Iomeprol

• 78649-41-9
• Iomeprolum
• Iomeron
• Iomeprolo

WeightAverage: 777.089
Monoisotopic: 776.8541

Chemical FormulaC₁₇H₂₂I₃N₃O₈

FDA APPROVED, 11/27/2024, Iomervu, For use as a radiographic contrast agent

1-N,3-N-bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)-methylamino]-2,4,6-triiodobenzene-1,3-dicarboxamide

• N1,N3-Bis(2,3-dihydroxypropyl)-5-(2-hydroxy-N-methylacetamido)-2,4,6-triiodoisophthalamide
• 1-N,3-N-bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)-methylamino]-2,4,6-triiodobenzene-1,3-dicarboxamide
• DTXCID2028987
• E7337
• N,N’-bis(2,3-dihydroxypropyl)-5-[glycoloyl(methyl)amino]-2,4,6-triiodoisophthalamide

• UNII-17E17JBP8L
• E-7337

Iomeprol, sold under the brand name Imeron among others, is a medication used as a radiocontrast agent in X-ray imaging.^[1][2][3]

Iomeprol was approved for medical use in the United States in November 2024.^[1][4][5]

Experimental Properties

U.S. Patent No. 4,364,921 discloses three preparation processes of iopromide. One of them is shown in the following reaction scheme 1.

[Reaction scheme 1]

U.S. patent No. 4,364,921 are those basically under the same concept as shown in the following reaction schemes 3 and 4.

[Reaction scheme 3]

[Reaction scheme 4]

References:

M F C Co., Ltd.;Park Yung-ho;Hwang Seong-gwan;Park Jang-ha;Seo Rak-seok;Kim Gyeong-deok KR2020/77762, 2020, A Location in patent:Paragraph 0133-0136

Yield:78649-41-9 95%

Reaction Conditions:

with sodium hydroxide in N,N-dimethyl acetamide at 10 – 60; for 16 h;

Steps:

6 Synthesis of Iomeprole
Prepared N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide 20 g (0.026 mol) in a reactor and 60 g of N,N-dimethylacetamide was added, followed by heating and stirring at 60 °C to dissolve.1.3 g (0.033 mol) of caustic soda was added to the reactor and stirred to dissolve. The reactor was cooled to 10 °C or less, and 4.5 g (0.032 mol) of iodomethane was added to the reactor, followed by stirring at 25 °C for 14 to 16 hours. After confirming the completion of the reaction, acetic acid was added to neutralize the reaction solution.The solvent was removed through concentration under reduced pressure at 60 to 65 °C and 60 g of ethanol was added to crystallize. The wet body was obtained by filtration and dried under reduced pressure in an oven at 60 °C for 12 hours to obtain iomeprol (yield 95%, purity 99.8%).

Iomeprol (CAS NO.: ), with its systematic name of , N,N’-bis(2,3-dihydroxypropyl)-5-((hydroxyacetyl)methylamino)-2,4,6-triiodo-, could be produced through many synthetic methods.

Following is one of the synthesis routes: 
Firstly, 5-Amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (I) is treated with chloride to produce the dichloride (II). Secondly, compound (II) is treated with acetoxyacetyl chloride to afford compound (III), which is methylated with iodomethane. Lastly, condensation with 3-amino-1,2-propanediol of the N-methyl derivative (IV) thus obtained, followed by deacetylation with alkali metal hydroxide, yields iomeprol.

PATENT

https://patents.google.com/patent/WO2009134030A1/en

The process for preparing iopromide of formula (1) according to the present invention is shown in the following reaction scheme 5.

[Reaction scheme 5]

Step 1

5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) is used as a starting material. The compound of formula (2) is reacted with methoxyacetyl chloride in dimethylacetamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3) which is then used without an additional purification procedure for the next step. The compound of formula (3) is reacted with 2,3-dihydroxypropylamine in dimethylacetamide solvent in the presence of triethylamine to form 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride of formula (4), as shown in the following reaction scheme 6.

[Reaction scheme 6]

In the above reaction scheme, if 2,3-dihydroxypropylamine is used preferably in 0.6 to 1 equivalents, more preferably in 0.7 equivalents, the compound of formula (4) can be obtained in reasonable yield with minimizing the generation of the compound of formula (5) which is a bismer by-product.

In addition, since the unreacted compound of formula (3) existing in the filtrate obtained along with the compound of formula (4) can be recycled to the next batch without an additional recovery procedure, the loss of the yield of iopromide which occurs during the removal procedure of the bismer by-product generated in a large amount in conventional process can be prevented ultimately.

