WO2025014292A1 - Method of preparing intermediates for synthesizing xanthine oxidase inhibitor - Google Patents

Abstract

The present invention relates to a method of preparing intermediates for synthesizing a xanthine oxidase inhibitor and, more specifically, to a method of efficiently preparing a compound of chemical formula 3 through a work-up process using ammonia water and citric acid.

Description

Method for preparing intermediates for the synthesis of xanthine oxidase inhibitors

The present invention relates to a method for producing an intermediate for synthesizing a xanthine oxidase inhibitor, and more specifically, to a method for efficiently producing a compound of the following chemical formula 3 through a work up process using ammonia water and citric acid:

[Chemical Formula 3]

In the above chemical formula 3, R1, R2, R3, R4 and R5 are as defined in the specification.

Xanthine oxidase is known as an enzyme that converts hypoxanthine into xanthine, and the formed xanthine into uric acid. Since uricase, which exists in most mammals, does not exist in humans and chimpanzees, uric acid is known as the final product of purine metabolism (S. P. Bruce, Ann. Pharm., 2006, 40, 2187~2194). Uric acid, which is maintained at a high concentration in the blood, causes various diseases, a representative example being gout.

As mentioned above, gout is a disease caused by high uric acid levels in the body, and uric acid crystals accumulate in the cartilage, ligaments, and surrounding tissues of the joints, causing severe inflammation and pain. Gout is a type of inflammatory joint disease, and its incidence has been steadily increasing over the past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587~2590).

Accordingly, various studies have been conducted to develop new xanthine oxidase inhibitors, and Korean Patent Publication No. 10-2011-0037883 discloses a novel compound having the following chemical formula, which is effective as a xanthine oxidase inhibitor:

.

.

In Korean Patent Publication No. 10-2011-0037883, which describes a conventional manufacturing step of 5-bromo-3-cyano-1-isopropyl-indole, an intermediate of the above-mentioned xanthine oxidase inhibitor, CsCO ₃ was used, which is inconvenient to use due to its low economic efficiency and high density. Therefore, there was a need to secure a substitute for it. In addition, since there was no established purification method, the organic layer obtained after the reaction and work up processes was concentrated and then the next reaction was performed right away. However, since it was not purified at this time, there was a problem that 5-bromo-3-cyano-1H-indole included in the reaction mixture acted as a causative substance that generated impurity in the next reaction, which adversely affected the product quality.

In addition, the existing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester manufacturing step has a very long reaction time of 35 to 48 hours, and the starting material, 5-bromo-3-cyano-1-isopropyl-indole, remains and various impurities are generated, which ultimately affect the raw pharmaceutical product, so improvement in terms of quality and yield was needed.

To solve the above problem, Korean Patent Publication No. 10-2023-0006408 discloses a manufacturing method using low-cost starting materials and ligands, and a chelating extraction purification technique.

In the above manufacturing method, the following schematic diagram is disclosed regarding the work up process after completion of the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester reaction.

In the above manufacturing method, a chelating agent such as citric acid or EDTA, which is used as a copper catalyst for the C-N coupling reaction, is used, and the pH is adjusted with HCl. However, the Cu removal rate, which is the purpose of introducing the work up process, is not constant, the work up is repeated in several stages, so the efficiency of the process is low, and a large amount of carbon dioxide is suddenly generated during the injection of HCl, so there may be a risk in terms of safety.

[Prior art literature]

[Patent Document]

Republic of Korea Patent Publication No. 10-2011-0037883

Republic of Korea Patent Publication No. 10-2023-0006408

Accordingly, the present invention has as its technical task the provision of an improved new manufacturing method capable of reproducibly purifying a copper catalyst and minimizing the number of work-up repetitions without pH control in the production of a compound of the following chemical formula 3, which is a key intermediate in the synthesis of a xanthine oxidase inhibitor:

[Chemical Formula 3]

In the above chemical formula 3, R1, R2, R3, R4 and R5 are as defined in the specification.

