Continuous preparation method of iodixanol

Abstract

The invention relates to a continuous preparation method of iodixanol, and belongs to the technical field of pharmaceutical chemistry synthesis. The invention provides a continuous preparation method of iodixanol, which comprises the following steps: taking dimethyl 5-nitroisophthalate as an initial raw material, carrying out amidation reaction with 3-aminoglycerol in the presence of a bifunctional catalyst to generate a compound as shown in a formula II, and carrying out catalytic hydrogenation reduction on the compound as shown in the formula II under nano palladium carbon to generate a compound as shown in a formula III, the method comprises the following steps: carrying out selective acetylation on a compound as shown in a formula III and an acetyl chloride-pyridine system at a low temperature to generate a compound as shown in a formula IV, hydrolyzing and dynamically crystallizing the compound as shown in the formula IV under an alkaline condition to generate a compound as shown in a formula V, carrying out dimerization on the compound as shown in the formula V and epichlorohydrin in a continuous flow reactor to generate an intermediate compound as shown in a formula VI, and separating the intermediate compound as shown in the formula VI. Carrying out iodination reaction on the compound shown in the formula VI and an iodine-sodium iodate system under a weak acid condition, and carrying out continuous countercurrent chromatography purification, nanofiltration and low-temperature spray drying to obtain iodixanol; the method has the advantages of high preparation efficiency, high yield and high purity on the whole.

Description

Technical Field

[0001] The present invention relates to a continuous preparation method of iodixanol, and belongs to the technical field of pharmaceutical chemical synthesis. Background Art

[0002] Iodixanol is a non-ionic isosmotic contrast agent, which is widely used in medical fields such as angiography and CT enhanced scanning. Traditional preparation methods have problems such as long reaction steps, difficult purification of intermediates, low total yield, unstable impurity control, especially the content of key impurities is difficult to meet the standard. In addition, existing processes mostly use batch reactions, with high energy consumption, long production cycles, and it is difficult to recycle precious metal catalysts.

[0003] Patent document CN110256503A discloses an intermediate of iodixanol and a method for preparing iodixanol. In this scheme, only a single amino glycerol is used as the catalyst for the acylation reaction. However, the 3-amino glycerol molecule contains multiple hydroxyl and amino groups, and intermolecular dehydration condensation is likely to occur in the acylation reaction system, generating oligomeric by-products. Moreover, in this scheme, a batch reaction is adopted, with a long production cycle and a complex transfer route of intermediate products, making it difficult to ensure efficient production.

[0004] Therefore, there is an urgent need to develop a high-purity iodixanol preparation method that is efficient, continuous, green and can accurately control impurities. Summary of the Invention

[0005] In view of the above-mentioned defects in the prior art, the present invention provides a continuous preparation method of iodixanol, and the problem to be solved is how to improve the production efficiency of the active pharmaceutical ingredient and reduce the generation of by-products.

[0006] The object of the present invention is achieved through the following technical solutions. A continuous preparation method of iodixanol, the method comprising the following steps:

[0007] S1: Using dimethyl 5-nitroisophthalate (compound of formula I) as the starting material, reacting with 3-amino glycerol in the presence of a bifunctional catalyst to carry out an amidation reaction to generate 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (compound of formula II);

[0008] S2: The compound of formula II is hydrogenated and reduced under the catalysis of nano-palladium carbon and a hydrogen pressure of 0.2 - 0.4 MPa to generate 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (compound of formula III);

[0009] S3: The compound of formula III is selectively acetylated with an acetyl chloride-pyridine system under low-temperature conditions to generate (5-acetamidophthaloyl)bis(azanediyl)tetraacetate (compound of formula IV);

[0010] S4: The compound of formula IV is hydrolyzed under alkaline conditions and crystallized dynamically to form 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V).

[0011] S5: The compound of formula V dimerizes with epichlorohydrin in a continuous flow reactor to form the intermediate 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (the compound of formula VI).

[0012] S6: The compound of formula VI undergoes an iodination reaction with an iodine-sodium iodate system under weakly acidic conditions, and is purified by continuous countercurrent chromatography, nanofiltration and low-temperature spray drying to obtain iodixanol (the compound of formula VII).

[0013] Preferably, in the step S1, the bifunctional catalyst is at least one of the systems of DMAP and DCC, and DMAP and HOBt; the reaction solvent is a mixed solvent of methanol and tetrahydrofuran with a volume ratio of 3:1; the molar ratio of the compound of formula I to aminoglycerol is 1:1 to 1.05.

[0014] Furthermore, DCC and HOBt are responsible for the activation of carboxylic esters, while DMAP further reduces the reaction energy barrier through nucleophilic catalysis. The two have clear division of labor, enabling the amidation reaction to be completed within 1.5 h (traditional single catalysts require 4 - 6 h), and the reaction temperature only needs to be 30 - 35 °C (traditional processes often require above 50 °C). The short reaction time and mild conditions make this step easy to integrate into a continuous flow system, avoiding frequent batch switching in traditional batch reactions.

[0015] Furthermore, the strong nucleophilicity of DMAP preferentially binds to the acyl intermediate, shortening the reaction time and reducing the free state of aminoglycerol, thereby inhibiting the self-condensation side reaction; the synergistic effect of DCC or HOBt and DMAP enables the reaction to be completed quickly, avoiding over-acylation caused by the long-term existence of the acyl intermediate; the by-product dicyclohexylurea of DCC can be removed by filtration, and DMAP can be recycled, saving production costs.

