Synthesis method of diatrizoic acid impurities B and C

Abstract

The invention discloses a synthesis method of diatrizoic acid impurities B and C. The synthesis method comprises the following steps: taking diatrizoic acid as a raw material, firstly carrying out a salt forming reaction with MOH to generate diatrizoic acid salt, carrying out a deiodination reaction on the diatrizoic acid salt in the presence of a deiodination reagent, then acidifying with an acidifying reagent to generate a mixture of the diatrizoic acid impurity B and the diatrizoic acid impurity C, pulping the mixture with methanol, and separating to obtain the diatrizoic acid impurity B and the diatrizoic acid impurity C, performing high performance liquid chromatography separation to obtain a diatrizoic acid impurity B and a diatrizoic acid impurity C; wherein M is selected from K, Na and Li. According to the method, high-purity diatrizoic acid impurities B and C can be obtained, the HPLC purity of the diatrizoic acid impurity B can reach 98% or above, the HPLC purity of the diatrizoic acid impurity C can reach 99% or above, and important impurity guarantee is provided for production and medication safety of diatrizoic acid.

Description

Technical Field

[0001] This invention relates to a method for preparing diatrizoic acid impurities B and C. Background Technology

[0002] Diatrizoic acid, chemically known as 3,5-diacetamido-2,4,6-triiodobenzoic acid dihydrate, is a positive contrast agent used in X-ray diagnosis. It is generally formulated into meglumine diatrizoate, sodium diatrizoate, or compound meglumine diatrizoate injections for use. It is suitable for arteriovenous angiography, excretory or retrograde urinary tract angiography, and also for enhanced whole-body computed tomography (CT) scans. As a commonly used active pharmaceutical ingredient (API) for diagnostic injections, the impurity content of diatrizoic acid directly affects the safety, efficacy, and stability of the drug, as well as the health of consumers. API impurities are a core risk source for formulation quality. Through scientific risk assessment, advanced technical methods, and strict regulatory compliance, the hazards of impurities can be minimized, ensuring the safety and effectiveness of medication for patients.

[0003] The structures of the diatrizoic acid impurities of concern to the European Pharmacopoeia (EP), namely impurities A, B, C, and D, are as follows:

[0004]

[0005] Impurity A of diatrizoate: There are many methods for its synthesis, and it is readily available and inexpensive with many market suppliers.

[0006] Impurity B of diatrizoate: There are no literature or patent reports on its synthesis method at home and abroad, there are few suppliers on the market, it is not easy to obtain, and it is expensive.

[0007] Impurity C of diatrizoate: There are very few reports in domestic and international literature and patents, and it is difficult to obtain as there are no suppliers on the market. Only its synthesis method is reported in the literature (Journal of the American Chemical Society, 1956, vol. 78, pp. 3210, 3215), and the synthesis method is as follows:

[0008]

[0009] This method cannot obtain high-purity diatrizoate impurity C. Analysis of its reaction characteristics confirms, without any apparent reason, that the iodination process inevitably produces 2,4-diiodocyanine byproducts, which can generate impurity B during the final acylation process. Impurity B has a structure similar to EP impurity C and is difficult to remove by crystallization. Furthermore, the Raney nickel catalyst (Ra-Ni) is easily ignited.

[0010] Impurity D in diatrizoate: No literature or patent reports.

[0011] In summary, impurities B, C, and D in diatrizoate acid suffer from drawbacks such as limited suppliers, high prices, and difficulty in obtaining high-purity impurities. These limitations restrict companies from conducting systematic quality studies and developing efficient analytical methods for the active pharmaceutical ingredient (API) diatrizoate acid, directly impacting the safety, efficacy, and stability of the API. To overcome these shortcomings, exploring a sustainable, simple, and readily available synthetic and purification method for impurities B and C in diatrizoate acid EP is urgently needed. Summary of the Invention

[0012] The purpose of this invention is to provide a method for synthesizing diatrizoic acid impurities B and C.