To solve the above problem,

A step of subjecting a compound of chemical formula 1 and a compound of chemical formula 2 to a C-N coupling reaction in an organic solvent with a copper catalyst, a base, and a ligand; and

A method for preparing a compound of formula 3 is provided, comprising the step of purifying the compound of formula 3 using 10 to 20 wt% of ammonia water (NH ₄ OH) or 10 to 20 wt% of ammonium chloride (NH ₄ Cl) aqueous solution and citric acid:

[Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

In the above chemical formula,

X is F, Cl, Br or I;

R1 is hydrogen or CN;

R2 is hydrogen, halogen, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy-C ₁ -C ₇ alkyl or It's phenyl;

이며, 여기에서 R6는 C₁-C₄ 알킬을 나타내고, W는 O 또는 S를 나타내며, R7은 수소 또는 C₁-C₄ 알킬을 나타내고, n은 0 내지 3의 정수이며;R3 is hydrogen; C ₁ -C ₇ alkyl which is unsubstituted or substituted by one or more substituents selected from halogen, C ₃ -C ₇ cycloalkyl and O-R6; C ₃ -C ₇ cycloalkyl; or

, wherein R6 represents C ₁ -C ₄ alkyl, W represents O or S, R7 represents hydrogen or C ₁ -C ₄ alkyl, and n is an integer from 0 to 3;

R4 is hydrogen, halogen or C ₁ -C ₇ alkyl;

R5 is -C(O)OR8, where R8 is hydrogen, C ₁ -C ₇ alkyl, or C ₃ -C ₇ cycloalkyl.

According to the manufacturing method of the present invention, the residual amount of copper catalyst in the manufactured compound of chemical formula 3 can be reproducibly maintained at a constant level of less than 50 ppm. According to the manufacturing method of the present invention, the number of repetitions of the work-up process can be reduced to three, thereby reducing the process time and the amount of waste liquid generated, thereby increasing the manufacturing efficiency. In addition, according to the manufacturing method of the present invention, the pH adjustment step can be omitted, and the rapid generation of carbon dioxide can be blocked, thereby increasing the process safety.

The present invention will be described in more detail below.

According to one specific embodiment of the present invention, the ligand may be selected from the group consisting of N,N-dimethylethylenediamine, tetramethylethylenediamine, 1,2-cyclohexanediamine, N,N'-dimethyl-1,2-cyclohexanediamine, 1,10-phenanthroline, and proline, but is not limited thereto. According to one specific embodiment of the present invention, the ligand may be N,N-dimethylethylenediamine. The amount of the ligand used may be 0.2-1.0 equivalents, or preferably 0.4 equivalents, relative to the weight of the compound of formula 1.

According to one specific embodiment of the present invention, the organic solvent may be selected from the group consisting of toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and mixtures thereof, but is not limited thereto. According to one specific embodiment of the present invention, the organic solvent may be toluene. The amount of the organic solvent used may be 4-fold (mL/g) to 8-fold (mL/g), preferably 4-fold (mL/g) to 6-fold (mL/g), relative to the weight of the compound of formula 1.

According to one specific example of the present invention, the copper catalyst may be selected from the group consisting of copper (I) iodide (CuI), copper (II) acetate (Cu(OAc) ₂ ), copper (Cu), copper (I) oxide (Cu ₂ O), copper (II) oxide (CuO), and mixtures thereof, but is not limited thereto. According to one specific example of the present invention, the copper catalyst may be CuI. The amount of the copper catalyst used may be 0.1 equivalent to 0.5 equivalent, preferably 0.1 equivalent to 0.3 equivalent, or more preferably 0.2 equivalent, relative to the weight of the compound of formula 1.

According to one specific example of the present invention, the base may be selected from the group consisting of potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), potassium phosphate tribasic (K ₃ PO ₄ ), triethylamine, sodium tert-butoxide, and mixtures thereof, but is not limited thereto. According to one specific example of the present invention, the base may be potassium carbonate. The amount of the base used may be 1 equivalent to 4 equivalents, preferably 1 equivalent to 3 equivalents, or more preferably 2 equivalents, relative to the weight of the compound of formula 1.

According to one specific embodiment of the present invention, 12 to 16 wt% of ammonia water (NH ₄ OH) can be used. According to one specific embodiment of the present invention, 15 wt% of ammonia water (NH _{4 OH) can be used. According to one specific embodiment of the present invention, 10 to 20 wt% of ammonium chloride (NH 4 Cl} ) can be used.

According to one embodiment of the present invention, 5 to 15 wt% of citric acid may be used. According to one embodiment of the present invention, 7 to 12 wt% of citric acid may be used. According to one embodiment of the present invention, 10 wt% of citric acid may be used.