Step 2

The compound of formula (4) is reacted with acetic anhydride in acetic acid solvent in the presence of sulfuric acid as a catalyst to convert into the compound of formula (19). Sulfuric acid of preferably 0.01 to 0.2 moles, more preferably 0.05 to 0.1 moles per 1 molar reaction is added at a temperature of preferably from 0 to 30°C, more preferably from 5 to 25°C. Acetic anhydride of preferably 0.19 to 1 L, more preferably 0.35 to 0.7 L per 1 molar reaction is used.

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid-N,N’-bis-(2,3-diacetoxypropyl) diamide of the compound of following formula (21), which is generated by a simultaneous conversion of the bismer by-product of formula (5) already produced in the step 1 with the conversion of the compound of formula (4) into the compound of formula (19), is easily removed by the simple crystallization procedure of the compound of formula (19). That is, the by-product of the compound of formula (21) can be removed even without an additional removal procedure. It consequently means that the bismer by-product of the compound of formula (5) which is hard to remove according to conventional process can be effectively removed in the present invention even without any additional purification procedures.

[Formula 5]

[Formula 21]

Step 3

The compound of formula (19) is reacted with 2,3-dihydroxy-N-methypropylamine in dimethylacetamide solvent in the presence of triethylamine as a base to convert into the compound of formula (20). By the hydrolysis of the compound of formula (20) in aqueous NaOH solution without further purification therefor, iopromide of formula (1) can be obtained.

The present invention will be explained more specifically by the following examples. However, the examples are not intended to limit the scope of the present invention thereto.

Example 1: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Formula 4)

5-amino-2,4,6-triiodoisophthalic acid dichloride (13.7 kg, 23 mol) was dissolved in dimethylacetamide (17.2 kg) and the mixture was cooled to 15 ℃ . Methoxyacetyl chloride (3.74 kg, 34.5 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred for 15 hours. After confirming the disappearance of the starting material by HPLC analysis for reaction, methylene chloride (45.7 kg) and water (11.5 kg) were subsequently added to the reaction mixture upon being stirred, and then the stirring was stopped and the layers became separated. The obtained organic layer was washed with aqueous sodium bicarbonate solution and concentrated by distillation under reduced pressure. To a solution of the obtained concentrate dissolved in dimethylacetamide (43.1 kg), triethylamine (1.95 kg, 19.32 mol) was added and then a solution of 2,3-dihydroxypropylamine (1.47 kg, 16.13 mol) dissolved in dimethylacetamide (10.78 kg) was added dropwise thereto for 5 hours with maintaining 0 to 5 ℃ . After additional 3 hours with stirring, the reaction mixture was concentrated by distillation under reduced pressure and to the concentrate, methylene dichloride (213.33 kg) was added dropwise for 5 hours to form solid. The solid was filtered and the title compound was obtained as a white solid (10.98 kg, yield 66.1 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.2,10.06(2s, 1H); 8.79, 8.71, 8.63 (3t, 1H); 4.5~4.0(br, 2H); 4.04, 4.00(2s, 2H); 3.71~3.66(m, 1H); 3.48, 3.47(2s, 3H); 3.40~3.36(m, 2H); 3.36~3.27(m, 1H); 3.2~3.09 (m, 1H)

Example 2: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (Formula 19)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (9.97 kg, 13.8 mol) was dispersed in acetic acid, and then anhydrous acetic acid (7.45 kg) was added thereto and the mixture was cooled to 5 ℃ . Sulfuric acid (135 g) was slowly added thereto and the mixture was stirred for 1 hour. To the obtained clear solution, sodium acetate trihydrate (376 g) was added and dissolved at 0 to 5 ℃ . And then water (96.6 kg) was added for 3 hours with maintaining 0 to 10 ℃ to produce solid. The produced solid was filtered and the title compound was obtained as a white solid (10.04 kg, yield 90.2 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.12, 9.99(2s, 1H); 8.91, 8.80(2t, 1H); 5.10~5.06(m, 1H); 4.32~4.27(m, 1H); 4.20~4.16(m, 1H); 4.01, 4.00(2s, 2H); 3.52~3.37(m, 2H); 3.47, 3.46(2s, 3H); 2.02(s, 6H)

