 0.20% in the product; the clarity of the obtained trexammonium chloride did not meet the requirements of EP11.8; and the detection level of impurity C in the product was 0.27%, exceeding the limit requirements of USP NF2025.

[0009] Trisamine chloride is a quaternary ammonium salt. According to the principle of "like dissolves like", it is generally purified and purified by solvents with high polarity such as alcohols. However, under the condition that most alcohol solvents are used as purification solvents, the purified trisamine chloride is prone to the problem of excessive residual solvent content, which may lead to unqualified product quality.

[0010] Meanwhile, the trex chloride impurity C (azaspirol chloride) listed in EP11.8 and USP NF2025 is also a quaternary ammonium salt, and the two have similar solubility properties. The currently disclosed purification methods are all ineffective in removing this impurity.

[0011]

[0012] Furthermore, clarity is also a key challenge severely restricting the quality of troxammonium chloride, influenced by factors such as product purity and solvent residue. According to currently available methods for preparing troxammonium chloride, the resulting product is unlikely to meet the clarity requirements for troxammonium chloride specified in the EP11.8 edition of the Pharmacopoeia.

[0013] In summary, all currently disclosed methods for preparing trox chloride suffer from low yields, ineffective control of impurities such as impurity C, high solvent residues, and clarity that fails to meet one or more of the requirements in EP11.8. Therefore, it is urgent to develop a method for preparing trox chloride that is easy to operate, has a high yield, allows for effective control of impurities such as impurity C, meets ICH Q3C requirements for solvent residues, and achieves clarity that meets the EP11.8 version of the pharmacopoeia standard. Summary of the Invention

[0014] To address the shortcomings of existing technologies, this invention provides a method for preparing tromethamine chloride. The preparation method of this invention is simple and feasible, yields a high target product, effectively controls impurities such as C, has low solvent residue, high purity, and clarity that meets the EP11.8 edition of the Pharmacopoeia standard, demonstrating promising prospects for industrial application.

[0015] The technical solution of the present invention is as follows: A method for preparing tromethamine chloride, comprising the following steps: (1) Dissolve crude trexammonium chloride in a mixture of methanol and ethanol, and filter; (2) Add methyl tert-butyl ether to the filtrate from step (1), mix thoroughly, cool to crystallize, filter, and dry to obtain triammonium chloride.

[0016] According to the present invention, in step (1), crude troxammonium chloride is prepared by existing methods. The crude troxammonium chloride can be prepared according to the method reported in the literature "Research on the Synthesis Process of Troxammonium Chloride" published by Zhao Wenjing et al. Preferably, the preparation method of crude troxammonium chloride includes the following steps: adding (3α-nortropinol)-8-spiro-1'-pyrrole ammonium chloride to acetonitrile, heating under reflux, adding 4-dimethylaminopyridine, then adding imidazole diphenylglycolic acid, reacting under reflux and stirring, reacting under room temperature stirring, filtering, and drying to obtain crude troxammonium chloride. (3α-nortropinol)-8-spiro-1'-pyrrole ammonium chloride and imidazole diphenylglycolic acid have the following structures respectively:

[0017] According to a preferred embodiment of the present invention, in step (1), the weight ratio of methanol to ethanol is 1:1 to 4, and more preferably 1:2 to 4.

[0018] According to a preferred embodiment of the present invention, in step (1), the weight ratio of the mixed solution of methanol and ethanol to crude trexammonium chloride is 4:0.5~1.5, preferably 4:1.

[0019] According to a preferred embodiment of the present invention, in step (2), the weight ratio of methyl tert-butyl ether to crude tromethamine chloride is 10-15:1, preferably 12:1.

[0020] The technical features and beneficial effects of this invention are as follows: (1) The present invention uses a methanol / ethanol / methyl tert-butyl ether system for purification. The methanol and ethanol purification system can effectively remove impurities such as C, while having poor solubility for insoluble substances that affect the clarity of the product. The insoluble substances can be removed by filtration.

[0021] (2) The yield of the target product is low when using a methanol / ethanol mixture alone, and there is a large amount of solvent residue in the product. Adding methyl tert-butyl ether to the purification solvent can improve the yield and effectively reduce the solvent residue in the product.

[0022] (3) The present invention uses a specific type and ratio of solvent as a refining solvent to obtain a product with low solvent residue, high yield and high purity. It can effectively reduce impurity C to 0 and the clarity can meet the EP11.8 version of the pharmacopoeia standard.

