KR20040095799A - Improved process for preparing Iodixanol - Google Patents

Abstract

PURPOSE: A method for preparing iodixanol derivatives is provided to improve the process efficiency and yield with reduced cost, thereby being economic as compared to the conventional methods. CONSTITUTION: The method for preparing iodixanol derivatives used as a contrast medium in X-ray diagnosis comprises: (a) carrying out amination of 5-nitro-1,3-dimethyl isophthalate represented by formula 2 to obtain a compound represented by formula 3; (b) reducing the nitro group of the compound of formula 3 to an amino group and carrying out iodization thereof to obtain a compound represented by formula 4; (c) carrying out acetylation of the compound of formula 4 to obtain a compound of formula 6; and (d) reacting the compound of formula 6 with o-acetyl-1,3-dichloro-2-propanol.

Description

Improved process for preparing iodisanol derivatives {Improved process for preparing Iodixanol}

The present invention relates to an improved method for preparing an iodisanol derivative, and more particularly, to produce an iodixanol derivative used as a nonionic X-ray angiography agent more economically, and to improve process efficiency and An improved manufacturing method having the effect of improving the yield.

Contrast medium is a substance that is used to express the target area on the X-ray image by using the X-ray absorption difference between the main elements included in the component and the human tissue. As the condition of the excellent contrast agent, the contrast effect and the safety to the human body are absolute conditions. In recent years, development has been focused on the more stable contrast agent. The history of X-ray diagnostics is the starting point of X-ray discovery by Roentgen in 1895, and despite the emergence of other superior imaging, X-ray diagnostics are still developing as an established diagnostic method. Background of the development is the development of apparatus, equipment, and contrast technology, which greatly contributes to the advancement and improvement of contrast agents.

There are many types of contrast agents such as urinary tract, blood vessel contrast agent, digestive tract contrast agent, gallbladder and bile duct contrast agent (biliary contrast contrast agent), ventricular and spinal cord contrast agent, bronchial contrast agent, lymph vessel contrast agent, uterine fallopian tube contrast agent, and other salivary glands, joints, fistulas, and seminal vesicles. . Depending on the target site, the type of contrast medium used and the administration site are different. Looking at the development of the contrast medium, it can be divided into 5 stages as follows.

1) Inorganic iodine contrast agent: The use of sodium iodide as a contrast agent started in 1918, but iodine was administered to the human body because it was effective in treating infectious diseases such as sexually transmitted diseases. On the basis of this, the safety of inorganic iodine was confirmed as compared with the preparation using mercury, bismuth, etc. was the biggest reason for selecting iodine as a basic element of contrast agent. In 1923, Osborne discovered that the urinary tract was contrasted in patients who received intravenous or large doses of iodine sodium, and it became the basis for current venous urinary tract angiography. I did a preliminary shooting, but it happened that the urinary tract was inadvertently photographed. However, sodium iodine is highly toxic and has not been established in the dosage for clinical use. In the meantime, in addition to urinary tract blood vessels, various types were developed, and LIPIODOL, which is currently used as a useful contrast agent, was produced.In 1923, Sicard et al. In 1924, Graham et al. Synthesized tetraiodine phenol pretain and performed gallbladder imaging.

2) Mono-iodine contrast agent era (first generation): In 1927, Binz et al. Synthesized uro-cerekuta, which increased the water solubility of cerectan. This enabled large-capacity infusions, and in 1929 Swick succeeded in intravenous urinary tract contrasting, making it the first practical urovascular contrast agent.

3) The iodine contrast agent era (first generation): In 1930, urocerecutan B was synthesized from urocerecutan with one iodine added, which is an excellent urinary vascular contrast agent because of its increased water solubility and increased iodine content. It has been provided to the clinic for about 20 years before the appearance of contrast.

4) Ionic Tri-Iodine Contrast Era (Second Generation): Since the first-generation contrast agent uses pyriton rings as the basic skeleton, two iodine sites are limited in one molecule. Since 1933, attempts have been made to develop triiodine compounds using benzene rings (benzoic acid) with the aim of increasing iodine again. Originally, due to toxicity problems, it has not been put to practical use, but in 1950, the US Hoppe and others succeeded in developing the first sodium acetrizoic acid, which became the prototype of the ionic triiodine contrast agent. Subsequently, UROGRAFIN (1954), Metrizoed (Isope, 1961), and Iotalamet (CONRAY, 1962), which are excellent in terms of safety, have been developed and improved. . Such triiodine benzoic acid contrast agent is ionic in the form of Na salt, Mg (megurumin) and the like. This is because benzene itself is insoluble, and in order to make it water-soluble, it was necessary to form it as a salt as benzoic acid.