Example 3: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-dihydroxypropyl)]diamide (iopromide)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (7.23 kg, 8.97 mol) was dissolved in dimethylacetamide (12.6 kg), and triethylamine (1.95 kg, 19.32 mol) was added thereto and a solution of 2,3-dihydroxy-N-methylpropylamine (943 g, 8.97 mol) dissolved in dimethylacetamide (4.2 kg) was added dropwise thereto at room temperature. After additional 2 hours with stirring, the solution was concentrated by distillation under reduced pressure. To an aqueous solution of the obtained 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-diacetoxypropyl)]diamide dissolved in water, a solution of sodium hydroxide (897 g, 22.43 mol) dissolved in water was added and the reaction mixture was stirred for 10 hours with maintaining 20 to 25 ℃ . The reaction solution was passed through cation exchange resin column and anion exchange resin column to produce a colorless and transparent aqueous solution. The obtained aqueous solution was distilled under reduced pressure to remove water completely, crystallized in ethanol and filtered to obtain a white crystalline iopromide (6.032 kg, yield 85 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.07, 10.03, 9.97, 9.90(4s,1H); 8.66, 8.57, 8.52(3t, 1H); 4.76~4.74(m, 1H); 4.72, 4.67(2t, 1H); 4.59~4.58(m, 1H); 4.54~4.44(m, 1H); 4.00(s, 2H); 3.89~3.88(m, 1H); 3.69~3.68(m, 2H); 3.47(s, 3H); 3.44~3.38(m, 4H); 3.23~3.17(m, 3H), 2.85~2.83(4s, 3H)

Example 4: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-diacetoxypropyl)]diamide (Formula 20)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (80.65 g, 0.1 mol) was dissolved in dimethylacetamide (140.5 g), and then triethylamine (11.13 g, 0.11 mol) was added thereto and a solution of 2,3-dihydroxy-N-methylpropylamine (10.5 g, 0.1 mol) dissolved in dimethylacetamide (46.9 g) was added dropwise thereto at room temperature. After additional 2 hours with stirring, the produced solid was filtered and then the filtrate was concentrated by distillation under reduced pressure. To the obtained concentrate, diethyl ether was added dropwise to form solid. The formed solid was filtered and the title compound was obtained as a white solid (85.8 g, yield 98 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.10, 10.06, 10.00, 9.92(4s,1H); 8.93, 8.83, 8.78(3m, 1H); 5.09(br, 1H); 4.78~4.74(m, 1H); 4.62~4.58(m, 1H); 4.34~4.26(m, 1H); 4.22~4.16(m, 1H); 4.00(s, 2H); 3.89(br, 1H); 3.72~3.65,(m, 1H); 3.49~3.40(br, 2H);3.47(s, 3H); 3.48~3.38(m, 2H); 3.22~3.12,(m, 1H); 3.07~3.04(m, 1H); 2.87~2.82(m, 2H); 2.03(s, 3H); 2.02(s, 3H)

PATENT

https://patents.google.com/patent/RU2563645C2/ru

Scheme 3

Example 1Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH 

₂ -CH(OH)CH 

₂ OH groups using a starting solution heated to 60 

° C.In a 2 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was heated to 60 °C and then solid I 

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO 

₃ (173.6 g; 0.494 mol) was slowly added over 2 h. The reaction mixture was maintained at 60 °C for an additional 4 h, during which time the pH spontaneously remained in the range of 5-5.5. The red solution was cooled to 25°C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached a stable negative value in the range from 0 to -20 mV.During quenching of the reaction mixture, the pH was maintained at 5 by adding minimal amounts of 30% (w/w) aqueous NaOH solution.HPLC analysis (the results of which are shown in Fig. 1) showed the degree of conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (by area % on the HPLC chromatogram), and the resulting solution was used in the next stage of the synthesis without any further processing.Example 2Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH 

₂ -CH(OH)CH 

₂ OH groups using a starting solution heated to 40 

° CIn a 2 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, solid I 

₂ (250.6 g, 0.988 mol) was added in one portion to an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution, 0.816 mol; pH 9.6) heated to 40 °C. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO 

₃ (173.6 g, 0.494 mol) was slowly added over 3 h. The reaction mixture was then heated for 2 h at 40°C, 1 h at 50°C and 1 h at 60°C, during which time the pH spontaneously remained in the range of 5-5.5. The resulting red solution was cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution during quenching, which was carried out by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values ​​in the range of -20 to -50 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 3Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH 

₂ -CH(OH)CH 

₂ OH groups using a stock solution heated to 30 

° C and quenching the reaction mixture with bisulfite at pH5 in the final stepIn a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g of solution; 0.816 mol; pH 9.6) was diluted with H 

_{2 O (1054 g), heated to 30 °C and then solid I} 

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO 

₃ (173.6 g; 0.494 mol) was slowly added over 4 h. The temperature of the reaction mixture was raised to 60°C and maintained at this temperature for a further 4 h, with the pH spontaneously remaining in the range of 5-5.5. The resulting red solution was cooled to 25°C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5 by adding 30% (w/w) aqueous NaOH solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values ​​in the range of 0 to -20 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 4Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH 

