Synthesis of nonionic contrast agents

Abstract

The present invention relates to a non-ionic contrast agent intermediate N 1 ,N 3 The invention discloses a method for preparing bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide, specifically comprising reacting 5-halogenated-isophthalic acid diester with 3-amino-1,2-propylene glycol under the conditions of copper reagent / base / additive / solvent.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and to the preparation of a non-ionic contrast agent intermediate. 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] In the 1950s, triiodobenzene, the famous Amidotrezoic Acid, was discovered. Various contrast agents derived from it are still widely used today. This was the first leap forward in the history of modern contrast agents. In the late 1960s, Swedish radiologist Almen proposed the concept of non-ionic contrast agents and reported the first non-ionic monomer contrast agent, Metrizamide (Amipaque), in 1971. The emergence of non-ionic monomer contrast agents was the second leap forward in the history of modern contrast agents. Metrizamide has the advantages of low osmotic pressure [485mmol / L] and good tolerance. Therefore, the first generation of contrast agents was quickly replaced by the second generation of non-ionic monomer contrast agents.

[0004] Compared with the first generation of ionic contrast agents, non-ionic contrast agents have the advantages of high water solubility, non-ionization in water, low viscosity, and low permeability. In clinical practice, the incidence and severity of toxic and side effects of non-ionic contrast agents are significantly lower than those of ionic contrast agents.

[0005] The most commonly used non-ionic contrast agents are iohexol, iodixanol, ioversol, iopromide, and iopamidol. These non-ionic contrast agents are all polyhydroxy compounds containing triiodine-substituted benzene. Among them, iohexol was first developed by Nycomed and is a second-generation non-ionic monomer contrast agent. It was first launched in Norway and Sweden in 1982 under the trade name Iodixanol is a third-generation X-ray contrast agent, first developed by Nycomed Amersham in Norway, and is marketed under the name (Vision Parker), the drug was first launched in Sweden, the United Kingdom, Switzerland and other European countries in 1994, and launched in China in 2001. Ioversol was successfully developed by Wanlin Pharmaceutical Co., Ltd. (later merged into Tyco Healthcare) in the United States. Its preparation, Ioversol injection, was approved by the FDA for marketing in the United States in 1988. (Ansheli) is one of the main contrast agents in the US market. Iopromide, with the trade name Ultravist, was developed by Schering of Germany and first launched in Germany in 1985. Schering of Germany was first approved to export iopromide to my country in 2003. To date, no domestic pharmaceutical company has obtained a production license for this generic drug, and all clinical use of iopromide depends on imports. Iopamidol is a contrast agent developed by Bracco of Italy. It was first approved in Italy in 1981 and was subsequently launched in the United States, Japan and other countries. In 2002, the drug was approved for import in China. The structures of these non-ionic contrast agents are as follows:

[0006]

[0007] Iohexol, iodixanol and other non-ionic contrast agents all contain triiodine-substituted benzene ring structures. By looking up the synthetic routes of these compounds, it is found that the synthesis of the previous steps is similar. Taking the synthesis of iohexol as an example, the nitro group is introduced into the benzene ring through a nitration reaction, followed by an aminolysis reaction between 5-nitroisophthalate and 3-amino-1,2-propanediol to obtain N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-nitroisophthalamide, N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-nitroisophthalamide was reduced to prepare 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide, then from 5-amino-N 1 ,N 3 -bis(2,3-dihydroxypropyl)isophthalamide, through iodination, acetylation, deacyl protection and reaction with chloroglycerol, iohexol is prepared. The relevant reaction formula is as follows:

[0008]

