KR100574087B1 - Process for the preparing Iodixanol as X-ray contrast media - Google Patents

Abstract

The present invention relates to a method for preparing iodisanol, and more particularly, in the preparation of iodisanol represented by the following general formula (1) by a dimerization reaction using epichlorohydrin to a compound represented by the following general formula (3), Specific reaction conditions such as selective use of specific reaction solvents and dimerization reaction catalysts were specifically designed to minimize the formation of by-products, and after the dimerization reaction, non-ionic X-rays were passed through an efficient purification process without dissociation of iodine. The present invention relates to a method for economically preparing iodixanol used as an angiography agent.

Iodixanol, nonionic X-ray contrast agent, 5,5 '-[(2-hydroxytrimethylene) -bis (acetylimino)]-bis (2,3-dihydroxypropyl) -2 , 4,6-triiodoisophthalamide

Description

Process for the preparing Iodixanol as X-ray contrast media}

The present invention relates to a method for preparing iodisanol, and more particularly, in the preparation of iodisanol represented by the following general formula (1) by a dimerization reaction using epichlorohydrin to a compound represented by the following general formula (3), Specific reaction conditions such as selective use of specific reaction solvents and dimerization reaction catalysts were specifically designed to minimize the formation of by-products, and after the dimerization reaction, non-ionic X-rays were passed through an efficient purification process without dissociation of iodine. Iodixanol (Iodixanol) to be used as an angiographic agent relates to a method of economically manufacturing.

Contrast medium refers to a diagnostic agent used to obtain a clear X-ray of a target organ or tissue by injecting it into a region that is difficult to take by simple X-ray.

 As an X-ray angiography agent, Iodixanol, a nonionic dimer derivative currently on the market, has an excellent effect on contrast of cardiovascular, arterial, cerebrovascular, abdominal vessels, urinary tract and veins. In addition, it was developed in 1983 by Nycomed (US Patent No. 108,638; US Patent No. 5,824,821) as a very useful compound for CT contrast enhancement and peripheral arterial 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 the iodixanol derivatives, the compound represented by the following general formula (1), namely, 5,5 '-[(2-hydroxytrimethylene) -bis (acetylimino)]-bis (2,3-dihydroxy Propyl) -2,4,6-triiodoisophthalamide has an excellent effect on cardiovascular imaging.

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, EP-A-108,638 performed dimerization under basic conditions using epichlorohydrin. However, in the above dimerization reaction conditions, the conversion to iodisanol is very low (40 to 60%), and is produced by generating a large amount of by-products due to a plurality of hydroxyl groups and amide groups present in the compound represented by Formula 3 above. The yield is very low, below 20%. On the industrial scale, after the dimerization reaction under the above conditions, the product of the required content cannot be purified by conventional crystallization techniques, and the expensive purification method (liquid chromatography) is the only method of obtaining pure product. There are many limitations in applying the method to the process of.

In addition, Priv et al . Proposed a preparation method that does not require a complicated purification step such as EP 108,638 [Priebe et al ., Acta Radiol . 36 (1995), Suppl. 399 , 21-31. However, the method proposed by Priv et al. Proceeds with several reaction steps from 5-nitroisophthalic acid, and particularly includes a conversion reaction to thionyl chloride which is highly corrosive by chlorination reaction. In addition, since expensive iodine reagents are introduced at the initial stage of production, they cannot be said to be economical methods, and the yield and final purification method are not described at all.

In addition, US Pat. No. 6,232,499 discloses a technique of improving the production yield by 30% using 2-methoxyethanol as a solvent in order to increase the solubility of the reactants. However, this method is also not industrially suitable because the reason why the production yield did not reach a satisfactory level is due to side reactions caused by a plurality of hydroxyl groups present in the compound represented by Formula 3, as mentioned above. .

As a recently released technique, a method of synthesizing a compound represented by the above formula (3) which is not reacted in a dimerization batch during the preparation of iodisanol and recovering it is reused in a subsequent batch. [Korean Patent Publication No. 2001-0102005, International Patent Publication WO 2000/47549]. This reaction is based on dissolving the compound represented by Chemical Formula 3 in a caustic soda solution in a non-aqueous solvent such as 2-methoxyethanol or methanol, even though the compound represented by Chemical Formula 3 is recovered. The ratio of conversion to knol is very low, such as 5.1%, and the ratio of conversion of the compound represented by the formula (3) to iodisanol is not more than 40 to 60% through industrial continuous batch, and there is a limit to increase the production yield. There is a disadvantage that can not suppress the production of by-products.

The production techniques of iodixanol reported so far have focused on improving the dimerization process of iodixanol and the separation and purification of the synthesized iodisanol. In other words, the 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, thereby acting as a factor in raising the price of the product. Focused on improvement. In particular, in the separation and purification process of iodisanol, iodine, which is characteristically bound in the molecule as an X-ray angiography agent, may be dissociated and thus may be an important cause of a fatal life threat, thereby minimizing free iodide expression of iodine. Technology can be 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 production of the compound represented by the formula (1) and the development of low-cost manufacturing cost is urgently required have.

