KR100524146B1 - New process for preparing Iodixanol - Google Patents

Abstract

The present invention relates to a novel method for preparing iodisanol, and more particularly, can be more economically prepared iodixanol (Iodixanol) used as a nonionic X-ray angiography agent, improving the efficiency and yield of the process It relates to a novel manufacturing method having an effect to.

Description

New process for preparing iodisanol {New process for preparing Iodixanol}

The present invention relates to a novel method for preparing iodisanol, and more particularly, can be more economically prepared iodixanol (Iodixanol) used as a nonionic X-ray angiography agent, improving the efficiency and yield of the process It relates to a novel manufacturing method having an effect to.

Contrast medium is composed of iodine or barium sulfate (BaSO ₄ ) in its composition, which temporarily changes the X-ray shading concentration of any organ or tissue in the human body. Absorption difference is used to make a difference in the target area by contrast and to be used to image the organ and internal structure on the X-ray image. Contrast agents are classified into negative contrast agents that appear in black shades by increasing the transmission due to their low radiation absorption and positive contrast agents that appear in white shades by decreasing the transmission due to the high absorption of radiation. As a negative contrast agent, air is mainly used, which is used alone, such as pharyngeal and laryngeal angiography, air reduction, or mixed with a positive contrast agent for gastrointestinal relationship double contrast test and joint cavity double contrast test. Is used. Amphoteric contrast agents are classified into water-soluble and oil-soluble contrast agents according to their solubility in water. Soluble contrast agents are used in most imaging studies, and soluble contrast agents are the only situation in which lipiodol is used for lymph node contrast. Water-soluble contrast agents are classified into second-generation and third-generation contrast agents according to their ionization, and the conditions for water-soluble contrast agents should be as follows: They should be harmless to the human body and have a high contrast with tissue. Images can be obtained, summarized as being biochemically safe and well absorbed and excreted after testing. As such water-soluble contrast agents, nonionic contrast agents, which are third generation contrast agents, include Iohexol, Iopromide, Iotrolan, and recently developed Iodixanol. Water-soluble third-generation contrast agent does not cause ionization in the body has the advantage that can significantly reduce the side effects.

Most of the manufacturing techniques for X-ray angiography are found in Shering AG, Amersham Nycomed, Mallinckrodt, Merck KgaA, Braco and Guerbet. The world's leading pharmaceutical companies have unique technologies for related products.

The X-ray contrast agent is a contrast agent used for the diagnosis of diseases such as urinary tract, digestive tract, gallbladder and bile ducts (sugar), ventricular spine, bronchus, lymphatic vessels, uterine fallopian tubes, etc. The site of administration is different. X-ray angiography agents mainly used at home and abroad are ionic monomer derivatives (eg, acetizoate, metrizoic acid, iomeglamic acid, etc.) depending on the properties of the compound. , Ionic dimer derivatives [e.g. Iozaglic acid], nonionic monomer derivatives [e.g. Iopamidol, Iohexol, Ioversol, iopromide ( Iopromide, etc.] and nonionic dimer derivatives (eg, Iotrolan, Iotasul, Iodixanol, Iosmin, etc.). Most of the X-ray angiography agent is an aromatic compound in which a large number of iodine is substituted, and a plurality of hydroxyl groups (-OH groups) are included in the side chain of the aromatic amide. Has characteristics. Many of these derivatives have the disadvantage of having a 1% mortality rate depending on the patient used due to problems such as increased osmotic pressure, renal toxicity in the human body.

As a new X-ray angiography to compensate for these shortcomings, iodixanol, a nonionic dimer derivative, is currently available on the market for cardiovascular, arterial, cerebrovascular, abdominal, urinary and venous It was developed by Nycomed (European Patent No. 108,638; U.S. Patent No. 5,824,821) in 1983 as a compound having an excellent effect on contrast and a very useful compound for CT contrast enhancement and peripheral artery contrast. Iodixanol is a highly hydrophilic contrast agent that is particularly effective in cardiovascular imaging, and is nonionic and has 9 hydroxyl groups in an optimal position. There is an advantage.