[0016] Preferably, in the step S2, the palladium loading of the nano-palladium carbon is 5%, and the particle size is 10 - 50 nm; the hydrogenation temperature is 30 - 50 °C, and the reaction time is 2 - 3 h; the hydrogenation reaction is carried out continuously in a microchannel reactor.

[0017] Furthermore, continuous hydrogenation is carried out using a nano-palladium on carbon catalyst in a microchannel reactor. The synergistic effect of the high specific surface area of nano-scale palladium on carbon and the enhanced mass transfer characteristics of the microreactor enables the nitro reduction reaction to be rapidly completed under mild conditions of 0.2 - 0.4 MPa low pressure and 30 - 50 °C. The catalyst dosage is reduced by 50%, and the formation of deamination by-products caused by local overheating in traditional batch reactions is avoided.

[0018] Preferably, in the S3 step, the acetylation temperature is 0 - 5 °C, and the molar ratio of acetyl chloride to the compound of formula III is 1.2:1 - 1.5:1; the addition amount of pyridine in the reaction system is 1.1 - 1.3 times the molar ratio of the compound of formula III.

[0019] Furthermore, the defined molar ratio of acetyl chloride to the compound of formula III and the dosage of pyridine ensure that acetylation occurs only at the amino site and the hydroxyl group is not acetylated, avoiding the complexity of subsequent hydrolysis steps.

[0020] Preferably, in the S4 step, dynamic crystallization adopts a gradient cooling program: the initial temperature of 50 °C is cooled to 20 °C at a rate of 2 °C / min, and then cooled to 0 °C at a rate of 0.5 °C / min; ultrasonic oscillation is assisted during the crystallization process, with a frequency of 20 - 40 kHz.

[0021] Furthermore, by controlling the nucleation rate and crystal growth rate through the dynamic crystallization process of gradient cooling (50 °C → 20 °C → 0 °C) combined with ultrasonic oscillation, crystals of the compound of formula V with uniform particle size are obtained, and the purity is increased to 99.8%, and the problem of wrapped impurities in traditional cooling crystallization is avoided.

[0022] Preferably, in the S5 step, the molar ratio of epichlorohydrin to the compound of formula V is 0.5:1 - 0.6:1; the dimerization reaction is continuously carried out in a series of microreactors, with a residence time of 20 - 24 h; the pH of the reaction system is dynamically regulated to 8.0 - 9.0 by an on-line sensor.

[0023] Furthermore, to achieve the efficient progress of the dimerization reaction, the residence time is precisely controlled using the continuous flow characteristics of the microreactor, reducing unreacted monomers and by-products.

[0024] Preferably, in the S6 step, the iodination reaction uses a molar ratio of iodine to sodium iodate of 1:0.8 - 1.2, and the reaction pH is 4.0 - 5.0; the mobile phase of continuous countercurrent chromatography is 0.02 M phosphate buffer and acetonitrile, and the gradient elution slope is 0.15% - 0.25%; the inlet temperature of spray drying is 50 - 60 °C, and the outlet temperature is 30 - 40 °C.

[0025] Preferably, the method further includes: the acetyl chloride distilled off in step S3 is recycled after dehydration by molecular sieve; the waste palladium-carbon is regenerated by pickling with nitric acid and calcination at 400-500 °C, and the number of recycling times is ≥10 times.

[0026] Furthermore, the acetyl chloride is recycled after dehydration by molecular sieve, and the recovery rate is >90%; the waste palladium-carbon is regenerated by pickling with nitric acid and calcination at 400-500 °C, solving the problem of waste of precious metal resources and reducing the production cost by more than 30%.

[0027] Preferably, the total molar yield of the final product ioxagol is 18.51% - 27.3%, the total impurity content is ≤0.2%, and the content of impurity G is ≤0.02%;

[0028] The chemical structural formula of impurity G is:

[0029]

[0030] Preferably, the purity of the final product ioxagol is ≥99.95%, which is suitable for pharmaceutical preparations for angiography.

[0031] In summary, compared with the prior art, the present invention has the following advantages:

[0032] 1. In the solution of the present invention, the bifunctional catalytic system realizes a high-efficiency, highly selective and low-cost process breakthrough in the amidation step of ioxagol through an activation-nucleophilic synergistic mechanism. Its advantages are not only reflected in shortening the reaction time, improving the yield and purity, but also significantly reducing the consumption of raw materials and energy, providing key technical support for continuous production and green pharmacy;

[0033] 2. In the solution of the present invention, compared with the traditional batch process, the processes such as microchannel reactor, dynamic crystallization, and continuous countercurrent chromatography involved in this solution shorten the production cycle from 120 h to 72 h, and the production capacity per unit time is increased by nearly 2 times;

[0034] 3. In the solution of the present invention, the low-temperature dropping of acetyl chloride avoids the side reaction between acetyl chloride and hydroxyl group at high temperature, reducing the generation of acetoxy impurities; by gradient crystallization and ultrasonic control of the crystal nucleation rate and crystal growth rate, chiral isomers are effectively removed; the pH of iodination is precisely controlled to inhibit the excessive substitution of iodine and avoid the formation of polyiodides. Through the above adjustments, precise control of impurity generation is achieved, thereby improving the yield and purity of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is the synthesis route of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0036] The technical solution of the present invention will be further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0037] Example 1

[0038] 1) Preparation of Compound of Formula II by amidation reaction

[0039] A mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) was added to a 3 L three-necked glass bottle and stirred for 15 min. The temperature of the reaction solution was controlled at 20 - 30 °C, and a bifunctional catalyst obtained by mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol) was slowly added. The temperature was raised to 30 - 35 °C and the reaction was stirred for 1.5 h. After the reaction was completed, the temperature was lowered to 15 - 25 °C, and glacial acetic acid was added dropwise to adjust the pH to 5.0 - 5.5 to obtain a reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula II), which was directly used for the next hydrogenation after filtration.

