KR100294621B1 - Manufacturing method of Iopamidol - Google Patents

Abstract

In the present invention, in preparing iopamidol of Chemical Formula 1 according to Scheme 1, Step 1 of reacting 5-aminoisophthalic acid of Chemical Formula 6 with KICl ₂ in the presence of a catalytic amount of iodine is carried out in lactic acid. Toluene was added to remove water by azeotropic distillation, and then 0-acetyllactic acid chloride prepared by reacting acetic anhydride with acetic acid and thionyl chloride was reacted with 5-amino-2,4,6-triiodoisophthalic acid chloride of the formula (4). It relates to a method characterized by sikkim.

Description

How to prepare Iopamidol

The present invention relates to an improved method for preparing iopamidol.

Known methods for preparing iopamidol, which are widely used as X-ray contrast agents, include L-5- (2-acetoxypropionylamino) -2,4,6-triiodoisophthalic acid halide and 2-amino-1 The method of Savac AG, Switzerland (BP1,472,050), which is prepared by amidation of, 3-propanediol ("serinol") in a dimethylacetamide solvent in the presence of a basic substance, is known. Studies on the synthesis of phosphorus 5-amino-2,4,6-triiodoisophthalic acid have been actively conducted.

However, these known methods not only require several filtration and drying processes in the manufacturing process, but also have caused serious pollution problems due to reaction by-products of iodine, resulting in lowered yields due to such complex processes.

Thus, the present inventors divided the above known methods into stages and compared and studied the reaction conditions of each process in various ways. As a result, the present invention confirmed the simplification of the innovative process and the improvement of the yield and completed the present invention.

As a known method for preparing iopamidol represented by Chemical Formula 1, a representative method may be represented by the following Scheme 1.

However, in the preparation method according to Scheme 1, the iodide reaction of the first step of preparing the compound of Formula 5 by reacting KICl ₂ with the compound of Formula 6 uses KICl ₂ prepared according to Scheme 2 below. Since the iodine anion is in an equilibrium state as in Scheme 3, iodine is generated and released in the reaction system, thereby reducing the effective concentration of iodine dichloride.

To prevent this phenomenon, the addition of excess HCl to the reaction liquid can cause the equilibrium to be shifted to the left, increasing the concentration of iodine dichloride anion, whereas 5-amino, which is a reactive group of aromatic electrophilic substitution reaction due to the presence of excessive acid. Isophthalic acid is protonated, resulting in poor reactivity. Therefore, the present inventors have tried to develop a method capable of properly maintaining the concentration of iodine dichloride ion in the reaction solution, and as a result, the addition of a catalytic amount of I ₂ in the reaction system can achieve this purpose. It has been found that the iodide reaction can be easily carried out from the compound with the compound of formula 5.

As such, when the catalytic amount of iodine is added, the yield of the compound of Formula 5 may be increased from 85% to 96% or more, and the improvement of the yield is difficult to predict easily. Therefore, a feature of the present invention is that the yield of the compound of formula (5) is improved by adding a catalytic amount of I ₂ to the starting compound (6) together with KICl ₂ .

Another feature of the present invention lies in the improvement of the manufacturing process 3 in the known production method according to Scheme 1. That is, when amidation of 5-amino-2,4,6-triiodoisophthalic acid chloride, a compound of Formula 4, with 0-acetyllactic acid chloride, there is a high possibility that racemization occurs, especially when a base catalyst is used. This racemization is accelerated. Enantiomers produced by racemization affect physical properties such as optical activity, biochemical activity, and solubility in water of the final compound. Therefore, the use of tertiary amines should be suppressed to minimize racemization. This lowers and the yield decreases cannot be avoided.

In order to solve this problem, the inventors of the present invention, while studying to develop a reactant that can be maintained without the use of a tertiary amine, sufficient time at room temperature using 0-acetyl lactic acid chloride dissolved in excess toluene It was confirmed that the reaction can be completed by the reaction. 0-acetyllactic acid chloride dissolved in excess toluene can be prepared according to Scheme 4 below.