Among iodixanol derivatives, in particular, compounds having the structure of formula (1), namely 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 the case of general contrast agent, there is a problem of renal toxicity when high doses are used, but the effect on glomerular filtration rate is similar to that of other contrast agents in Iodixanol, whereas the effect on renal tubule is Compared with other contrast agents such as Iopromide, Iopamidol and Ioxaglate, they can be selectively used for X-ray imaging where kidney function is feared due to less effect on the kidney compared to the same dosage. have. 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 epichloro hydrin, but the reaction thereof is represented by Chemical Formula B. Reaction under basic conditions by a number of hydroxyl groups and amide groups present in the compound represented by can not inhibit the formation of by-products, and thus has a problem that the production yield is 20% or less. In addition, in the case of US Pat. No. 6,232,499, the production yield was improved to 30% using 2-methoxyethanol as a solvent in order to increase the solubility of the reactants, but as mentioned above, the reason why the production yield did not reach a satisfactory level was mentioned. 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 formula (B).

In the general preparation method according to Scheme 1, the compounds represented by Formulas A and B are synthesized as essential intermediates. In particular, the compound represented by the formula (A) 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 compounds represented by formula (A) as intermediates 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 A 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 1-amino-2,4,6-triiodoisophthalic acid as a starting material and reacts with thionyl chloride (SOCl ₂ ), which is a toxic substance. 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 A 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, the allyl group is made into an epoxide by using metachloroperbenzene acid ( m CPBA) or hydrogen peroxide, which is an oxidizing agent, and reacted in acetic acid aqueous solution, followed by reduction of 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 related to the preparation of the compound represented by Chemical Formula B, 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%. Since this method uses excessive amount of DMAc with high boiling point (bp) and expensive solvents, it is expensive to manufacture in mass production, and it is industrially suitable because it has a problem due to the difficulty of removing excessive DMAc in the process. Not.

Therefore, the production technology of iodixanol reported so far focused on improving the dimerization process of iodixanol and the separation and purification of the synthesized compounds. In other words, the dimerization (dimerization) has a significant effect on the yield and purity of the compound due to the low production yield and complex separation and purification, thereby causing the complexity of the manufacturing process it was a factor causing the price increase of the product. In particular, since the free iodide of iodine in the molecule, which is characteristic of X-ray angiography, becomes an important factor of lethal life threat in the separation and purification of compounds, the separation is more effective and minimizes the free iodide expression of iodine. The technology of purification is very important.

As described above, the production method of iodixanol represented by Chemical Formula 1, which has been reported to date, has required a solution to problems such as low yield, use of expensive raw materials, and serious environmental pollution wastewater generation. That is, the development of a more economical manufacturing method and the improvement of the yield by the development of a new manufacturing technology for suppressing the by-products generated during the preparation of the compound represented by the formula (1) and the development of a low cost manufacturing cost is urgently required. .

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel production method of iodixanol derivatives of high yield and purity using low cost raw materials, simple manufacturing process, high yield, and improved problems of environmental pollution wastewater generation. will be.

A novel method for preparing iodixanol represented by Formula 1 according to the present invention is shown in the following scheme 2,

(a) acylating the 5-aminoisophthalic acid represented by the following formula (2) to obtain a compound represented by the following formula (3);

(b) converting an amino group of the compound represented by Chemical Formula 3 into an acetylamino group to obtain a compound represented by the following Chemical Formula 4;

(c) reacting the compound represented by Formula 4 with 2,2-dimethyloxolane-3-methylamine represented by Formula 5 to obtain a compound represented by Formula 6; And

(d) reacting the compound represented by Chemical Formula 6 with 3-dichloro-2-propanol compound and deprotecting an acetonide protecting group to obtain iodixanol represented by the following Chemical Formula 1. It is characterized by that.

Referring to the present invention in more detail as follows.

