A process for the preparation of iopromide and intermediates thereof

Abstract

The application discloses a preparation method of iopromide and intermediates thereof, and particularly relates to the fields of organic synthesis and medicinal chemistry, and the preparation method route is as follows: a compound of formula I is subjected to chlorination reaction, acylation reaction, reduction reaction and iodination reaction to prepare a compound of formula V, and then iopromide is further prepared, the method can not only avoid the generation of diacylation by-products (formula 18), but also effectively reduce the generation of diiodo compounds (formula 24) in the preparation process, the intermediates are easy to separate and purify, and high-purity products can be obtained at a high yield.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthesis and medicinal chemistry, and specifically relates to a method for preparing iopromide and its intermediates. Background Technology

[0002] Iopromide, chemically known as N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl-1,3-phenylenediamide, has the structure shown in Formula I. It can be used for angiography, renal artery angiography, urography, contrast-enhanced CT examinations, and body cavity visualization (including arthrography, hysterosalpingography, and fistula angiography).

[0003]

[0004] Methods for preparing iopromide are disclosed in US patent US4364921A, PCT patent WO2009134030A1, and Chinese applications CN102351735B, CN102964269B, CN102015624B, CN107778191A, and CN111410615A.

[0005] US Patent 4364921A discloses three preparation routes, the reaction routes of which are as follows:

[0006] Route 1:

[0007]

[0008]

[0009]

[0010] .

[0011] Route 2:

[0012]

[0013] .

[0014] Route 3:

[0015]

[0016]

[0017]

[0018]

[0019] .

[0020] In route two above, during the preparation of compound 11 from compound 10, the diacylation byproduct (bismer) shown in formula 18 is readily generated:

[0021]

[0022] Although routes one and three can avoid the formation of the diacylation byproducts shown in Equation 18, the routes are lengthy, and the iodination reaction steps produce many byproducts with low purity, making separation and purification difficult. This results in a low overall yield and increased costs, which is not conducive to industrial production.

[0023] The preparation routes of iopromide disclosed in Chinese patents CN107778191A and CN111410615A are as follows:

[0024]

[0025]

[0026]

[0027]

[0028] .

[0029]

[0030] Although this route can avoid the formation of the diacylation byproduct shown in Formula 18, the iodination process in Formulas 21 and 22 is affected by the methyl group, resulting in incomplete iodination and the formation of a large number of diiodolated compounds (Formula 24). Purification and treatment are difficult, which in turn affects the quality of the finished product. Summary of the Invention

[0031] To address the above problems, this invention provides a method for preparing iopromide and its intermediates suitable for industrial production.

[0032] To achieve the above objectives, the technical solution of the present invention is as follows:

[0033] A method for preparing a compound of formula V, the preparation route is as follows:

[0034] ;

[0035] ;

[0036] ;

[0037] ;

[0038] Wherein, R1 is methyl or hydrogen;

[0039] Step (1): Compound I reacts with a chlorinating agent to obtain compound II;

[0040] Step (2): Compound II undergoes an acylation reaction with aminoglycerol or its derivatives to obtain compound III;

[0041] Step (3): Compound III undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain compound IV;

[0042] Step (4): Compound IV undergoes an iodination reaction in the presence of an iodizing agent and a solvent to obtain compound V.

[0043] As a preferred technical solution of the present invention, the chlorination reagent in step (1) is one or more of oxaloyl chloride, phosphorus trichloride, phosphorus pentachloride, carbon tetrachloride, phosgene, and thionyl chloride, and the molar ratio of compound I to chlorination reagent in step (1) is 1:1.0 to 3.0.

[0044] As a preferred embodiment of the present invention, the acylation reaction in step (2) is carried out in the presence of a solvent, which is one or more mixed solvents selected from DMF, dichloromethane, tetrahydrofuran, acetonitrile, NMP, and 1,4-dioxane. The acylation reaction temperature in step (2) is -40℃ to -10℃. The molar ratio of compound II to methylaminoglycerol or its derivative in step (2) is 1:1.0 to 3.0.

