A method for industrial production of ioversol

Abstract

The invention relates to the field of pharmaceutical chemicals, and in particular to a method for industrially producing ioversol. The method is carried out according to the following reaction equation. The technical scheme of the invention can effectively reduce the generation of impurities and is suitable for industrial production to obtain ioversol with high purity and high yield.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemicals, and mainly relates to a method for industrially producing ioversol. Background Art

[0002] Ioversol, as one of the widely used contrast agents, is often used in angiography, digital venous silhouette angiography, arthrography, urography, chest and cervical spine angiography and gastrointestinal examination, etc. It has the advantages of high water solubility, low viscosity, low osmotic pressure and low adverse reaction rate.

[0003] The chemical name of ioversetol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-hydroxyacetamido]-2,4,6-triiodo-1,3-benzenedicarbamide, and its structural formula is as follows:

[0004]

[0005] Regarding the preparation method of ioversol, patent document CN1477093A discloses a method of preparing ioversol using 5-chloroacetylamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide as a raw material, adding chloroethanol, and using sodium acetate as a catalyst. The excess chloroethanol added in this method will generate the impurity N,N'-bis(2,3 dihydroxypropyl)-5-[(2-(2-hydroxyethoxy)-N-(2-hydroxyethyl)-acetamido]-2,4,6-triiodo-1,3-benzenedicarbamide (compound of formula 5) after hydrolysis again. This impurity is not easy to remove, which affects the yield and purity of the final product.

[0006]

[0007] In the process of preparing iodine alcohol from 5-amino-N,N'-bis(2,5-dihydroxy-propyl)-2,4,6-triiodo-toluene dicarboxamide as raw material, after aromatic hydrogen is replaced by iodine, intramolecular coupling is easy to occur to generate a six-membered heterocyclic structure, especially in the last step of hydrolysis under alkaline conditions, coupling products are inevitably generated. Patent text CN106749323A discloses a method for preparing an iodine alcohol impurity (compound of formula 6) that undergoes intramolecular coupling.

[0008]

[0009] The synthesis of 5-(N-2-hydroxyethyl)hydroxyacetylamino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide published by Luo Shineng et al. describes the selective reaction of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide with acetoxyacetyl chloride in N,N-dimethylformamide, and the hydrolyzed product reacts with chloroethanol to obtain ioversol. This route is more suitable for industrial production than before, but the yield of ioversol obtained by this method is only 62%.

[0010] Therefore, there is an urgent need to develop a more optimized industrial production method for ioversesol to further improve the product yield and reduce the content of various impurities. Summary of the invention

[0011] In order to solve the problems existing in the prior art, the present invention provides a method for industrially producing ioversol, by which ioversol with high yield and high purity can be prepared.

[0012] To achieve the purpose of the present invention, a preparation method is provided, wherein the compound of formula 3 is used as a raw material, and is hydrolyzed in the presence of an alkaline agent to obtain iodine (compound of formula 4), and the reaction formula is shown below:

[0013]

[0014] Preferably, the alkaline agent is selected from sodium acetate, sodium acetate / acetic acid, sodium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, more preferably sodium acetate, sodium acetate / acetic acid, triethylamine, most preferably triethylamine.

[0015] Preferably, the pH of the reaction system is adjusted to 3 to 10, more preferably 5 to 7, and most preferably 6.5.

[0016] Preferably, the reaction time is 8 to 36 hours, more preferably 16 to 26 hours, and most preferably 20 hours.

[0017] Preferably, the reaction temperature is 26°C to reflux, more preferably 35°C to reflux, and even more preferably 65°C to reflux.

[0018] Furthermore, after the reaction is completed, electrodialysis is used for desalination, preferably to reduce the conductivity to below 10 μS / cm.

[0019] Furthermore, the product obtained after desalting is separated using a DAC column.

[0020] Furthermore, the product obtained after separation is filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of ioversesol.

[0021] Preferably, the recrystallization solvent for the crude ioversol obtained by the reaction is selected from methanol, isopropanol, ethanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and more preferably ethanol.