[0023] (4) The purification conditions of the present invention are mild, the operation is simple, the production cost is reduced, and it is suitable for industrial production. Attached Figure Description

[0024] Figure 1 The image shows the 1H NMR spectrum of troxammonium chloride obtained under the experimental conditions shown in Table 7-5 of Example 5 of this invention.

[0025] Figure 2 The mass spectrum (HRMS) of trexammonium chloride obtained under the experimental conditions shown in Table 7-5 of Example 5 of this invention is shown.

[0026] Figure 3 The high-performance liquid chromatogram (HPLC) of tromethamine obtained under the experimental conditions shown in Table 7-5 of Example 5 of this invention is shown.

[0027] Figure 4 The differential refractive index chromatogram of troxammonium chloride obtained under the experimental conditions shown in Table 7-5 of Example 5 of this invention is shown.

[0028] Figure 5 The image shows the gas chromatogram (GC) of tromethamine obtained under the experimental conditions shown in Table 7-5 of Example 5 of this invention. Detailed Implementation

[0029] The following detailed embodiments further illustrate the above-mentioned content of the present invention. However, the embodiments should not be construed as any limitation on the present invention. The scope of protection of the present invention is determined by the claims. Unless otherwise specified, the following embodiments are all carried out using conventional prior art.

[0030] 1. Related substances detection method: High performance liquid chromatography (HPLC) Method: USP NF2025 Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Kromasil 100-5-C18, 4.6 mm × 250 mm, 5 μm recommended); water-triethylamine-phosphate-acetonitrile (v / v 700:1:3:300) was used as the mobile phase; the flow rate was 1.0 mL / min; the column temperature was 40 °C; the detection wavelength was 215 nm; and the injection volume was 20 μL.

[0031] 2. Residual solvent detection method: Gas chromatography Chromatographic conditions: A capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary phase was used (Agilent DB-624, 30m × 0.53mm × 3µm or equivalent column is recommended); the initial temperature was 40℃, maintained for 10 minutes, then increased to 140℃ at a rate of 20℃ / min, and then increased to 240℃ at a rate of 50℃ / min, maintained for 10 minutes; the carrier gas flow rate was 2mL / min; the injection port temperature was 230℃; the detector was a flame ionization detector (FID) at a temperature of 250℃; the split ratio was 20:1; the headspace vial equilibration temperature was 80℃, and the equilibration time was 30 minutes.

[0032] 3. Tris-chlorine impurity C: Differential refractive index detection method Source: USP NF2025 Chromatographic conditions: Use an octadecylsilane-bonded silica column (GL Sciences Inertsil ODS-3, 4.6 mm × 250 mm, 5 μm or equivalent column recommended); use water-acetonitrile-formic acid (80:20:0.2 v / v) as the mobile phase; flow rate: 0.8 mL / min; column temperature: 40 °C; detector: differential refractive index detector; injection volume: 10 μL.

[0033] 4. Method for testing the clarity of ammonium chloride. Source: EP11.8 Test method: Clarity and color of solution: Take 3.0g of this product and dissolve it in 30mL of freshly boiled and cooled purified water. The solution should be clear and colorless. If it is turbid, compare it with turbidity standard solution No. 1 (European Pharmacopoeia General Chapter 2.2.1). It should not be more concentrated. If it is colored, compare it with standard solution B7 (European Pharmacopoeia General Chapter 2.2.2 Method II). It should not be more dark.

[0034] 5. Preparation method of crude tromethamine chloride The crude trexammonium chloride used in this invention was prepared according to the method reported in the literature "Research on Synthesis Process of Trexammonium Chloride" published by Zhao Wenjing et al. (Zhao Wenjing, Gao Lihu, Zhu Nianqing. [J]. Guangdong Chemical Industry, 2009, 036(012):65-66.). The specific process is as follows: 1.0 kg of (3α-nortropinol)-8-spiro-1'-pyrrole ammonium chloride and 31.3 L of acetonitrile were added to a reaction flask, and the mixture was heated and stirred under reflux. 0.6 g of 4-dimethylaminopyridine was added, followed by 1.25 kg of imidazole diphenylglycolic acid. The reaction mixture was heated to reflux with acetonitrile and stirred under reflux for 4 hours. After stirring overnight at room temperature, the mixture was filtered and dried to obtain crude trexammonium chloride, yielding 933.0 g, a yield of 60.30%. The crude product contained 0.22% impurity A, 0.31% impurity B, and 0.63% impurity C. All comparative examples and embodiments in this invention used this batch of crude product for purification.

