Synthesis method of diatrizoic acid impurity D

Abstract

The invention discloses a synthesis method of a diatrizoic acid impurity D. The synthesis method comprises the following steps: by taking diatrizoic acid as a raw material, carrying out hydrolysis reaction on the diatrizoic acid in the presence of alkali as shown in a chemical formula M1OH to generate a compound 1; under the action of a catalyst, carrying out esterification reaction on the compound 1 and alcohol as shown in the chemical formula R1OH to generate a compound 2; in the presence of alkali, carrying out amidation reaction on the compound 2 and chloroacetyl chloride to generate a compound 3; the compound 3 and iodide as shown in the chemical formula M2I are subjected to halogen exchange reaction to generate a compound 4; in the presence of alkali as shown in the chemical formula M3OH. NH2O, hydrolyzing the compound 4 to generate a diatrizoic acid impurity D crude product, and performing post-treatment and purification on the diatrizoic acid impurity D crude product to obtain a high-purity diatrizoic acid impurity D finished product. The method is high in sustainability and efficiency, the obtained product is high in purity, and an important impurity guarantee is provided for production and medication safety of diatrizoic acid.

Description

Technical Field

[0001] This invention relates to a method for synthesizing diatrizoate impurity D. Background Technology

[0002] Diatrizoic acid, chemically known as 3,5-diacetamido-2,4,6-triiodobenzoic acid dihydrate, is a positive contrast agent for X-ray diagnosis and is currently listed in the Chinese Pharmacopoeia. Diatrizoic acid is generally formulated into meglumine diatrizoate, sodium diatrizoate, or compound meglumine diatrizoate injections for use in cardiovascular, aortic, various venous, excretory, or retrograde urinary tract imaging, and is also used in brain or whole-body computed tomography (CT) enhanced scans. As a commonly used raw material for diagnostic injectables, the impurity content of diatrizoic acid directly affects the safety, efficacy, and stability of the drug, as well as the health of consumers. Impurities in raw materials are a core risk source for formulation quality. Through scientific risk assessment, advanced technical means, and strict regulatory compliance, the hazards of impurities can be minimized, ensuring the safety and effectiveness of medication for patients.

[0003] The structure of diatrizoate impurity D, which is of interest to the European Pharmacopoeia (EP), is as follows:

[0004]

[0005] The scarcity and high cost of impurity D in diatrizoate, coupled with the difficulty in obtaining high-purity impurities, limit companies' ability to conduct systematic quality studies and develop efficient analytical methods for the active pharmaceutical ingredient diatrizoate. This directly impacts the safety, efficacy, and stability of diatrizoate API. To overcome these shortcomings, developing a sustainable, simple, readily available, and high-purity method for the synthesis and purification of diatrizoate impurity D is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing diatrizoate impurity D that is easy to obtain, has strong reaction sustainability, and is highly efficient and pure, in order to address the difficulty in obtaining diatrizoate impurity D and reduce enterprise R&D costs.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A method for synthesizing diatrizoic acid impurity D, the synthetic route is as follows:

[0009]

[0010] Among them, M1OH is one of NaOH, KOH, etc.; M2I is one of potassium iodide, sodium iodide, etc.; R1OH is selected from one of methanol (MeOH), ethanol (EtOH), propanol, isopropanol, n-butanol, tert-butanol, etc.; M2I is selected from one of potassium iodide, sodium iodide, etc.; M3OH·nH2O is selected from one of NaOH, KOH, LiOH·H2O, etc.

[0011] include:

[0012] Step (1): Using diatrizoate as a raw material, in the presence of a base as shown in the chemical formula M1OH, diatrizoate undergoes a hydrolysis reaction to generate compound 1;

[0013] Step (2): Under the action of a catalyst, compound 1 and an alcohol represented by the chemical formula R1OH undergo an esterification reaction to generate compound 2;

[0014] Step (3): In the presence of a base, compound 2 and chloroacetyl chloride undergo an amidation reaction to generate compound 3;

[0015] In step (4), compound 3 and the iodide shown by chemical formula M2I undergo a halogen exchange reaction to generate compound 4;

[0016] Step (5): In the presence of a base as shown in the chemical formula M3OH·nH2O, compound 4 is hydrolyzed to generate crude diatrizoic acid impurity D. The crude diatrizoic acid impurity D is then purified by post-treatment to obtain high-purity diatrizoic acid impurity D product.