5) Nonionic triiodine contrast agent (3rd generation): Second generation triiodine benzoic acid contrast agent has superior characteristics in both contrast effect and safety compared to the first generation contrast agent, but has few side effects in clinical practice. There remains a problem in improving safety. Among these backgrounds, Almen of Sweden gave the theoretical basis for nonionic contrast agents. He suggested that contrast agent non-ionization theory is solved by using the structure itself as a nonionic compound in order to try to reduce osmotic pressure without reducing iodine concentration because the main cause of the side effect of contrast medium is high osmotic pressure. In 1972, based on this theory, the first nonionic low osmotic contrast agent methazamide was developed and the third generation of contrast agents arrived. Metrizamide was released in Japan as amipakyu. The compound is lyophilized because it is unstable in heat or in aqueous solution and needs to be dissolved only during use, making it inadequate for large doses in angiography, with adaptive spinal cord imaging. Therefore, the development was progressed again, and Iopamidol (Iopamiron) and Iohexol (OmniPaku) appeared as full-fledged nonionic contrast agents for urinary tract and angiography. The reason why the nonionic contrast agent is water-soluble even if it is not in the form of ions is that methazamide contains glucose in its structure, and iopamidol and iohexole contain hydroxyl (OH) on the benzene ring side. Because. The hydroxyl groups of five Iopamidol and six Iohexol have a very strong affinity with water, thus preserving the water solubility of the whole compound. In order to increase hydrophilicity, ioversol (Opti-ray), which is a hydroxyl group, was developed in 1979 to remove the hydrophobic methyl group at the lateral end of the benzene ring. Osmotic pressure was attempted. As a result, Iosakuret was developed. This is an ionic but low osmotic pressure by polymerizing two triiodine benzenes into so-called dimers. In addition, the contrast agent, which attempted to reduce osmotic pressure as it changed from nonionic to dimer type, was developed in 1980 by IsoBist in 1980 and Ioji Kisanol in 1985.

As injections of non-ionic X-ray contrast agents, the iodixanol derivatives include cardiovascular, arterial, angiographic (conventional and arterial DSA), cerebrovascular, abdominal angiography (arterial DSA), urinary, intravenous, It is well known to be very useful for CT contrast enhancement and peripheral angiography (conventional imaging and arterial DSA). Among iodixanol derivatives, in particular, compounds having the structure of Formula 1, ie, 5,5 '-[(2-hydroxytrimethylene) -bis (acetylimino)]-bis (2,3-dihydride Roxypropyl) -2,4,6-triiodoisophthalamide has an excellent effect on cardiovascular imaging.

Iodixanol derivatives are similar in use to other iodine contrast agents, but due to their isotonic properties, sufficient diagnostic information can be obtained at lower iodine concentrations than other contrast agents.

In addition, in the case of general contrast agent, there is a problem of renal toxicity when high dose is used, but the effect on glomerular filtration rate of iodixanol is similar to that of other contrast agents, whereas the effect on renal tubule is iohexol, io Compared with other contrast agents, such as iopromide, iopamidol, and ioxaglate, the effects on the kidneys are minimal compared to the same dosage, so they can be selectively used for X-ray imaging where renal function is a concern. Can be. In general, patients at high risk, such as severe heart disease, allergic history, asthma, and severe renal disease, have a higher incidence of adverse effects caused by contrast agents than those of general patients. It can be chosen as a good contrast agent.

A typical method for preparing iodixanol represented by Formula 1 is shown in Scheme 1 below. The preparation method of Scheme 1 was carried out in 1983 by Nyegaard & Co. Developed by A / S [European Patent Publication No. 108,638; US Patent No. 5,824,821; US Patent No. 6,232,499.

As a method for preparing iodixanol according to Scheme 1, according to European Patent Publication No. 108,638, dimerization was carried out using epichlorohydrin, but the reaction thereof is represented by Formula 5 above. The reaction under basic conditions by several hydroxyl groups and amide groups present in the compound cannot suppress the formation of by-products, and thus has a problem in that the production yield is 20% or less. In addition, in the case of US Pat. No. 6,232,499, in order to increase the solubility of the reactants, the production yield was improved to 30% using 2-methoxyethanol as a solvent, but the reason why the production yield did not reach a satisfactory level was as described above. The method is also not industrially suitable because it is due to the generation of side reactions by several hydroxyl groups present in the compound of 5.

In the general preparation method according to Scheme 1, the compounds represented by Formulas 4 and 5 are synthesized as essential intermediates. In particular, the compound represented by the formula (4) is a nonionic X-ray contrast agent currently used in general Iohexol [Iohexol; U.S. Patent 4,250,113, U.S. Patent 5,948,940, U.S. Patent 6,153,796, U.S. Patent 4,396,598, Ioversol; It is also a key intermediate of U.S. Patent 4,396,598, U.S. Patent 5,648,536, U.S. Patent 5,489,708.

Known methods related to the preparation of the compound represented by Formula 4 as an intermediate are as follows. U.S. Patent No. 4,250,113 discloses a reflux method for heating at reflux in an organic solvent such as 1-amino-2,3-propanediol and methanol using 5-nitro-1,3-dimethylisophthalate as a starting material as a starting material. After reducing the nitro group under 10% PdO / C and hydrogen, the compound represented by the formula (4) using KICl ₂ or NaICl ₂ as the iodide reaction by a known method ( Journal of American Chemical Society , 1956, 78 , 3210) Was prepared. However, although the method of US Pat. No. 4,250,113 uses a low cost starting material, the manufacturing cost is increased due to the installation of special equipment for the reaction hydrogenation, and industrially, there are many disadvantages in mass production. As another preparation method, U.S. Patent No. 4,396,598 uses an expensive raw material, 1-amino-2,4,6-triiodoisophthalic acid, as a starting material and reacts with thionyl chloride (SOCl ₂ ), which is a toxic material. After the reaction of 1-amino-2,3-propanediol using a potassium carbonate (K ₂ CO ₃ ) or sodium carbonate (Na ₂ CO ₃ ) as a base in an organic solvent such as dimethylformamide (DMF) The compound represented by 4 was obtained. However, due to the use of expensive raw materials and the use of toxic substances such as thionyl chloride (SOCl ₂ ), air and environmental pollution and the overall manufacturing yield are very low. Not. As another well-known method, U.S. Patent No. 5,824,821 uses dimethyl-5-nitroisophthalate as a starting material to replace existing 1-amino-2,3-propanediol in order to increase the cost of manufacturing and the ease of separation. After using allylamine, allyl groups were made into epoxides by using methoxidase metachloroperbenzene acid ( m CPBA) or hydrogen peroxide, and reacted in acetic acid aqueous solution to reduce the nitro group. The compound represented by was obtained. However, because the manufacturing process is long, there is a risk of explosion in a large amount of reaction and expensive oxidizing agent metachloroperbenzene acid ( m CPBA), etc. are not industrially suitable.