An object of the present invention is to provide a method for producing iodixanol in high yield by the dimerization reaction of the compound represented by the formula (3).

Another object of the present invention is to provide a method for separating and purifying high purity iodixanol from an iodisanol crude product through an efficient purification process without dissociation.

The present invention is a method for producing an iodisanol represented by the following formula (1) by dimerization of the compound represented by the following formula (3),

The dimerization reaction is characterized in that it is carried out under the conditions using epichlorohydrin, caustic soda base, magnesium acetate (Mg (OAc) ₂ ) catalyst and an alkoxyalcohol solvent.

[Formula 1]

In addition, the present invention is obtained by dissolving the crude product of iodisanol obtained as a result of the above-mentioned dimerization reaction in ethanol and then adding isopropanol as a precipitate, which is filtered through activated carbon, HP-20, XAD-2 and XAD- Another feature of the purification method of iodisanol is purified by passing through the ion exchange resin column selected from four.

Referring to the present invention in more detail as follows.

The present invention is a reaction catalyst and reaction in a known method for preparing the iodisanol represented by the formula (1) by performing a dimerization reaction of the compound represented by the formula (3) under conditions using epichlorohydrin and caustic soda base The reaction conditions by the selection of the solvent are uniquely configured, which has the biggest characteristic in technical construction. In other words, in the dimerization reaction according to the present invention, epichlorohydrin and caustic soda base are used, but magnesium acetate (Mg (OAc) ₂ ) is selected as a catalyst for the dimerization reaction, and as the reaction solvent, By selecting and using an alkoxy alcohol having excellent solubility in the compound represented by 3, it was possible to synthesize iodisanol at a high yield even at a temperature of 10 ° C to 30 ° C, particularly at room temperature.

The dimerization reaction according to the invention is carried out under conditions using epichlorohydrin, caustic soda base, magnesium acetate (Mg (OAc) ₂ ) catalyst and alkoxyalcohol solvent. The alkoxyalcohol solvent used by this invention is a C2-C10 aliphatic alkoxy alcohol compound, Especially preferably, 2-methoxy ethanol is used.

To explain the dimerization reaction according to the present invention in more detail, after adding powdered caustic soda to the alkoxyalcohol solvent and dissolving epichlorohydrin and a catalytic amount of magnesium acetate (Mg (OAc) ₂ ), Chemical Formula 3 To the compound represented by the addition is carried out under the conditions of stirring at room temperature.

Based on 1.0 equivalent of the compound represented by Formula 3, the amount of the compound used in the dimerization reaction is as follows. Epichlorohydrin is used in the range of 1.0 to 3.0 equivalents. Caustic soda (NaOH) may be used in an amount that can adjust the pH of the reaction solution in the range of 9 to 12, using an amount corresponding to about 2.0 to 3.0 equivalents. Magnesium acetate uses a catalytic amount and an amount corresponding to approximately 10 to 30% by weight. Alkoxy alcohol is to be used within the range of 5 to 10 volume ratio.

The dimerization reaction is carried out under stirring conditions for 3 to 5 days at a temperature of 10 ℃ to 30 ℃, when the above-mentioned dimerization reaction is terminated, the pH of the reaction mixture is acidified to 3 to 4 and distilled under reduced pressure Obtain the sanol crude product.

On the other hand, the present invention is also characterized by a method for purifying an iodisanol crude product obtained as a result of the dimerization reaction.

In the purification method according to the present invention, after dissolving the crude product of iodisanol obtained in ethanol and crystallizing with isopropanol to obtain a precipitate, activated carbon filtration and ion exchange resin such as HP-20, XAD-2 or XAD-4 It consists of a column passing, thereby recovering the desired iodisanol in high purity by a more efficient purification method without dissociation of iodine (I). In more detail, ethanol is added to the crude iodisanol product, the mixture is stirred at a temperature of 80 ° C. to 90 ° C. for 1 to 2 hours, and then cooled to room temperature. 5-10 volume ratio of isopropanol is added to the reaction, and it stirred at room temperature for 3 to 4 hours, and a white solid precipitate is produced. The resulting precipitate is filtered, dissolved in water, 3 to 10% by weight of activated carbon is added, stirred at room temperature for 3 to 5 hours, filtered to remove the activated carbon and concentrated under reduced pressure to obtain iodisanol. As a result of performing the purification process by the dimerization reaction and crystallization, iodisanol was obtained in a yield of 90 to 95%, and the purity confirmed by HPLC was 90%.