[0017] In step (1), the alkali (M1OH) is one of NaOH, KOH, etc., preferably NaOH.

[0018] The molar ratio of the alkali to diatrizoate is 2:1 to 2.2:1, preferably 2.1:1.

[0019] The reaction solvent for the hydrolysis reaction is methanol. The mass-to-volume ratio of diatrizoate to methanol is 1:20 to 1:30 g / mL, preferably 1:25 g / mL.

[0020] The hydrolysis reaction is carried out at a temperature of 20–25°C and for 7 days.

[0021] Specifically, diatrizoic acid and the reaction solvent are mixed, cooled to 10°C, and then alkali is added. The temperature is then raised, and in the presence of alkali, diatrizoic acid undergoes a hydrolysis reaction to generate compound 1.

[0022] After the hydrolysis reaction is complete, the reaction solution is cooled to 10°C, the pH is adjusted to 6-7 with hydrochloric acid, and the mixture is filtered. The filter cake is then slurried with methanol 2-3 times, preferably 2 times, for 1-3 hours each time, preferably 2 hours. After each slurrying, the mixture is filtered and dried to obtain compound 1. The mass-to-volume ratio of diatrizoic acid to methanol used in each slurrying is 1:7-1:8 g / mL, preferably 1:7.5 g / mL.

[0023] In step (2), the alcohol (R1OH) is one of methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, etc., preferably ethanol. R1OH serves as both a raw material and a reaction solvent for the esterification reaction. The mass-to-volume ratio of compound 1 to the alcohol is 1:20 to 1:30 g / mL, preferably 1:25 g / mL.

[0024] The catalyst is concentrated sulfuric acid, p-toluenesulfonic acid, or benzenesulfonic acid. The concentrated sulfuric acid has a mass fraction of ≥70%, preferably 98%.

[0025] The molar ratio of compound 1 to the catalyst is 1:0.6 to 1:0.8, preferably 1:0.68 to 1:0.7.

[0026] The esterification reaction temperature is the same as the reflux reaction temperature, and the esterification reaction time is 20–24 h.

[0027] After the esterification reaction is completed, the reaction solution is concentrated to 1 / 6 to 1 / 8 of the volume of purified water, cooled to 0 to 5°C, and the pH of the system is adjusted to 7-8 with saturated Na2CO3 solution. The solution is then filtered, washed with purified water, and slurried with methanol 2 to 3 times, preferably 2 times, for 1 to 3 hours each time, preferably 1 hour. After each slurry, the solution is filtered and dried to obtain compound 2. The mass-to-volume ratio of compound 1 to methanol used in each slurry is 1:3 to 1:5 g / mL.

[0028] In step (3), the molar ratio of compound 2 to chloroacetyl chloride is 1:1 to 1:1.2, preferably 1:1.1 to 1:1.15.

[0029] The alkali is one of triethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine.

[0030] The molar ratio of the alkali to compound 2 is 2.0:1 to 4.0:1, preferably 2.9:1 to 3.1:1, and more preferably 3.0:1.

[0031] The reaction solvent for the amidation reaction is one of tetrahydrofuran, dichloromethane, etc., preferably tetrahydrofuran.

[0032] The mass-to-volume ratio of compound 2 to the reaction solvent is 1:20 to 1:30 g / mL, preferably 1:25 g / mL.

[0033] The amidation reaction is carried out at a temperature of 20–25°C for 12–16 hours.

[0034] Specifically, compound 2, alkali, and reaction solvent are mixed and cooled to 5–10°C. Chloroacetyl chloride is added dropwise. After the addition is complete, an amidation reaction is carried out. After the reaction is complete, the mixture is concentrated to dryness, washed with purified water, and pulped with methanol 2–3 times, preferably 2 times, for 1–3 hours each time, preferably 1 hour. After each pulping, the mixture is filtered and dried to obtain compound 3. The mass-to-volume ratio of compound 2 to methanol used in each pulping is 1:3–1:5 g / mL.