As another intermediate, a known method for preparing a compound represented by Chemical Formula 5, US Pat. No. 5,648,536 discloses acetic anhydride as N, N' -dimethylacetamide (DMAC) 4-dimethylaminopyridine (DMAP) was used in a catalytic amount, and the reaction was carried out in a solvent such as 1,1,2-trichloroethane to give a yield of 80 to 83%. This method uses excessive amount of DMAC with high boiling point (bp) and expensive solvents, so it is expensive to manufacture during mass production, and it is industrially suitable because it has a problem due to the difficulty of removing excessive DMAC in the process. Not.

As described above, a method for preparing an iodixanol derivative represented by Formula 1, which has been published so far, solves problems such as low yield, use of expensive raw materials, and serious environmental pollution wastewater and low-cost manufacturing method. And there is an urgent need for the development of low cost manufacturing technology according to the improvement of the yield by the new manufacturing technology by the suppression of by-products generated during the production of formula (1).

Accordingly, it is an object of the present invention to provide a method for producing a high purity iodixanol derivative which uses a low cost raw material, has a simple manufacturing process, and has a high yield and improves the problem of environmental pollution wastewater generation. .

An improved method for preparing an iodixanol derivative represented by Formula 1 according to the present invention is shown in Scheme 2 below.

(a) amination of 5-nitro-1,3-dimethylisophthalate represented by the following formula (2) to obtain a compound represented by the following formula (3);

(b) reducing the nitro group of the compound represented by Formula 3 to convert it to an amino group, and then iodizing to obtain a compound represented by Formula 4 below;

(c) acetylating the compound represented by Formula 4 to obtain a compound represented by Formula 6; And

(e) reacting the compound represented by Formula 6 with O -acetyl-1,3-dichloro-2-propanol represented by Formula 8 to obtain an iodixanol derivative represented by Formula 1 It is characterized by being included.

The manufacturing method according to the present invention will be described in more detail by dividing each step as follows.

(a) First, 5-nitro-1,3-dimethylisophthalate represented by Chemical Formula 2 is subjected to an amination reaction using an amination agent, a base, and an appropriate organic solvent to prepare a compound represented by Chemical Formula 3.

As an aminating agent, any one selected from the group consisting of 1-amino-2,3-propanediol, urea (NH ₂ CONH ₂ ) and acetamide (CH ₃ CONH ₂ ) may be selected.

For reactions using 1-amino-2,3-propanediol as an amination agent, the organic solvent is methanol, ethanol, butanol, isopropanol, propanol, t-butanol and dimethylformamide (N, N-dimethylformamide), dimethylsulfoxide, dimethylsulfoxide, polyethyleneglycol, toluene, benzene, xylene, chlorobenzene, and the like. Any one selected from the group is used, and preferably methanol is used. The base is sodium carbonate (Na₂CO₃), Potassium Carbonate (K₂CO₃), Ammonium Carbonate ((NH₄)₂CO₃), Caustic Soda (NaOH), Potassium Hydroxide (KOH), Sodium Methoxide (NaOCH)₃, Powder or 28% methanol solution) and sodium ethoxide (NaOCH₂CH₃) And any one selected from the group consisting of, and preferably to use a powdery potassium carbonate. For example, 1.0 equivalent of 5-nitro-1,3-dimethylisophthalate represented by Formula 2 and 2.0 to 3.0 equivalents of 1-amino-2,3-propanediol are used, and 0.1 to 4.0 equivalents of base is used. When the solvent is reacted for 17 to 20 hours at a temperature range of 20 ° C. to 90 ° C. using a solvent in a volume ratio of 10 to 20 with respect to the compound of Formula 2, the compound of Formula 3 may be obtained in a yield of 95 to 98%. have. Preferably, 1.0 equivalent of the compound of Formula 2 and 2.0 equivalents of 1-amino-2,3-propanediol are used, and the powdery sodium methoxide (NaOCH) is used as a base.₃) Using 0.1 equivalent, and using ethanol solvent in 10 times the volume ratio with respect to the compound of Formula 2 When reacted for 16 hours at a temperature range of ℃, the compound of Formula 3 can be obtained in 95% yield. In the above-mentioned amination reaction, ethanol is most suitable as a solvent. After completion of the reaction, the compound represented by Chemical Formula 3 is produced as crystals in ethanol as a solvent, and thus powdered sodium methoxide (NaOCH) used in a catalytic amount.₃) Can be removed by washing in ethanol, and the used solvent can be recovered by concentrating under reduced pressure. For the next reaction, the compound represented by Formula 3 is vacuum (60) Dry completely under (° C / 750 mmHg).