More preferably, the purification method according to the present invention is filtered through the activated carbon and then purified by passing through an ion exchange resin such as HP-20, XAD-2 or XAD-4. By treating the iodisanol solids with ion exchange resins such as HP-20, XAD-2 or XAD-4, other product salts that might be contained in the crystals could be removed. As a result of the above-mentioned dimerization reaction and purification process by crystallization and passage of ion exchange resin, pure iodisanol was obtained in high yield of 60% or more, and the purity confirmed by HPLC was 99.2% or more.

Activated carbon filtration or ion exchange resin treatment method to be performed to purify iodisanol by the present invention is a general purification method, but the present invention is a low-cost ion exchange resin (HP-20, XAD-2 or XAD-4 Pure iodinanol using the ion exchange resin treatment method, which is a chemical separation method, rather than the expensive equipment used in the conventional separation method (the separation method using a high capacity MPLC). It has its characteristics.

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

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

0.79 g of powdered caustic soda was added to 30 mL of 2-methoxyethanol, and the mixture was stirred and dissolved. 7.47 g of 5-acetamino-N, N-bis (2,3-dihydroxypropyl) -2,4,6-triiodo-isophthalamide (Formula 3) were added to the mixture and stirred for 30 minutes at room temperature. It was. 0.87 g of epichlorohydrin and 1.5 g of magnesium acetate were added to the reaction, followed by stirring at room temperature for 4 days. After confirming that the reaction was completed, the reaction mixture was acidified (pH 3-4) with 20% hydrochloric acid aqueous solution, and then the reaction solvent was concentrated under reduced pressure to obtain an iodisanol crude product.

150 mL of ethanol was added to the crude iodisanol product, and the mixture was stirred at a temperature of 80 ° C. for 3 hours. After cooling the reaction, 500 mL of ispropanol was added and stirred at room temperature for 5 hours to form a white precipitate. The resulting precipitate was filtered off and washed with isopropanol. The filtered solid was dissolved in 50 mL of water, 0.7 g of activated carbon was added thereto, stirred at room temperature for 3 hours, the reaction mixture was filtered to remove the activated carbon, and concentrated under reduced pressure to obtain 7.36 g (95% yield) of iodisanol. . (75% purity confirmed by HPLC)

It was then passed through a 100 mL HP-20 ion exchange resin column to give 5.1 g (65.1% yield) of pure iodisanol. (99.1% purity confirmed by HPLC) In addition, pure iodisanol was obtained in a yield of 67% when passing through the XAD-2 ion exchange resin column instead of the HP-20 ion exchange resin column. (Pure 99.3% as confirmed by HPLC). In addition, when passed through an XAD-4 ion exchange resin column, pure iodisanol was obtained in a yield of 68%. (Pure 99.5% confirmed by HPLC).

The solution of the separated iodisanol crude product was concentrated under reduced pressure, and 200 mL of isopropanol was added to the remaining surplus and stirred at room temperature for 1 hour. The resulting precipitate was filtered, washed with 50 mL of isopropanol and dried under reduced pressure to give 5.0 g (65.0% yield) of pure iodisanol. (99.2% purity confirmed by HPLC)

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 1.5 mL / min, Temp 40 ℃, Detector UV 254 nm, Retention time 7.34 (58.3%), 7.50 (38.0%), 7.80 (2.7%), 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

In the method for preparing iodisanol according to the present invention, a small amount of magnesium acetate was added as a catalyst during the dimerization reaction of the compound represented by Chemical Formula 3 to obtain a sufficient inhibitory effect on the formation of by-products, and as a purification method, By using ion exchange resins such as cheap HP-20, XAD-2, or XAD-4, sufficient separation and purification efficiency can be obtained, and the eye represented by Chemical Formula 1 in higher yield and higher purity than any known method so far disclosed. It's an economical way to get the benefits of Iodixanol.

Claims (7)

In the method for producing iodisanol represented by the following formula 1 by dimerization of the compound represented by the following formula (3), The dimerization reaction is carried out under the conditions using epichlorohydrin, caustic soda base, magnesium acetate (Mg (OAc) ₂ ) catalyst and an alkoxyalcohol solvent. [Formula 3]

[Formula 1]

The method for preparing iodisanol according to claim 1, wherein the dimerization reaction solvent is performed using 2-methoxyethanol. The method of claim 1, wherein the dimerization reaction is carried out at a temperature range of 10 ° C to 30 ° C. The method of claim 1, wherein the dimerization reaction is performed at a pH of 9 to 12. The method of claim 1, wherein after the completion of the dimerization reaction, the pH of the reaction mixture is adjusted to a range of 3 to 4 to obtain an iodisanol crude product. The method according to any one of claims 1 to 5, After dissolving the crude product of iodisanol obtained as a result of the dimerization reaction in ethanol, isopropanol was added to form a precipitate, The production method characterized in that the purified by filtering the produced precipitate with activated carbon. 7. The method according to claim 6, wherein the filtrate is further purified by passing through one or two or more ion exchange resin columns selected from HP-20, XAD-2 and XAD-4.