Synthesis of Iohexol

Abstract

The present invention relates to 1 ,N 3 Preparation of bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide and its analogs (Formula III), specifically 5-amino-N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide or 5-amino-N 1 ,N 3 ‑Bis(2,3‑dihydroxypropyl)isophthalamide and hydroxyl-protected glyceraldehyde, acetone acetal glyceraldehyde or glyceraldehyde undergo reductive amination reaction under the action of solvent, reducing agent and additive.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and particularly to the synthesis of a non-ionic contrast agent, iohexol. Background Art

[0002] Contrast media (also known as contrast media) are chemicals injected (or taken) into human tissues or organs to enhance the effect of image observation. The density of these products is higher or lower than that of the surrounding tissues, and the contrast formed is used to display images with certain instruments. In recent years, the development momentum and potential of contrast agents are very large, and the application areas have gradually expanded from X-ray photography / CT scanning imaging to the diagnosis and detection of ultrasound, magnetic resonance angiography, etc. With the continuous improvement of the accuracy requirements of medical examinations, the popularity of contrast diagnosis is increasing, the contrast agent preparation market at home and abroad is expanding, and the demand for contrast agent APIs is also increasing.

[0003] Iohexol was first developed by Nycomed and is a second-generation non-ionic contrast agent. It was first marketed in Norway and Sweden in 1982 under the trade name (Omnipaque). The chemical name of iohexol is 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide. It is white or off-white powder or crystalline powder, odorless and hygroscopic. Iohexol is very soluble in water or methanol, and is almost insoluble in chloroform or ether. The chemical structure of iohexol is as follows:

[0004]

[0005] A current method for synthesizing iohexol involves the synthesis of an intermediate 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide, firstly, 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide; then all hydroxyl groups and phenylamino groups are acetylated, and the acetyl groups of the hydroxyl groups are removed using hydrolysis conditions to prepare 5-acetylamino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide; finally, under alkaline conditions, 5-acetylamino-N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide and chloroglycerol are reacted to prepare iohexol. The relevant synthetic route is as follows:

[0006]

[0007] Another method for synthesizing iohexol (CN100494166) involves starting from 5-amino-2,4,6-triiodoisophthaloyl chloride, first acetylation of the amino group to prepare 5-acetamido-2,4,6-triiodoisophthaloyl chloride; then condensation reaction of 5-acetamido-2,4,6-triiodoisophthaloyl chloride and acetone formate-protected aminoglycerol to prepare 5-acetamido-N 1 ,N 3 -bis((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2,4,6-triiodoisophthalamide; then react with chloroglycerol to produce 5-(N-(2,3-dihydroxypropyl)acetylamino)-N 1 ,N 3 -bis((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2,4,6-triiodoisophthalamide; finally, iodine protection is removed under acidic conditions to prepare iohexol. The relevant synthetic route is as follows:

[0008] The final steps of the two methods for preparing iohexol reported above involve nucleophilic substitution reactions involving chloroglycerol. Chloroglycerol is a potential genotoxic impurity of halogenated alkanes. During the reaction, in addition to a small amount of chloroglycerol remaining and not reacting completely, halogenated glycerol will also undergo intramolecular reactions under alkaline conditions to produce glycidol (epoxypropanol). Glycidol itself contains an epoxy three-membered ring structure, which is also a potential genotoxic impurity. Since iohexol is an injection variety, there is strict control over the residual genotoxic impurities and potential genotoxic impurities of the final raw material drug. The residual chloroalkane compounds and epoxy three-membered ring structure compounds in the raw material drug prepared by the above method can still cause potential damage to the human body even at very low concentrations, may induce gene mutations and lead to tumors, and are potential genotoxic substances, and their content in the raw material drug needs to be strictly controlled. At present, the iohexol API prepared by these methods can only control the residual potential genotoxic impurities within the range that meets the quality requirements through continuous recrystallization or other purification methods. It is impossible to completely remove these potential genotoxic compounds simply by continuous recrystallization or other purification methods. In addition, when the last step uses chloroglycerol to carry out nucleophilic substitution reaction under alkaline conditions, it is inevitable to produce hydroxyl groups participating in the nucleophilic substitution reaction of chloroglycerol to produce peralkylated impurities, and because iohexol and peralkylated impurities are both polyhydroxy compounds, they are highly polar and difficult to remove. The quality standards of iohexol API disclosed by the Chinese Pharmacopoeia, the United States Pharmacopoeia and the European Pharmacopoeia all have impurity limit control requirements for peralkylated impurities caused by chloroglycerol. The relevant structures of peralkylated impurities listed in the European Pharmacopoeia are as follows:

[0009]

[0010] Based on the above reasons, developing new synthetic routes that avoid the use of chlorinated alkanes is of great significance for improving the quality of iohexol. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a new synthetic route for preparing iohexol without using chloroglycerol.

[0012] The study found that compound I (5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (R=I) or 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide (R=H)) and compound II (hydroxy protected glyceraldehyde, acetone acetal glyceraldehyde or glyceraldehyde) undergo reductive amination reaction in the presence of solvent, reducing agent and additive to achieve N 1 ,N 3 - Preparation of bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide and its analogs (Formula III). Formula III (R1=I, R2=R3=H) is acetylated under Ac2O / AcOH conditions, and then the acetyl protection of the hydroxyl group is removed to achieve the preparation of iohexol. The relevant reaction formula is as follows:

[0013]

[0014] R1 in Formula I and Formula III is H, I.

[0015] In formula II and formula III, R2=R3=H, TBS, Ac or R2, R3=acetone formate.