₂ -CH(OH)CH 

₂ OH groups using a starting solution heated to 30 

° C and quenching the reaction mixture with bisulfite at pH7 in the final stepIn a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was diluted with H 

_{2 O (1054 g), heated to 30 °C and then solid I} 

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO 

₃ (173.6 g; 0.494 mol) was slowly added over 4 h. The temperature of the reaction mixture was raised to 60°C and maintained at this temperature for a further 4 h, during which time the pH spontaneously remained in the range of 5-5.5. The resulting red solution was cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution during quenching, which was carried out by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values ​​in the range of -20 to -50 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 5Preparation of a compound of formula 2, in which both substituents R and R’ are -NH-CH 

₂ -CH(OH)CH 

₂ OH groups, using a starting solution at room temperature (approximately 20 

° C)In a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of 3,5-disubstituted phenol 1 sodium salt corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was first diluted with H 

_{2 O (1054 g) maintaining the temperature at 20 °C, and then solid I} 

_{2 (250.6 g; 0.988 mol) was added in one portion. The resulting solution was then heated to 40 °C and when the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO} 

₃ (173.6 g; 0.494 mol) was slowly added over 4 h . The temperature of the reaction mixture was raised to 60°C over 2 h and maintained at this temperature for a further 3 h, during which time the pH spontaneously remained in the range of 5-5.5. The red solution was then cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution, and quenched with sodium bisulfite (18% (w/w) aqueous solution) until color loss and stable negative values ​​(in the range of -20 to -50 mV) of the oxidation-reduction potential were reached, measured with suitable redox electrodes.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 6Preparation of a compound of formula 2 in which the substituent R is a -NH-CH 

₂ -CH(OH)CH 

₂ OH group and R’ is -NH-CH(CH 

₂ OH) 

₂ using a starting solution heated to 60 

° C.In a 1 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser, and combination pH/temperature electrode, N-(2,3-dihydroxypropyl)-N’-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-1,3-benzenedicarboxamide (100.3 g, 0.305 mol) was dissolved in H 

₂ O (430 g) and converted to the corresponding sodium salt by adding 30% (w/w) NaOH (40.6 g, 0.305 mol) (pH 9.5). The solution was heated to 60 °C and solid I 

₂ (93.1 g, 0.367 mol) was added in one portion; When the pH spontaneously dropped to 5, 50% (w/w) aqueous HIO3 (64.5 g, 0.183 mol) was added slowly over 2 h 

_. The reaction temperature was maintained at 60 °C for a further 4 h, during which time the pH of the reaction mixture spontaneously remained in the range 5-5.5. The resulting red solution was cooled to 25 °C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5, by adding 30% (w/w) aqueous NaOH until colourlessness and a stable negative oxidation-reduction potential, measured with a suitable oxidation-reduction electrode, in the range 0 to -20 mV.HPLC analysis (Fig. 2) showed the degree of conversion of the starting compound to N-(2,3-dihydroxypropyl)-N’-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide >98% (by area % on the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any additional processing.Example 7Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH(CH 

₂ OH) 

₂ groups using a starting solution heated to 60 

° C.In a 0.5 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser, and combination pH/temperature electrode, N,N’-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-1,3-benzenedicarboxamide (50 g, 0.152 mol) was dissolved in H 

₂ O (215 g) and converted to the corresponding sodium salt by adding 30% (w/w) NaOH (20.3 g, 0.152 mol) (pH 9.5). The solution was heated to 60 °C and solid I 

₂ (46.4 g, 0.183 mol) was added in one portion; When the pH spontaneously dropped to 5, 50% (w/w) aqueous HIO3 (32.2 g, 0.091 mol) was added slowly over 2 h 

_. The reaction temperature was maintained at 60 °C for an additional 4 h, during which time the pH of the reaction mixture spontaneously remained in the range 5-5.5. The resulting red solution was cooled to 25 °C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5, with 30% (w/w) aqueous NaOH until colorlessness and a stable negative oxidation-reduction potential (in the range of -20 to -50 mV), as measured by a suitable oxidation-reduction electrode.HPLC analysis showed the conversion of the starting compound to N,N’-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further processing.Comparative example 1This test was carried out to evaluate the efficiency of the iodination reaction disclosed by Patil et al., in ARKIVOC, 2006, 104 and Tetrahedron Lett., 2005, 46, 7179.In a 50 mL three-necked round-bottomed flask equipped with a thermometer and a reflux condenser, solid 3,5-disubstituted phenol 1 (16.4 g, 50 mmol) was suspended in ethanol (30 mL). Then, to the resulting suspension, heated to 38-40 °C, solid I 