[0045] As a preferred embodiment of the present invention, the reducing agent in step (3) is one or more of Raney-Ni, Pd / C, zinc powder, iron powder, tin dichloride, sodium sulfide, FeOOH / hydrazine hydrate, FeOOH / activated carbon / hydrazine hydrate, FeCl3 / hydrazine hydrate, and FeCl3 / activated carbon / hydrazine hydrate. The amount of Pd / C used in step (3) is 1% to 20% of the mass of the compound of formula III, preferably 1% to 10%, and more preferably 1% to 5%.

[0046] As a preferred technical solution of the present invention, the solvent in step (3) is one or a mixture of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, water, methanol, and ethanol.

[0047] As a preferred technical solution of the present invention, the iodizing reagent in step (4) is one or more of elemental iodine, iodic acid, iodosuccinimide, NaICl2, and potassium iodate, and the molar ratio of the compound of formula IV to the iodine atom of the iodizing reagent in step (4) is 1:3.0 to 6.0.

[0048] As a preferred technical solution of the present invention, the solvent in step (4) is one or a mixture of water, C1-C4 lower alcohols, acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetic acid.

[0049] A method for preparing iopromide, the preparation route is as follows:

[0050] ;

[0051] ;

[0052] ;

[0053] Step (5): Compound V undergoes an acylation reaction with aminoglycerol or its derivative to obtain compound VI. When R1 is hydrogen, R2 is methyl; when R1 is methyl, R2 is hydrogen.

[0054] Step (6): Compound VI undergoes an acylation reaction to obtain intermediate compound VII; wherein, when R is acetyl or benzoyl, Ra is methoxyacetyl; or, when R is methoxyacetyl, Ra is always methoxyacetyl.

[0055] Step (7): Compound VII of Formula VII is further reacted to obtain compound VIII of Formula VIII, namely iopromide.

[0056] As a preferred technical solution of the present invention, the molar ratio of compound V to aminoglycerol or its derivative in the acylation reaction of step (5) is 1:1.0~2.0.

[0057] As a preferred technical solution of the present invention, when R is acetyl or benzoyl and Ra is methoxyacetyl, step (6) is performed twice for acylation reaction; the molar ratio of compound VI to acetyl or benzoyl is 1:5.0~8.0; the molar ratio of compound VI to 2-methoxyacetyl chloride is 1:1.0~2.0.

[0058] As a preferred embodiment of the present invention, when both R and Ra are methoxyacetyl groups, the molar ratio of compound VI to 2-methoxyacetyl chloride is 1:5.0~8.0.

[0059] The beneficial effects of this invention are as follows:

[0060] The method for preparing iopromide provided in this application not only avoids the formation of diacylation byproducts (Formula 18), but also effectively reduces the formation of diiodolated compounds (Formula 24) during the preparation process. The intermediates are easy to separate and purify, and high-purity products can be obtained with high yields, making it suitable for industrial production. Detailed Implementation

[0061] The following detailed embodiments further illustrate the present invention. It should be understood that the following detailed embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0062] Example 1: Preparation of 2-methoxyacetyl chloride

[0063]

[0064] 2-Methoxyacetic acid (20 mL, 0.26 mol) was dissolved in dichloromethane (170 mL), and oxaloyl chloride (30 mL, 0.34 mol) and a few drops of dimethylformamide (DMF) were added dropwise at 0 °C. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was distilled to give 2-methoxyacetyl chloride (25.4 g, 90% yield).