That is, the starting material lactic acid contains about 8% of water, the low amount of acetylation by the presence of a small amount of water in this way. Therefore, the present inventors have tried to devise a method of acetylation while removing water in lactic acid, and as a result of this effort, lactic acid was azeotropically distilled in toluene to remove water, reacted with acetic anhydride and acetic acid, and then distilled It was surprisingly found that removal of acetic acid and reaction with thionyl chloride can increase the yield from 50% to over 80% in preparing 0-acetyllactyl chloride. Moreover, in the past, since the yield was low at about 50%, the prepared 0-acetyllactic acid chloride had to be separated once by vacuum fractional distillation and then used in the next reaction. It is now possible to carry out the next process directly without being dissolved in toluene. In the process 3 according to the present invention, 0-acetyllactic acid chloride prepared according to the above method is preferably used in an amount of 1.5 to 1.8 equivalents based on 5-amino-2,4,6-triiodoisophthalic acid chloride of the formula (4). . In addition, the compound of the formula (3) thus obtained is surprisingly stable against water, and thus it is possible to separate and purify using water.

Accordingly, the present invention is to prepare the iopamidol of the formula (1) according to Scheme 1, the step 1 of reacting 5-aminoisophthalic acid of formula 6 and KICl ₂ in the presence of a catalytic amount of iodine and in the step 3 to lactic acid Toluene was added to remove water by azeotropic distillation, and then 0-acetyllactic acid chloride prepared by reacting acetic anhydride with acetic acid and thionyl chloride was reacted with 5-amino-2,4,6-triiodoisophthalic acid chloride of the formula (4). It is an object of the present invention to provide a method characterized by the use of the system. In particular, according to a preferred embodiment of the present invention, the amount of iodine added in step 1 is preferably 1 to 5% by weight relative to 5-aminoisophthalic acid.

Other processes in addition to the characteristic process according to the present invention can be carried out according to a known method, for example, process 2 is a 5-yl-2,4,6-triiodoisophthalic acid of the formula (5) thionyl chloride It is a process of preparing acid halide by reacting with, and there is no difficulty in synthesis, but it requires reaction conditions that use a minimum amount of thionyl chloride as a method of minimizing the discharge of environmentally harmful gases or treatment of waste due to industrialization. The reaction of step 2 may use only an excess of thionyl chloride without a solvent or a solvent such as DMF, DMA, ethyl acetate, etc. as a reaction solvent, but in the present invention, it is cheaper while using a minimum amount of thionyl chloride. Reaction conditions using ethyl acetate as a solvent were established. In addition, by using this solvent for recrystallization of the product, it was possible to recrystallize with an excellent recovery rate of 95%.

In step 4, N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -2,4,6-triiodo-5- (0-acetyl of the formula (2) which is a precursor of iopamidol In order to synthesize-(S) -lactamido) isophthalamide, the compound of formula 3 produced in step 3 is reacted with cerinol. Serinol is a primary amine with greater nucleophilicity than water molecules and can be completed by allowing sufficient reaction time. In addition, in the past, triethylamine was used as a base to capture HCl generated during the reaction, but in the present invention, 2,6-lutidine was used as a base, thereby preventing a small amount of side reactions caused by triethylamine. By doing this, the iopamidol precursor could be obtained with high purity.

In step 5, the hydrolysis of the ester bond can be easily carried out in the presence of an acid or a base, and in the present invention, the hydrolysis step was performed by using calcium hydroxide as a base in consideration of the removal of various hydrophilic inorganic salts produced as by-products during the reaction. . That is, when sulfuric acid is added to the reaction solution after the reaction is completed, calcium ions are precipitated as calcium sulfate, which is generally small in water solubility.