[0016] The solvent used in the first step of the reaction is MeOH, EtOH, ethylene glycol monomethyl ether, DMF, CH3CN, toluene or a mixed solvent of these solvents.

[0017] The additives used in the first step of the reaction are TFA, AcOH, molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, titanium tetrachloride, and tetraisopropyl titanate.

[0018] The reducing agents used in the first step of the reaction are Et3SiH, NaBH3CN, NaBH4, NaBH(OAc)3, pyridine borane complex, and 2-methylpyridine borane complex.

[0019] Compared with the previously reported synthesis method, the process for preparing iohexol of the present invention has the advantages of not involving potential genotoxic impurities such as chloroglycerol, not generating potential genotoxic impurities such as propylene oxide during the reaction, and avoiding the generation of over-alkylated impurities; in addition, the synthesis method does not involve the use of metal reagents, and can avoid metal residues in the raw material drug. This is of great significance to the quality improvement of the final raw material drug. DETAILED DESCRIPTION

[0020] The present invention can be more specifically understood through the following examples, which are intended to illustrate rather than limit the scope of the present invention.

[0021] Example 1. Preparation of N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide (Formula III, R1=H, R2=R3=H).

[0022] In a three-necked flask, add 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide (30.0 g, 91.6 mmol), glyceraldehyde (16.5 g, 183.17 mmol), NaBH3CN (11.50 g, 183.0 mmol). Methanol (200 mL) and AcOH (5.0 mL) were slowly added to the reaction system. After the addition was completed, the system was heated to reflux for 6 hours. The system was cooled to room temperature, the organic solvent was removed under reduced pressure, and then 6M HCl (60 mL) was added to quench the unreacted reducing agent. Saturated NaHCO3 aqueous solution was carefully added to the system to adjust the pH value to neutral. Toluene / heptane / THF (1:1:1, 200 mL) was added to the system, and it was vigorously stirred at room temperature for 24 hours, filtered, and the filter cake was slurried with toluene / heptane / THF (1:1:1, 100 mL). The solid obtained after filtration was vacuum dried to obtain a white solid (32.81 g, 89.2%).

[0023] Example 2, Preparation of N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)-2,4,6-triiodoisophthalamide (Formula III, R1=I, R2=R3=H).

[0024] 5-Amino-N 1 ,N 3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (50.5g, 71.63mmol), glyceraldehyde (9.70g, 107.68mmol), NaBH3CN (6.80g, 108.21mmol). Methanol (200mL), DMF (25mL) and TFA (2.0mL) were slowly added to the reaction system. After the addition was completed, the system was heated to reflux for 12 hours. The system was cooled to room temperature, the organic solvent was removed under reduced pressure, and then 6M HCl (30mL) was added to quench the unreacted reducing agent. Saturated NaHCO3 aqueous solution was carefully added to the system to adjust the pH value to neutral. Methanol / heptane (1:1, 200mL) was added to the system, and it was vigorously stirred at room temperature for 24 hours, filtered, and the filter cake was slurried with methanol / heptane (1:1, 80mL). The solid obtained after filtration was dried under vacuum at 50°C to obtain an off-white solid (51.35g, 92.0%).

[0025] Example 3, Preparation of N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-(((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)amino)isophthalamide (Formula III, R1=H, R2, R3=acetoneidene).

[0026] 5-Amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide (25.1g, 76.68mmol), acetone glyceraldehyde (20.0g, 153.68mmol), NaBH(OAc)3 (40.65g, 191.80mmol). Slowly add ethanol (250mL) and AcOH (4.0mL) to the reaction system. After the addition is complete, the system is heated to reflux for 3 hours. The system is cooled to room temperature, the organic solvent is removed under reduced pressure, and then 6M HCl (50mL) is added to quench the unreacted reducing agent, and then the system is carefully added with saturated NaHCO3 aqueous solution to adjust the pH value to neutral. Toluene / heptane (1:1, 250mL) is added to the system, and it is vigorously stirred at room temperature for 24 hours, filtered, and the filter cake is slurried with toluene / heptane (1:1, 100mL). The solid obtained after filtration is dried under vacuum at 50°C to obtain a white solid (27.12g, 80.1%).

[0027] Example 4: Preparation of iohexol

[0028] Add N 1 ,N 3-bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)-2,4,6-triiodoisophthalamide (Formula III, R1=I, R2=R3=H) (39.0g, 50.06mmol), acetic acid (100mL) and acetic anhydride (55.0g, 0.54mol). After the addition is complete, the system is heated to 80℃ and reacted overnight. The system is cooled to room temperature, and the solvent and unreacted acetic anhydride are removed under high vacuum and reduced pressure. MeOH (150mL) is added to the residue and stirred, and then concentrated HCl (2mL) is added dropwise. The system is heated to 60℃ and reacted overnight. The temperature is lowered, the system is desolvated under high vacuum and reduced pressure, and the residue is dissolved by adding H2O (200mL), and purified by macroporous resin. The obtained aqueous solution containing the product is decompressed to remove water, and the residue is recrystallized using ethylene glycol monomethyl ether as a solvent to obtain a white solid (iohexol, 34.92g, 84.9%).

Claims

1. N 1 ,N 3 - A method for preparing bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide and its analogs (Formula III), using compounds of the structures shown in Formula I and Formula II as raw materials, and preparing Formula III through reductive amination in a polar solvent under the action of an additive and a reducing agent, the reaction formula is as follows: The additives used in the reaction were TFA and AcOH; The reducing agents used in the reaction are NaBH3CN, NaBH(OAc)3.

2. The preparation method according to claim 1, characterized in that The polar solvent used in the reaction is one or more of MeOH, EtOH, ethylene glycol monomethyl ether, DMF, and CH3CN.

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