[0065] Example 2: Preparation of methyl 3-chloroformyl-5-nitrobenzene (compound of formula II)

[0066]

[0067] Compound I (30 g, 0.133 mol) was added to a 500 mL three-necked flask, along with dichloromethane (100 mL) and DMF (0.15 mL). The mixture was heated in a water bath at 20–30 °C and stirred for 10–20 minutes. Oxaloyl chloride (25.4 g, 0.21 mol) was slowly added dropwise. After the reaction solution became clear, stirring was continued for 0.5–1 hour. The solution was then concentrated. When the solution was almost dry, dichloromethane (30 mL × 2) was added and the solution was concentrated twice more to obtain a white solid compound, methyl 3-chloroformyl-5-nitrobenzene. The compound was dissolved in dichloromethane (60 mL) and set aside for later use.

[0068] The chlorinating agent in this embodiment is one or more of oxaloyl chloride, phosphorus trichloride, phosphorus pentachloride, carbon tetrachloride, phosgene, and thionyl chloride, preferably oxaloyl chloride or thionyl chloride, and more preferably oxaloyl chloride.

[0069] Example 3: Preparation of methyl 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzene (compound of formula III-a)

[0070]

[0071] Add aminoglycerol (320 mmol), triethylamine (340 mmol) and DMF (20 mL) to a three-necked flask and stir at room temperature until dissolved. Then cool the reaction solution to -30°C to -20°C and slowly add it dropwise to a dichloromethane solution of compound II (133 mmol). During the dropwise addition, control the temperature of the solution to not exceed -5°C. After the addition is complete, continue stirring for 0.5 to 1 hour. After the reaction was complete, 1 mol / L dilute hydrochloric acid was added dropwise to adjust the pH to 1-2, and the mixture was stirred for half an hour. The temperature was then raised to room temperature, and the mixture was separated. The organic phase was washed with 100 mL of water, and the two aqueous phases were combined. The mixture was extracted twice with a dichloromethane / ethanol mixed solvent (dichloromethane / ethanol = 2:1) (150 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A small amount of ethyl acetate was added, and the mixture was concentrated. Ethyl acetate (100 mL) was added, and the mixture was heated and stirred at 50-60 °C for 1-2 hours. The temperature was lowered to room temperature, and the mixture was stirred overnight. The mixture was filtered, and the filter cake was dried to give a white solid compound methyl 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzene (31.2 g, 105 mmol), with a yield of 78.9%.

[0072] In this embodiment, the solvent is one or more of the following: DMF, dichloromethane, tetrahydrofuran, acetonitrile, NMP, and 1,4-dioxane, preferably a mixture of DMF and dichloromethane. The acylation reaction temperature in this embodiment needs to be maintained between -40°C and -10°C.

[0073] Example 4: Preparation of methyl 3-((2,3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzene (compound of formula III-b)

[0074]

[0075] Following the preparation method of Example 3, aminoglycerol was replaced with methylaminoglycerol to obtain methyl 3-((2,3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzoate.

[0076] In this embodiment, the solvent is one or more of the following: DMF, dichloromethane, tetrahydrofuran, acetonitrile, NMP, and 1,4-dioxane, preferably a mixture of DMF and dichloromethane. The acylation reaction temperature in this embodiment needs to be maintained between -40°C and -10°C.

[0077] Example 5: Preparation of methyl 3-amino-5-((2,3-dihydroxypropyl)carbamoyl)benzoate (compound of formula IV-a)

[0078]

[0079] The compound of formula III-a prepared in Example 3 was dissolved in methanol (100 mL), and then 10% by mass of Pd / C (dry basis: 0.3 g, i.e., the mass of Pd / C is 0.3 g) of the compound III-a was added. The mixture was then transferred into a hydrogenation reactor and reacted at 4.0-4.5 MPa and 60°C for 7-9 hours. After the reaction was completed, the mixture was filtered and the filtrate was kept for use with a purity of 96%.

[0080] The reducing agent in this embodiment is one or more of Raney-Ni, Pd / C, zinc powder, iron powder, tin dichloride, sodium sulfide, FeOOH / hydrazine hydrate, FeOOH / activated carbon / hydrazine hydrate, FeCl3 / hydrazine hydrate, and FeCl3 / activated carbon / hydrazine hydrate, preferably Pd / C or zinc powder, and more preferably Pd / C.