[0022] Furthermore, the compound of formula 3 is prepared by an alkylation reaction of the compound of formula 2 with an alkylating agent, and the reaction formula is as follows:

[0023]

[0024] Preferably, the reaction alkylating agent is selected from chloroethanol, chloroacetyl chloride, and bromoethanol, more preferably chloroethanol and chloroacetyl chloride, and most preferably chloroethanol.

[0025] The method further comprises the step of adding an inorganic base into the reaction system, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide, more preferably sodium hydroxide and potassium hydroxide, and most preferably potassium hydroxide.

[0026] Preferably, the molar equivalent ratio of the compound of reaction formula 2 to the alkylating agent is 1:(0.9-3.6), more preferably 1:(1.2-2.8), more preferably 1:(1.6-2.2), and most preferably 1:1.8.

[0027] Furthermore, the reaction of preparing the compound of formula 3 from the compound of formula 2 further includes a step of adjusting the pH value of the reaction system.

[0028] Preferably, the pH value of the system is adjusted with an acid, wherein the acid is selected from concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid, and more preferably concentrated hydrochloric acid.

[0029] Preferably, the pH of the reaction system is adjusted to 3-10, more preferably 5-7.

[0030] Preferably, the reaction temperature is 35°C to 85°C, more preferably 45°C to 55°C, most preferably 50°C.

[0031] Preferably, the reaction time is 5 to 36 hours, more preferably 10 to 18 hours, and most preferably 15 hours.

[0032] Furthermore, the compound of formula 2 is obtained by reacting the compound of formula 1 with an alkylation reagent and then hydrolyzing it, and the reaction formula is as follows:

[0033]

[0034] Preferably, the alkylation reagent is selected from chloroethanol, chloroacetyl chloride, and bromoethanol, more preferably chloroethanol and chloroacetyl chloride, and most preferably chloroacetyl chloride.

[0035] Preferably, the reaction temperature is 26°C to 96°C, more preferably 35°C to 85°C, and even more preferably 45°C to 55°C.

[0036] Preferably, the reaction time is 0.5 to 8 hours, more preferably 1 to 5 hours, and most preferably 3 hours.

[0037] Preferably, the reaction solvent that can be used in the present invention is selected from at least one of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N,N-dimethylacetamide, more preferably N,N-dimethylformamide and N,N-dimethylacetamide, and most preferably N,N-dimethylformamide.

[0038] Preferably, the hydrolysis step is carried out in the presence of an inorganic base. Preferably, the inorganic base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide, more preferably sodium hydroxide and potassium hydroxide, and most preferably sodium hydroxide.

[0039] Preferably, after the hydrolysis is completed, the step of adjusting the pH of the reaction system is further included, and the pH reagent is selected from concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid, and concentrated hydrochloric acid is more preferred.

[0040] Preferably, the pH of the reaction system is adjusted to 1-10, more preferably 3-8, and even more preferably 5-6.

[0041] Furthermore, the present invention provides a method for detecting ioversol:

[0042] According to the high performance liquid chromatography method, octadecyl bonded silica gel was used as the filler (250mm*4.6um, 5um), the column temperature was 35°C, the detection wavelength was 254nm, the flow rate was 1.0ml / min, the injection volume was 50μl, acetonitrile and water (0.5:99.5) were used as the mobile phase, and the diluent was water; isocratic elution, and the collection time was 50min.

[0043] In a preferred technical solution, the preparation method of the present invention comprises the following steps:

[0044] 1) Using the compound of formula 1 as a raw material, reacting with an alkylation reaction reagent and then hydrolyzing to prepare a compound of formula 2, the reaction formula is as follows:

[0045]

[0046] Preferably, the alkylation reagent is selected from chloroethanol, chloroacetyl chloride, and bromoethanol, more preferably chloroethanol and chloroacetyl chloride, and most preferably chloroacetyl chloride.

[0047] Preferably, the reaction temperature is 26°C to 96°C, more preferably 35°C to 85°C, and even more preferably 45°C to 55°C.

[0048] Preferably, the reaction time is 0.5 to 8 hours, more preferably 1 to 5 hours, and most preferably 3 hours.