[0035] In step (4), the iodide (M2I) is one of potassium iodide, sodium iodide, etc., preferably potassium iodide.

[0036] The molar ratio of compound 3 to iodide is 1:3.0 to 1:6.0, preferably 1:4.0 to 1:4.5.

[0037] The reaction solvent for the halogen exchange reaction is one of acetone, acetonitrile, etc., preferably acetone.

[0038] The mass-to-volume ratio of compound 3 to the reaction solvent is 1:20 to 1:30 g / mL, preferably 1:25 g / mL.

[0039] The temperature of the halogen exchange reaction is the temperature corresponding to reflux; the time of the halogen exchange reaction is 16-18 hours.

[0040] After the halogen exchange reaction was completed, the mixture was concentrated, washed with purified water, and slurried twice with methanol for 1 hour each time. After each slurry, the mixture was filtered and dried under vacuum to obtain compound 4. The mass-to-volume ratio of compound 3 to methanol used in each slurry was 1:3 to 1:5 g / mL.

[0041] In step (5), the alkali (M3OH·nH2O) is one of NaOH, KOH, LiOH·H2O, etc., preferably LiOH·H2O.

[0042] The molar ratio of the alkali to compound 4 is 2.0:1 to 3.0:1, preferably 2.5:1;

[0043] The reaction solvent for the hydrolysis reaction is a 40% to 60% alcohol-water solvent, wherein the alcohol is methanol or ethanol.

[0044] Preferably, the reaction solvent for the hydrolysis reaction is a 50% alcohol-water solvent. Specifically, the reaction solvent for the hydrolysis reaction is methanol / water (V:V = 1:1), ethanol / water (V:V = 1:1), etc., preferably ethanol / water (V:V = 1:1).

[0045] The volume-to-mass ratio of the reaction solvent to compound 4 is 20:1 to 30:1 g / mL, preferably 25:1 g / mL.

[0046] The hydrolysis reaction is carried out at a temperature of 40–50°C, preferably 45°C. The hydrolysis reaction takes place for 4–6 hours, preferably 5 hours.

[0047] The post-processing is as follows: After the reaction is completed, the alcohol is concentrated and removed, the temperature is lowered to 5-10℃, the pH of the system is adjusted to 4-5 with an acidifying reagent, the mixture is filtered, washed with purified water, and slurried with methanol to obtain crude impurity D. Then, high performance liquid chromatography is performed to separate the crude impurity D and obtain the finished product of diatrizoic acid impurity D.

[0048] For those skilled in the art, the method of concentrating to remove alcohol is a conventional method in the field.

[0049] The methanol pulping is performed 2 to 3 times, preferably 2 times. The mass-to-volume ratio of compound 4 and methanol used in each pulping is 1:2 to 1:3 g / mL. Each pulping session lasts 1 to 3 hours, preferably 1 hour. The pulp is filtered after each pulping session.

[0050] The acidifying agent is one of hydrochloric acid, sulfuric acid, citric acid aqueous solution, etc., preferably hydrochloric acid.

[0051] Specifically, the concentration of the acidifying reagent is 1N.

[0052] The acidification temperature is 5–10°C.

[0053] 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 (30:0.05 V / V); gradient elution: 0.00-30 min, 0%-40% mobile phase B; 30-100 min, 40%-95% mobile phase B; flow rate 5 mL / min; column temperature 30 °C; detection wavelength 254 nm.

[0054] The beneficial effects of this invention are:

[0055] This invention provides a method for synthesizing high-purity impurity D in diatrizoate. This method is sustainable, efficient, and yields a high-purity product. It provides reliable impurity assurance for enterprises to conduct systematic quality research on the active pharmaceutical ingredient diatrizoate and develop efficient analytical methods, thus providing important impurity assurance for the production and safe use of diatrizoate. Attached Figure Description

[0056] Figure 1 The 1H NMR spectrum of the diatrizoic acid impurity D prepared in Example 1 is shown.

[0057] Figure 2 The image shows the LCMS spectrum of diatrizoate impurity D obtained in Example 1.