[0081] The solvent used in this embodiment is one or a mixture of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, water, methanol, and ethanol, preferably water or methanol, and more preferably water.

[0082] Example 6: Preparation of methyl 3-amino-5-((2,3-dihydroxypropyl)(methyl)carbamoyl)benzoate (compound of formula IV-b)

[0083]

[0084] Following the preparation method of Example 5, methyl 3-amino-5-((2,3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzoate can be obtained using the product of Example 4 (methyl 3-((2,3-dihydroxypropyl)methylcarbamoyl)benzoate).

[0085] The reducing agent in this embodiment is one or more of Raney-Ni, Pd / C, zinc powder, iron powder, tin dichloride, sodium sulfide, FeOOH / hydrazine hydrate, FeOOH / activated carbon / hydrazine hydrate, FeCl3 / hydrazine hydrate, and FeCl3 / activated carbon / hydrazine hydrate, preferably Pd / C or zinc powder, and more preferably Pd / C.

[0086] The solvent used in this embodiment is one or a mixture of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, water, methanol, and ethanol, preferably water or methanol, and more preferably water.

[0087] Example 7: Preparation of methyl 3-amino-5-((2,3-dihydroxypropyl)carbamoyl)-2,4,6-triiodobenzoate (compound Va)

[0088]

[0089] Iodine (120 mmol) and potassium iodate (65 mmol) were added to methanol (120 ml) and water (200 ml). While stirring, a solution of compound IV-a (100 mmol) prepared in Example 5 was added, followed by 50% sulfuric acid solution (200 mmol). The mixture was stirred at 80°C for 8–12 hours. After the reaction was complete, the solution of sodium sulfite (51.2 mmol, dissolved in 10 g of water) was added and the mixture was stirred for 1–2 hours. 20% sodium hydroxide (10.8 g dissolved in 43 g of water) was added dropwise to adjust the pH to 5–6. The mixture was cooled to -5–5°C and stirred for 10–12 hours. The mixture was then filtered, the filter cake was washed with a small amount of water, and dried by forced air for 20–24 hours to obtain compound Va in approximately 90% yield.

[0090] The iodizing agent used in this embodiment is one or more of elemental iodine, iodic acid, iodosuccinimide, NaICl2, and potassium iodate, preferably one or a combination of elemental iodine, NaICl2, iodic acid, or potassium iodate, and more preferably a combination of potassium iodate and elemental iodine. The molar ratio of compound IV to iodine in the iodizing agent is 1:3.0 to 6.0, preferably 1:4.0 to 5.0.

[0091] The solvent used in this embodiment is one or more of the following: water, lower C1-C4 alcohols, acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetic acid. Water or a mixture of water and methanol is preferred, and a mixture of water and methanol is even more preferred.

[0092] Example 8: Preparation of methyl-3-amino-5-((2,3-dihydroxypropyl)(methyl)carbamoyl)-2,4,6-triiodobenzoate (compound Vb)

[0093]

[0094] Referring to the preparation method of Example 7, methyl-3-amino-5-((2,3-dihydroxypropyl)(methyl)carbamoyl)benzoate can be obtained using the product of Example 6 (methyl 3-amino-5-((2,3-dihydroxypropyl)(methyl)carbamoyl)-2,4,6-triiodobenzoate).

[0095] The iodizing agent used in this embodiment is one or more of elemental iodine, iodic acid, iodosuccinimide, NaICl2, and potassium iodate, preferably one or a combination of elemental iodine, NaICl2, iodic acid, or potassium iodate, and more preferably a combination of potassium iodate and elemental iodine. The molar ratio of iodine atoms in compound IV to the iodizing agent is 1:3.0 to 6.0, preferably 1:4.0 to 5.0.

[0096] The solvent used in this embodiment is one or more of the following: water, lower C1-C4 alcohols, acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetic acid. Water or a mixture of water and methanol is preferred, and a mixture of water and methanol is even more preferred.