[0049] Preferably, the reaction solvent that can be used in the present invention is selected from at least one of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, and N,N-dimethylacetamide, more preferably N,N-dimethylformamide and N,N-dimethylacetamide, and most preferably N,N-dimethylformamide.

[0050] Preferably, the hydrolysis step is carried out in the presence of an inorganic base. Preferably, the inorganic base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide, more preferably sodium hydroxide and potassium hydroxide, and most preferably sodium hydroxide.

[0051] Preferably, after the hydrolysis is completed, the step of adjusting the pH of the reaction system is further included, and the pH reagent is selected from concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid, and concentrated hydrochloric acid is more preferred.

[0052] Preferably, the pH of the reaction system is adjusted to 1-10, more preferably 3-8, and even more preferably 5-6.

[0053] 2) The compound of formula 2 is subjected to an alkylation reaction with an alkylating agent to obtain a compound of formula 3, and the reaction formula is shown below:

[0054]

[0055] The alkylating agent is selected from chloroethanol, chloroacetyl chloride, and bromoethanol, more preferably chloroethanol and chloroacetyl chloride, and most preferably chloroethanol.

[0056] Preferably, the method further comprises the step of adding an inorganic base to the reaction system, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide, more preferably sodium hydroxide and potassium hydroxide, and most preferably potassium hydroxide.

[0057] Preferably, the molar equivalent ratio of the compound of formula 2 to the alkylating agent is 1:(0.9-3.6), more preferably 1:(1.2-2.8), more preferably 1:(1.6-2.2), and most preferably 1:1.8.

[0058] Furthermore, the reaction of preparing the compound of formula 3 from the compound of formula 2 further includes a step of adjusting the pH value of the reaction system.

[0059] Preferably, the pH value of the system is adjusted with an acid, wherein the acid is selected from concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid, and more preferably concentrated hydrochloric acid.

[0060] Preferably, the pH of the reaction system is adjusted to 3-10, more preferably 5-7.

[0061] Preferably, the reaction temperature is 35°C to 85°C, more preferably 45°C to 55°C, most preferably 50°C.

[0062] Preferably, the reaction time is 5 to 36 hours, more preferably 10 to 18 hours, and most preferably 15 hours.

[0063] 3) Using the compound of formula 3 as a raw material, hydrolyzing in the presence of an alkaline agent to obtain a crude product of iodine (compound of formula 4), the reaction formula is as follows:

[0064]

[0065] Preferably, the alkaline agent is selected from sodium acetate, sodium acetate\acetic acid, sodium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, more preferably sodium acetate, sodium acetate\acetic acid, triethylamine, most preferably triethylamine.

[0066] Preferably, the method further comprises adding an alkaline agent to adjust the pH of the reaction system to 3 to 10, more preferably 5 to 7, and most preferably 6.5.

[0067] Preferably, the reaction time is 8 to 36 hours, more preferably 16 to 26 hours, and most preferably 20 hours.

[0068] Preferably, the reaction temperature is 26°C to reflux, more preferably 35°C to reflux, and even more preferably 65°C to reflux.

[0069] Furthermore, after the reaction is completed, electrodialysis is used for desalination, preferably to reduce the conductivity to below 10 μS / cm.

[0070] Furthermore, the product obtained after desalting is separated using a DAC column.

[0071] Furthermore, the product obtained after separation is filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of ioversesol.

[0072] Preferably, the recrystallization solvent for the crude ioversol obtained by the reaction is selected from methanol, isopropanol, ethanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and more preferably ethanol.

[0073] Beneficial effects of the present invention

[0074] The present invention provides a method for industrial production of refined iohexol products. Compared with the existing preparation method, the technical scheme of the present invention can improve the purity of the product and reduce the generation of various impurities. In addition, the present invention selects triethylamine as an alkaline reagent in the reaction of hydrolyzing the compound of formula 3 into iohexol, which can better perform selective hydrolysis. At the same time, the inventor controls the molar ratio between the two reaction substances in the reaction of generating the compound of formula 3 from the compound of formula 2, finds the optimal ratio between the two, greatly reduces the generation of impurities, and improves the reaction yield and purity. The reaction yield reaches 92.5%, and the purity can reach more than 99.86%, which is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 : HPLC spectrogram of the ioversol prepared in Example 1.