Scheme 3 illustrates the reaction of amination using any one selected from the group such as urea (NH ₂ CONH ₂ ) or acetamide (CH ₃ CONH ₂ ) as an aminating agent.

In the amination reaction according to Scheme 3, urea (NH) is used as an aminating agent.₂CONH₂) Or acetamide (CH₃CONH₂), And any one selected from the group consisting of Organic solvents include methanol, ethanol, butanol, isopropanol, propanol, t-butanol and dimethylformamide (N, N-dimethylformamide), dimethylsulfoxide, dimethylsulfoxide, polyethyleneglycol, toluene, benzene, xylene, chlorobenzene, and the like. The base is sodium carbonate (Na₂CO₃), Potassium Carbonate (K₂CO₃), Ammonium Carbonate ((NH₄)₂CO₃), Caustic Soda (NaOH), Potassium Hydroxide (KOH), Sodium Methoxide (NaOCH)₃) And any one selected from the group consisting of. For example, 1.0 equivalent of 5-nitro-1,3-dimethylisophthalate represented by Formula 2 and acetamide (CH₃CONH₂) Or 2.2 to 4.0 equivalents of urea and sodium methoxide or sodium ethoxide in powder form or 5-28% sodium methoxide or sodium ethoxide alcohol solution or powdered potassium-tButoxide, and the like, and 100 to 140 ° C. under solvents such as toluene, benzene, xylene, chlorobenzene, and tetrahydrofuran based on the compound of Formula 2 React for 1 to 4 hours at a temperature of < RTI ID = 0.0 > Cool to below ℃. Subsequently, the reaction was terminated using water in a volume ratio of 10 to 20 times based on the compound of Formula 2, followed by layer separation, and then glycidol (Glycidol) 2.0 to 3.5 represented by Formula 9 in the aqueous solution layer. 30 to 60 degree by adding equivalent When the reaction is carried out for 10 to 12 hours at a temperature of 5 ℃, adjusted to pH 6.0-6.5 with 5% aqueous hydrochloric acid solution and then treated with 0.05 to 0.06 weight ratio of activated carbon, the aqueous solution is concentrated under reduced pressure, represented by the formula (3) The compound can be obtained in a yield of 90 to 95%. Preferably, 1.0 equivalent of 5-nitro-1,3-dimethylisophthalate represented by Formula 2 and acetamide (CH₃CONH₂) And 3.0 equivalents and 4.0 equivalents of 28% sodium methoxide alcohol solution, and based on the compound of Formula 2, under a 10 volume ratio of toluene solvent, 100 Reacted for 3 hours at a temperature of < RTI ID = 0.0 > Cool to below ℃. Subsequently, the reaction was terminated using 10 vol. Ratio of water based on the compound of Formula 2, and the layers were separated. Then, 2.5 equivalents of glycidol represented by Formula 9 was added to the aqueous solution layer. ~ 60 When the reaction was carried out at a temperature of ℃ for 12 hours, adjusted to pH 6.0 with 5% aqueous hydrochloric acid solution, treated with 0.05 carbon by weight of activated carbon, and then concentrated under reduced pressure, the compound represented by the formula (3) yielded 93% yield. You can get

(b) Then, the nitro group of the compound represented by Chemical Formula 3 is reduced to be converted to an amino group, and then iodized to prepare a compound represented by Chemical Formula 4.

The reduction reaction for converting the nitro group to an amino group is carried out under the condition of using powdered iron (Fe) and a catalytic amount of concentrated hydrochloric acid aqueous solution. For example, after adding 3.0 to 4.0 equivalents of powdered iron (Fe) to 1.0 equivalent of the compound represented by Chemical Formula 3 and water of 5 to 10 times the volume ratio, 70 to 90 by adding a catalytic amount of concentrated hydrochloric acid solution The reaction is carried out for 5 to 6 hours at a temperature of 캜 to reduce the nitro group to an amino group. Preferably, 1.0 equivalent of the compound represented by Chemical Formula 3 and 3.0 equivalents of powdered iron (Fe) in water of 8-fold volume ratio are added, followed by adding a catalytic amount of a concentrated hydrochloric acid solution. The reaction is carried out at a temperature of 占 폚 for 5 hours to reduce the nitro group to an amino group.

The iodide reaction is 2N to 3.88M sodium iodide chloride (NaICl₂) Or potassium iodine chloride (KICl₂Known method using any one of the iodinating agent (Iodinating agent) selected from the group consisting ofJournal of American Chemical Society, 1956,78, 3210;Journal of Organic Chemistry1994,59 (6), 1344]. For example, the known method in 1.0 equivalent of the compound obtained as a result of the reduction reaction and 20 to 30 times the volume ratio of water [Journal of Organic Chemistry1994,59 (6)3.88M NaICl, manufactured by 1344₂50 ° C. to 90 ° using solution at 8.5 to 10-fold volume ratio When reacted for 10 to 15 hours at ℃, the compound represented by the formula (4) can be obtained in a yield of 75 to 80%. Preferably, the known method in water of 20-fold volume ratio to 1.0 equivalent of the compound obtained as a result of the reduction reaction [Journal of Organic Chemistry1994,59 (6)3.88M NaICl, manufactured by 1344₂90 using a volume ratio of 8.5 times When reacted at 10 ° C. for 10 hours, the compound represented by Chemical Formula 4 may be obtained in a yield of 75%. After completion of the reaction by treatment with activated carbon to remove the color of the compound represented by the formula (4).