[0097] Example 9: Preparation of 5-amino-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-N1-methylisophthalamide (compound of formula VI)

[0098] Method 1

[0099]

[0100] Methamidoglycerol (105 mmol) and DMF (50 mL) were placed in a three-necked flask and dissolved by stirring at room temperature. Compound Va (95 mmol) was added and dissolved completely. DBU (10 mmol) was then added. The reaction was carried out at 20–30 °C for 2.5–3 hours. After the reaction was completed, the temperature was lowered to 0 °C and glacial acetic acid (15.5 mmol) was added dropwise, with the temperature controlled not to exceed 10 °C during the dropwise addition. Then, water (100 mL) was added at a temperature controlled below 10 °C. The mixture was stirred and allowed to crystallize overnight at -5–5 °C. The mixture was filtered, and the filter cake was rinsed with a small amount of water, dried under vacuum, and dried by forced air to obtain 5-amino-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-N1-methylisophthalamide (yield: 89%).

[0101] Example 10: Preparation of 5-amino-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-N1-methylisophthalamide (compound of formula VI)

[0102] Method 2

[0103]

[0104] Referring to the preparation method of Example 9, 5-amino-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-N1-methylisophthalamide can also be obtained by replacing compound Va with compound Vb and methylaminoglycerol with aminoglycerol.

[0105] Example 11: Preparation of 3-(3-((2,3-diacetoxypropyl)(methyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxybenzamide)propane-1,2-disubstituted diacetate (compound of formula VII-1)

[0106]

[0107]

[0108] Compound VI (50 mmol) and DMAc (40 mL) were added to a 250 mL three-necked flask and dissolved at room temperature. After the solution was clear, acetic anhydride (250 mmol) was rapidly added dropwise. After the reaction solution became clear, triethylamine (225 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at 50 °C for 5-8 hours, and the reaction was monitored by HPLC. After the reaction was completed, dichloromethane (200 mL) was added for dilution, and then the solution was washed twice with water (400 mL × 2). The aqueous phases were combined, and the aqueous phase was back-extracted once with dichloromethane (200 mL). The organic phases were combined, washed once with 10% saturated sodium chloride aqueous solution (400 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate to obtain an oily compound. The oily compound and DMAc (42.2 mL) were added to a 100 mL three-necked flask and dissolved at room temperature. The solution was cooled to about 10 °C, and 2-methoxyacetyl chloride (100 mmol) was slowly added dropwise. After the addition was complete, the solution was heated in a hot water bath at 30 °C for 3.5 hours until the reaction was completed. After the reaction is complete, the reaction solution is set aside for later use.

[0109] Example 12: Preparation of 3-(3-((2,3-bis(benzoyloxy)propyl)(methyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamyl)benzoylamino)propane-1,2-disubstituted dibenzoate (compound of formula VII-2)

[0110]

[0111]

[0112] Compound VI (100 mmol) and DMAc (80 mL) were added to a 100 mL three-necked flask and dissolved at room temperature. DMAP (10 mmol) was added, and the mixture was cooled to 10 °C. Then, a solution of benzoyl chloride (500 mmol) in DMAc (80 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 30 °C until the reaction was finished. After the reaction was complete, the solution was diluted with dichloromethane (240 mL) and washed successively with water (480 mL), 1 mol / L sodium bicarbonate (480 mL × 2), and water (480 mL × 2). Finally, the organic phase was dried, the solvent was evaporated, and the solution was purified with an organic solvent to obtain a white solid. 75 mmol of the white solid was dissolved in DMAc (100 mL) at room temperature, cooled to 10 °C, and 2-methoxyacetyl chloride (100 mmol) was added dropwise. After the addition was complete, the mixture was reacted at 30 °C for 5 hours. After the reaction was complete, the reaction solution was set aside for later use.