After the reaction is completed, various separation and purification methods can be performed to obtain the desired iopamidol in its pure state. For example, the amine impurities remaining in the reaction mixture exist as ammonium cations under acidic conditions, so they are treated with cation exchange resins to remove organic amines and inorganic cations, and anion exchange resins to remove anion impurities. You can get a stone. In addition, crystalline iopamidol can be obtained by performing recrystallization in ethanol.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Example 1 Synthesis of Potassium Iodide Dichloride Solution (2.1M KICl ₂ solution)

100 ml of concentrated hydrochloric acid (0.1 mol) was added to a mixture of 75.Og (0.35 mol) of potassium iodide, 42.Og (0.56 mol) of potassium chloride, 1 g of catalytic amount of iodine and 9O ml of water, and stirred well to prepare a white dispersion mixture. It was. The mixture was vigorously stirred with a mechanical stirrer and slowly added an aqueous solution of 116.6 g (0.07 mol) of potassium iodide in 100 ml of water and concentrated hydrochloric acid (conc. HCl, 180 ml, 1.8 mol) simultaneously to form a pale yellow dispersion. It became a dark yellow solution. At this time, potassium iodide solution is added at a speed such that black iodine is not produced, and takes about 1-2 hours. The mixture was continuously stirred to prepare a dark red solution. After stirring for 30 minutes at room temperature, water was added so that the volume of the total solution was 500 ml to obtain 2.1 M potassium iodide dichloride (KlCl ₂ ) solution. .

Example 2 Synthesis of 5-amino-2,4,6-triiodoisophthalic acid

30.84 g (0.16 mol) of 5-aminoisophthalic acid was dispersed in 1,250 ml of water to prepare a light yellow dispersion. A catalytic amount of iodine (1 g) was added thereto, followed by heating to maintain 60 ° C. 250 ml (2.1 M) of potassium iodide dichloride solution obtained in Example 1 was added dropwise to this dispersion over 1 hour, and reacted at 60 degreeC for 18 hours. The resulting pale brown dispersion was cooled to room temperature, again cooled in an ice bath and filtered. The wet solid product was air dried until no more filtrate flowed out and then dissolved in aqueous potassium hydroxide solution (0.66 M, 300 mL). 3.Og of activated carbon was added thereto, the pH was lowered to 7.0, decolorized, filtered, and the activated carbon was washed with water (20 mL × 2). The filtrate was added slowly with concentrated hydrochloric acid while stirring vigorously to prepare a dispersion and the pH was adjusted to 1.0-2.0. The mixture was cooled at 0-5 [deg.] C., filtered and the resulting solid was dried in vacuo at 60 [deg.] C. to give 86.Og (96% yield) of a light brown solid title compound.

¹³ C NMR (75 MHz, DMSO) δ 170.3, 150.5, 147.4, 77.4, 70.7

Example 3 Synthesis of 5-amino-2,4,6-triiodoisophthalic acid chloride

65.O1 g (0.116 mol) of 5-amino-2,4,6-triiodoisophthalic acid obtained in Example 2 was dispersed in 420 ml of ethyl acetate. 55.2 g (0.46 mol) of thionyl chloride was slowly added to the dispersion, and the resulting mixture was heated to reflux for 3-4 hours and then cooled to room temperature. Excess thionyl chloride and solvent were removed by distillation, and 135 ml of ethyl acetate was added to the distillation residue, followed by distillation under reduced pressure to completely remove volatile components. 940 ml of ethyl acetate was added to the evaporated residue, followed by dissolution. The mixture was washed with 1.12 L of saturated aqueous sodium bicarbonate solution and then with 0.6 L of saturated aqueous sodium bicarbonate solution, and then the organic layer was separated. The separated organic layer was dried over 200 g of anhydrous potassium carbonate-anhydrous magnesium sulfate (1: 1, w / w) mixed desiccant and filtered to obtain a clear filtrate. The solvent in the filtrate was crystallized while slowly evaporating under reduced pressure (730 mmHg), then filtered and the obtained crystals were washed with about 20 g of n-hexane. Vacuum drying at 50 ° C. gave the primary product (52.4 g, 80% yield). The procedure was repeated again for the filtrate obtained in the previous step to give a secondary product (13.2 g, 15%, 95% overall yield).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.5, 150.5, 149.2, 84.9, 79.1