[0040] 2) Continuous hydrogenation to prepare Compound of Formula III

[0041] The reaction solution of the Compound of Formula II was pumped into a microchannel reactor system (volume 10 L), and at the same time, a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension was added. Hydrogen was introduced and the pressure was maintained at 0.4 MPa, the reaction temperature was 45 - 50 °C, and the residence time was 2 h. The reaction solution was filtered through a ceramic membrane (pore size 0.1 μm) and then concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula III).

[0042] 3) Low-temperature acetylation to prepare Compound of Formula IV

[0043] The solution of the Compound of Formula III was transferred to a 20 L low-temperature reaction kettle, the temperature was lowered to 2 - 5 °C, and acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol) were slowly added dropwise. The temperature was maintained at ≤5 °C and the reaction was stirred for 4 h. After the reaction was completed, the excess acetyl chloride was removed by distillation under reduced pressure, and 4.1 L of purified water was added for dissolution to obtain a solution of (5-acetamidoisophthaloyl)bis(aza-diyl)tetraacetate (Compound of Formula IV).

[0044] 4) Dynamic crystallization to prepare Compound of Formula V

[0045] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, and add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at 2 °C / min, and then cool to 0 °C at 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction. The filter cake is recrystallized with purified water (10 L) to finally obtain 1211.5 g of the wet product of 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and vacuum dried (80 °C, 24 h) to constant weight to obtain 605.77 g of a off-white solid, (molar yield from step 1 to step 4: 82%, HPLC purity: 99.6%).

[0046] 5) Preparation of the compound of formula VI by continuous dimerization

[0047] Mix the compound of formula V (591 g, 1.6 mol), potassium hydroxide (180 g, 3.2 mol), boric acid (185.5 g, 3 mol) and purified water (2 L), and pump them into a series microreactor system (volume 20 L). Control the temperature of the reaction solution at 10 - 15 °C, continuously inject epichlorohydrin (81.4 g, 0.88 mol, molar ratio 1:0.55), adjust the pH of the reaction system to 8.0, and the residence time is 24 h. The effluent is adjusted to pH 2.0 with sulfuric acid to obtain a solution of 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (the compound of formula VI).

[0048] 6) Iodination and continuous purification to prepare the compound of formula VII

[0049] Pass the solution of the compound of formula VI, iodine (507.6 g, 2 mol) and sodium iodate (316.6 g, 1.6 mol) into an iodination reaction kettle, control the pH at 4.5 - 5.0 and the temperature at 75 - 80 °C, and react for 12 h. The crude product solution is purified by continuous countercurrent chromatography (mobile phase: 0.02 M phosphate buffer / acetonitrile, gradient 0.2%), and then ultrafiltered and concentrated. Spray drying is carried out using a low-temperature process (inlet 55 °C, outlet 35 °C) to obtain 423.35 g of the pure product of iodixanol (the compound of formula VII) (two-step molar yield from step 5 to step 6: 33.29%, HPLC purity: 99.96%), the total molar yield is 27.3%, the content of impurity G is 0.01%, and the total impurities are 0.04%.

[0050] Example 2

[0051] In this example, DCC was replaced with HOBt, and other conditions remained unchanged. The experimental procedure was only stopped after obtaining the compound of formula V and the reaction was not continued.

[0052] 1) Amidation reaction to prepare the compound of formula II

[0053] Add the mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) into a 3 L three-necked glass bottle and stir for 15 min. Control the temperature of the reaction solution at 20 - 30 °C, slowly add the bifunctional catalyst after mixing DMAP (40.32 g, 0.33 mol) and HOBt (52.7 g, 0.39 mol), raise the temperature to 30 - 35 °C, and stir the reaction for 1.5 h. After the reaction is completed, cool down to 15 - 25 °C, add glacial acetic acid dropwise to adjust the pH to 5.0 - 5.5 to obtain the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula II), and directly use it for the next hydrogenation after filtration.

[0054] 2) Continuously hydrogenate to prepare the compound of Formula III

[0055] Pump the reaction solution of the compound of Formula II into a microchannel reactor system (volume 10 L), and at the same time add a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension. Introduce hydrogen and maintain the pressure at 0.4 MPa, the reaction temperature at 45 - 50 °C, and the residence time at 2 h. After the reaction solution is filtered through a ceramic membrane (pore size 0.1 μm), it is concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula III).

[0056] 3) Acetylate at low temperature to prepare the compound of Formula IV

[0057] Transfer the solution of the compound of Formula III to a 20 L low-temperature reaction kettle, cool down to 2 - 5 °C, and slowly add acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol). Maintain the temperature ≤ 5 °C and stir the reaction for 4 h. After the reaction is completed, distill off the excess acetyl chloride under reduced pressure, add 4.1 L of purified water to dissolve it to obtain a solution of (5-acetamidophthaloyl)bis(aza-diyl)tetraacetate (Compound of Formula IV).