The present invention is characterized by a series of production method shown in Scheme 2, in particular, the production method according to the present invention has an important feature in the technical configuration in the synthesis and via the compound represented by the formula (6). The compound represented by Chemical Formula 6 has a structure in which hydroxyl groups at both ends are protected, and a 2,2-dimethyl-1,3-dioxolane ring is introduced, so that crystallization is easy, and thus separation and purification can be easily obtained. And, it is possible to obtain the effect of improving the production yield by inhibiting side reactions in the dimerization reaction carried out next.

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

(a) First, 5-aminoisophthalic acid represented by Chemical Formula 2 is heated and refluxed with thionyl chloride (SOCl ₂ ) to prepare a compound represented by Chemical Formula 3.

In the acylation reaction with thionyl chloride described above, a single or mixed organic solvent selected from the group consisting of ethyl acetate, toluene, benzene, xylene, chlorobenzene, and the like is used. Preferably, ethyl acetate is selected and used as a reaction solvent. It is. In addition, an excess of thionyl chloride (SOCl ₂ ) may be used without using an organic solvent. In this case , the reaction may be accelerated by adding a catalytic amount of dimethylformamide ( N, N- dimethyl formamide). For example, using 80 equivalents of 5-aminoisophthalic acid represented by Formula 2 and 4 to 20 equivalents of thionyl chloride, and using an organic solvent in a volume ratio of 10 to 20 with respect to the compound of Formula 2, 80 ° C. to 90 ° When reacted for 14 to 20 hours at a temperature range of ℃, the compound represented by the formula (3) can be obtained in a yield of 95 to 98%. Preferably, 1.0 equivalent of the compound represented by Formula 2 and 4.0 equivalents of thionyl chloride are used, and ethyl acetate solvent is used at a ratio of 10 times the volume of the compound represented by Formula 2 at 80 ° C. to 90 °. When reacted for 16 hours at a temperature range of ℃, the compound represented by the formula (3) can be obtained in a yield of 95%. In addition, when no organic solvent is used, 1.0 equivalent of the compound represented by Formula 2 and 10 to 20 equivalents of thionyl chloride are used, and 5 to 10 mol% of dimethylformamide is added, followed by 80 to 90 ° C. When reacted for 16 hours at a temperature range of ℃, the compound represented by the formula (3) can be obtained in a yield of 95%. When the acylation reaction with thionyl chloride is completed, the compound represented by Chemical Formula 3 is generated as crystals in an aqueous solution, so dimethylformamide used in catalytic amounts can be removed by washing with an aqueous solution. For the next reaction, the compound represented by Formula 3 is vacuum (60) Dry thoroughly under C / 750 mmHg).

(b) Then, the amino group of the compound represented by Chemical Formula 3 is acetylated to convert to an acetylamino group, thereby preparing a compound represented by Chemical Formula 4.

Examples of the reaction solvent is an organic solvent such as dimethylformamide (N, N -Dimethylformamide) or dimethylacetamide (N, N -Dimetylacetamide) is used. For example, 1.0 equivalent of the compound represented by Chemical Formula 3 is reacted with 5 to 10 equivalents of acetyl chloride in an dimethylacetamide ( N, N- dimethylacetamide) solvent in a volume ratio of 3 to 5 to obtain a compound represented by the chemical formula. Manufacture.

(c) Then, the compound represented by Chemical Formula 4 is reacted with the compound represented by Chemical Formula 5 under an inorganic base to prepare a compound represented by Chemical Formula 6.