[0013] The objective of this invention is achieved through the following technical solution:

[0014] A method for synthesizing diatrizoic acid impurities B and C, the synthetic route is as follows:

[0015]

[0016] Wherein: M is selected from K, Na, Li, etc.;

[0017] The process includes: using diatrizoic acid as a raw material, first reacting it with MOH to form a salt to generate diatrizoic acid salt, then, in the presence of a deiodizing reagent, the diatrizoic acid salt undergoes a deiodization reaction, and then is acidified with an acidifying reagent to generate a mixture of diatrizoic acid impurity B and diatrizoic acid impurity C. The mixture is then slurried with methanol to remove a large number of impurities, and finally separated by high performance liquid chromatography to obtain diatrizoic acid impurity B and diatrizoic acid impurity C.

[0018] The MOH is one of NaOH, KOH, LiOH, etc., preferably LiOH.

[0019] The molar ratio of MOH to diatrizoate is 1:1 to 5:1, preferably 2:1 to 2.2:1.

[0020] The reaction solvent for the salt formation reaction is purified water; the mass-to-volume ratio of diatrizoate to purified water is 1:10 to 1:30 g / mL, preferably 1:20 g / mL.

[0021] The temperature of the salt-forming reaction is 20–50°C, preferably 40°C; the time of the salt-forming reaction is 4–6 hours, preferably 5 hours.

[0022] Specifically, the salt formation reaction is as follows: MOH is dissolved in purified water, and diatrizoic acid is added in batches at a temperature of 10-15℃; the temperature is raised to the salt formation reaction temperature to carry out the salt formation reaction; after the reaction is completed, the reaction solution is concentrated to 1 / 3 to 1 / 6 of the volume of purified water, cooled to 10-20℃, filtered, and vacuum dried at 50-60℃ to obtain diatrizoic acid salt.

[0023] The deiodine removal reagent is one of n-butyllithium (n-BuLi), isopropyl magnesium chloride (i-PrMgCl), isopropyl magnesium bromide (i-PrMgBr), etc., preferably i-PrMgCl.

[0024] The molar ratio of the deiodination reagent to diatrizoate is 1:1 to 1.5:1, preferably 1.2:1.

[0025] The reaction solvent for the deiodination reaction is one of tetrahydrofuran (THF), methyltetrahydrofuran, etc., preferably tetrahydrofuran. The mass-to-volume ratio of diatrizoate to the reaction solvent is 1:20 to 1:50 g / mL, preferably 1:25 to 1:28 g / mL.

[0026] The temperature of the deiodination reaction is 20–60°C, preferably 40–60°C, and more preferably 50°C.

[0027] The deiodination reaction is carried out by mixing diatrizoate and reaction solvent, and adding a solution of deiodination reagent dropwise to the above system under nitrogen protection.

[0028] Specifically, the deiodination reaction is as follows: diatrizoate and reaction solvent are mixed and cooled to 5-10°C. Under nitrogen protection, the solution of the deiodination reagent is added dropwise to the above system. After the addition is complete, the temperature is raised to the deiodination reaction temperature to carry out the deiodination reaction.

[0029] The solution of the deiodination reagent is prepared using the reaction solvent of the deiodination reaction.

[0030] The acidifying agent is one of hydrochloric acid, sulfuric acid, citric acid aqueous solution, acetic acid aqueous solution, etc., preferably hydrochloric acid.

[0031] Specifically, the concentration of the acidifying reagent is 1N.

[0032] Preferably, the pH of the system is adjusted to 2-3 using an acidifying agent.

[0033] The acidification temperature is 5-10°C; the acidification reaction time is 8-12 hours, preferably 10 hours.

[0034] Specifically, the acidification process involves: after the deiodination reaction is completed, the temperature is lowered to 5-10°C, and the pH of the system is adjusted to 2-3 using an acidification reagent to generate a mixture of diatrizoic acid impurity B and diatrizoic acid impurity C.

[0035] Preferably, after acidification, the mixture is filtered, and the filter cake is washed with purified water to obtain a crude product consisting of a mixture of diatrizoic acid impurity B and diatrizoic acid impurity C.

[0036] The pulping process is repeated 1 to 3 times; the pulping temperature is room temperature; each pulping session lasts 1 hour; and the pulp is filtered after each pulping session.