[0058] 4) Dynamically crystallize to prepare the compound of Formula V

[0059] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, and add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at a rate of 2 °C / min, and then cool to 0 °C at a rate of 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction. The filter cake is recrystallized with purified water (10 L) to finally obtain 1211.5 g of the wet product of 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and vacuum dry (80 °C, 24 h) to constant weight to obtain 593.2 g of an off-white solid, (molar yield from step 1 to step 4: 80.3%, HPLC purity: 99.6%).

[0060] Example 3

[0061] In this example, the molar ratio of the feed of 3-aminoglycerol was changed from 1:1.05 to 1:1, and other conditions remained unchanged. The experimental procedure was only stopped after the compound of formula V was prepared and the reaction was not continued.

[0062] 1) Preparation of the compound of formula II by amidation reaction

[0063] Add a mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (182.2 g, 2 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) to a 3 L three-necked glass bottle and stir for 15 min. Control the temperature of the reaction solution at 20 - 30 °C, slowly add the bifunctional catalyst after mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol), raise the temperature to 30 - 35 °C, and stir the reaction for 1.5 h. After the reaction is completed, cool to 15 - 25 °C, add glacial acetic acid dropwise to adjust the pH to 5.0 - 5.5 to obtain the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula II), and filter it directly for the next hydrogenation step.

[0064] 2) Continuous hydrogenation to prepare the compound of formula III

[0065] Pump the reaction solution of the compound of formula II into a microchannel reactor system (volume 10 L), and at the same time add a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension. Introduce hydrogen and maintain the pressure at 0.4 MPa, the reaction temperature is 45 - 50 °C, and the residence time is 2 h. The reaction solution is filtered through a ceramic membrane (pore size 0.1 μm) and then concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula III).

[0066] 3) Low-temperature acetylation to prepare the compound of formula IV

[0067] Transfer the solution of the compound of formula III to a 20 L low-temperature reactor, cool down to 2 - 5 °C, and slowly add acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol). Maintain the temperature ≤ 5 °C and stir for 4 h. After the reaction, distill off the excess acetyl chloride under reduced pressure, add 4.1 L of purified water to dissolve, and obtain a solution of (5-acetamidoisophthaloyl) bis(aza-diyl) tetraacetic acid ester (the compound of formula IV).

[0068] 4) Preparation of the compound of formula V by dynamic crystallization

[0069] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at 2 °C / min, and then to 0 °C at 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction, and recrystallize the filter cake with purified water (10 L). Finally, obtain 1211.5 g of wet product of 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and dry it under vacuum (80 °C, 24 h) to constant weight to obtain 604.3 g of off-white solid (molar yield from step 1 to step 4: 81.8%, HPLC purity: 99.6%).

[0070] Example 4

[0071] In this example, the particle size of the nano-palladium carbon is replaced from 20 nm to 10 nm, the pressure of hydrogen introduced is adjusted to 0.2 MPa, and other conditions remain unchanged. The experimental steps are only stopped after obtaining the compound of formula V and the reaction does not continue.

[0072] 1) Preparation of the compound of formula II by amidation reaction

[0073] Add a mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) to a 3 L three-necked glass bottle and stir for 15 min. Control the temperature of the reaction solution at 20 - 30 °C, slowly add a bifunctional catalyst obtained by mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol), raise the temperature to 30 - 35 °C, and stir for 1.5 h. After the reaction, cool down to 15 - 25 °C, add glacial acetic acid dropwise to adjust the pH to 5.0 - 5.5 to obtain a reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula II), and filter it directly for the next hydrogenation step.

[0074] 2) Continuous hydrogenation to prepare the compound of formula III

[0075] Pump the reaction solution of the compound of formula II into a microchannel reactor system (volume 10 L), and simultaneously add a 5% suspension of palladium-carbon nanoparticles (particle size 10 nm, dry basis 70 g). Introduce hydrogen and maintain the pressure at 0.2 MPa, the reaction temperature at 45 - 50 °C, and the residence time at 2 h. After the reaction solution is filtered through a ceramic membrane (pore size 0.1 μm), it is concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula III).

[0076] 3) Preparation of the compound of formula IV by low-temperature acetylation

[0077] Transfer the solution of the compound of formula III to a 20 L low-temperature reaction kettle, cool down to 2 - 5 °C, and slowly add acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol). Maintain the temperature ≤ 5 °C and stir the reaction for 4 h. After the reaction is completed, evaporate the excess acetyl chloride under reduced pressure, add 4.1 L of purified water to dissolve it, and obtain a solution of (5-acetamidoisophthaloyl)bis(aza-diyl)tetraacetic acid ester (the compound of formula IV).

[0078] 4) Preparation of the compound of formula V by dynamic crystallization

[0079] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, add 20% aqueous sodium hydroxide solution to adjust the pH to 10.0. Start the gradient cooling program: from 50 °C to 20 °C at a rate of 2 °C / min, and then from 20 °C to 0 °C at a rate of 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction, and recrystallize the filter cake with purified water (10 L). Finally, obtain 1211.5 g of wet product of 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and dry it under vacuum (80 °C, 24 h) to constant weight to obtain 605.74 g of an off-white solid (molar yield from step 1 to step 4: 81.99%, HPLC purity: 99.6%).