[0113] Example 13: Preparation of 3-(3-((2,3-bis(2-methoxyacetoxy)propyl)(methyl)carbamoyl)-2,4,6-triiodo-5-(2-methoxyacetamido)phenylamino)propane-1,2-disubstituted bis(2-methoxyacetyl) (compound of formula VII-3)

[0114]

[0115] Dissolve compound VI (85 mmol) in DMAc (140 mL), add triethylamine (700 mmol) to dissolve, cool to 0 °C, add 2-methoxyacetyl chloride (680 mmol) dropwise, and react at 30 °C until the reaction is complete. After the reaction is complete, set aside the reaction solution.

[0116] Example 14: Preparation of iopromide (compound of formula VIII)

[0117]

[0118] The reaction solution prepared in Example 13 was cooled to 0-10°C, and 520g of 10% sodium hydroxide solution was added dropwise. After the addition was complete, the mixture was stirred at 60°C. After the reaction was completed, the pH was adjusted to neutral with 10% hydrochloric acid, filtered, and the filtrate was concentrated to obtain crude iopromide (yield calculated based on the raw material in Example 13), with a purity of 96% and a yield of 81%.

[0119] Similarly, referring to the preparation method of Example 14, the reaction solutions obtained in Examples 11 and 12 can also be used to obtain crude iopromide after hydrolysis.

[0120] Example 15: Purification of crude iopromide

[0121] The crude iopromide (10g) obtained in Example 12 was added to a 100mL single-necked flask, and then propylene glycol monomethyl ether (30mL) was added. The mixture was stirred at 90℃~100℃ for 6 hours, allowed to cool naturally to room temperature, filtered after 1 hour, and dried at 60℃ for 8~10 hours to obtain the purified product with a purity of 99.4% and a yield of 77%.

[0122] MS m / z [ESI]: 813.85 [M+Na] + .

[0123] In the high-resolution mass spectrometry of the sample, the quasi-molecular ion peak of the cation was 813.85802. Based on the accurate charge-to-weight ratio calculation and confirmed by the system software, the reasonable molecular formula of this ion is considered to be C. 18 H 24 The structure I3N3O8Na matches the molecular structure of iopromide with a sodium ion. Therefore, the mass spectrometry data of the sample are consistent with the structure of iopromide.

[0124] 1H-NMR (500MHz, DMSO-d6): δ = 10.05-9.89 (m,1H); 8.64-8.50 (t,1H); 4.0 (s,2H); 3.90 (m,1H); 3.69 (m,2H); 3.47 (m,7H); 3.30-3.18 (m,3H) ;2.85-2.84 (t,3H).

[0125]

[0126] Proton NMR spectral data and assignment of iopromide

[0127]

[0128] Analysis:

[0129] 1 The H-NMR spectrum yielded eight proton peaks, corresponding to 20 protons, consistent with the 18 inactive protons and 2 active protons in the iopromine structure. Specifically:

[0130] (1) There is a triplet at δ2.84ppm-δ2.85ppm, which is equivalent to 3 protons and belongs to the methyl proton at position 24 in the structure.

[0131] (2) There is a set of multiple peaks in the range of δ3.18ppm-δ3.30ppm, which is equivalent to 3 protons and belongs to the methyl proton at position 20.

[0132] (3) There is a set of multiple peaks at δ3.47ppm, which are equivalent to 7 protons, belonging to the methylene protons at positions 9, 10, and 14 and the methine proton at position 12, respectively.

[0133] (4) There is a set of multiple peaks at δ3.69ppm, which is equivalent to two protons and belongs to the 13-methylene proton.

[0134] (5) There is a set of multiple peaks at δ3.90ppm, which is equivalent to one proton and belongs to the methyl proton at position 11.

[0135] (6) There is a single peak at δ4.00ppm, which is equivalent to two protons and belongs to the methylene proton at position 23.

[0136] (7) There is a triplet at δ8.50ppm-δ8.64ppm, which is equivalent to one proton and belongs to the amide proton at position 19 in the structure.