[0035] The crude trozine chloride was purified using the purification method described in the literature "Study on Synthesis Process of Trozine Chloride" published by Zhao Wenjing et al. (Zhao Wenjing, Gao Lihu, Zhu Nianqing. [J]. Guangdong Chemical Industry, 2009, 036(012):65-66.). The specific steps are as follows: 18.0 g of crude trexammonium chloride was added to a reaction flask, and isopropanol was added under reflux until dissolved. A total of 1134.0 g of isopropanol was added. The insoluble matter was filtered off, and the mixture was allowed to stand and cool. White crystals precipitated. The crystals were filtered and dried under vacuum (-0.07 MPa to -0.1 MPa) at 50-60°C for 6 hours to obtain 12.1 g of refined trexammonium chloride. The yield was 67.2%.

[0036] The test results of the obtained products are shown in Table 1 below: Table 1

[0037] Experimental results show that using isopropanol alone as the refining solvent results in low yield, excessive C impurity, and the obtained triammonium chloride product has high residual solvent and unqualified clarity.

[0038] The crude troxamine chloride was purified using the purification method reported in the literature "Study on the Synthesis Process of Troxamine Chloride" published by Song Weiguo et al. (Song Weiguo, Yang Dawei, Gao Dongsheng, et al. [J]. Chinese Journal of Medicinal Chemistry, 2016.). The specific steps are as follows: Add 5.0 g of crude trexammonium chloride to a reaction flask, add 40 mL of anhydrous ethanol, heat to reflux, dissolve, cool to room temperature and stir, filter, and dry under vacuum (vacuum degree -0.07 MPa to -0.1 MPa) at 50~60℃ for 6 h to obtain 2.8 g of white solid trexammonium chloride, yield 56.0%.

[0039] The test results of the obtained products are shown in Table 2 below: Table 2

[0040] Experimental results show that the ethanol purification method results in low product yield, excessive C impurity, and high ethanol residue and unqualified clarity of the obtained trexammonium chloride product.

[0041] Experimental Example 1: Effect of different recrystallization solvents on the yield and quality of trexammonium chloride Add 20g of different solvents to a 500mL three-necked flask, start stirring, add 5.0g of crude trexammonium chloride, heat to reflux, and stir under reflux until the crude product dissolves. If it does not dissolve, add more solvent until clear, then filter. Cool the filtrate to -5℃ to 0℃ and stir at -5℃ to 0℃ for 4 hours to allow crystals to precipitate. Filter and dry under vacuum (-0.07MPa to -0.1MPa) at 50℃ for 6 hours to obtain trexammonium chloride.

[0042] The effects of different recrystallization solvents on the yield of trox ammonium chloride, residual solvent, impurity C content and clarity (EP11.8 standard) are shown in Table 3.

[0043] Table 3

[0044] Experimental results show that when recrystallizing with water, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, the product did not precipitate after cooling because these solvents have good solubility in the product.

[0045] When recrystallizing using ethyl acetate, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, methyl tert-butyl ether, isopropyl ether, or n-heptane, tres chloride has poor solubility in these solvents due to its quaternary ammonium salt structure; even when the solvent is added to 100 times the weight of the crude product, none of them dissolve.

[0046] When using alcohol solvents for crystallization, methanol can effectively reduce the content of impurity C, but the purified product has a low yield, a large amount of solvent residue, and the product clarity does not meet the EP standard. Other single alcohol solvents such as anhydrous ethanol, isopropanol, tert-butanol, and n-butanol can be used for recrystallization, but the resulting products have unacceptable levels of impurity C and clarity.

[0047] Experimental Example 2: Effect of different mixed solvents on the yield and quality of trexammonium chloride Add 20g of different solvents to a 500mL three-necked flask, start stirring, add 5.0g of crude trexammonium chloride, heat to reflux, and stir under reflux until the crude product dissolves. If it does not dissolve, add more solvent until clear, then filter. Cool the filtrate to -5℃ to 0℃ and stir at -5℃ to 0℃ for 4 hours to allow crystals to precipitate. Filter and dry under vacuum (-0.07MPa to -0.1MPa) at 50℃ for 6 hours to obtain trexammonium chloride.