[0080] Example 5

[0081] In this example, the hydrogenation temperature is adjusted to 30 - 40 °C, the hydrogenation reaction time is extended to 3 h, and other conditions remain unchanged. The experimental procedure stops after obtaining the compound of formula V and does not continue the reaction.

[0082] 1) Preparation of the compound of formula II by amidation reaction

[0083] Dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), a mixed solvent of anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) were added to a 3 L three-necked glass flask and stirred for 15 min. The temperature of the reaction solution was controlled at 20 - 30 °C, and a bifunctional catalyst prepared by mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol) was slowly added. The temperature was raised to 30 - 35 °C and the reaction was stirred for 1.5 h. After the reaction was completed, the temperature was lowered to 15 - 25 °C, and glacial acetic acid was added dropwise to adjust the pH to 5.0 - 5.5 to obtain a reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula II), which was directly used for the next hydrogenation step after filtration.

[0084] 2) Continuous hydrogenation to prepare the compound of Formula III

[0085] The reaction solution of the compound of Formula II was pumped into a microchannel reactor system (volume 10 L), and at the same time, a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension was added. Hydrogen was introduced and the pressure was maintained at 0.4 MPa, the reaction temperature was 30 - 40 °C, and the residence time was 3 h. The reaction solution was filtered through a ceramic membrane (pore size 0.1 μm) and then concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula III).

[0086] 3) Low-temperature acetylation to prepare the compound of Formula IV

[0087] The solution of the compound of Formula III was transferred to a 20 L low-temperature reaction kettle, the temperature was lowered to 2 - 5 °C, and acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol) were slowly added dropwise. The temperature was maintained at ≤5 °C and the reaction was stirred for 4 h. After the reaction was completed, the excess acetyl chloride was removed by distillation under reduced pressure, and 4.1 L of purified water was added for dissolution to obtain a solution of (5-acetylaminoisophthaloyl)bis(aza-diyl)tetraacetate (Compound of Formula IV).

[0088] 4) Dynamic crystallization to prepare the compound of Formula V

[0089] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, and add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at a rate of 2 °C / min, and then cool to 0 °C at a rate of 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction. The filter cake is recrystallized with purified water (10 L) to finally obtain 1211.5 g of the wet product of 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V). Vacuum dry (80 °C, 24 h) to constant weight to obtain 605.62 g of an off-white solid, (molar yield from step 1 to step 4: 81.98%, HPLC purity: 99.6%).

[0090] Example 6

[0091] In this example, the acetylation temperature was adjusted to 0 °C, and other conditions remained unchanged. The experimental procedure was only stopped after obtaining the compound of formula V and no further reaction was continued.

[0092] 1) Preparation of the compound of formula II by amidation reaction

[0093] Add a mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) to a 3 L three-necked glass bottle and stir for 15 min. Control the reaction solution temperature at 20 - 30 °C, slowly add the bifunctional catalyst obtained by mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol), heat up to 30 - 35 °C, and stir the reaction for 1.5 h. After the reaction is completed, cool to 15 - 25 °C, add glacial acetic acid dropwise to adjust the pH to 5.0 - 5.5 to obtain the reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula II), and filter it directly for the next hydrogenation step.

[0094] 2) Continuous hydrogenation to prepare the compound of formula III

[0095] Pump the reaction solution of the compound of formula II into a microchannel reactor system (volume 10 L), and at the same time add a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension. Introduce hydrogen and maintain the pressure at 0.4 MPa, the reaction temperature at 45 - 50 °C, and the residence time at 2 h. The reaction solution is filtered through a ceramic membrane (pore size 0.1 μm) and then concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula III).

[0096] 3) Low-temperature acetylation to prepare the compound of formula IV

[0097] Transfer the solution of the compound of formula III to a 20 L low-temperature reactor, cool down to 0 °C, and slowly add acetyl chloride (188.4 g, 2.4 mol) and pyridine (205.7 g, 2.6 mol). Maintain the temperature ≤ 5 °C and stir the reaction for 4 h. After the reaction is completed, evaporate the excess acetyl chloride under reduced pressure, add 4.1 L of purified water to dissolve it, and obtain a solution of (5-acetamidoisophthaloyl)bis(azanediyl)tetraacetic acid ester (the compound of formula IV).

[0098] 4) Preparation of the compound of formula V by dynamic crystallization

[0099] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at a rate of 2 °C / min, and then cool to 0 °C at a rate of 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction, and recrystallize the filter cake with purified water (10 L). Finally, obtain 1211.5 g of wet product of 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and dry it under vacuum (80 °C, 24 h) to constant weight to obtain 605.77 g of off-white solid (molar yield from step 1 to step 4: 82%, HPLC purity: 99.7%).

[0100] Example 7

[0101] In this example, the molar ratio of acetyl chloride to the compound of formula III was adjusted from 1.2:1 to 1.5:1, and the molar ratio of pyridine to the compound of formula III was adjusted from 1.3 to 1.1, with other conditions remaining unchanged. The experimental procedure was only stopped after obtaining the compound of formula V and the reaction was not continued.

[0102] 1) Preparation of the compound of formula II by amidation reaction

[0103] Add the mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (191.33 g, 2.1 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) to a 3 L three-necked glass bottle and stir for 15 min. Control the temperature of the reaction solution at 20 - 30 °C, slowly add the bifunctional catalyst obtained by mixing DMAP (40.32 g, 0.33 mol) and DCC (80.47 g, 0.39 mol), raise the temperature to 30 - 35 °C, and stir the reaction for 1.5 h. After the reaction is completed, cool down to 15 - 25 °C, add glacial acetic acid dropwise to adjust the pH to 5.0 - 5.5 to obtain a reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula II), and filter it directly for the next hydrogenation step.