[0058] Figure 3 The HPLC chromatograms of diatrizoic acid impurity D obtained in Example 1 are shown (detection wavelengths are 210 nm and 254 nm, respectively). Detailed Implementation

[0059] 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.

[0060] Example 1

[0061]

[0062] Step (1): Preparation of Compound 1: Methanol (500 mL) and diatrizoate (20.0 g) were added to a 1000 mL jacketed bottle, cooled to 10 °C, and NaOH (2.6 g) was added. The temperature was adjusted to 25 °C and reacted at this temperature for 7 days. After the reaction was completed, the reaction solution was cooled to 10 °C, and the pH of the reaction solution was adjusted to 6-7 with 1 N dilute hydrochloric acid. The solution was filtered, and the filter cake was slurried twice with methanol (150 mL × 2) at 25 °C, with 2 small-scale tests each time. After each slurry, the mixture was filtered and dried under vacuum at 55 °C to obtain Compound 1 (12.5 g, yield 71.0%, light yellow solid), which was directly used in the next step.

[0063] Step (2): Preparation of compound 2a: Anhydrous ethanol (375 mL) and compound 1 (15.0 g) were added to a 1000 mL jacketed bottle, and concentrated sulfuric acid (1.8 g) with a mass fraction of 98% was added. After the addition was complete, the mixture was refluxed for 22 h. After the reaction was complete, the mixture was concentrated to a volume of about 55 mL, cooled to 5 °C, and the pH of the system was adjusted to 7-8 with saturated Na2CO3 solution. The mixture was filtered, and the filter cake was washed with purified water (100 mL × 2) to obtain the crude product. The crude product was slurried with methanol (50 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 2a (11.8 g, yield 75.0%, light yellow solid), which was directly used in the next step.

[0064] Step (3): Preparation of compound 3a: Tetrahydrofuran (250 mL), compound 2a (10.0 g), and triethylamine (5.2 g) were added to a 500 mL jacketed flask and cooled to 5 °C. Chloroacetyl chloride (2.1 g) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 20 °C and the reaction was carried out at this temperature for 14 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was slurried with methanol (100 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 3a (8.1 g, yield 71.9%, white solid), which was directly used in the next step.

[0065] Step (4): Preparation of compound 4a: Acetone (325 mL), compound 3a (13.0 g), and sodium iodide (11.5 g) were added to a 500 mL jacketed flask. After the addition was complete, the mixture was refluxed for 16 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was slurried with methanol (75 mL × 2) for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 4a (8.6 g, yield 58.3%, white solid), which was directly used in the next step.

[0066] Step (5): Synthesis of diatrizoic acid impurity D: EtOH / H2O (V:V = 1:1, 250 mL) and compound 4a (10.0 g) were added to a 500 mL jacketed bottle. LiOH·H2O (1.36 g) was added to the above system. After the addition was complete, the reaction was carried out at 45 °C for 5 h. After the reaction was complete, the ethanol was removed by concentration, the temperature was lowered to 10 °C, and the pH of the system was adjusted to 4-5 with 1N HCl. When the amount of solid produced no longer increased, the mixture was filtered. The filter cake was washed with purified water (50 mL × 3) to obtain the crude product. The crude product was slurried with methanol (25 mL × 2) at 25 °C for 1 h each time. After slurrying, the mixture was filtered to obtain crude diatrizoic acid impurity D (6.7 g, light yellow solid). The crude diatrizoic acid impurity D was separated by high performance liquid chromatography. The fraction was concentrated under reduced pressure at 50 °C and freeze-dried to obtain impurity D (4.9 g, yield 50.6%).

[0067] 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 (30:0.05 V / V); gradient elution: 0.00-30 min, 0%-40% mobile phase B; 30-100 min, 40%-95% mobile phase B; flow rate 5 mL / min; column temperature 30 °C; detection wavelength 254 nm.

[0068] 1 H-NMR(DMSO,400MHz):10.409-10.324(d,1H),9.924-9.841(d,1H),3.827(s,2H),2.060(s,3H).

[0069] MS:[M+H + ]=740.80,:[M+Na + =762.80.

[0070] HPLC purity: 98.01% (210nm), 98.72% (254nm).