In addition, in the present invention, the above-described reduction reaction and iodide reaction may be carried out continuously without performing a separate purification process. For example, after performing the reduction reaction by the above-described method, the reduction product is separated and purified and then iodide reaction. Although it may be carried out, even if the iodide reaction is carried out by adding an iodide agent or the like directly to the reaction without purification, the desired product can be obtained in high yield. Therefore, the method of continuously performing the above reduction reaction and iodide reaction without further purification may be a feature of the present invention.

(c) Then, the compound represented by Chemical Formula 6 is prepared by acetylation of the compound represented by Chemical Formula 4.

The acetylation reaction is 1 equivalent of the compound represented by Formula 4 and 2.2 to 2.4 equivalents of acetic anhydride and a catalytic amount of sulfuric acid orp90 to 95 using toluenesulfonic acid After stirring at 6 ° C. for 6 to 8 hours, and cooling to room temperature, the resulting solid was filtered and dried under reduced pressure to obtain the compound represented by Chemical Formula 6 as a white solid. According to the acetylation reaction according to the invention it is possible to obtain a compound represented by the formula (6) in a high yield of 98% or more.

In particular, it should be noted that, since the known method synthesizes the compound represented by Chemical Formula 5 as an intermediate, the production yield is inevitably lowered due to the generation of side reactions caused by a plurality of hydroxyl and amide groups present in the intermediate compound. In the present invention, by synthesizing the compound represented by Chemical Formula 6 as an intermediate, various side reactions generated in the known method may be minimized and the yield of the reaction may be increased.

(d) Then react the compound represented by the formula (6) and O -acetyl-1,3-dichloro-2-propanol represented by the formula (8) under a base to the iodine represented by the formula (1) Sanol (Iodixanol) is prepared.

For example, 1.0 equivalent of the compound represented by Chemical Formula 6 is dissolved in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in a volume ratio of 2 to 5, and 1.2 to 1.5 equivalents of base are added thereto, followed by the general formula at room temperature. By adding 1.0 to 1.3 equivalents of O -acetyl-1,3-dichloro-2-propanol represented by 8 and stirring at room temperature for 1 to 2 days, iodixanol represented by Formula 1 can be obtained. Preferably, 1.0 equivalent of the compound represented by Chemical Formula 6 is dissolved in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in a 5 volume ratio, and 1.5 equivalents of potassium carbonate (K ₂ CO ₃ ) or sodium carbonate ( Na ₂ CO ₃ ), etc. After adding 1.0 equivalent of O -acetyl-1,3-dichloro-2-propanol (Formula 8) at room temperature and stirring at room temperature for 1 day, Iodixanol (Iodixanol) ) Can be obtained.

On the other hand, the present invention also includes a method for purifying a crude product of iodixanol obtained by the above production method.

Briefly summarized the purification method of the iodixanol crude product according to the present invention, (i) using the Amberlite IR 120 ion exchange resin and Dowex anion exchange resin at room temperature after dissolving the iodisanol crude product in a solvent (Ii) adjusting the pH of the solution purified by the ion exchange resin to 4.9 to 5.1 with aqueous hydrochloric acid, and then concentrating the aqueous solution under reduced pressure, (i) dissolving the concentrated solution in n -butanol and filtering the filtrate. The solid is dissolved in water and then treated with activated carbon to obtain high purity iodisanol.

Detailed description of the purification method of the iodixanol crude product is as follows. To the iodisanol crude product, a solvent selected from the group consisting of 5 to 10 volume ratios of solvents such as methanol, ethanol, butanol, t-butanol and water is added and 0.8 to 0.9 weight ratio of Amberlite IR 120 ion exchange resin and Dowex anion exchange resin in a weight ratio of 0.9 to 1.5 was added, stirred at room temperature for 2 to 3 hours, filtered to remove the ion exchange resin, and the pH of the reaction was adjusted to 4.9 to 5.1 with 5-10% aqueous hydrochloric acid solution. The aqueous solution was removed by concentration under reduced pressure, and the volume ratio of 20 to 30n-5 ℃ to -15 after breaking the solid compound by adding butanol It is left overnight at a temperature of ℃. The resulting solid compound was filtered, the filtered solid compound was dissolved in 5 to 8 volume ratio of water, treated with 0.05 to 0.1 weight ratio of activated carbon, and concentrated under reduced pressure to obtain high purity iodisanol represented by Chemical Formula 1 above from 65 to Obtained in a yield of 68%.

The method for purifying iodixanol crude product will be described in more detail as follows. To the crude iodisanol product, 5 parts by weight of water, 0.8 parts by weight of Amberlite IR 120 ion exchange resin and 0.9 parts by weight of Dowex anion exchange resin were added, stirred at room temperature for 3 hours, and filtered to remove the ion exchange resin, 10% The pH of the reaction was adjusted to 4.9 with aqueous hydrochloric acid solution. The aqueous solution was concentrated under reduced pressure to remove 20 vol.n-10 after breaking the solid compound by adding butanol It is left overnight at a temperature of ℃. The resulting solid compound was filtered, and the filtered solid compound was dissolved in 5 volume ratio of water, and then treated with 0.05 weight ratio of activated carbon to concentrate under reduced pressure to obtain high purity iodisanol represented by Chemical Formula 1 in a yield of 68%. have.