[0009] The nitration reaction in the above-mentioned synthesis process is a dangerous process, and the 5-nitroisobenzoic acid diester (nitrobenzene compound), N 1 ,N 3-bis(2,3-dihydroxypropyl)-5-nitroisophthalamide (nitrobenzene compounds), 5-amino-N 1 ,N 3 -Bis(2,3-dihydroxypropyl)isophthalamide (aniline compound) and chloroglycerol (halogenated alkane compound) are all potential genotoxic compounds. Since these non-ionic contrast agents are all injectable varieties, there is a strict control on the residual genotoxic impurities and potential genotoxic impurities in the final API. The residual nitro compounds, aniline compounds and chloroalkane compounds in the API prepared by the above method can still cause 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 API needs to be strictly controlled. At present, the APIs such as iohexol prepared by this method can only control the residual potential genotoxic impurities within the range that meets the quality requirements through continuous recrystallization. It is impossible to completely remove these potential genotoxic compounds simply through continuous recrystallization. Therefore, it is of great significance to develop new synthetic routes that avoid the use of nitration reactions and do not involve the use of nitro compounds and chloroalkane compounds for improving the quality of these non-ionic contrast agents.

[0010] In addition, for the intermediate N 1 ,N 3 The reduction of the nitro group of -bis(2,3-dihydroxypropyl)-5-nitroisophthalamide has been reported in numerous patent literatures. Patents CN109912445, CN113831256, CN113968826 and EP1186305 all report the use of Pd / C as a catalyst to catalyze the hydrogenation of the nitro group in an alcohol solvent to achieve the 5-amino-N 1 ,N 3- Preparation of bis(2,3-dihydroxypropyl)isophthalamide, some catalytic hydrogenation processes also involve the addition of concentrated HCl (CN1078201C), which places high demands on the material of the hydrogenation reactor (the hydrogenation reaction with the addition of concentrated HCl cannot use a conventional stainless steel reactor). Since Pd / C is expensive as a precious metal catalyst, and the subsequent steps using Pd / C as a catalyst will involve the process of removing Pd residues, resulting in an increase in the final cost of raw materials. Patent WO2013 / 063737 uses Raney Ni for catalytic hydrogenation, but since Raney Ni has a very high catalytic activity, it is very easy to encounter air ignition during transfer, weighing, feeding, and post-treatment, and since the residue containing metallic nickel is a hazardous waste solid, the reaction is greatly limited. Since non-ionic contrast agents such as iohexol, iodixanol, iofosmol, and iopromide are all injections, the residual limit requirements for elemental impurities such as Pd are very strict, which undoubtedly puts forward an urgent need for the development of new methods that do not involve nitro reduction steps. Therefore, developing new synthetic routes for the synthesis of APIs such as iohexol that do not involve the use of precious metal catalysts is of great significance for reducing the cost of APIs and improving product quality. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a new synthesis route for preparing iohexol which does not involve the use of nitration reaction, nitro compounds, chloroglycerol and noble metal catalysts.

[0012] The study found that 5-halogenated isophthalic acid diester (Formula I) reacts with 3-amino-1,2-propanediol (aminoglycerol) under the conditions of copper reagent / base / additive / solvent, and the reaction simultaneously undergoes the aminolysis of the ester group and the coupling reaction of the aryl halide to prepare N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide (Formula II); then the compound of Formula II is subjected to iodination reaction to prepare N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)-2,4,6-triiodoisophthalamide (Formula III); after the compound of Formula III reacts with acetic anhydride or AcCl, the intermediate product obtained is directly hydrolyzed to remove the acetyl group protected by the alcoholic hydroxyl group to obtain iohexol. The synthetic route of the present invention is as follows:

[0013]

[0014] X in formula I is Cl, Br, or I.

[0015] In formula I, R is Me, Et, n Pr,n Bu.

[0016] The copper reagents used in the first step of the reaction are CuI, CuBr, Cu 2 O.

[0017] The base used in the first step of the reaction is t BuOK,K 3 PO 4 , t BuONa, KOH, NaOH.

[0018] The additive used in the first step of the reaction is an oxalyl diamide compound, including N 1 -Benzyl-N 2 -(2-methylnaphthalene-1-yl)oxalyl diamide, N 1 ,N 2 -bis(2-phenyl-4-methylphenyl)oxalamide, N 1 ,N 2 -Bis(2,4,6-trimethoxyphenyl)oxalyl diamide, N 1 -(1-naphthyl)-N 2 -Alkyl oxalyl diamide, N 1 ,N 2 -Bis(phenylethyl)oxalyl diamide, N 1 ,N 2 -Bis([1,1'-biphenyl]-2-diyl)oxalyl diamide, N 1 -Benzyl-N 2 -([1,1'-biphenyl]-2-yl)oxalyl diamide, N 1 ,N 2 -bis(naphthalene-1-ylmethyl)oxalyl diamide, N 1 ,N 2 -Bis(benzyl)oxalyl diamide.