[0104] 2) Continuous hydrogenation to prepare the compound of formula III

[0105] Pump the reaction solution of the compound of formula II into a microchannel reactor system (volume 10 L), and simultaneously add a 5% suspension of palladium-carbon nanoparticles (particle size 20 nm, dry basis 70 g). Introduce hydrogen and maintain the pressure at 0.4 MPa, the reaction temperature at 45 - 50 °C, and the residence time at 2 h. After filtering the reaction solution through a ceramic membrane (pore size 0.1 μm), concentrate it under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula III).

[0106] 3) Preparation of the compound of formula IV by low-temperature acetylation

[0107] Transfer the solution of the compound of formula III to a 20 L low-temperature reaction kettle, cool it to 2 - 5 °C, and slowly add acetyl chloride (235.5 g, 3 mol) and pyridine (174 g, 2.2 mol). Maintain the temperature ≤ 5 °C and stir for 4 h. After the reaction is completed, distill off the excess acetyl chloride under reduced pressure, add 4.1 L of purified water to dissolve it, and obtain a solution of (5-acetamidoisophthaloyl)bis(aza-diyl)tetraacetic acid ester (the compound of formula IV).

[0108] 4) Preparation of the compound of formula V by dynamic crystallization

[0109] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, add 20% aqueous sodium hydroxide solution to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at a rate of 2 °C / min, and then cool to 0 °C at a rate of 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction, and recrystallize the filter cake with purified water (10 L). Finally, obtain 1211.5 g of wet product of 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V), and dry it under vacuum (80 °C, 24 h) to constant weight to obtain 596.16 g of an off-white solid (molar yield from step 1 to step 4: 80.7%, HPLC purity: 98.9%).

[0110] Example 8

[0111] In this example, the molar ratio of epichlorohydrin is adjusted from 1:0.55 to 1:0.5, and the pH of the reaction system is regulated from 8.0 to 9.0, with other conditions remaining unchanged.

[0112] 5) Continuous dimerization to prepare the compound of formula VI

[0113] Compound of formula V (591 g, 1.6 mol), potassium hydroxide (180 g, 3.2 mol), boric acid (185.5 g, 3 mol) and purified water (2 L) were mixed and pumped into a series of microreactor systems (volume 20 L). The temperature of the reaction solution was controlled at 10 - 15 °C, epichlorohydrin (74 g, 0.8 mol, molar ratio 1:0.5) was continuously injected, the pH of the reaction system was adjusted to 9.0, and the residence time was 24 h. The pH of the effluent was adjusted to 2.0 with sulfuric acid to obtain a solution of 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (compound of formula VI).

[0114] 6) Preparation of the compound of formula VII by iodination and continuous purification

[0115] The solution of the compound of formula VI, iodine (507.6 g, 2 mol) and sodium iodate (316.6 g, 1.6 mol) were introduced into an iodination reactor, the pH was controlled at 4.5 - 5.0, the temperature was 75 - 80 °C, and the reaction was carried out for 12 h. The crude product solution was purified by continuous countercurrent chromatography (mobile phase: 0.02 M phosphate buffer / acetonitrile, gradient 0.2%), and then ultrafiltered and concentrated. Spray drying was carried out using a low-temperature process (inlet 55 °C, outlet 35 °C) to obtain 419.9 g of pure iodixanol (compound of formula VII) (two-step molar yield from step 5 to step 6: 33.02%, HPLC purity: 99.9%), the content of impurity G was 0.01%, and the total impurities were 0.04%.

[0116] Example 9

[0117] In this example, the molar ratio of epichlorohydrin was adjusted from 1:0.55 to 1:0.6, and the residence time was adjusted to 20 h, with other conditions remaining unchanged.

[0118] 5) Continuous dimerization to prepare the compound of formula VI

[0119] Compound of formula V (591 g, 1.6 mol), potassium hydroxide (180 g, 3.2 mol), boric acid (185.5 g, 3 mol) and purified water (2 L) were mixed and pumped into a series of microreactor systems (volume 20 L). The temperature of the reaction solution was controlled at 10 - 15 °C, epichlorohydrin (88.8 g, 0.96 mol, molar ratio 1:0.6) was continuously injected, the pH of the reaction system was adjusted to 8.0, and the residence time was 20 h. The pH of the effluent was adjusted to 2.0 with sulfuric acid to obtain a solution of 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (compound of formula VI).

[0120] 6) Preparation of the compound of formula VII by iodination and continuous purification

[0121] The solution of the compound of formula VI, iodine (507.6 g, 2 mol) and sodium iodate (316.6 g, 1.6 mol) were introduced into an iodination reactor, and the pH was controlled at 4.5 - 5.0 and the temperature at 75 - 80 °C for reaction for 12 h. The crude product solution was purified by continuous countercurrent chromatography (mobile phase: 0.02 M phosphate buffer / acetonitrile, gradient 0.2%), and then concentrated by ultrafiltration. Spray drying was carried out using a low-temperature process (inlet 55 °C, outlet 35 °C) to obtain 422.7 g of pure iodixanol (compound of formula VII) (two-step yield 33.24%, purity 99.96%), the content of impurity G was 0.01%, and the total impurities were 0.04%.