Example 4 Synthesis of 0-Acetyl- (S) -Lactic Acid Chloride

Toluene 900ml was added to 295g (3.Omol) of 92%-(S) -lactic-acid aqueous solution, and water was removed by azeotropy at 85-88 degreeC and vacuum. 1000 ml of acetic acid and a catalytic amount of concentrated sulfuric acid (98% -H ₂ SO ₄ , 0.7g) ol were added to the solution and heated to about 90 ° C. 617 g (6.O5 mol) of acetic anhydride was added over 1 hour, followed by heating. The temperature of was raised to 105 ° C. Continuously refluxing for 7 hours leads to 116 ° C. Acetic acid was removed by distillation under reduced pressure, and DMF (0.28 g) was added to the resulting 0-acetyl- (S) -lactic acid and heated to 60 ° C. When 395 g (3.3 mol) of thionyl chlorides were dripped here over 2 hours, it reached 70 degreeC, and further heated for 3 hours after that. Excess thionyl chloride was removed by distillation under reduced pressure at 60 DEG C to give 430.1 g (80% yield) of the title compound as a colorless transparent.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 5.11 (q, J = 7.2 μs, 1H), 2.09 (s, 3H), 1.54 (d, J = 7.2 μs, 3H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.6, 169.7, 74.8, 20.4, 15.9

Example 5 Synthesis of 5-[(0-acetyl)-(S) -lactamido] -2,4,6-triiodoisophthalic acid chloride

40.Og (0.067 mol) of 5-amino-2,4,6-triiodoisophthalic acid chloride obtained in Example 3 was dissolved by adding 40 g of anhydrous DMA and cooled in an ice bath. While stirring the resulting mixture, 40.96 g (0.27 mol) of 0-acetyl- (S) -lactic acid chloride dissolved in toluene obtained in Example 4 was slowly added dropwise over 4 hours and reacted for another 10 hours. While slowly stirring the ice water (1 L), the reaction mixture was slowly added dropwise to prepare a white dispersion, which was further stirred for about 15 minutes. The white solid was filtered and stirred with 20 ml of acetonitrile to prepare a dispersion. The white solid product was filtered again, washed with toluene (20 mL × 2), air dried and vacuum dried at 50 ° C. to give 45.22 g (95% yield) of the title compound.

¹ H-NMR (300 MHz, (CD ₃ ) ₂ CO) δ 9.51 (bs, 1H), 5.38 (q, J = 6.9 ㎐, 1H), 2.15 (s, 3H), 1.59 (d, J = 6.9 ㎐ , 3H);

¹³ C NMR (75 MHz, (CD ₃ ) ₂ CO) δ 170.0, 169.5, 169.4, 151.7, 145.5, 98.2, 83.0, 70.7, 20.9, 17.9

Example 6 N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -2,4,6-triiodo-5- (0-acetyl- (S) -lactamido Synthesis of Isophthalamide

Under nitrogen atmosphere with light blocking, 4.Og (0.044 mol) of cerinol was dissolved in 28 g of DMA and 5.8 g (0.054 mol) of 2,6-lutidine was added to the solution. Into this stirred solution, 12.52 g (0.18 mol) of 5-[(0-acetyl)-(S) -lactamido] -2,4,6-triiodoisophthalic acid chloride obtained in Example 5 was added to 65 g of DMA. The solution dissolved in was slowly added dropwise at room temperature over 4 hours, and the mixed solution was further reacted for about 20 hours. The resulting salt in the reaction mixture was filtered and washed with 5 g of DMA (dimethylacetamide). The filtrate was distilled under vacuum and crystallized by adding 100 g of acetone to the remaining solid. The resulting white solid was filtered, washed with about 10 g of acetone, and dried under reduced pressure to obtain 17.3 g (yield 100%, purity 83%) of the title compound as a white powder.