As the reaction solvent , an organic solvent selected from dimethylformamide ( N, N- Dimethylformamide) and dimethylacetamide ( N, N- Dimetylacetamide) is used, and as inorganic bases, sodium carbonate (Na ₂ CO ₃ ) and potassium carbonate (K ₂ CO ₃ ) and the like are used. In this reaction, dimethylformamide ( N, N- Dimethylformamide) is suitable as the organic solvent , and sodium carbonate (Na ₂ CO ₃ ) is suitable as the inorganic base. For example, 1.0 equivalent of the compound represented by Formula 4 is represented by 2.0 to 3.0 equivalents of Formula 5 in an organic solvent of 3 to 5 volume ratios of dimethylformamide ( N, N -Dimethylformamide) or dimethylacetamide ( N, N -Dimetylacetamide). Reacting the compound with an inorganic base of 2.0 to 4.0 equivalents of sodium carbonate (Na ₂ CO ₃ ) or potassium carbonate (K ₂ CO ₃ ) at room temperature (specifically, a reaction temperature of 10 ° C. to 25 ° C.) for 24 hours. The compound represented by the formula (6) is obtained in a yield of 90 to 93%. Preferably, 1.0 equivalent of the compound represented by the formula (4) is added to the compound represented by the formula (5) and 2.5 equivalents of sodium carbonate (Na ₂ CO) in an organic solvent of dimethylformamide ( N, N- Dimethylform amide) in a 3 volume ratio. Reaction with the inorganic base of ₃ ) for 24 hours at a reaction temperature of 10 ℃ to 25 ℃ to obtain a compound represented by the formula (6) in a yield of 93%.

(d) Then, after reacting the compound represented by the formula (6) with the 3-dichloro-2-propanol compound under the conditions using an aqueous solution of caustic soda and a catalytic amount of alcohol, the acetonide group bound with a protecting group is deprotected. Iodixanol (Iodixanol) represented by the formula (1) aimed at the invention is prepared.

For example, 1.0 equivalent of the compound represented by Chemical Formula 6 is suspended in 2.0-3.0 equivalents of 1N-caustic soda (NaOH) aqueous solution, 5 mol% of methanol or ethanol is added to dissolve the reactants, and then 2.0 to 4.0 equivalents of the reactant. 1.3-dichloro-2-propanol is added and stirred for 48 hours at room temperature (specifically, a reaction temperature of 10 ° C to 25 ° C). After completion of the reaction, the reaction solvent was neutralized with 1.0 to 5.0% hydrochloric acid aqueous solution, and then concentrated under reduced pressure. 5 to 10 volume ratio of methanol or ethanol was added to the remaining surplus, and 50% by weight (g%) of strong acidic DOWEX-50 ion exchange resin was mixed with respect to the compound represented by Chemical Formula 6, and the temperature was 20 to 45 ° C. Stir for 3 to 5 hours. The reaction mixture was filtered to remove ion exchange resins and insoluble insolubles, and then activated carbon at a weight ratio of 5.0% was added to the filtrate and stirred for 3 to 5 hours at room temperature. The reaction product is filtered to remove activated carbon and concentrated under reduced pressure to obtain iodisanol represented by Formula 1 in a yield of 70 to 75%. Preferably, 1.0 equivalent of the compound represented by Chemical Formula 6 is suspended in 2.4 equivalents of 1N-caustic soda (NaOH) aqueous solution, 5 mol% of methanol is added to dissolve the reactant, and 4.0 equivalents of 1.3-dichloro-2 are reacted with the reactant. Propanol is added and stirred for 48 hours at a reaction temperature of 25 ° C. After completion of the reaction, the reaction was neutralized (pH = 7.0) with 3.0% aqueous hydrochloric acid solution, and then the reaction solvent was concentrated under reduced pressure. 5 volume ratio of methanol is added to the remaining surplus, and 50% by weight (g%) of strongly acidic DOWEX-50 ion exchange resin is mixed with respect to the compound represented by Formula 6, and stirred at a temperature of 40 ° C. for 5 hours. . The reaction mixture was filtered to remove ion exchange resins and insoluble insolubles, and then activated carbon at a weight ratio of 5.0% was added to the filtrate and stirred at room temperature for 3 hours. The reaction product is filtered to remove activated carbon and concentrated under reduced pressure to obtain iodisanol represented by Chemical Formula 1 in a yield of 73%.