₂ (15.2 g, 60 mmol) was added in one portion and a solution of HIO 

₃ (5.3 g, 30 mmol) in H 

₂ O (3 mL) was added in the indicated order over 5 min. The resulting dark brown mixture was stirred at 38-40 °C for about 1 h and then the change in appearance of the reaction mixture was recorded, which turned into a clear dark brown solution. The reaction mixture was maintained at the above temperature for a total of 3.5 h, then cooled to room temperature, which caused crystallization of the pale yellow solid product. After 15 h at room temperature, the solid was isolated by filtration and dried to give the desired 3,5-disubstituted-2,4,6-triiodophenol (12.1 g, 17 mmol). Yield 34.3%.During the iodination reaction, the reaction mixture was analyzed by HPLC. In particular, the first analysis was performed 1.5 hours after the start of iodination (the reaction time was chosen based on the literature sources cited), and its results are shown in Fig. 3, and the second analysis was performed after another 2 hours (the total reaction time was 3.5 hours), and its results are shown in Fig. 4. The results show that even after 3.5 hours, the conversion is not complete and a significant amount (13% based on the area on the HPLC chromatogram) of the original substrate is still present. On the other hand, a longer reaction time leads to the formation of a significant amount of impurities, which are decay products, which are easily detected after 3.5 hours of reaction (Fig. 4). This is certainly a factor that adversely affects the reaction yields. However, the low reaction yields can also be attributed to the solubility of 3,5-disubstituted-2,4,6-triiodophenol 2b in an alcohol medium, as confirmed by the analysis of the mother liquor shown in Fig. 5, which interferes with the quantitative isolation of the iodination product.In this regard, the increase in both the reaction yield and the product purity due to the use of an aqueous medium and reaction conditions, expressed in the above results, is evident from a comparison of Figs. 3-5 with Figs. 1 and 2, which show chromatograms (HPLC) of crude reaction solutions (Examples 1 and 6, respectively) obtained using the method of the present invention.

PATENT

https://patents.google.com/patent/KR20200032280A/en

[Scheme 3]

Example  One.

Iomeproletic  Produce

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) 5g (1 equivalent) and 3.6 g (5 equivalents) of calcium chloride was added to 25 g of methanol together, and dissolved at reflux at room temperature or 70 ° C. for 60 minutes.

After cooling the temperature of the solution to 10 ℃ to 15 ℃ 0.3g (0.62 equivalents) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred for 3 hours at the same temperature until the reaction was completed.

After completion of the reaction, 1 mL of HCl (35%) was added to acidify, 25 mg of 2-butanol was added, stirred at a temperature of 70 to 80 ° C. for 2 hours, cooled, filtered and washed with 2-butanol to obtain an iomeprole crude product.

The above prepared omeprolol was added to a mixture of 25 mL of methanol and 10 mL of water, heated to 50 ° C. to dissolve, put 20 mL of 2-butanol, refluxed at 90 ° C. for 3 hours, cooled to room temperature, and the resulting crystal was filtered.

After washing with 2-butanol and drying under reduced pressure at 90 ° C. for 12 hours, 4.17 g of Iomeprole (HPLC: 99.3%) was obtained.

Example 2.

Preparation of Iomeprole

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) 5g (1 equivalent) and 3.6 g (5 equivalents) of calcium chloride was added to 25 g of methanol together and refluxed at 70 ° C for 30 minutes to dissolve.

After cooling the solution to 0-5 ° C., 0.3 g (0.62 equivalents) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred for 7 hours at the same temperature until the reaction was completed.

After completion of the reaction, 1 mL of HCl (35%) was added to acidify, 30 mL of 2-butanol was added, refluxed at a temperature of 70-80 ° C. for 2 hours, stirred, filtered and washed with 2-butanol to obtain an iomeprole crude product.

After adding the above prepared omeprolol to a mixture of 25 mL of methanol and 10 mL of water, the temperature was raised to 50 ° C. to dissolve, 20 mL of 2-butanol was added, refluxed at 90 ° C. for 3 hours, cooled to room temperature, and the resulting crystal was filtered. .

After washing with 2-butanol and drying under reduced pressure at 90 ° C. for 12 hours, 4.21 g of Iomeprole (HPLC: 99.1%) was obtained.