On the other hand, O -acetyl-1,3-dichloro-2-propanol represented by the formula (8) used to perform the preparation method according to the present invention shown in Scheme 2 by the known method [US Patent No. 4,250,113] It was obtained in a yield of 98% by adding a catalytic amount of concentrated sulfuric acid from the 1,3-dichloro-2-propanol represented by the formula (7) in an acetic anhydride solvent.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1. 5-nitro- N, N ' Preparation of -bis (2,3-dihydroxypropyl) -isophthalamide (Formula 3)

239 g of 5-nitro-1,3-dimethylisophthalate (Formula 2) was suspended in 500 mL of ethanol, 182 g of 1-amino-2,3-propanediol was added to the solution, and the mixture was heated to reflux for 17 hours. The reaction mixture was cooled to room temperature, the resulting solid was filtered, washed with 200 mL of cold ethanol and dried under reduced pressure (50 ° C / 760 mmHg) to obtain a compound represented by the formula (3) of 339.5 g (95% yield) as a white solid.

m.p. 190-195 ℃;^OneH-NMR (CD₃OD) δ 3.95 (s, 6H), 3.35 to 3.72 (m, 20H), 7.62 (d,J =0.004Hz, 2H), 7.99 (d,J =0.004Hz, 1H); Mass (EI,m / e): 358 (M⁺+1), 340 (M⁺), 324 (M⁺), 290 (M⁺), 256 (M⁺), 244 (M⁺), 233 (M⁺), 121 (M⁺, basepeak); IR (KBr) 3388, 3298, 3066, 2927, 2815, 1713, 1623, 1560, 1350cm ^-One ; HPLC Column μC₁₈reverse phase, Eluent EtOAc / MeOH = 70/30, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 3.65 min, Purity: 99.2%; Elemental Analysis C₁₄H₁₉N₃O₈Base value C, 47.06; H, 5. 36; N, 11.76; 0, 35.82, found C, 47.07; H, 5. 37; N, 11.79; O, 35.84

Example 2. 5-amino-2,4,6-triiodo- N, N ' Preparation of -bis (2,3-dihydroxypropyl) -isophthalamide (Formula 4)

5-nitro-N, N '89.3 g of bis (2,3-dihydroxypropyl) -isophthalamide (Formula 3) was dissolved in 150 mL of water. 42.5 g of powdered iron (Fe, 100-200 mesh) was added thereto, and 5.2 mL of concentrated aqueous hydrochloric acid solution was added slowly, followed by heating to reflux for 5 hours. The reaction mixture was cooled, filtered under a Celite pad and washed with 200 mL of water to remove the iron compound from the residue. The aqueous solution of water was concentrated under reduced pressure to make the total volume 200 mL. 3.88M KICl₂solution(Journal of American Chemical Society1956,78213 mL was added over 1 hour. 70 to 80 after complete application Stir at 18 ° C. for 18 hours, and after cooling to room temperature, the brown solid was filtered off. 120 mL of 0.66N KOH aqueous solution was added to the filtrate, and the insoluble material was filtered off. The filtrate was further neutralized with 1N aqueous hydrochloric acid solution and treated with activated carbon. The aqueous solution was concentrated under reduced pressure, 200 mL of methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. Insoluble insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and 100 mL of ethyl acetate (EtOAc) was added thereto, followed by stirring at room temperature. The resulting solid was filtered, washed with 50 mL of ethyl acetate (EtOAc) and dried under reduced pressure (50 ℃ 760 mmHg) to give 128.1 g (75% yield) of the compound represented by the formula (4) as a white solid.

m.p. 200 Decompose;^OneH-NMR (DMSO-d ₆ ) δ 2.87 to 3.70 (m, 14H), 8.20 (bs, 1H), 8.48 (bs, 2H); IR (KBr) 3375, 3263, 3034, 2900, 2885, 1723, 1621, 1540, 1372cm ^-One ; HPLC Column μC₁₈reverse phase, Eluent H₂O / CH₃CN = 60/40, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 3.00 min, Purity 99.5%; Elemental Analysis C₁₄H₁₈I₃N₃O₆Base value C, 23.85; H, 2.57; N, 5.96; I, 54.00; 0, 13.62, found C, 24.08; H, 2. 65; N, 6.04; I, 54.35; O, 13.88

Example 3. 5-acetylamido-2,4,6-triiodo- N, N ' Preparation of -bis (2,3-diacetylpropanediol) -isophthalamide (Formula 6)

5-amino-2,4,6-triiodo-N, N '30 g of bis (2,3-dihydroxypropyl) -isophthalamide (Formula 4) are suspended in 150 mL of acetic anhydride,p0.3 g of toluenesulfonic acid was added. 90-95 reaction compound After stirring for 5 hours at room temperature, the resulting solid was filtered after cooling to room temperature. Wash with 50 mL of acetic anhydride and dry under reduced pressure (50 C./760 mmHg) to give 38.2 g (98% yield) of the compound represented by the formula (6) as a white solid.

m.p. 270 Decompose;^OneH-NMR (D₂O) δ 2.19 (s, 3H), 3.12 to 3.67 (m, 14H), 4.73 (bs, 4H), 8.18 (s, 2H), 8.49 (s, 1H); IR (KBr) 3385, 3283, 3064, 2963, 2891, 1703, 1631, 1560, 1351cm ^-One ; HPLC Column μC₁₈reverse phase, Eluent H₂O / CH₃CN = 60/40, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 9.80 min, Purity 99.5%; Elemental Analysis C₁₆H₂₀I₃N₃O₇Base value C, 25.72; H, 2. 70; N, 5.62; I, 50.96; 0, 14.99, found C, 25.75; H, 2.71; N, 5.66; I, 50.99; O, 14.99