According to one specific example of the present invention, a step of purifying the compound of formula 3 using purified water may be additionally included.

According to one specific example of the present invention, in the chemical formula, X may be Br, R1 may be CN, R2 may be hydrogen, R3 may be isopropyl, R4 may be hydrogen, and R5 may be ethoxycarbonyl (-C(O)OEt).

According to one specific example of the present invention, unlike the conventional method in which the removal efficiency deviation is large, the residual amount of copper catalyst in the manufactured compound of chemical formula 3 can be reproducibly maintained at a constant level of less than 50 ppm. More specifically, when using ammonia water (NH ₄ OH), it can be maintained at a constant level of less than 1 ppm, or when using an ammonium chloride (NH ₄ Cl) aqueous solution, it can be maintained at a constant level of less than 50 ppm.

According to one specific example of the present invention, the amount of waste liquid generated in a manufacturing method can be reduced, and the rapid generation of carbon dioxide can be blocked, thereby increasing the stability of the process.

Hereinafter, the present invention will be described more specifically through examples. However, the following examples are provided only to help understand the present invention, and the scope of the present invention is not limited thereto.

Example 1

5-Bromo-3-cyano-1-isopropyl-indole (100.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (58.6 g), K ₂ CO ₃ (105.1 g), and toluene (400 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (14.5 g) and N,N-dimethylethylenediamine (DMEDA) (13.4 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming that the reaction is completed under reflux conditions, cool to 30-40°C, add 15% (w/w) ammonia water (NH ₄ OH) (400 ml) and ethyl acetate (EtOAc) (400 ml), stir and leave for 30 minutes each, and then remove the water layer. Add 10 wt% citric acid (400 ml), stir and leave for 30 minutes each, and remove the water layer. Finally, add purified water (400 ml), stir and leave for 30 minutes each, and remove the water layer. The organic layer thus obtained was distilled as much as possible, then isopropyl alcohol (IPA) (500 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (400 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Example 2

5-Bromo-3-cyano-1-isopropyl-indole (400.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (234.3 g), K ₂ CO ₃ (420.2 g), and toluene (1,600 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (57.9 g) and N,N-dimethylethylenediamine (DMEDA) (53.6 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming that the reaction is completed under reflux conditions, cool to 30-40°C, add 15 wt% ammonia water (NH ₄ OH) (1,600 ml) and ethyl acetate (EtOAc) (1,600 ml), stir and leave for 30 minutes each, and then remove the water layer. Add 10 wt% citric acid (1,600 ml), stir and leave for 30 minutes each, and remove the water layer. Finally, add purified water (1,600 ml), stir and leave for 30 minutes each, and remove the water layer. The organic layer thus obtained was distilled as much as possible, then IPA (2,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (1,600 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Example 3

5-Bromo-3-cyano-1-isopropyl-indole (1,600.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (937.3 g), K ₂ CO ₃ (1,680.8 g), and toluene (6,400 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (231.6 g) and N,N-dimethylethylenediamine (DMEDA) (214.4 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming that the reaction is completed under reflux conditions, cool to 30-40°C, add 15 wt% ammonia water (NH ₄ OH) (6,400 ml) and ethyl acetate (EtOAc) (6,400 ml), stir and leave for 30 minutes each, and then remove the water layer. Add 10 wt% citric acid (6,400 ml), stir and leave for 30 minutes each, and remove the water layer. Finally, add purified water (6,400 ml), stir and leave for 30 minutes each, and remove the water layer. The organic layer thus obtained was distilled as much as possible, then IPA (8,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (6,400 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Example 4

1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (Cu content: 50000 ppm/50 g), toluene (175 ml), EtOAc (175 ml), and 15 wt% ammonia water (175 ml) obtained in Comparative Example 1-2 were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. 10 wt% citric acid (175 ml) was added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. Finally, purified water (175 ml) was added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. The organic layer thus obtained was distilled as much as possible, IPA (220 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (175 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Example 5

In Example 4, 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (Cu content: less than 1 ppm/40 g), toluene (140 ml), EtOAc (140 ml), and 15 wt% ammonia water (140 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. 10 wt% citric acid (140 ml) was added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. Finally, purified water (140 ml) was added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. The organic layer thus obtained was distilled as much as possible, IPA (176 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (140 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Example 6