[0122] Example 10

[0123] In this example, the molar ratio of iodine to sodium iodate was adjusted from 1:0.8 to 1:1.2, and the reaction pH was adjusted to 4.0 - 4.5, with other conditions remaining unchanged.

[0124] 5) Continuous dimerization to prepare the compound of formula VI

[0125] The compound of formula V (591 g, 1.6 mol), potassium hydroxide (180 g, 3.2 mol), boric acid (185.5 g, 3 mol) and purified water (2 L) were mixed and pumped into a series of microreactor systems (volume 20 L). The temperature of the reaction solution was controlled at 10 - 15 °C, epichlorohydrin (81.4 g, 0.88 mol, molar ratio 1:0.55) was continuously injected, the pH of the reaction system was adjusted to 8.0, and the residence time was 24 h. The pH of the effluent was adjusted to 2.0 with sulfuric acid to obtain a solution of 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (compound of formula VI).

[0126] 6) Iodination and continuous purification to prepare the compound of formula VII

[0127] The solution of the compound of formula VI, iodine (507.6 g, 2 mol) and sodium iodate (474.9 g, 2.4 mol) were introduced into an iodination reactor, and the pH was controlled at 4.0 - 4.5 and the temperature at 75 - 80 °C for reaction for 12 h. The crude product solution was purified by continuous countercurrent chromatography (mobile phase: 0.02 M phosphate buffer / acetonitrile, gradient 0.2%), and then concentrated by ultrafiltration. Spray drying was carried out using a low-temperature process (inlet 55 °C, outlet 35 °C) to obtain 416.48 g of pure iodixanol (compound of formula VII) (two-step yield 32.75%, purity 98%), the content of impurity G was 0.01%, and the total impurities were 0.09%.

[0128] Example 11

[0129] This example is a comparative example of Example 1.

[0130] 1) Preparation of the compound of formula II by amidation reaction

[0131] A mixed solvent of dimethyl 5-nitroisophthalate (478.36 g, 2 mol), 3-aminoglycerol (182.2 g, 2 mol), anhydrous methanol (510 ml) and tetrahydrofuran (170 ml) was added to a 3 L three-necked glass bottle and stirred for 15 min. The temperature of the reaction solution was controlled at 20 - 30 °C, and a bifunctional catalyst obtained by mixing DMAP (40.32 g, 0.33 mol) and HOBt (52.7 g, 0.39 mol) was slowly added. The temperature was raised to 30 - 35 °C and the reaction was stirred for 1.5 h. After the reaction was completed, the temperature was lowered to 15 - 25 °C, and glacial acetic acid was added dropwise to adjust the pH to 5.0 - 5.5 to obtain a reaction solution of 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula II), which was directly used for the next hydrogenation after filtration.

[0132] 2) Continuous hydrogenation to prepare the compound of formula III

[0133] The reaction solution of the compound of formula II was pumped into a microchannel reactor system (volume 10 L), and at the same time, a 5% nano-palladium on carbon (particle size 20 nm, dry basis 70 g) suspension was added. Hydrogen was introduced and the pressure was maintained at 0.2 MPa, the reaction temperature was 30 °C, and the residence time was 3 h. The reaction solution was filtered through a ceramic membrane (pore size 0.1 μm) and then concentrated under reduced pressure to obtain a solution of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula III).

[0134] 3) Low-temperature acetylation to prepare the compound of formula IV

[0135] The solution of the compound of formula III was transferred to a 20 L low-temperature reaction kettle, the temperature was lowered to 0 °C, and acetyl chloride (235.5 g, 3 mol) and pyridine (174 g, 2.2 mol) were slowly added dropwise. The temperature was maintained at ≤5 °C and the reaction was stirred for 4 h. After the reaction was completed, the excess acetyl chloride was removed by distillation under reduced pressure, and 4.1 L of purified water was added for dissolution to obtain a solution of (5-acetamidoisophthaloyl)bis(aza-diyl)tetraacetate (the compound of formula IV).

[0136] 4) Dynamic crystallization to prepare the compound of formula V

[0137] Transfer the solution of the compound of formula IV to a programmable temperature-controlled crystallization kettle, and add 20% aqueous sodium hydroxide solution to adjust the pH to 10.0. Start the gradient cooling program: cool from 50 °C to 20 °C at 2 °C / min, and then cool to 0 °C at 0.5 °C / min, while applying ultrasonic oscillation (frequency 30 kHz). After crystallization for 14 h, filter by suction. The filter cake is recrystallized with purified water (10 L). Finally, 1211.5 g of the wet product of 5-(acetylamino)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (the compound of formula V) is obtained. Vacuum dry (80 °C, 24 h) to constant weight to obtain 566.6 g of an off-white solid. (Total molar yield from step 1 to step 4: 76.7%, HPLC purity: 99.4%).

[0138] 5) Continuously dimerize to prepare the compound of formula VI

[0139] Mix the compound of formula V (565.1 g, 1.53 mol), potassium hydroxide (180 g, 3.2 mol), boric acid (185.5 g, 3 mol) and purified water (2 L), and pump them into a series microreactor system (volume 20 L). Control the temperature of the reaction solution at 10 - 15 °C, continuously inject epichlorohydrin (74 g, 0.8 mol, molar ratio 1:0.5), adjust the pH of the reaction system to 8.0, and the residence time is 20 h. Adjust the pH of the effluent to 2.0 with sulfuric acid to obtain a solution of 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (the compound of formula VI).