[0019] The solvents used in the first step of the reaction are tert-butyl alcohol, ethanol, 1,4-dioxane, DMF, acetonitrile, and DMSO.

[0020] The conditions used in the second step of the iodination reaction are the conventional conditions for the iodination reaction in the preparation of iohexol, including: 2 / KIO 3 ,ICl / H 2 O,NaIClO 2 / H 2 O.

[0021] The third step of the reaction involves using acetyl to protect the hydroxyl group and the amino group at position 5 in the compound of formula III. The reagents used include Ac 2 O,AcCl.

[0022] The fourth step of the reaction is to remove the acetyl group protected by the hydroxyl group under alkaline conditions.

[0023] Compared with the previously reported process, the process for preparing iohexol of the present invention has an advantage that it does not involve the use of a regulated process such as nitration reaction, nor does it involve separation, purification, drying, and transfer of nitro compounds, which is of great significance for the safety of the industrialization and amplification of the product. There are safety accidents caused by the uncontrolled exothermic reaction of nitration reaction in domestic chemical enterprises. Aromatic hydrocarbons are the most important reaction for introducing nitro groups to aromatic rings in organic chemistry through nitration reaction, and are an important way to prepare amino compounds. Nitration reaction is a highly exothermic reaction. Due to its concentrated exothermic reaction, the removal of heat is one of the outstanding problems in controlling the nitration reaction. Because the reaction rate of nitration reaction is fast, the dissipation of heat cannot be controlled well and can cause explosion. In addition, when preparing the commonly used mixed acid, the nitration reaction needs to ensure sufficient stirring and cooling conditions to prevent the impact or explosion caused by the sudden rise in temperature. At the same time, since most nitro compounds have explosion hazards, they are very easy to explode or catch fire when heated, rubbed, hit, or contacted with an ignition source. Therefore, special safety protection is required when separating, purifying, drying, and transferring nitro compounds.

[0024] Compared with the previously reported processes, the process for preparing iohexol of the present invention has the advantages that it does not involve the use of intermediates and reagents with potential genotoxicity (such as chloroglycerol), does not cause the risk of exceeding the standard of potential genotoxic impurities in the final raw material drug product, and does not involve taking multiple refining and purification steps to remove potential genotoxic impurities, resulting in increased costs, which is of great significance to the improvement of the quality of the final raw material drug product and cost control; in addition, since the process of the present invention does not involve the use of expensive precious metal catalysts, it is also of great significance to the cost control of the final raw material drug. DETAILED DESCRIPTION

[0025] 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.

[0026] Example 1. Preparation of N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide (Formula II)

[0027] 5-Chloro-isophthalic acid methyl ester (45.7 g, 0.20 mol), 3-amino-1,2-propanediol (91.1 g, 1.0 mol), CuI (1.9 g, 10 mmol), K 3 PO 4 (212.3 g, 1.0 mol) and N 1 ,N 2-Bis(2,4,6-trimethoxyphenyl)oxalyl diamide (4.2g, 10mmol) was added to the reaction flask, and then the system was replaced with nitrogen three times, and DMSO (300mL) was added to the reaction flask. The reaction system was replaced with nitrogen three times again, and the system was heated to 120±5℃ for 24h under stirring. After the reaction was completed, the system naturally cooled to room temperature. The reaction system was diluted with MeOH (500mL), and after vigorous stirring for 0.5 hours, it was filtered through diatomaceous earth. The filtrate was desolventized to remove the organic solvent under reduced pressure. The residue was purified twice by slurrying using a mixed solvent of heptane / MeOH (20:1, 150mL), filtered, and the obtained solid was vacuum dried at 50℃ for 24 hours to obtain an off-white solid (68.41g, 85.2%).