The present invention is also characterized in that the method for purifying the crude product of iodixanol obtained by the above-described method, briefly summarized the purification method is as follows: (i) dissolved in the solvent iodisanol crude product After purification using Amberlite IR 120 ion exchange resin and DOWEX anion exchange resin at room temperature, (ii) the pH of the solution purified by the ion exchange resin was adjusted to 4.9 to 5.1 with aqueous hydrochloric acid and then concentrated under reduced pressure. , (Iii) The concentrate is dissolved in n -butanol and filtered, and the filtered and recovered solid is dissolved in water and treated with activated charcoal to obtain high purity iodisanol.

The method for purifying the iodixanol crude product will be described in more detail as follows: In the iodisanol crude product, a solvent in a 5 to 10 volume ratio, for example, methanol, ethanol, butanol, t-butanol and water, etc. A solvent selected from the group consisting of 0.8 to 0.9 weight ratio of Amberlite IR 120 ion exchange resin and 0.9 to 1.5 weight ratio of Dowex anion exchange resin was added and stirred at room temperature for 2 to 3 hours, followed by filtration to remove the ion exchange resin. The pH of the reaction is adjusted to 4.9 to 5.1 with 5-10% aqueous hydrochloric acid. The aqueous solution was concentrated under reduced pressure to remove the solid compound by adding n -butanol in a volume ratio of 20 to 30, and then -5 ° C to -15 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 85% of iodisanol represented by Chemical Formula 1 above in high purity. Obtained in a yield of 88%.

A more detailed description of the purification method of the iodixanol crude product is as follows: 5 parts water and 0.8 weight Amberlite IR 120 ion exchange resin and 0.9 weight ratio DOWEX anion exchange resin in the iodisanol crude product. After stirring for 3 hours at room temperature and filtered to remove the ion exchange resin, the pH of the reaction was adjusted to 4.9 with 10% aqueous hydrochloric acid solution. And concentrated under reduced pressure to remove the aqueous solution, n of 20 volume - then by addition of butanol broke the solid compound of -10 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 88%. have.

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. Preparation of 5-amino-isophthalic acid chloride (Formula 3)

55.8 g of 5-aminoisophthalic acid was suspended in 500 mL of ethyl acetate, 116 g of thionyl chloride (SOCl ₂ ) was added to the solution, and the mixture was heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride (SOCl ₂ ), and then 200 mL of ethyl acetate was further added thereto, followed by concentration under reduced pressure to completely remove residual thionyl chloride (SOCl ₂ ). After cooling the reaction mass in an ice bath, 100 mL of water was added thereto, and the resulting solid was filtered by stirring at room temperature for 20 minutes, followed by drying under reduced pressure (50). C / 760 mmHg) to give 56.5 g (95% yield) of the title compound as a white solid.

mp 140-145 ℃; Mass (EI, m / e ) 596 (M ⁺ +1), 525 (M ⁺ ), 509 (M ⁺ ); IR (KBr) 3055, 2715, 1755 cm ⁻¹ ; HPLC Column μC ₁₈ reverse phase, Eluent EtOAc / MeOH = 70/30, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 5.40 min, Purity: 99.7%; Elemental Analysis C ₈ H ₂ Cl ₂ I ₃ N ₁ O ₂ Reference C, 16.13; H, 0.34; N, 2.35; 0, 5.37; C1, 11.90; I, 63.91, found C, 16.12; H, 0.34; N, 2.36; 0, 5.38; C1, 11.91; I, 63.95

Example 2. Preparation of 5-acetylamino-2,4,6-triiodo-isophthalic acid chloride (Formula 4)

59.5 g of 5-amino-isophthalic acid chloride were dissolved in 178 mL of dimethylacetamide. 39.4 g of acetyl chloride was added under an ice bath, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 500 mL of ice water and stirred to yield a white solid. The solid was filtered, washed with an aqueous solution and dried under reduced pressure (50 C / 760 mmHg) to give 60.5 g (95% yield) of the title compound as a white solid.