[0076] Figure 2 : HPLC spectrogram of the iodine alcohol prepared in Example 3. DETAILED DESCRIPTION

[0077] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0078] Example 1, preparation of ioversel

[0079] Add 400g of Formula 2 compound, 1600g of water and 72g of potassium hydroxide to a 5L reactor. After complete dissolution, add 74.18g of chloroethanol, react at 50°C for 15 hours, and adjust the pH to 5-7 with 100g of concentrated hydrochloric acid + 100g of water. Add 200g of sodium acetate and adjust the pH to 6.5 with acetic acid. Heat and reflux for 20 hours. Use electrodialysis to desalinate, reduce the conductivity to below 10μS / cm, and add 1000g of purified water to wash the electrodialyzer. The desalted liquid is concentrated to about 1.5-2L, and a DAC column is used for column separation. The collected liquid is concentrated to about 1L using nanofiltration, filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of iodine. Add 4000g of ethanol, heat, reflux for 2 hours for crystallization, and dry the filter cake under reduced pressure at 50-60°C to obtain 341.23g of iodine finished product, with a yield of 82.6% and a purity of 99.79%. HPLC spectrum see Figure 1 , the corresponding data are as follows:

[0080]

[0081] Example 2, Synthesis of Ioversol

[0082] Add 400g of Formula 2 compound, 1600g of water and 72g of potassium hydroxide to a 5L reactor. After complete dissolution, add 74.18g of chloroethanol, react at 50°C for 15 hours, and adjust the pH to 5-7 with 100g of concentrated hydrochloric acid + 100g of water. Add 200g of sodium acetate to adjust the pH to 6.5. Heat and reflux for 20 hours. Use electrodialysis to desalinate, reduce the conductivity to below 10μS / cm, and add 1000g of purified water to wash the electrodialyzer. The desalted liquid is concentrated to about 1.5-2L, and a DAC column is used for column separation. The collected liquid is concentrated to about 1L using nanofiltration, filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of iodine. Add 4000g of ethanol, heat, reflux for 2 hours for crystallization, and dry the filter cake under reduced pressure at 50-60°C to obtain 288.35g of iodine finished product, with a yield of 69.8% and a purity of 96.35%.

[0083] Example 3, Industrial production of ioversemol

[0084] Add 400kg of Formula 2 compound, 1600kg of water and 72kg of potassium hydroxide to a 5000L reactor. After complete dissolution, add 74.18kg of chloroethanol, react at 50°C for 15 hours, and adjust the pH to 5-7 with 100kg of concentrated hydrochloric acid + 100kg of water. Add 246kg of triethylamine to adjust the pH to 6.5. Heat to reflux for 20 hours. Use electrodialysis to desalinate, reduce the conductivity to below 10μS / cm, and add 1000kg of purified water to wash the electrodialyzer. The desalted liquid is concentrated to about 1500-2000L, and a DAC column is used for column separation. The collected liquid is concentrated to about 1000L using nanofiltration, filtered, microfiltered, ultrafiltered, and spray dried to obtain a crude product of iodine. Add 4000 kg of ethanol, raise the temperature, reflux for 2 hours for crystallization, and dry the filter cake under reduced pressure at 50-60°C to obtain 382.13 kg of iodine ethanol with a yield of 92.5% and a purity of 99.86%. Figure 2 , the corresponding data are as follows:

[0085]

[0086] Embodiment 4, the synthesis of ioversemol

[0087] Add 400g of Formula 2 compound, 1600g of water and 72g of potassium hydroxide to a 5L reactor. After complete dissolution, add 74.18g of chloroethanol, react at 50°C for 15 hours, and adjust the pH to 5-7 with 100g of concentrated hydrochloric acid + 100g of water. Add 205g of sodium bicarbonate to adjust the pH to 6.5. Heat and reflux for 20 hours. Use electrodialysis to desalinate, reduce the conductivity to below 10μS / cm, and add 1000g of purified water to wash the electrodialyzer. The desalted liquid is concentrated to about 1.5-2L, and a DAC column is used for column separation. The collected liquid is concentrated to about 1L using nanofiltration, filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of iodine. Add 4000g of ethanol, heat, reflux for 2 hours for crystallization, and dry the filter cake under reduced pressure at 50-60°C to obtain 306.24g of iodine finished product, with a yield of 74.12% and a purity of 90.28%.