[0037] During each pulping process, the mass-to-volume ratio of the diatrizoate to methanol is 1:3.5 to 1:4 g / mL.

[0038] The high-performance liquid chromatography (HPLC) separation conditions are as follows: PREP-ODS-C18 column (particle size 15 μm, length 250 mm × diameter 20 mm); mobile phase A: acetonitrile, mobile phase B: water-trifluoroacetic acid (40:0.05 V / V); gradient elution: 0.00-60 min, 0%-30% mobile phase B; 60-180 min, 30%-95% mobile phase B; flow rate 6 mL / min; column temperature 30 °C; detection wavelength 254 nm.

[0039] The beneficial effects of this invention are:

[0040] The method of this invention can obtain high-purity diatrizoate impurities B and C. The HPLC purity of diatrizoate impurity B can reach over 98%, and the HPLC purity of diatrizoate impurity C can reach over 99%. The method of this invention is sustainable and efficient, providing reliable impurity assurance for systematic quality research on the active pharmaceutical ingredient diatrizoate and the development of efficient analytical methods, and providing important impurity assurance for the production and safe use of diatrizoate. Attached Figure Description

[0041] Figure 1 The 1H NMR spectrum of diatrizoic acid impurity B prepared in Example 1.

[0042] Figure 2 The image shows the LCMS spectrum of diatrizoate impurity B obtained in Example 1.

[0043] Figure 3 The HPLC chromatogram of diatrizoate impurity B obtained in Example 1 is shown.

[0044] Figure 4 The 1H NMR spectrum of the diatrizoic acid impurity C prepared in Example 1 is shown.

[0045] Figure 5 The image shows the LCMS spectrum of diatrizoate impurity C obtained in Example 1.

[0046] Figure 6 The image shows the HPLC chromatogram of diatrizoate impurity C obtained in Example 1. Detailed Implementation

[0047] The following examples are helpful in understanding the technical solutions of the present invention, but the present invention includes, but is not limited to, the following related content.

[0048] Example 1

[0049] Preparation of lithium diatrizoate: Purified water (300 mL) and LiOH·H₂O (2.1 g) were added to a 500 mL jacketed flask and cooled to 15 °C. Diatrizoic acid (15.0 g) was added to the system in three portions, 5.0 g each time. The temperature was adjusted to 40 °C and the reaction was carried out at this temperature for 5 h. After the reaction was completed, the reaction system was concentrated to about 55 mL, cooled to 10 °C, filtered, and dried under vacuum at 55 °C to obtain lithium diatrizoate (13.5 g, yield 91.8%), a white solid, which was directly used in the next step.

[0050] Synthesis of diatrizoate impurities B and C: Anhydrous tetrahydrofuran (325 mL) and lithium diatrizoate (13.0 g) were added to a 500 mL jacketed flask to obtain a suspension. The suspension was cooled to 5-10 °C, and under nitrogen protection, a 2 mol / L tetrahydrofuran solution (12.6 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 40 °C, and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N hydrochloric acid. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 6.5g of crude product of diatrizoic acid impurities B and C, which was a light brown solid. The crude product of the mixture was separated by high performance liquid chromatography. The fraction was concentrated under reduced pressure at 50℃ and freeze-dried to obtain diatrizoic acid impurity B and diatrizoic acid impurity C, respectively.

[0051] High-performance liquid chromatography (HPLC) separation conditions: Shimadzu Prominence Prep HPLC preparative HPLC system; PREP-ODS-C18 column (particle size 15 μm, length 250 mm × diameter 20 mm); mobile phase A: acetonitrile, mobile phase B: water-trifluoroacetic acid (40:0.05 V / V); gradient elution: 0.00-60 min, 0%-30% mobile phase B; 60-180 min, 30%-95% mobile phase B; flow rate 6 mL / min; column temperature 30 °C; detection wavelength 254 nm.

[0052] Diazopic acid impurity B (1.4 g, yield 12.1%), a white solid, was identified as impurity B by comparison with the reference system. HPLC purity: 98.14% (210 nm), 98.30% (254 nm).