mp 200 Decompose; ¹ H-NMR (CDCl ₃ ) δ 2.15 (s, 3H), 8.20 (bs, 2H); IR (KBr) 2900, 2795, 1753, 1651 cm ⁻¹ ; Mass (EI, m / e ) 637 (M ⁺ +1), 594 (M ⁺ ), 523 (M ⁺ ), 507 (M ⁺ ); HPLC Column μC ₁₈ reverse phase, Eluent EtOAc / MeOH = 70/30, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 4.50 min, Purity 99.6%; Elemental Analysis C ₁₀ H ₄ Cl ₂ I ₃ N ₁ O ₃ Base C, 18.83; H, 0.63; N, 2.20; C1, 11.12; I, 59.71; 0, 7.53. Found C, 18.83; H, 0.64; N, 2.22; Cl, 11.14; I, 59.73; O, 7.52

Example 3. 5-acetylamino-2,4,6-triiodo- N, N ' Preparation of -bis (2 ', 2'-dimethyl-1,3-dioxolane-4-methyl) -isophthalamide (Formula 6)

63.6 g of 5-acetylamino-2,4,6-triiodo-isophthalic acid chloride were dissolved in 240 mL of dimethylformamide, and 6.1 g of powdered sodium carbonate (Na ₂ CO ₃ ) was added. A solution of 26.2 g of 2,2-dimethyl-1,3-dioxolane-4-methylamine in 20 mL of dimethylformamide was slowly added to the reaction compound. After stirring for 24 hours at room temperature, powdered sodium carbonate (Na ₂ CO ₃ ) was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, and then 200 mL of ethyl acetate (EtOAc) was added and stirred for 1 hour. The obtained solid was filtered, washed with ethyl acetate (EtOAc) and dried under reduced pressure (50). C / 760 mmHg) to give 77.6 g (94% yield) of the title compound as a white solid.

mp 270 Decompose; ¹ H-NMR (DMSO- d ₆ ) δ1.22 (s, 6H), 1.32 (s, 6H), 1.97 (s, 3H), 3.09-3.22 (m, 4H), 3.28-3.40 (m, 4H) , 3.73 to 3.80 (m, 4H), 4.00 to 4.04 (m, 4H), 4.16 to 4.23 (m, 4H), 8.65 to 8.76 (m, 2H), 9.90 (s, 1H); IR (KBr) 2953, 2890, 1713, 1651, 1540, 1341 cm ⁻¹ ; HPLC Column μC ₁₈ reverse phase, Eluent H ₂ O / CH ₃ CN = 60/40, Flow rate 1.0 mL / min, Temp 25 ℃, Detector UV 254 nm, Retention time 2.80 min, Purity 99.8%; Elemental Analysis C ₂₂ H ₂₈ I ₃ N ₃ O ₇ Reference C, 31.94; H, 3. 41; N, 5.08; I, 46.03; 0, 13.54; Found C, 31.94; H, 3. 41; N, 5.09; I, 46.05; O, 13.55

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

82.6 g of 5-acetylamino-2,4,6-triiodo- N, N' -bis (2 ', 2'-dimethyl-1,3-dioxolane-4-methyl) -isophthalamide 1N- It was suspended in 96 mL of caustic soda. 5 mL of methanol was added to the reaction mixture to completely dissolve the reaction. 38.6 g of 1,3-dichloro-2-propanol was added to the reaction. After stirring for 48 hours at room temperature, the reaction solvent was concentrated under reduced pressure after neutralization with 5.0% aqueous hydrochloric acid after the reaction was terminated. 400 mL of methanol was added to the remaining residue, and 42 g of strong acidic DOWEX-50 ion exchange resin was mixed and stirred at a temperature of 40 ° C. for 5 hours. The reaction product was filtered to remove the ion exchange resin and insoluble insolubles, and then 5 g of activated carbon was added to the filtrate and stirred at room temperature for 3 hours. The reaction was filtered to remove activated carbon and concentrated under reduced pressure to give 58 g (75% yield) of crude iodisanol.