[0071] Example 2

[0072]

[0073] Step (1): Preparation of Compound 1: Methanol (500 mL) and diatrizoate (20.0 g) were added to a 1000 mL jacketed bottle and cooled to 10 °C. KOH (80% content, 4.5 g) was added to the above system, and the temperature was adjusted to 25 °C. The reaction was carried out at this temperature for 7 days. After the reaction was completed, the reaction solution was cooled to 10 °C, and the pH was adjusted to 6-7 with 1N dilute hydrochloric acid. The mixture was filtered, and the filter cake was slurried twice with methanol (150 mL × 2) at 25 °C, slurrying for 2 hours each time. After each slurrying, the mixture was filtered and dried under vacuum at 55 °C to obtain Compound 1 (12.0 g, yield 68.2%, light yellow solid), which was directly used in the next step.

[0074] Step (2): Preparation of compound 2b: Anhydrous methanol (375 mL) and compound 1 (15.0 g) were added to a 1000 mL jacketed bottle. 98% concentrated sulfuric acid (1.8 g) was added dropwise to the system, and the mixture was refluxed for 20 h after the addition was complete. After the reaction was complete, the mixture was concentrated to a volume of 55 mL, cooled to 5 °C, and the pH was adjusted to 7-8 with saturated Na₂CO₃ solution. The mixture was filtered, washed with purified water (100 mL × 2), and the crude product was obtained. The crude product was then slurried with methanol (50 mL × 2) at 25 °C for 1 h each time, filtered after each slurry, and dried under vacuum at 45 °C to obtain compound 2b (10.9 g, yield 70.9%, light yellow solid), which was directly used in the next step.

[0075] Step (3): Preparation of compound 3b: Dichloromethane (250 mL), compound 2b (10.0 g), and triethylamine (5.1 g) were added to a 500 mL jacketed flask and cooled to 5 °C. Chloroacetyl chloride (2.2 g) was added dropwise to the above system. After the addition was complete, the temperature was adjusted to 25 °C and reacted at this temperature for 14 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was then slurried with methanol (100 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 3b (7.7 g, yield 68.1%, white solid), which was directly used in the next step.

[0076] Step (4): Preparation of compound 4b: Acetone (325 mL), compound 3b (13.0 g), and potassium iodide (14.7 g) were added to a 500 mL jacketed flask. After the addition was complete, the mixture was refluxed for 16 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was then slurried with methanol (75 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 4b (8.8 g, yield 59.5%, white solid), which was directly used in the next step.

[0077] Step (5): Synthesis of diatrizoic acid impurity D: MeOH / H2O (V:V = 1:1, 250 mL) and compound 4b (methyl ester, 10.0 g) were added to a 500 mL jacketed bottle. NaOH (1.32 g) was added to the above system. After the addition was complete, the reaction was carried out at 45 °C for 5 h. After the reaction was complete, the methanol was removed by concentration, the temperature was lowered to 10 °C, and the pH of the system was adjusted to 4-5 with 1 N HCl. When the amount of solid produced no longer increased, the mixture was filtered and washed with purified water (50 mL × 3) to obtain the crude product. The crude product was slurried with methanol (25 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered to obtain crude diatrizoic acid impurity D (6.1 g, light yellow solid). The crude diatrizoic acid impurity D was separated by high performance liquid chromatography. The fraction was concentrated under reduced pressure at 50 °C and freeze-dried to obtain diatrizoic acid impurity D (5.3 g, yield 54.0%).

[0078] 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 (30:0.05 V / V); gradient elution: 0.00-30 min, 0%-40% mobile phase B; 30-100 min, 40%-95% mobile phase B; flow rate 5 mL / min; column temperature 30 °C; detection wavelength 254 nm.

[0079] Example 3

[0080] Dichloromethane (250 mL), compound 2a (10.0 g), and triethylamine (5.2 g) were added to a 500 mL jacketed flask and cooled to 10 °C. Chloroacetyl chloride (2.1 g) was then added dropwise to the system. After the addition was complete, the temperature was adjusted to 25 °C, and the reaction was carried out at this temperature for 14 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was then slurried with methanol (50 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 3a (7.3 g, yield 64.8%, white solid), which was used directly in the next step.