[0028] Example 2, Preparation of N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide (Formula II)

[0029] 5-Bromo-isophthalic acid ethyl ester (90.34 g, 0.30 mol), 3-amino-1,2-propanediol (123.0 g, 1.35 mol), Cu 2 O (860 mg, 6.0 mmol), KOH (65.65 g, 1.17 mol) and N 1 -Benzyl-N 2 -(2-methylnaphthalene-1-yl)oxalyl diamide (1.91g, 6.0mmol) was added to the reaction flask, and then the system was replaced with nitrogen three times, and anhydrous ethanol (350mL) was added to the reaction flask. The reaction system was replaced with nitrogen three times again, and the system was heated to 80±5°C for 12h under stirring. After the reaction was completed, the system naturally cooled to room temperature. EtOH (300mL) was added to the reaction system for dilution, and the system was vigorously stirred for 0.5 hours and filtered through diatomaceous earth. The filtrate was filtered again through a silica gel short column, and the filtrate was desolventized to remove the organic solvent. The residue was purified twice by beating with a heptane / EtOH mixed solvent (20:1, 250mL), filtered, and the obtained solid was vacuum dried at 50°C for 24 hours to obtain an off-white solid (105.85g, 87.9%). Example 3, Preparation of N 1 ,N 3 -Bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)-2,4,6-triiodoisophthalamide (Formula III)

[0030] Add H 2 O(100mL),I 2 (47.6 g, 0.188 mol), KIO 3(20.10 g, 0.0939 mol) and sodium sulfate (2.5 g, 0.0176 mol), and H 2 SO 4 (15% aqueous solution, 53.0 g, 0.081 mol), after the addition, the system was heated to 40±5°C and stirred for 2 hours. Then the reaction system was heated to 60±5°C, and N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide (54.15 g, 0.135 mol) 2 O (400 mL) solution was added, and the reaction system was heated to 80±5°C for 12 hours. KIO 3 (2.4 g, 11.21 mmol), the reaction was continued at 80±5°C with stirring for 24 hours. Then, the reaction system was heated to 100°C, the stopper of the reaction bottle was opened and stirred for 6 hours. Then the system was naturally cooled to room temperature 25°C, filtered, and the obtained solid was used for H 2 O (500 mL) was slurried and purified (80±5°C). The reaction system was cooled to 10±5°C, stirred for 1 hour, filtered, and the obtained solid was vacuum dried at 40±5°C to obtain an off-white solid (91.72 g, 87.2%).

[0031] Example 4: Preparation of iohexol

[0032] Add N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)-2,4,6-triiodoisophthalamide (50g, 64.18mmol), acetic anhydride (100mL) and concentrated sulfuric acid (200mg) were added. After the addition was completed, the system was heated to 100℃ and stirred for 24 hours. The system was cooled to room temperature, and the unreacted acetic anhydride was removed under reduced pressure. Methanol (100mL) was added to the system, and the solvent was removed under reduced pressure again. NaOH (20.0g, 500mmol) was added to the residue. 2 O (150 mL), stirred at room temperature for 24 hours, then the reaction system was neutralized with dilute HCl to pH ≈ 7, the resulting solution containing iohexol was desalted with anion resin and cation resin, the resulting solution was decompressed to remove water, and the residue was purified with ethylene glycol methyl ether to obtain iohexol (41.22 g, 78.2%).

Claims

1. A method for preparing N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide, characterized in that 5-halogeno-isophthalic acid diester reacts with 3-amino-1,2-propanediol under the conditions of copper reagent / base / additive / solvent to prepare N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5-((2,3-dihydroxypropyl)amino)isophthalamide, the specific reaction formula is as follows: The copper reagent is CuI or Cu2O; The base is K3PO4 or KOH; The additive is N 1 -Benzyl-N 2 -(2-methylnaphthalene-1-yl)oxalyl diamide or N 1 ,N 2 -bis(2,4,6-trimethoxyphenyl)oxalyl diamide; The solvent is ethanol or DMSO.

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