Example 4. 5,5 '-[(2-hydroxytrimethylene) -bis (acetylimino)]-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthal Preparation of Amide (Formula 1)

5-acetylamido-2,4,6-triiodo-N, N '48.9 g of bis (2,3-diacetylpropanediol) -isophthalamide (Formula 6) was dissolved in 500 mL of dimethylformamide (DMF). Potassium carbonate (K in the reaction mixture₂CO₃) 8.9 g,O5.5 g of acetyl-1,3-dichloro-2-propanol were added. After stirring for 24 hours at room temperature, the filtrate was removed by concentration under reduced pressure after filtration. 200 mL of water was added, followed by 8.5 g of powdered caustic soda (NaOH), followed by 50 Stir at 1 ° C. for 1 h. The reaction solution was concentrated under reduced pressure, and then 39.0 g of Amberlite IR 120 ion exchange resin and 44 g Dowex anion exchange resin 1x4 were added and stirred at room temperature for 2 hours. The resin was removed by filtration and the pH of the filtrate was adjusted to 4.9 with 5% aqueous hydrochloric acid solution. The resulting solid is filtered,n-10 after suspending the filtered solid in 800 mL of butanol Cool to C and stir for 12 h. The obtained solid was filtered, dissolved in 200 mL of water, and 2.5 g of activated carbon was added thereto, followed by stirring at room temperature for 2 hours. The activated carbon was filtered off and concentrated under reduced pressure to remove the aqueous solution, followed by drying under reduced pressure (50). C./760 mmHg) to give 28.2 g (68% yield) of the compound represented by the formula (1) as a white solid.

m.p. 245-247 ℃;^OneH-NMR (D₂O) δ 1.78 (s, 6H), 1.81 (s, 4H, isomer), 3.27 to 3.67 (m, 20H & isomer proton 14H), 3.81 to 3.92 (bs, 4H); IR (KBr) 3377, 3260, 3072, 2926, 1776, 1649, 1555, 1402, 1259, 1110, 1041cm ^-One ; HPLC ColumnμC₁₈reverse phase, Eluent gradient 5 ~ 17% CH₃CN in H₂O, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 22.34 (5.1%), 24.50 (72.2%), 25.40 (20.7%), Purity 99.2%; Elemental Analysis C₃₅H₄₄I₆N₆O₁₅Base value C, 27.40; H, 3.0 3; N, 5.37; I, 48.40; 0, 15.31, found C, 27.42; H, 3.05; N, 5.40; I, 48.44; O, 15.35

Example 5. O Preparation of Acetyl-1,3-dichloro-2-propanol (Formula 8)

129 g (1.0 mole) of 1,3-dichloro-2-propanol (Formula 7) were suspended in 700 mL of acetic anhydride,p0.9 g of toluenesulfonic acid was added. 90-95 reaction compound Stir at 5 ° C. for 5 hours and concentrate under reduced pressure to remove acetic anhydride. 200 mL of ethyl acetate (EtOAc) was added to the remaining filtrate, and insoluble matters were removed by filtration. Anhydrous forget-me-not was added to remove water. The filtrate was concentrated under reduced pressure and dried under reduced pressure (50 C / 760 mmHg) to give 167 g (98% yield) of the compound represented by the formula (8) as a white liquid.

b.p. 110 to 120 ° C / 5 mmHg;^OneH-NMR (D₂O) δ 3.56 (s, 1H), 2.85 to 2.91 (m, 5H); Elemental Analysis C₅H₈Cl₂O₂Base value C, 35.11; H, 4.71; 0, 18.71; Cl, 41.46, found C, 35.21; H, 4. 74; O, 18.85

Example 6. 5-nitro- N, N ' Preparation of -bis (2,3-dihydroxypropyl) -isophthalamide (Formula 3) (method of using acetamide)

28% sodium methoxide (NaOCH₃184 g of methanol solution was concentrated under reduced pressure to remove the methanol solvent, and then suspended by adding 500 mL of toluene.₃CONH₂46.5 g were added and heated to reflux for 3 hours. 52 g of 5-nitro-1,3-dimethylisophthalate (Formula 2) were added to the reaction mixture, and the mixture was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, 500 mL of water was added, followed by stirring for 30 minutes. The mixture was stagnated to separate the layers, and the aqueous layer was extracted by extraction with 100 mL of toluene. 44.2 g of Glycidol (Formula 9) was added to the aqueous solution layer separately, and the mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH 6 with a 5% aqueous hydrochloric acid solution, and then 2.5 g of activated carbon was mixed and stirred at room temperature for 1 hour. Filter under a Celite pad, wash with 50 mL of water, concentrate the filtrate under reduced pressure, and dry under reduced pressure (50). C / 760 mmHg) to give 74.8 g (93% yield) of the compound represented by the formula (3) as a white solid.