[0137] (8) There is a set of multiple peaks in δ9.89ppm-δ10.05ppm, which is equivalent to one proton and belongs to the imine proton at position 21 in the structure.

[0138] As can be seen from the above, the hydrogen spectrum data of the sample is consistent with the structure of iopromide.

[0139] In this application, unless otherwise stated, the terminology is as follows:

[0140] The term "DMF" refers to N,N-dimethylformamide;

[0141] The term "DBU" refers to 1,8-diazabicycloundec-7-ene;

[0142] The term "DMAc" refers to N,N-dimethylacetamide;

[0143] The term "DMAP" refers to 4-dimethylaminopyridine;

[0144] The term "room temperature" refers to 20–30°C.

[0145] The term "iodide reagent" refers to a reagent that can donate iodine atoms to introduce iodine atoms onto carbon, silicon, nitrogen, phosphorus, or sulfur atoms in a substrate molecule.

[0146] The term "acetylation reagent" refers to a reagent that can provide an acetyl group to introduce an acetyl group onto a carbon, silicon, nitrogen, phosphorus, or sulfur atom in a substrate molecule;

[0147] The term "chlorination reagent" refers to a reagent that can provide chlorine atoms to introduce chlorine atoms onto carbon, silicon, nitrogen, phosphorus, or sulfur atoms in a substrate molecule.

[0148] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing iopromide, characterized in that, The preparation method is as follows: ； ； ； ； ； ； ； Wherein, R1 is hydrogen and R2 is methyl; Step (1): Compound I reacts with a chlorinating agent to obtain compound II; Step (2): Compound II undergoes an acylation reaction with aminoglycerol or its derivatives to obtain compound III; Step (3): Compound III undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain compound IV; Step (4): Compound IV undergoes an iodination reaction in the presence of an iodizing agent and a solvent to obtain compound V; Step (5): Compound V undergoes an acylation reaction with methylaminoglycerol to obtain compound VI; Step (6): Compound VI undergoes an acylation reaction to obtain intermediate compound VII; wherein R is acetyl, benzoyl, or methoxyacetyl, and Ra is methoxyacetyl. Step (7): Compound VII of Formula VII is further reacted to obtain compound VIII of Formula VIII, namely iopromide.

2. The method for preparing iopromide according to claim 1, characterized in that, The chlorination reagent in step (1) is one or more of oxaloyl chloride, phosphorus trichloride, phosphorus pentachloride, carbon tetrachloride, phosgene, and thionyl chloride.

3. The method for preparing iopromide according to claim 1, characterized in that, The acylation reaction in step (2) is carried out in the presence of a solvent, which is one or more mixed solvents selected from DMF, dichloromethane, tetrahydrofuran, acetonitrile, NMP, and 1,4-dioxane. The acylation reaction temperature in step (2) is -40℃ to -10℃.

4. The method for preparing iopromide according to claim 1, characterized in that, The reducing agent in step (3) is one or more of the following: Raney-Ni, Pd / C, zinc powder, iron powder, tin dichloride, sodium sulfide, FeOOH / hydrazine hydrate, FeOOH / activated carbon / hydrazine hydrate, FeCl3 / hydrazine hydrate, and FeCl3 / activated carbon / hydrazine hydrate.

5. The method for preparing iopromide according to claim 1, characterized in that, The solvent in step (3) is one or a mixture of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, water, methanol, and ethanol.

6. The method for preparing iopromide according to claim 1, characterized in that, The iodizing reagent in step (4) is one or more of elemental iodine, iodic acid, iodosuccinimide, NaICl2, and potassium iodate. The molar ratio of the iodine atoms of compound IV to the iodizing reagent in step (4) is 1:3.0 to 6.

0.

7. The method for preparing iopromide according to claim 1, characterized in that, The solvent in step (4) is one or a mixture of water, C1-C4 lower alcohols, acetonitrile, tetrahydrofuran, 1,4-dioxane, and acetic acid.

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