Comparative example  1 (Inorganic chloride Non-addition )

After adding 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) to 25 g of methanol It was refluxed for 30 minutes.

After the temperature of the turbid solution was cooled to 10 ° C to 15 ° C, 0.3 g (0.62 equivalent) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred at the same temperature for 5 hours.

As a result of reactivity review by HPLC, synthesis of iomeprole progressed 5%, 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6- Triiodoisophthalamide (1b) was found to be 90% or more remaining, so that the reactivity was very low.

Comparative example  2 (Inorganic base Non-addition )

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) and 3.6 g of calcium chloride are methanol After adding to 25 g, the mixture was refluxed for 30 minutes to dissolve.

After the temperature of the solution was cooled from 10 ° C to 15 ° C, 2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred at the same temperature for 5 hours.

As a result of reactivity review by HPLC, synthesis of iomeprole proceeds 0.5%, 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6- Triiodoisophthalamide (1b) was found to be very low reactivity with more than 99% remaining.

PATENT

https://patents.google.com/patent/CN102363600B/en

.Synthetic route is seen formula 1:

Embodiment

Embodiment 1

5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:

In the there-necked flask that agitator and reflux condensing tube are housed, 76g(0.133mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthalic acid is dissolved in 250mL(2.53mol) in the ethyl acetate, after waiting to stir, add 29mL(0.4mol) sulfur oxychloride, be warming up to 50 ℃ of acyl chloride reaction temperature then, stir and finished reaction in 6 hours.After treating that ethyl acetate and sulfur oxychloride boil off under the decompression, residue boils off solvent and washs through frozen water after adding the 100mL ethyl acetate, dry product 68.9g, yield is that 84.9%(is with 5-methylamino-2,4,6-triiodo m-phthalic acid meter), m.p.167 ~ 169 ℃.

Embodiment 2

5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:

The acyl chloride reaction temperature is 80 ℃, and in 3 hours reaction times, all the other are operated with embodiment 1.

Embodiment 3

5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:

In reaction flask, add 36.6g(0.06mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthaloyl chloride and 80mL N,N-dimethylacetamide, heating in water bath to 50 ℃, after the stirring and dissolving, be cooled to 10 ℃, begin to drip 10.2g(0.09mol) chloroacetyl chloride, dropwising the back heats up 50 ℃, stirred 3 hours, and be cooled to 10 ℃, be added dropwise to the 150mL frozen water.Filter, through the frozen water washing, dry product 38.7g, yield be 94%(with 5-methylamino-2,4,6-triiodo m-phthaloyl chloride meter), m.p.194 ~ 196 ℃.

Embodiment 4

5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:

The chlorine acylation temperature is 90 ℃, and in 1 hour reaction times, all the other are operated with embodiment 3.

Embodiment 5

5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

In reaction flask, add 41.2g(0.06mol under the room temperature) 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride and 80mL N, the N-N,N-DIMETHYLACETAMIDE after the stirring and dissolving, is cooled to 10 ℃, add 16g(0.16mol) triethylamine and 14.6g(0.16mol) 3-amino-1, the 2-propylene glycol is heated to 20 ℃ then, stirs and finishes reaction in 15 hours, be chilled to after-filtration below 10 ℃, after evaporated under reduced pressure, residue is dissolved in the 160mL methyl alcohol with filtrate, adds 200mL water and stirs evenly, leave standstill, with the solid filtering of separating out, the washing, dry product 43.4g, yield is that 91%(is with 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride meter), m.p.204 ~ 207 ℃.

Embodiment 6

5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

The amidate action temperature is 50 ℃, and in 8 hours reaction times, all the other are operated with embodiment 5.

Embodiment 7

5-[N-methyl-glycolamide base]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

In reaction flask, add 47.7g(0.06mol) 5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide, 250mL water, stir and to add 26g(0.32mol down) sodium acetate, back flow reaction is after 24 hours, the pressure reducing and steaming solvent.The residue dissolve with methanol filters, and filtrate boils off methyl alcohol, and vacuum-drying gets solid, is dissolved in the 150mL water, adds gac 1.8g, and reflux 30min filters.Filtrate is successively respectively by 732 Zeo-karbs and 717 anionite-exchange resin, and pressure reducing and steaming solvent again is after the resistates vacuum-drying, add 180mL ethanol and carry out recrystallization, get white solid 40.1g, HPLC detects purity greater than 99.0%, and yield is that 86%(is with 5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide meter), m.p.〉280 ℃. ¹H-NMR?(DMSO-D ₆)δ（ppm）：2.91(s,4H)，3.21~3.36（m,4H）,?3.41~3.65（m,4H）,?3.85（s,2H）,?3.98（m,2H）,?4.1~?4.5（m,5H）,?8.2~?8.4（d,?2H）； ¹³C-NMR（D ₂O）δ（ppm）33.2，44.7，60.7，64.6，71.2，90.1，99.8，99.9，145.5，150.5，150.6，171.3，171.4，173.9。