[0048] The effects of different recrystallization solvents on the yield of trox ammonium chloride, residual solvent, impurity C content and clarity (EP11.8 standard) are shown in Table 4.

[0049] Table 4

[0050] Experimental results show that, when recrystallizing using a mixed solvent of water and alcohol, the product fails to precipitate under the conditions of a water / methanol mixed solvent. In addition, the product obtained by recrystallization under the conditions of a mixed solvent of water and anhydrous ethanol, isopropanol, tert-butanol and n-butanol has unqualified impurity C and clarity.

[0051] When recrystallized from methanol with isopropanol, tert-butanol, and n-butanol as a mixed solvent, the resulting product failed to meet standards for impurity C and clarity. While a mixed solvent of methanol and ethanol (methanol:anhydrous ethanol weight ratio = 1:2) yielded products with acceptable impurity C and clarity, the solvent residue was unacceptable and the yield was low. Adjusting the methanol:anhydrous ethanol ratio to between 1:1 and 4 resulted in products with acceptable impurity C and clarity, but still suffered from low yield and unacceptable solvent residue.

[0052] Example 3: Effect of reverse solvent type and solvent ratio on the yield and quality of trexammonium chloride Add 20g of methanol / anhydrous ethanol mixed solvent to a 200mL three-necked flask, start stirring, add 5.0g of crude trexammonium chloride, heat to reflux, stir under reflux until the crude product dissolves, if it does not dissolve, add more solvent until clear, and filter.

[0053] After cooling the filtrate to 30℃, 50.0 g of the reverse solvent was added dropwise. After the addition was complete, the mixture was stirred thoroughly until homogeneous. The mixture was then cooled to -5℃ to 0℃ and stirred at -5℃ to 0℃ for 4 hours to induce crystallization. The mixture was then filtered and dried under vacuum at 50℃ (vacuum degree -0.07MPa to -0.1MPa) for 6 hours to obtain trexammonium chloride.

[0054] The effects of different recrystallization solvents on the yield of trox ammonium chloride, residual solvent, impurity C content and clarity (EP11.8 standard) are shown in Table 5.

[0055] Table 5

[0056] Experimental results show that the yield is improved to some extent by adding the reverse solvents methyl tert-butyl ether, isopropyl ether, and diethyl ether, but the removal effect of impurity C and solvent residue is poor under the conditions of isopropyl ether and diethyl ether. The yield is not improved by adding the reverse solvents n-heptane, n-hexane, toluene, acetonitrile, tetrahydrofuran, and 1,4-dioxane, and the removal effect of impurity C and solvent residue is poor.

[0057] Using methyl tert-butyl ether can significantly improve the yield, especially in controlling residual solvent, and it also has a good ability to remove impurity C. When the weight ratio of methanol to anhydrous ethanol is 1:1 to 4, adding 10 times the weight of the crude product of methyl tert-butyl ether yields the best product quality and the highest yield.

[0058] Example 4: Effect of methanol / anhydrous ethanol dosage on the yield and quality of trexammonium chloride Add a methanol / anhydrous ethanol (weight ratio = 1:3) mixture to a 200mL three-necked flask, start stirring, add 5.0g of crude trexammonium chloride, heat to reflux, stir under reflux until the crude product dissolves, and filter.

[0059] After cooling the filtrate to 30℃, 50.0 g of methyl tert-butyl ether was added dropwise. After the addition was complete, the mixture was stirred thoroughly until homogeneous. The mixture was then cooled to -5℃ to 0℃ and stirred at -5℃ to 0℃ for 4 hours to induce crystallization. The mixture was then filtered and dried under vacuum at 50℃ (vacuum degree -0.07MPa to -0.1MPa) for 6 hours to obtain trexammonium chloride.

[0060] The effects of different weight ratios of methanol / anhydrous ethanol to crude trox chloride on the yield, residual solvent, impurity C content, and clarity (EP11.8 standard) of trox chloride are shown in Table 6.