¹ H-NMR (300 MHz, D ₂ 0) δ 5.35 (q, J = 6.9 Hz, 1H), 4.17 (q, J = 5.1 Hz, 2H), 3.83 (bd, J = 5.1 Hz, 8H), 2.23 (s, 3H), 1.71 (d, J = 6.9 Hz, 3H);

¹³ C NMR (75 MHz, D ₂ 0) δ 174.7, 173.41 and 173.21, 172.65 and 172.56 and 172.48, 150.0, 142.3, 98.39 and 98.29, 89.9, 71.7, 59.3, 54.80 and 54.59, 21.O5 17.8;

Example 7 of N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -2,4,6-triiodo-5-lactamide isophthalamide (iofamido) synthesis

Dissolve 1.31 g (93% assay, 0.022 mol) of calcium hydroxide in 80 g of water to prepare a white suspension, wherein the N, N'-bis [2-hydroxy-1- (hydroxymethyl) obtained in Example 6 was obtained. Ethyl] -2,4,6-triiodo-5- (0-acetyl- (S) lactamido) isophthalamide 19.67g (83% purity, 0.02Omol) was dissolved in the reaction by heating and stirring at about 30 ℃ Proceeded. The contents were analyzed by TLC and HPLC and reacted until the start was gone. 2.5 g (0.24 mol) of concentrated sulfuric acid was slowly added to the reaction mixture, and the resulting solid was stirred for about 1 hour, and then filtered and washed twice with 600 L of water. 1N oxalic acid solution (10.Ommol) was added to the filtrate and maintained at pH 1.1 ± 0.1 for 10 hours or longer. Then, 1 g of powdered activated carbon was added and stirred for 1 hour. The reaction mixture was filtered and washed with 30 ml of water. The filtrate was passed through a cationic resin column (50 ml of resin) and an anion resin column (100 ml of resin), followed by HP-2O decolorizing resin to obtain a colorless transparent solution. This colorless transparent developing solution was distilled under reduced pressure at 45-50 ° C. to completely remove water to obtain a glassy solid. The solid product was recrystallized in ethanol and dried to give 16.23 g (95%) of white crystalline iopamidol.

¹ H-NMR (300 MHz, D ₂ 0) δ 4.33 (q, J = 6.9 Hz, 1H), 3.984 (quintet, J = 5.3 Hz, 2H), 3.66 (bd, J = 5.3 Hz, 8H), 1.40 (d, J = 6.9 Hz, 3H);

¹³ C-NMR (75 MHz, D ₂ 0) δ 177.56 and 177.34, 172.60 and 172.55 and 172.45, 149.95 and 149.88, 142.9, 98.82 and 98.71, 89.9, 68.9, 60.6, 53.92 and 53.85, 20.41

According to the manufacturing method of the present invention as described above, iopamidol, which is widely used as an X-ray contrast agent, can be effectively produced.

Claims (6)

In preparing the iopamidol of Chemical Formula 1 according to Scheme 1, Process 1 of reacting 5-aminoisophthalic acid of Chemical Formula 6 with KIC1 ₂ was carried out in the presence of 1 to 5% by weight of iodine relative to 5-aminoisophthalic acid. In step 3, toluene is added to lactic acid to remove water by azeotropic distillation, and then a solution of 0-acetyl lactic acid chloride toluene prepared by acetic anhydride, acetic acid and thionyl chloride, and 5-amino-2,4,6-tri represented by the formula (4) Characterized by reacting iodoisophthalic acid chloride. Scheme 1 The process of claim 1 wherein process 2 is carried out using a minimum of thionylchloride and ethyl acetate solvent. The process according to claim 1 or 2, characterized in that 0-acetyllactic acid chloride prepared from lactic acid is used directly in the reaction of Step 3 without separating and purification. The process according to claim 1 or 2, characterized in that in step 3 0-acetyllactic acid chloride is used at 1.5 to 1.8 equivalent times of 5-amino-2,4,6-triiodoisophthalic acid chloride of the formula (4). Way. The process according to claim 1 or 2, characterized in that in step 4 2,6-lutidine is used as the base. The process according to claim 1 or 2, wherein in step 5, impurities are removed using cation and anion exchange resin and recrystallized iopamidol using ethanol.