[0053] 1 H-NMR (MeOD, 400MHz): 7.766 (s, 1H), 2.177 (s, 6H); MS: [M+H + =489.00.

[0054] Diazopic acid impurity C (3.2 g, yield 27.6%), a white solid, was identified as impurity C by comparison with the reference system. HPLC purity: 99.33% (220 nm), 99.52% (254 nm).

[0055] 1 H-NMR(DMSO,400MHz):13.80(br,1H,COOH),9.534(s,2H,2NH),7.442(s,1H),2.079(s,6H); MS:[M+H + =489.0.

[0056] Example 2

[0057] Purified water (300 mL) and NaOH (1.95 g) were added to a 500 mL jacketed flask and cooled to 10 °C. Diazopiclone (15.0 g) was added to the system in three portions, 5.0 g each time. The temperature was adjusted to 40 °C, and the reaction was carried out at this temperature for 5 h. After the reaction was complete, the reaction system was concentrated to approximately 55 mL, cooled to 10 °C, filtered, and dried under vacuum at 60 °C to obtain sodium diazopiclone (13.58 g, yield 89.9%), a white solid, which was used directly in the next step.

[0058] Example 3

[0059] Purified water (300 mL) and KOH (85% purity, 3.2 g) were added to a 500 mL jacketed flask and cooled to 10 °C. Diazopiclone (15.0 g) was added to the system in three portions, 5.0 g each time. The temperature was adjusted to 40 °C, and the reaction was carried out at this temperature for 5 h. After the reaction was complete, the reaction system was concentrated to approximately 55 mL, cooled to 15 °C, filtered, and dried under vacuum at 55 °C to obtain potassium diazopiclone (13.4 g, yield 86.7%), a white solid, which was used directly in the next step.

[0060] Example 4

[0061] Anhydrous tetrahydrofuran (325 mL) and lithium diatrizoate (13.0 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1.6 mol / L n-BuLi tetrahydrofuran solution (14.0 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 50 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N sulfuric acid. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time to obtain 6.0g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (1.0g, yield 8.6%) and diatrizoic acid impurity C (2.7g, yield 23.3%).

[0062] Example 5

[0063] Anhydrous tetrahydrofuran (325 mL) and lithium diatrizoate (13.0 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1 mol / L tetrahydrofuran solution (25.2 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 60 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N citric acid aqueous solution. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 6.1g of crude product of diatrizoic acid impurities B and C, which was a light brown solid. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (1.1g, yield 10.8%) and diatrizoic acid impurity C (2.9g, yield 25.0%).

[0064] Example 6

[0065] Anhydrous tetrahydrofuran (335 mL) and sodium diatrizoate (13.4 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 2 mol / L tetrahydrofuran solution (12.6 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 40 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N hydrochloric acid. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 6.6g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (1.25g, yield 10.8%) and diatrizoic acid impurity C (3.1g, yield 26.8%).

[0066] Example 7

[0067] Anhydrous tetrahydrofuran (335 mL) and sodium diatrizoate (13.4 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1.6 mol / L n-BuLi tetrahydrofuran solution (14.5 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 50 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N sulfuric acid. After reacting for 10 hours, the mixture was filtered, and the filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time, and filtered after each slurry to obtain 5.4g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (0.96g, yield 8.3%) and diatrizoic acid impurity C (2.9g, yield 25.0%).

[0068] Example 8

[0069] Anhydrous tetrahydrofuran (335 mL) and sodium diatrizoate (13.4 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1 mol / L tetrahydrofuran solution (25.2 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 60 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N citric acid aqueous solution. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 5.1g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (0.91g, yield 7.9%) and diatrizoic acid impurity C (2.7g, yield 23.3%).

[0070] Example 9

[0071] Anhydrous tetrahydrofuran (343 mL) and potassium diatrizoate (13.7 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 2 mol / L tetrahydrofuran solution (12.6 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 40 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N hydrochloric acid. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 5.6g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (0.98g, yield 8.5%) and diatrizoic acid impurity C (3.0g, yield 25.9%).