[0088] Example 5-11, Synthesis of Ioversol

[0089] The preparation methods of Examples 5-11 refer to those of Example 3, with the dosage being one thousandth, except that the amount of chloroethanol used is different, as shown in the table below:

[0090]

[0091]

[0092] Example 12-18, Synthesis of Ioversol

[0093] The preparation methods of Examples 12-18 refer to Example 3, with the dosage being one thousandth, except that triethylamine is used to adjust the pH value of the reaction system, resulting in different final values, as shown in the table below:

[0094] Serial number pH of reaction system Finished product yield Purity of finished product Example 12 3 65.84％ 70.26％ Example 13 5 81.26％ 95.46％ Embodiment 14 5.5 89.79％ 97.58％ Embodiment 15 6 88.14％ 99.26％ Example 16 7 89.13％ 99.08％ Embodiment 17 7.5 42.18％ 85.22％ Embodiment 18 8 35.69％ 46.28％

[0095] Example 19-27, Synthesis of Ioversol

[0096] The preparation methods of Examples 19-27 refer to Example 3, with the dosage being one thousandth, except that the reaction temperature after adding triethylamine is different, as shown in the table below:

[0097]

[0098]

[0099] Example 28-34, Synthesis of Ioversol

[0100] The preparation methods of Examples 28-34 refer to those of Example 3, with the dosage being one thousandth of that of Example 3. The difference is that the reaction time after adding triethylamine is different, as shown in the table below:

[0101] Serial number Reaction time Finished product yield Purity of finished product Embodiment 28 8 hours 66.71％ 60.48％ Embodiment 29 12 hours 65.27％ 65.68％ Embodiment 30 16 hours 87.36％ 98.10％ Embodiment 31 24 hours 91.62％ 99.75％ Embodiment 32 26 hours 89.63％ 99.83％ Embodiment 33 32 hours 86.69％ 95.19％ Embodiment 34 36 hours 84.47％ 94.16％

[0102] Examples 35-38, Synthesis of Ioversol

[0103] The preparation methods of Examples 35-38 refer to Example 3, with the dosage being one thousandth, except that the recrystallization solvents of the crude ioversol are different, as shown in the table below:

[0104] Serial number Solvents Finished product yield Purity of finished product Embodiment 35 Methanol 87.38％ 95.64％ Embodiment 36 Isopropyl alcohol 90.26％ 92.75％ Embodiment 37 N,N-Dimethylformamide 85.98％ 89.16％ Embodiment 38 Tetrahydrofuran 90.66％ 94.57％

[0105] Examples 39-40, Synthesis of Ioversol

[0106] The preparation method of Examples 39-40 refers to that of Example 3, with the dosage being one thousandth, except that the alkylating agents are different, as shown in the table below:

[0107] Serial number Alkylating agents Finished product yield Purity of finished product Embodiment 39 Chloroacetyl chloride 82.25％ 89.56％ Embodiment 40 Bromoethanol 81.64％ 92.51％

[0108] Examples 41-46, Synthesis of Ioversol

[0109] The preparation methods of Examples 41-46 refer to those of Example 3, with the dosage being one thousandth of that of Example 3. The difference is that the reaction temperature after adding chloroethanol is different, as shown in the table below:

[0110]

[0111]

[0112] Examples 47-52, Synthesis of Ioversol

[0113] The preparation methods of Examples 47-52 refer to those of Example 3, with the dosage being one thousandth of that of Example 3. The difference is that the reaction time after adding chloroethanol is different, as shown in the table below:

[0114] Serial number Reaction time Finished product yield Purity of finished product Embodiment 47 5 hours 66.74％ 70.28％ Embodiment 48 10 hours 74.13％ 76.94％ Embodiment 49 18 hours 91.56％ 98.69％ Embodiment 50 25 hours 85.31％ 94.62％ Embodiment 51 30 hours 88.42％ 93.44％ Embodiment 52 36 hours 86.47％ 92.35％

[0115] Example 53-54, Synthesis of Ioversol

[0116] The preparation method of Examples 53-54 refers to that of Example 3, with the dosage being one thousandth. The difference is that different acids are added to the reaction system to adjust the pH after the alkylation reaction. See the table below for details:

[0117] Serial number acid Finished product yield Purity of finished product Embodiment 53 Concentrated sulfuric acid 85.56％ 88.27％ Embodiment 54 Concentrated nitric acid 75.62％ 89.86％

[0118] Example 55, Industrial Production of Ioversol Intermediate (Compound of Formula 2)

[0119] Add 400kg of the compound of formula 1 and 800kg of N,N-dimethylacetamide to a 3L glass-lined reactor and dissolve at 50°C. Cool to 10°C, slowly add 420kg of chloroacetyl chloride, and react at 50°C for 3 hours. Recover under reduced pressure, add 250kg of sodium hydroxide solid + 550kg of water, and hydrolyze the solution. After the hydrolysis is completed, add 500kg of water, add concentrated hydrochloric acid and aqueous hydrochloric acid to adjust the pH to 5-6. Crystallize for 2 hours, filter, dry, and reduce pressure to obtain 423.88kg of the compound of formula 2, with a yield of 95.96% and a purity of 99.71%.

[0120] Example 56, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0121] Add 400g of the compound of formula 1 and 800g of N, N-dimethylacetamide to a 3L glass-lined reactor and dissolve at 50°C. Cool to 10°C, slowly drop 420g of chloroethanol, and react at 50°C for 3 hours. Recover under reduced pressure, add 250g of sodium hydroxide solid + 550g of water, and hydrolyze the solution. After the hydrolysis is completed, add 500g of water, add concentrated hydrochloric acid and aqueous hydrochloric acid to adjust the pH to 5-6. Crystallize for 2 hours, filter, dry, and reduce pressure to obtain 423.88g of the compound of formula 2, with a yield of 92.62% and a purity of 92.53%.

[0122] Example 57, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0123] Add 400g of the compound of formula 1 and 800g of N, N-dimethylacetamide to a 3L glass-lined reactor and dissolve at 50°C. Cool to 10°C, slowly drop 420g of bromoethanol, and react at 50°C for 3 hours. Recover under reduced pressure, add 250g of sodium hydroxide solid + 550kg of water, and hydrolyze the solution. After the hydrolysis is completed, add 500g of water, add concentrated hydrochloric acid and aqueous hydrochloric acid to adjust the pH to 5-6. Crystallize for 2 hours, filter, dry, and reduce pressure to obtain 423.88g of the compound of formula 2, with a yield of 88.56% and a purity of 85.47%.

[0124] Example 58-60, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0125] The preparation methods of Examples 58-60 refer to those of Example 55, with the dosage being one thousandth of that of Example 55. The difference is that different inorganic bases are added in the hydrolysis step, as shown in the table below:

[0126] Serial number Inorganic base Finished product yield Purity of finished product Embodiment 58 Potassium hydroxide 93.36％ 96.27％ Embodiment 59 Calcium hydroxide 82.47％ 85.75％ Embodiment 60 Barium Hydroxide 71.05％ 78.62％

[0127] Examples 61-69, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0128] The preparation methods of Examples 61-69 refer to those of Example 55, with the dosage being one thousandth of that of Example 55. The difference is the reaction temperature, as shown in the table below:

[0129] Serial number Reaction temperature Finished product yield Purity of finished product Embodiment 61 26℃ 46.28％ 53.46％ Embodiment 62 30℃ 63.17％ 55.77％ Embodiment 63 35℃ 67.50％ 79.63％ Embodiment 64 45℃ 88.74％ 99.08％ Embodiment 65 55℃ 91.05％ 99.66％ Embodiment 66 65℃ 83.35％ 88.80％ Embodiment 67 75℃ 76.52％ 86.48％ Embodiment 68 85℃ 69.74％ 74.13％ Embodiment 69 96℃ 62.59％ 65.19％