5-Bromo-3-cyano-1-isopropyl-indole (1,600.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (937.3 g), K ₂ CO ₃ (1,680.8 g), and toluene (6,400 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (231.6 g) and N,N-dimethylethylenediamine (DMEDA) (214.4 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming that the reaction is completed under reflux conditions, cool to 30-40°C, add 10 wt% ammonium chloride (NH ₄ Cl) (6,400 ml) and ethyl acetate (EtOAc) (6,400 ml), stir and leave for 30 minutes each, and then remove the water layer. Add 10 wt% citric acid (6,400 ml), stir and leave for 30 minutes each, and remove the water layer. Finally, add purified water (6,400 ml), stir and leave for 30 minutes each, and remove the water layer. The organic layer thus obtained was distilled as much as possible, then IPA (8,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (6,400 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Comparative examples 1-1 to 1-7

5-Bromo-3-cyano-1-isopropyl-indole (220 kg), 1H-pyrazole-4-carboxylic acid ethyl ester (129 kg), K ₂ CO ₃ (231 kg) and toluene (880 L) were added, stirred and N ₂ purging was performed for about 30 minutes. CuI (32 kg) and DMEDA (30 kg) were additionally added, heated and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming the completion of the reaction under reflux conditions, it was cooled to 30-40°C and 10 wt% citric acid (880 L) and EtOAc (880 L) were added, and then 6 N HCl was slowly added until the pH = 2-3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes and the water layer was removed. After adding 5 wt% EDTA (880 L), the process of stirring and allowing to stand for 30 minutes each to remove the water layer was performed twice. Finally, purified water (880 L) was added, stirred and allowed to stand for 30 minutes each to remove the water layer. The organic layer thus obtained was distilled as much as possible, and then IPA (880 L) was added, heated to completely dissolve, and then slowly cooled and recrystallized. The obtained solid was filtered, washed with IPA (880 L), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester. The same process was repeated 7 times to confirm reproducibility.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Comparative Example 2

5-Bromo-3-cyano-1-isopropyl-indole (20.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming the completion of the reaction under reflux conditions, it was cooled to 30-40°C, and 10 wt% citric acid (80 ml) and EtOAc (80 ml) were added, and then 6 N HCl was slowly added until the pH = 2-3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes, and then the water layer was removed. After adding 5 wt% EDTA (80 ml), the process of stirring and allowing to stand for 30 minutes each to remove the water layer was performed twice. Finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes each to remove the water layer. The organic layer thus obtained was distilled as much as possible, and then IPA (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (80 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Comparative examples 3-1 and 3-2

5-Bromo-3-cyano-1-isopropyl-indole (20.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and N ₂ purging was performed for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were additionally added, heated, and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming the completion of the reaction under reflux conditions, it was cooled to 30-40°C, and 10% (w/w) citric acid (80 ml) and EtOAc (80 ml) were added, and then 6 N HCl was slowly added until the pH = 2-3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes, and the water layer was removed. After adding 5% (w/w) ammonia water (80 ml), the mixture was stirred and allowed to stand for 30 minutes to remove the aqueous layer. Finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes to remove the aqueous layer. The organic layer thus obtained was distilled as much as possible, after which IPA (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (80 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester. The same process was repeated twice to confirm reproducibility.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Comparative examples 4-1 and 4-2

5-Bromo-3-cyano-1-isopropyl-indole (20.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred and N ₂ purged for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were additionally added, heated and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming the completion of the reaction under reflux conditions, the mixture was cooled to 30-40°C and 5 wt% ammonia water (80 ml) and EtOAc (80 ml) were added, stirred and left to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt% citric acid (80 ml), the mixture was stirred and allowed to stand for 30 minutes to remove the aqueous layer, and finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes to remove the aqueous layer. The organic layer thus obtained was distilled as much as possible, and then IPA (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (80 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester. The same process was repeated twice to confirm reproducibility.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Comparative Example 5