m.p. 180-183 ℃;^OneH-NMR (CD₃OD) δ3.91 (s, 6H), 3.27-3.67 (m, 20H), 7.54 (d,J =0.004Hz, 2H), 7.91 (d,J =0.004Hz, 1H); Mass (EI,m / e328 (M⁺+1), 327 (M⁺), 284 (M⁺), 256 (M⁺), 250 (M⁺), 233 (M⁺), 216 (M⁺), 177 (M^+,basepeak); IR (KBr) 3383, 3285, 3050, 2929, 2819, 1716, 1625, 1554, 1361cm ^-One ; HPLC Column μC₁₈reverse phase, Eluent EtOAc / MeOH = 70/30, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 5.30 min, Purity 99.2%; Elemental Analysis C₁₄H₂₁N₃O₆Base value C, 51.37; H, 6. 47; N, 12.84; 0, 29.33, found C, 51.42; H, 6. 55; N, 12.96; O, 29.54

Example 7. 5-nitro- N, N ' Preparation of -bis (2,3-dihydroxypropyl) -isophthalamide (Formula 3) (method of using urea)

Example _{6 using} 184 g of 28% sodium methoxide (NaOCH ₃ ) methanol solution, 57.4 g of powdered urea (H ₂ NCONH ₂ ) and 50 g of 5-nitro-1,3-dimethylisophthalate (Formula 2) The reaction was carried out in the same manner as to obtain 72.8 g (93% yield) of the compound represented by Chemical Formula 3 as a white solid.

The production method according to the present invention is much more effective and economical in terms of yield, purity and production cost than known methods, and in particular, in the preparation of the compound represented by Formula 4 synthesized as an intermediate, the conventional production method is PdO. Since the use of hydrogen gas at / C conditions had to be equipped with the risk of fire and expensive facilities, in the present invention is carried out under the conditions using a powdered iron (Fe) and a catalytic amount of hydrochloric acid aqueous solution is higher than in any conventional manufacturing method Obtaining the reducing reactants in yield has the effect of lowering the manufacturing price with an increase in overall yield.

In addition, the present invention is an intermediate of the general formula (6) in which a hydroxyl group is protected instead of via the synthesis of the compound of the general formula (5) which is a cause of the production of a secondary reactant in the general manufacturing method (Scheme 1) in the preparation of the compound represented by the formula (1) At the same time, by using O -acetyl-1,3-dichloro-2-propanol (Formula 8) instead of epichloro hydrin as a reactant to suppress the production of various by-products generated during the reaction to the maximum Iodixanol represented by the formula (1) has a merit that can be obtained in a higher yield than any known method disclosed up to now.

Claims (10)

(a) amination of 5-nitro-1,3-dimethylisophthalate represented by the following formula (2) to obtain a compound represented by the following formula (3); (b) reducing the nitro group of the compound represented by Formula 3 to convert it to an amino group, and then iodizing to obtain a compound represented by Formula 4 below; (c) acetylating the compound represented by Formula 4 to obtain a compound represented by Formula 6; And (e) reacting the compound represented by Formula 6 with O -acetyl-1,3-dichloro-2-propanol represented by Formula 8 to obtain an iodixanol derivative represented by Formula 1 Improved process for the preparation of iodisanol derivatives, characterized in that it comprises: [Formula 1] The method of claim 1, wherein the (a) amination reaction is carried out using 1-amino-2,3-propanediol as an aminating agent under conditions in the presence of a base to prepare an amine compound represented by the formula (3). The manufacturing method to make. According to claim 1, wherein the (a) amination reaction is a compound represented by the formula (3) by reacting with a glycidol represented by the following formula (9) after the reaction in the presence of a base using acetamide or urea as an amination agent Manufacturing method characterized in that the manufacturing. The method of claim 2 or 3, wherein the base of the (a) amination reaction is sodium carbonate (Na ₂ CO ₃ ), Potassium carbonate (K ₂ CO ₃ ), Ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) , Sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOCH ₃ , powder or 28% methanol solution) and sodium ethoxide (NaOCH ₂ CH ₃ ) Characterized in the manufacturing method. The method of claim 2 or 3, wherein the (a) amination reaction solvent is methanol, ethanol, butanol, isopropanol, propanol, t-butanol and dimethylformamide ( N, N -dimethylformamide), dimethyl sulfoxide (Dimethylsulfoxide) , Polyethylene glycol (Polyethyleneglycol), toluene, benzene, xylene and any one selected from the group consisting of chlorobenzene. The method according to claim 1, wherein the reduction reaction (b) is performed under conditions using powdered iron (Fe) and a catalytic amount of concentrated hydrochloric acid solution. The method of claim 1, wherein (b) the iodide reaction is performed under conditions using sodium iodide chloride (NaICl ₂ ) or potassium iodide chloride (KICl ₂ ) as an iodide agent. The method according to claim 1, 6 or 7, wherein the iodide reaction is carried out immediately after the reduction reaction without purification. The method according to claim 1, wherein the (c) acetylation reaction is performed under conditions using a catalytic amount of sulfuric acid or p -toluenesulfonic acid in an acetic anhydride solvent. According to claim 1, wherein the crude product of iodixanol represented by the formula (1) obtained as a result of the reaction (i) dissolved in a solvent selected from methanol, ethanol, butanol, t-butanol and water and purified using Amberlite IR 120 ion exchange resin and Dowex anion exchange resin at room temperature; (Ii) adjusting the pH of the solution purified by the ion exchange resin to 4.9 to 5.1 with an aqueous hydrochloric acid solution and then concentrating the aqueous solution under reduced pressure, (Iii) The concentrated solution is dissolved in n -butanol and filtered, and the filtered and recovered solid is dissolved in water and treated with activated carbon to obtain high purity iodixanol.