To purify the crude iodisanol product, 18.0 g of Amberlite IR 120 ion exchange resin and 22 g of DOWEX anion exchange resin were added to 200 mL of methanol, followed by stirring 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 was filtered off and the filtered solid was suspended in 200 mL of n -butanol and then -10 Cool to C and stir for 12 h. The obtained solid was filtered, dissolved in 50 mL of water, and 5.8 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 49.3 g (85% yield) of the title compound as a white solid.

mp 245-247 ℃; ¹ H-NMR (D ₂ O) 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, 1041 cm ⁻¹ ; HPLC Column μC ₁₈ reverse phase, Eluent gradient 5 ~ 17% CH ₃ CN in H ₂ O, 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 C ₃₅ H ₄₄ I ₆ N ₆ O ₁₅ Reference C, 27.40; H, 3.03; 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

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 the compound represented by the above formula (6), which is synthesized as an intermediate, in particular, is a novel intermediate material, solubility in aqueous solution. Since it is low, it is possible to crystallize in an organic solvent to maximize the efficiency of separation and purification, thereby maximizing the production yield and the effect of lowering the manufacturing price.

In addition, the present invention is a hydride without the synthesis of the compound represented by the formula (A) or formula (B) which causes the increase in the production cost and the production of the side reactants in the general manufacturing method (Scheme 1) in the preparation of the compound represented by the formula (1) The compound represented by the above formula (6) can be efficiently produced by synthesizing the new intermediate represented by the above formula (6) in which the oxyl group is protected, and also the compound represented by the above formula (5), which is dimerized at the same time. In the reaction, by using 1,3-dichloro-2-propanol as a reactant instead of epichloro hydrin, the production of various by-products generated during the reaction is suppressed to the maximum, and the yield is higher than that of any known method. Iodixanol represented by the formula (1) has the advantage of obtaining.

Claims (9)

(a) acylating the 5-aminoisophthalic acid represented by the following formula (2) to obtain a compound represented by the following formula (3); (b) converting an amino group of the compound represented by Chemical Formula 3 into an acetylamino group to obtain a compound represented by the following Chemical Formula 4; (c) reacting the compound represented by Chemical Formula 4 with 2,2-dimethyloxolane-3-methylamine to obtain a compound represented by Chemical Formula 6; And (d) reacting the compound represented by Chemical Formula 6 with 3-dichloro-2-propanol compound and deprotecting an acetonide protecting group to obtain iodixanol represented by the following Chemical Formula 1. Method for producing iodisanol, characterized in that it comprises: [Formula 1] The method according to claim 1, wherein the acylation reaction (a) is carried out by heating and refluxing in the presence of an organic solvent using 10 to 20 equivalents of thionyl chloride (SOCl ₂ ). The method according to claim 1, wherein the acylation reaction (a) is carried out by heating and refluxing in the presence of a dimethylformamide catalyst using 10 to 20 equivalents of thionyl chloride (SOCl ₂ ). The method according to claim 1, wherein (b) the conversion to the acetylamino group is performed under a dimethylacetamide solvent using 5 to 10 equivalents of acetyl chloride. The method of claim 1, wherein the reaction (c) is performed in the presence of a solvent selected from dimethylformamide and dimethylacetamide, and an inorganic base selected from sodium carbonate and potassium carbonate. The method according to claim 1, wherein the reaction with (d) 1,3-dichloro-2-propanol is carried out in the presence of caustic soda (NaOH) and a catalytic amount of alcohol. The method of claim 1, wherein the (d) deprotection reaction is performed using an alcohol solvent and a strongly acidic DOWEX-50 ion exchange resin. 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) the pH of the solution purified by the ion exchange resin was adjusted to 4.9 to 5.1 with aqueous hydrochloric acid, and the aqueous solution was concentrated 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. Compound represented by the following formula (6), characterized in that it is useful as an intermediate for synthesizing iodixanol represented by the formula (1): [Formula 1] [Formula 6]