[0081] Example 4

[0082] Tetrahydrofuran (250 mL), compound 2a (10.0 g), and potassium carbonate (6.9 g) were added to a 500 mL jacketed flask and cooled to 10 °C. Chloroacetyl chloride (2.1 g) was then added dropwise to the system. After the addition was complete, the temperature was adjusted to 25 °C, and the reaction was carried out at this temperature for 14 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was then slurried with methanol (50 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 3a (6.2 g, yield 54.9%, white solid), which was directly used in the next step.

[0083] Example 5

[0084] Dichloromethane (250 mL), compound 2b (10.0 g), and sodium carbonate (5.4 g) were added to a 500 mL jacketed flask and cooled to 10 °C. Chloroacetyl chloride (2.2 g) was then added dropwise to the system. After the addition was complete, the temperature was adjusted to 25 °C, and the reaction was carried out at this temperature for 14 h. After the reaction was complete, the mixture was concentrated to dryness and washed with purified water (100 mL × 3) to obtain a crude product. The crude product was then slurried with methanol (50 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 3b (6.0 g, yield 53.1%, white solid).

[0085] Example 6

[0086] Acetonitrile (325 mL), compound 3a (13.0 g), and sodium iodide (11.5 g) were added to a 500 mL jacketed flask. After the addition was complete, the mixture was refluxed for 16 h. After the reaction was complete, the mixture was concentrated to dryness, washed with purified water (100 mL × 3), and the crude product was obtained. The crude product was then slurried with methanol (75 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 4a (8.0 g, yield 54.2%, white solid), which was directly used in the next step.

[0087] Example 7

[0088] Acetonitrile (325 mL), compound 3b (13.0 g), and potassium iodide (14.7 g) were added to a 500 mL jacketed flask. After the addition was complete, the mixture was refluxed for 16 h. After the reaction was complete, the mixture was concentrated to dryness, washed with purified water (100 mL × 3), and the crude product was obtained. The crude product was then slurried with methanol (50 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered and dried under vacuum at 45 °C to obtain compound 4 (7.9 g, yield 53.4%, white solid), which was directly used in the next step.

[0089] Example 8

[0090] EtOH / H2O (V:V = 1:1) (250 mL) and compound 4b (10.0 g) were added to a 500 mL jacketed flask. KOH (80% content, 2.3 g) was added to the above system. After the addition was complete, the reaction was carried out at 45 °C for 5 h. After the reaction was complete, the methanol was removed by concentration, the temperature was lowered to 10 °C, and the pH of the system was adjusted to 4-5 with 1N HCl. When the amount of solid produced no longer increased, the mixture was filtered. The filter cake was washed with purified water (50 mL × 3) to obtain the crude product. The crude product was slurried with methanol (25 mL × 2) at 25 °C for 1 h each time. After each slurry, the mixture was filtered to obtain crude diatrizoic acid impurity D (5.9 g, light yellow solid). The crude diatrizoic acid impurity D was separated by high performance liquid chromatography. The fraction was concentrated under reduced pressure at 50 °C and freeze-dried to obtain diatrizoic acid impurity D (4.6 g, yield 46.9%).

[0091] 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 = 30:0.05 V / V; gradient elution: 0.00-30 min, 0%-40% mobile phase B; 30-100 min, 40%-95% mobile phase B; flow rate 5 mL / min; column temperature 30 °C; detection wavelength 254 nm.

Claims

1. A method for synthesizing diatrizoic acid impurity D, characterized in that: The synthesis route is as follows: Among them, M1OH is one of NaOH and KOH; M2I is one of potassium iodide and sodium iodide; R1OH is selected from one of methanol, ethanol, propanol, isopropanol, n-butanol, and tert-butanol; M2I is selected from one of potassium iodide and sodium iodide; and M3OH·nH2O is selected from one of NaOH, KOH, and LiOH·H2O.