[0072] Example 10

[0073] Anhydrous tetrahydrofuran (343 mL) and potassium diatrizoate (13.7 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1.6 mol / L n-BuLi tetrahydrofuran solution (14.5 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 50 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N sulfuric acid. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 5.4g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (1.1g, yield 9.5%) and diatrizoic acid impurity C (2.96g, yield 25.6%).

[0074] Example 11

[0075] Anhydrous tetrahydrofuran (343 mL) and potassium diatrizoate (13.7 g) were added to a 500 mL jacketed flask and cooled to 5-10 °C. Under nitrogen protection, a 1 mol / L tetrahydrofuran solution (25.2 mL) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 60 °C and the reaction was carried out at this temperature for 10 h. After the reaction was complete, the temperature was lowered to 5-10℃, and the pH of the system was adjusted to 2-3 with 1N citric acid aqueous solution. The reaction was carried out for 10 hours, and the mixture was filtered. The filter cake was washed with purified water (100mL×3) to obtain the crude product. The crude product was slurried with methanol (50mL×2) at 25℃ for 1 hour each time. After each slurry, the mixture was filtered to obtain 5.3g of crude product (light brown solid) of diatrizoic acid impurities B and C. The crude product was separated by high performance liquid chromatography (HPLC separation conditions were the same as in Example 1) to obtain diatrizoic acid impurity B (1.03g, yield 8.9%) and diatrizoic acid impurity C (2.9g, yield 25.0%).

Claims

1. A method for synthesizing diatrizoic acid impurities B and C, characterized in that: The synthesis route is as follows: Wherein: M is selected from K, Na, and Li; The process includes: using diatrizoic acid as a raw material, first reacting it with MOH to form a salt to generate diatrizoic acid salt, then, in the presence of a deiodizing reagent, the diatrizoic acid salt undergoes a deiodization reaction, and then is acidified with an acidifying reagent to generate a mixture of diatrizoic acid impurity B and diatrizoic acid impurity C. The mixture is then slurried with methanol and separated by high performance liquid chromatography to obtain diatrizoic acid impurity B and diatrizoic acid impurity C.

2. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The molar ratio of MOH to diatrizoate is 1:1 to 5:1, preferably 2:1 to 2.2:

1.

3. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The reaction solvent for the salt-forming reaction is purified water; the temperature of the salt-forming reaction is 20–50°C, preferably 40°C; and the reaction time is 4–6 hours, preferably 5 hours.

4. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The deiodination reagent is one of n-butyllithium, isopropyl magnesium chloride, and isopropyl magnesium bromide, preferably isopropyl magnesium chloride.

5. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The molar ratio of the deiodination reagent to diatrizoate is 1:1 to 1.5:1, preferably 1.2:

1.

6. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The reaction solvent for the deiodination reaction is one of tetrahydrofuran and methyltetrahydrofuran, preferably tetrahydrofuran; the mass-volume ratio of diatrizoate to the reaction solvent is 1:20 to 1:50 g / mL, preferably 1:25 to 1:28 g / mL.

7. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The temperature of the deiodination reaction is 20–60°C, preferably 40–60°C, and more preferably 50°C.

8. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The acidifying agent is one of hydrochloric acid, sulfuric acid, citric acid aqueous solution, acetic acid aqueous solution, etc., preferably hydrochloric acid; the pH of the system is adjusted to 2-3 using the acidifying agent.

9. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The pulping process is repeated 1 to 3 times; during each pulping, the mass-to-volume ratio of the diatrizoate to methanol is 1:3.5 to 1:4 g / mL.

10. The method for synthesizing diatrizoic acid impurities B and C according to claim 1, characterized in that: The high-performance liquid chromatography (HPLC) separation conditions are as follows: PREP-ODS-C18 column (particle size 15 μm, length 250 mm × diameter 20 mm); mobile phase A: acetonitrile, mobile phase B: water-trifluoroacetic acid = 40:0.05 V / V; gradient elution: 0.00-60 min, 0%-30% mobile phase B; 60-180 min, 30%-95% mobile phase B; flow rate 6 mL / min; column temperature 30 °C; detection wavelength 254 nm.

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