[0140] 6) Iodination and continuous purification to prepare the compound of formula VII

[0141] Pass the solution of the compound of formula VI, iodine (507.6 g, 2 mol) and sodium iodate (474.9 g, 2.4 mol) into an iodination reaction kettle, control the pH at 5.0, and the temperature at 75 - 80 °C, and react for 12 h. The crude product solution is purified by continuous countercurrent chromatography (mobile phase: 0.02 M phosphate buffer / acetonitrile, gradient 0.2%), and then ultrafiltered and concentrated. Spray drying is carried out using a low-temperature process (inlet 55 °C, outlet 35 °C) to obtain 342.93 g of pure iodixanol (the compound of formula VII) (two-step yield 28.2%, purity 99.5%), total molar yield 18.51%, impurity G content 0.02%, total impurities 0.19%.

[0142] The embodiments of the present invention are not limited to those described in the above examples. Without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements in form and details, and all of these are considered to fall within the protection scope of the present invention.

Claims

1. A continuous preparation method of iodixanol, characterized in that, The method comprises the following steps: S1: Using dimethyl 5-nitroisophthalate (Compound of Formula I) as the starting material, reacting with 3-aminoglycerol in the presence of a bifunctional catalyst to carry out an amidation reaction to produce 5-nitro-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula II); S2: Hydrogenating and reducing the Compound of Formula II under the catalysis of nano palladium-carbon and at a hydrogen pressure of 0.2 - 0.4 MPa to produce 5-amino-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula III); S3: Selectively acetylating the Compound of Formula III with an acetyl chloride - pyridine system under low-temperature conditions to produce (5-acetamidoisophthaloyl)bis(aza-diyl)tetraacetate (Compound of Formula IV); S4: Hydrolyzing the Compound of Formula IV under alkaline conditions and dynamically crystallizing to produce 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide (Compound of Formula V); S5: Dimerizing the Compound of Formula V with epichlorohydrin in a continuous flow reactor to produce the intermediate 5,5'-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide] (Compound of Formula VI); S6: Reacting the Compound of Formula VI with an iodine - sodium iodate system under weakly acidic conditions, purifying by continuous countercurrent chromatography, nanofiltration and low-temperature spray drying to obtain iodixanol (Compound of Formula VII).

2. The continuous preparation method of iodixanol according to claim 1, characterized in that: In the step S1, the bifunctional catalyst is at least one of the systems of DMAP and DCC, DMAP and HOBt; the reaction solvent is a mixed solvent of methanol and tetrahydrofuran with a volume ratio of 3:1; the molar ratio of the Compound of Formula I to aminoglycerol in the feed is 1:1 - 1.

05.

3. A continuous preparation method of iodixanol according to claim 2, characterized in that: In the step S2, the palladium loading of the nano palladium-carbon is 5%, and the particle size is 10 - 50 nm; the hydrogenation temperature is 30 - 50 °C, and the reaction time is 2 - 3 h; the hydrogenation reaction is carried out continuously in a microchannel reactor.

4. A continuous preparation method of iodixanol according to claim 3, characterized in that: In the step S3, the acetylation temperature is 0 - 5 °C, and the molar ratio of acetyl chloride to the Compound of Formula III is 1.2:1 - 1.5:1; the addition amount of pyridine in the reaction system is 1.1 - 1.3 times the molar ratio of the Compound of Formula III.

5. A continuous preparation method of iodixanol according to claim 4, characterized in that: In the step S4, the dynamic crystallization adopts a gradient cooling program: the initial temperature is 50 °C, which is cooled to 20 °C at a rate of 2 °C / min, and then cooled to 0 °C at a rate of 0.5 °C / min; during the crystallization process, ultrasonic oscillation is assisted, and the frequency is 20 - 40 kHz.

6. A continuous preparation method of iodixanol according to claim 5, characterized in that: In the step S5, the molar ratio of epichlorohydrin to the Compound of Formula V is 0.5:1 - 0.6:1; the dimerization reaction is carried out continuously in a series of microreactors, and the residence time is 20 - 24 h; the pH of the reaction system is dynamically regulated to 8.0 - 9.0 by an on-line sensor.

7. A continuous preparation method of iodixanol according to claim 6, characterized in that: In the step S6, the molar ratio of iodine to sodium iodate in the iodination reaction is 1:0.8 - 1.2, and the reaction pH is 4.0 - 5.0; the mobile phase of the continuous countercurrent chromatography is 0.02M phosphate buffer solution and acetonitrile, and the gradient elution slope is 0.15% - 0.25%; the inlet temperature of the spray drying is 50 - 60°C, and the outlet temperature is 30 - 40°C.

8. A continuous preparation method of iodixanol according to claim 7, characterized in that, The method further includes: the acetyl chloride distilled out in the step S3 is recycled after dehydration by molecular sieves; the waste palladium carbon is regenerated by pickling with nitric acid and calcining at 400 - 500°C, and the number of recycling times is ≥10 times.

9. A continuous preparation method of iodixanol according to claim 8, characterized in that: The total molar yield of the final product ioxagol is 18.51% - 27.3%, the total impurity content is ≤0.2%, and the content of impurity G is ≤0.02%.

10. A continuous preparation method of iodixanol according to any one of claims 1 to 9, characterized in that: The purity of the final product ioxagol is ≥99.95%, which is applicable to pharmaceutical preparations for angiography agents.

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