[0130] Examples 70-74, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0131] The preparation methods of Examples 70-74 refer to those of Example 55, with the dosage being one thousandth of that of Example 55. The difference is that the reaction time is different, as shown in the table below:

[0132] Serial number Reaction time Finished product yield Purity of finished product Embodiment 70 0.5 hours 56.47％ 58.20％ Embodiment 71 1 hour 63.41％ 66.49％ Embodiment 72 2 hours 92.46％ 92.60％ Embodiment 73 4 hours 90.24％ 98.58％ Embodiment 74 5 hours 86.47％ 93.37％

[0133] Examples 75-76, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0134] The preparation method of Examples 75-76 refers to that of Example 55, with the dosage being one thousandth. The difference is that different acids are added to the reaction system to adjust the pH, as shown in the table below:

[0135] Serial number acid Finished product yield Purity of finished product Embodiment 75 Concentrated sulfuric acid 86.55％ 87.28％ Embodiment 76 Concentrated nitric acid 76.25％ 68.96％

[0136] Examples 77-80, Synthesis of Ioversol Intermediate (Compound of Formula 2)

[0137] The preparation methods of Examples 77-80 refer to those of Example 55, with the dosage being one thousandth of that of Example 55. The difference is that the reaction solvents are different. For details, see the table below:

[0138] Serial number Solvents Finished product yield Purity of finished product Embodiment 77 Acetonitrile 88.37％ 86.24％ Embodiment 78 Dimethyl sulfoxide 80.56％ 82.57 Embodiment 79 N,N-Dimethylacetamide 88.59％ 99.51％ Embodiment 80 Tetrahydrofuran 86.26％ 97.54％

Claims

1. A method for industrially producing ioversol, using the compound of formula (3) as a raw material, hydrolyzing in the presence of an alkaline agent to obtain a crude ioversol product, the reaction formula is as follows: The alkaline reagent is selected from triethylamine; the pH of the hydrolysis reaction system is adjusted to 6-7; the hydrolysis reaction time is 16-26 hours; the hydrolysis reaction temperature is 65°C to reflux; After the hydrolysis reaction is completed, electrodialysis is used for desalination to reduce the conductivity to below 10 μS / cm; the product obtained after desalination is separated by a DAC column; the product obtained after separation is filtered, microfiltered, ultrafiltered, and spray-dried to obtain a crude product of iodine; The method further comprises a step of recrystallizing the crude product, wherein the recrystallization solvent is ethanol.

2. The method according to claim 1, characterized in that The pH of the hydrolysis reaction system is 6.

5.

3. The method according to claim 1, characterized in that The hydrolysis reaction time is 20 hours.

4. The method according to any one of claims 1 to 3, wherein the compound of formula (3) is prepared by an alkylation reaction of a compound of formula (2) with an alkylating agent, and the reaction formula is as follows: The alkylating agent is chloroethanol; Adding inorganic base potassium hydroxide into the reaction system; The molar equivalent ratio of the compound of reaction formula (2) to the alkylating agent is 1:1.8; The alkylation reaction temperature is 45°C to 55°C; the alkylation reaction time is 15 to 18 hours; After the alkylation reaction is completed, the pH is adjusted to 5-7 with concentrated hydrochloric acid.

5. The method according to claim 4, characterized in that The alkylation reaction temperature is 50° C.; the alkylation reaction time is 15 hours.

6. The method according to claim 1, characterized in that Ioversol can be detected by the following detection methods: According to the high performance liquid chromatography method, octadecyl bonded silica gel was used as the filler 250mm*4.6um, 5um, the column temperature was 35°C, the detection wavelength was 254nm, the flow rate was 1.0mL / min, the injection volume was 50μL, acetonitrile and water 0.5:99.5 was used as the mobile phase, and the diluent was water; Isocratic elution, acquisition time 50 min.

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