PATENT

https://patents.google.com/patent/CN114213273A/en

synthetic route is as follows:

Example 1

The synthesis process of iomeprol with 5-amido-N, N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide as initial material includes successive chloroacetylation, methylation, hydrolysis and hydroxylation to synthesize iomeprol product, and includes the following steps:

the specific process comprises 4 reaction steps:

s1, chloroacetylation (preparation of 5- (2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

12g of 5-amino-N.N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodoisophthalamide was dissolved in 24g N, N-dimethylacetamide and stirred at room temperature. 12g of chloroacetyl chloride were added while controlling the temperature below 60 ℃. After the addition, the temperature is kept between 50 and 60 ℃, the stirring is carried out for 4 hours, and after the reaction is finished, the vacuum concentration is carried out below 65 ℃ until the reaction is dried. 36ml of ethyl acetate and 36ml of a 5% aqueous solution of sodium hydrogencarbonate were added to the concentrate to conduct extraction. The aqueous layer after separation was extracted twice with 10ml of ethyl acetate. The organic solutions thus extracted were mixed, 15ml of 5% saline was added thereto, and the mixture was washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 18.5g of an oily substance.

S2, methylation reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

dissolving 18.5g of the oily substance in the previous step by using 37ml of acetone, cooling to 0 ℃, adding 3.8g of potassium carbonate, keeping the temperature and stirring, dropwise adding 5.8g of dimethyl sulfate while stirring, keeping the temperature and reacting for 8 hours, after the reaction is finished, carrying out vacuum concentration to dryness at 60 ℃, dissolving the concentrated solution in 50ml of ethyl acetate and 50ml of water, and adding 10ml of ethyl acetate into the separated water layer for secondary extraction. The organic solutions thus extracted were mixed, 15ml of 5% saline was added thereto, and the mixture was washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 19.3g of an oily substance.

S3, ester hydrolysis reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide):

the above oily substance was dissolved in 20ml of methanol, 6.0g of water was added, 30.0g of 30% aqueous sodium hydroxide solution was added, and the reaction was carried out at 15 ℃ for 4 hours, and after the completion of the reaction, methanol was distilled off under reduced pressure to obtain an aqueous solution containing the objective compound.

S4 hydroxylation reaction (preparation of 5- (N-methyl-2-hydroxyacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide, i.e. iomeprol):

adding 6.0g of sodium acetate into the aqueous solution, heating to reflux for 24 hours, distilling under reduced pressure to remove the solvent, adding methanol into the residue to dissolve, filtering, evaporating the methanol from the filtrate, dissolving the residue in pure water, adding activated carbon, heating to reflux for 30 minutes, filtering, sequentially passing the filtrate through cation resin and anion resin, evaporating to remove the solvent, adding 70ml of ethanol to recrystallize, filtering, drying under reduced pressure at 50 ℃ to obtain 8.5g of white solid, wherein the HPLC purity is 99.2%, and the molar yield is 64%.

Example 2

S1, chloroacetylation (preparation of 5- (2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

500g of 5-amino-N.N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodoisophthalamide was dissolved in 1000g N, N-dimethylacetamide and stirred at room temperature. 500g of chloroacetyl chloride was added while controlling the temperature below 60 ℃. After the addition, the temperature is kept between 50 and 60 ℃, the stirring is carried out for 4 hours, and after the reaction is finished, the vacuum concentration is carried out below 65 ℃ until the reaction is dried. 1500ml of ethyl acetate and 1500ml of 5% aqueous sodium bicarbonate solution were added to the concentrate to extract. The aqueous layer after separation was extracted twice with 480ml of ethyl acetate. The organic solutions thus extracted were mixed, and 650ml of 5% brine was added thereto, followed by washing, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 772.6g of an oil.

S2, methylation reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

dissolving 772.6g of the oily matter in the previous step by 1545ml of acetone, cooling to 0 ℃, adding 158.5g of potassium carbonate, keeping the temperature and stirring, dropwise adding 241.5g of dimethyl sulfate while stirring, keeping the temperature and reacting for 8 hours, after the reaction is finished, vacuum concentrating at 60 ℃ to dryness, dissolving the concentrated solution in 1500ml of ethyl acetate and 1500ml of water, and adding 480ml of ethyl acetate into the separated water layer for secondary extraction. The organic solutions thus extracted were mixed, and then 650ml of 5% saline was added thereto, followed by washing, and after recovering the organic solution layer, magnesium sulfate was added thereto to remove water, followed by filtration and distillation under reduced pressure to obtain 805.7g of an oily substance.