[0061] Table 6

[0062] Experimental results show that when recrystallizing using a fixed amount of methanol / anhydrous ethanol mixed solvent, the weight ratio of the methanol / anhydrous ethanol mixed solvent to crude trastium chloride also has a certain impact on the yield and product quality. When the amount of mixed solvent is relatively small compared to crude trastium chloride, crude trastium chloride cannot be dissolved. When the weight ratio of methanol / anhydrous ethanol mixed solvent to crude trastium chloride is between 4:0.5 and 1.5, the purified trastium chloride product is qualified and has a high yield.

[0063] Example 5: Effect of different ratios of methyl tert-butyl ether to crude trox chloride on the quality of trox chloride Add 20.0 g of methanol / anhydrous ethanol (weight ratio = 1:3) mixed solvent to a 200 mL three-necked flask, start stirring, add 5.0 g of crude trexammonium chloride, heat to reflux, stir the crude product under reflux until dissolved, and filter.

[0064] After cooling the filtrate to 30°C, methyl tert-butyl ether was added dropwise. After the addition was complete, the mixture was stirred thoroughly until homogeneous. The temperature was then lowered to -5°C to 0°C, and the mixture was stirred at -5°C to 0°C for 4 hours to induce crystallization. The mixture was then filtered and dried under vacuum at 50°C (vacuum degree -0.07MPa to -0.1MPa) for 6 hours to obtain trexammonium chloride.

[0065] The effects of different ratios of methyl tert-butyl ether to crude trox chloride on the yield, residual solvent, impurity C content, and clarity (EP11.8 standard) of trox chloride are shown in Table 7.

[0066] Table 7

[0067] Experimental results show that the amount of methyl tert-butyl ether has a certain impact on the yield and product quality. When the amount of methyl tert-butyl ether used is small, the yield is low; when the amount of methyl tert-butyl ether used is high, although the yield increases, the content of impurity C increases significantly; when the ratio of methyl tert-butyl ether used to crude product exceeds 12:1, the yield does not change significantly. Considering factors such as product quality and yield, a weight ratio of methyl tert-butyl ether to crude tromethorphan chloride of 10~15:1 results in better recrystallization.

[0068] Table 7-5 1H NMR spectra of trexammonium chloride obtained under experimental conditions ( 1 H-NMR) such as Figure 1 As shown; HRMS mass spectrum as shown Figure 2 As shown; High Performance Liquid Chromatography (HPLC) chromatogram as shown. Figure 3 As shown; Differential refractive index high performance liquid chromatogram of trexammonium chloride (detection of impurity C) is as follows. Figure 4 As shown; Gas chromatogram (GC) as follows Figure 5As shown in the figure. The test data indicates that the present invention successfully obtained the target product. The high-performance liquid chromatography (HPLC) chromatogram shows that no impurities were detected in the troxammonium chloride prepared according to the optimal method of the present invention, and impurity C was also not detected under differential refractive index detection. The gas chromatogram (the upper curve is the residual solvent localization chromatogram, and the lower curve is the product residual solvent detection chromatogram) shows that no residual purified solvent was detected in the troxammonium chloride prepared according to the optimal method of the present invention. The quality of the product obtained by the present invention meets the pharmacopoeia standards of ICH, EP, and USP.

Claims

1. A method for preparing troxammonium chloride, comprising the following steps: (1) Dissolve crude trexammonium chloride in a mixture of methanol and ethanol, and filter; (2) Add methyl tert-butyl ether to the filtrate from step (1), mix thoroughly, cool to crystallize, filter, and dry to obtain triammonium chloride.

2. The method for preparing trexammonium chloride according to claim 1, characterized in that, In step (1), the weight ratio of methanol to ethanol is 1:1 to 4.

3. The method for preparing trexammonium chloride according to claim 2, characterized in that, The weight ratio of methanol to ethanol is 1:2~4.

4. The method for preparing trexammonium chloride according to claim 1, characterized in that, In step (1), the weight ratio of the mixture of methanol and ethanol to crude trexammonium chloride is 4:0.5~1.

5.

5. The method for preparing trexammonium chloride according to claim 4, characterized in that, The weight ratio of the methanol and ethanol mixture to crude triammonium chloride was 4:

1.

6. The method for preparing trexammonium chloride according to claim 1, characterized in that, In step (2), the weight ratio of methyl tert-butyl ether to crude triammonium chloride is 10~15:

1.

7. The method for preparing trexammonium chloride according to claim 6, characterized in that, The weight ratio of methyl tert-butyl ether to crude triammonium chloride is 12:1.

Images