2. The method for synthesizing diatrizoic acid impurity D according to claim 1, characterized in that: include: Step (1): Using diatrizoate as a raw material, in the presence of a base as shown in the chemical formula M1OH, diatrizoate undergoes a hydrolysis reaction to generate compound 1; Step (2): Under the action of a catalyst, compound 1 and an alcohol represented by the chemical formula R1OH undergo an esterification reaction to generate compound 2; Step (3): In the presence of a base, compound 2 and chloroacetyl chloride undergo an amidation reaction to generate compound 3; In step (4), compound 3 and the iodide shown by chemical formula M2I undergo a halogen exchange reaction to generate compound 4; Step (5): In the presence of a base as shown in the chemical formula M3OH·nH2O, compound 4 is hydrolyzed to generate crude diatrizoic acid impurity D. The crude diatrizoic acid impurity D is then purified by post-treatment to obtain high-purity diatrizoic acid impurity D product.

3. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (1), the molar ratio of the alkali to diatrizoate is 2:1 to 2.2:1, preferably 2.1:1; the reaction solvent for the hydrolysis reaction is methanol; and the reaction temperature for the hydrolysis reaction is 20 to 25°C.

4. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (2), the mass-to-volume ratio of compound 1 to alcohol is 1:20 to 1:30 g / mL, preferably 1:25 g / mL; the catalyst is concentrated sulfuric acid, p-toluenesulfonic acid, or benzenesulfonic acid; the molar ratio of compound 1 to catalyst is 1:0.6 to 1:0.8, preferably 1:0.68 to 1:0.

7.

5. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (3), the molar ratio of compound 2 to chloroacetyl chloride is 1:1 to 1:1.2, preferably 1:1.1 to 1:1.

15.

6. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (3), the alkali is one of triethylamine, potassium carbonate, and sodium carbonate, preferably triethylamine; the molar ratio of the alkali to compound 2 is 2.0:1 to 4.0:1, preferably 2.9:1 to 3.1:1, and more preferably 3.0:

1.

7. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (3), the reaction solvent for the amidation reaction is one of tetrahydrofuran and dichloromethane; the mass-volume ratio of compound 2 to the reaction solvent is 1:20 to 1:30 g / mL, preferably 1:25 g / mL; the temperature of the amidation reaction is 20 to 25°C; and the reaction time is 12 to 16 h.

8. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (4), the molar ratio of compound 3 to iodide is 1:3.0 to 1:6.0, preferably 1:4.0 to 1:4.5; the reaction solvent for the halogen exchange reaction is one of acetone and acetonitrile, preferably acetone; the mass-volume ratio of compound 3 to the reaction solvent is 1:20 to 1:30 g / mL, preferably 1:25 g / mL; the temperature of the halogen exchange reaction is the temperature corresponding to reflux; and the time of the halogen exchange reaction is 16 to 18 h.

9. The method for synthesizing diatrizoic acid impurity D according to claim 2, characterized in that: In step (5), the molar ratio of the alkali to compound 4 is 2.0:1 to 3.0:1, preferably 2.5:1; the reaction solvent for the hydrolysis reaction is a 40% to 60% alcohol-water solvent, wherein the alcohol is methanol or ethanol; the volume-to-mass ratio of the reaction solvent to compound 4 is 20:1 to 30:1 g / mL, preferably 25:1 g / mL; the temperature of the hydrolysis reaction is 40 to 50°C, preferably 45°C; and the time of the hydrolysis reaction is 4 to 6 hours, preferably 5 hours.

10. The method for synthesizing diatrizoic acid impurity D according to claim 9, characterized in that: In step (5), the post-processing is as follows: after the reaction is completed, the alcohol is concentrated and removed, the temperature is lowered to 5-10℃, the pH of the system is adjusted to 4-5 with an acidifying reagent, the system is filtered, washed with purified water, and slurried with methanol to obtain crude impurity D. Then, high performance liquid chromatography is performed to separate the crude impurity D and obtain the finished product of diatrizoate acid impurity D. The acidifying agent is one of hydrochloric acid, sulfuric acid, or citric acid aqueous solution; The acidification temperature is 5–10°C; The high-performance liquid chromatography (HPLC) separation conditions were 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 (30: 0.05V / V); Gradient elution: 0.00-30 min, 0%-40% mobile phase B; 30-100 min, 40%-95% mobile phase B; Flow rate 5 mL / min; Column temperature 30℃; Detection wavelength 254 nm.

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