S3, ester hydrolysis reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide):

the above oil was dissolved in 800ml of methanol, 250g of water was added, 1250g of a 30% aqueous solution of sodium hydroxide was added, and the reaction was carried out at 15 ℃ for 4 hours, and after the completion of the reaction, methanol was distilled off under reduced pressure to obtain an aqueous solution containing the objective compound.

S4 hydroxylation reaction (preparation of 5- (N-methyl-2-hydroxyacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide, i.e. iomeprol):

adding 250g of sodium acetate into the aqueous solution, heating to reflux for 24 hours, distilling under reduced pressure to remove the solvent, adding methanol into the residue to dissolve, filtering, evaporating the filtrate to remove the methanol, dissolving the residue in pure water, adding activated carbon, heating to reflux for 60 minutes, filtering, sequentially passing the filtrate through cation resin and anion resin, evaporating to remove the solvent, adding 3000ml of ethanol to recrystallize, filtering, drying under reduced pressure at 50 ℃ to obtain 365.0g of white solid, wherein the HPLC purity is 99.1%, and the molar yield is 66%.

Compared with two synthesis methods in patent EP0026281A1, the synthesis method of iomeprol developed by the invention does not use thionyl chloride, reduces the difficulty of waste gas treatment, does not use acetoxy acetyl chloride, and ensures the process stability. Meanwhile, the used starting material (compound II) is a common intermediate of other contrast agents iohexol and ioversol, so that corresponding supporting construction is reduced.

Therefore, the synthetic route designed by the invention has the advantages of mild reaction conditions, stable quality, high yield, low cost, environmental protection and suitability for industrial production.

The embodiments are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same or similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.

Side effects

It is classified as a water-soluble, nephrotrophic, low osmolar X-ray contrast medium.^[2] Low osmolar non-ionic agents are better tolerated and less likely to cause side effects than the high osmolar ionic agents.^[2]

Society and culture

Iomeprol is not metabolized in the human body but excreted in unchanged form.^{[medical citation needed]} It is decomposed slowly and can therefore accumulate in the environment.^[6]

Legal status

Iomeprol was approved for medical use in the United States in November 2024.^[1][4]

Brand names

Iomeprol is sold under the brand name Iomervu.^[1]

References

1. ^ Jump up to:^{a b c d e} https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216017s000,216017s000lbl.pdf
2. ^ Jump up to:^a b c Rossiter D (2014). South African medicines formulary (11th ed.). Rondebosch, South Africa: Health and Medical Pub. Group .of the South African Medical Association. ISBN 978-1-875098-30-9. OCLC 869772940.
3. ^ Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Iomeron 300 mg J/ml-Infusionsflasche.
4. ^ Jump up to:^a b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
5. ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
6. ^ Pfundstein P, Martin C, Schulz W, Seitz W, Ruth KM, Wille A, et al. (January 2015). “IC-ICP/MS-Analytik”. GIT Labor-Fachzeitschrift (in German): 29–31.
7. Dooley M, Jarvis B: Iomeprol: a review of its use as a contrast medium. Drugs. 2000 May;59(5):1169-86. doi: 10.2165/00003495-200059050-00013. [Article]
8. Katayama H, Spinazzi A, Fouillet X, Kirchin MA, Taroni P, Davies A: Iomeprol: current and future profile of a radiocontrast agent. Invest Radiol. 2001 Feb;36(2):87-96. doi: 10.1097/00004424-200102000-00004. [Article]
9. Rosati G: Clinical pharmacology of iomeprol. Eur J Radiol. 1994 May;18 Suppl 1:S51-60. doi: 10.1016/0720-048x(94)90094-9. [Article]
10. EMC Summary of Product Characteristics: Iomeron (iomeprol) solution for injection [Link]
11. FDA Approved Drug Products: IOMERVU (iomeprol) injection, for intra-arterial or intravenous use [Link]
12. Medsafe NZ: IOMERON® (iomeprol) safety data sheet [Link]

////////////Iomeprol, Iomervu, FDA 2024, APPROVALS 2024, 78649-41-9, Iomeprolum, Iomeron, Iomeprolo, UNII-17E17JBP8L, E-7337, E 7337, E-7337, E7337, XRAY CONTRAST AGENT