5-Bromo-3-cyano-1-isopropyl-indole (20.0 g), 1H-pyrazole-4-carboxylic acid ethyl ester (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred and N ₂ purged for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were additionally added, heated and N ₂ purging was continued until the internal temperature reached 45-50°C. After confirming the completion of the reaction under reflux conditions, the mixture was cooled to 30-40°C and 5 wt% ammonia water (110 ml) and EtOAc (80 ml) were added, stirred and left to stand for 30 minutes each, and then the aqueous layer was removed. After adding 5 wt% ammonia water (80 ml), the mixture was stirred and allowed to stand for 30 minutes to remove the aqueous layer. Finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes to remove the aqueous layer. The organic layer thus obtained was distilled as much as possible, and then IPA (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, washed with IPA (80 ml), and dried to obtain 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ 8.45 (1H, s), 8.13 (1H, s), 8.03 (1H, d), 7.80 (1H, s), 7.75 (1H, dd), 7.54 (1H, d) , 4.79-4.69 (1H, m), 4.36 (2H, q), 1.61 (6H, d), 1.40 (3H, t)

Experimental example

The Cu content remaining in the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester prepared in the above examples and comparative examples was measured and is shown in Table 1.

division How to work up Cu content transference number Comparative Example 1-1 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 1.03%
(10300 ppm) 92.8% Comparative Example 1-2 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 5.0%(50000 ppm) 98.8% Comparative Example 1-3 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 0.43%(4300 ppm) 90.9% Comparative Example 1-4 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 0.08%(800 ppm) 93.3% Comparative Example 1-5 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 0.22%(2200 ppm) 93.7% Comparative Example 1-6 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 30 ppm 94.7% Comparative Example 1-7 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 31 ppm 94.0% Comparative Example 2 10 wt% citric acid & 6 N HCl → 5 wt% EDTA → 5 wt% EDTA → purified water 39 ppm 87.5% Comparative Example 3-1 10 wt% citric acid & 6 N HCl → 5 wt% NH ₄ OH → purified water 254 ppm 86.9% Comparative Example 3-2 10 wt% citric acid & 6 N HCl → 5 wt% NH ₄ OH → purified water 453 ppm 88.4% Comparative Example 4-1 5 wt% _NH4OH → 10 wt% citric acid → purified water 2.7 ppm 89.1% Comparative Example 4-2 5 wt% _NH4OH → 10 wt% citric acid → purified water 8.8 ppm 90.1% Comparative Example 5 5 wt% NH ₄ OH → 5 wt% NH ₄ OH → purified water 201 ppm 88.5% Example 1 15 wt% _NH4OH → 10 wt% citric acid → purified water < 1.0 ppm 89.9% Example 2 15 wt% _NH4OH → 10 wt% citric acid → purified water < 1.0 ppm 88.6% Example 3 15 wt% _NH4OH → 10 wt% citric acid → purified water < 1.0 ppm 90.9% Example 4 15 wt% _NH4OH → 10 wt% citric acid → purified water < 1.0 ppm 92.4% Example 5 15 wt% _NH4OH → 10 wt% citric acid → purified water < 1.0 ppm 94.1% Example 6 10 wt% _NH4Cl → 10 wt% citric acid → purified water 40 ppm 88.3%

Claims (11)

A step of subjecting a compound of chemical formula 1 and a compound of chemical formula 2 to a C-N coupling reaction in an organic solvent with a copper catalyst, a base, and a ligand including N,N-dimethylethylenediamine; and A method for producing a compound of formula 3, comprising the step of purifying a compound of formula 3 using 10 to 20 wt% of ammonia water (NH ₄ OH) or 10 to 20 wt% of ammonium chloride (NH ₄ Cl) aqueous solution and citric acid: [Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

In the above chemical formula, X is F, Cl, Br or I; R1 is hydrogen or CN; R2 is hydrogen, halogen, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy-C ₁ -C ₇ alkyl or It's phenyl; R3 is hydrogen; C ₁ -C ₇ alkyl which is unsubstituted or substituted by one or more substituents selected from halogen, C ₃ -C ₇ cycloalkyl and O-R6; C ₃ -C ₇ cycloalkyl; or

, wherein R6 represents C ₁ -C ₄ alkyl, W represents O or S, R7 represents hydrogen or C ₁ -C ₄ alkyl, and n is an integer from 0 to 3; R4 is hydrogen, halogen or C ₁ -C ₇ alkyl; R5 is -C(O)OR8, where R8 is hydrogen, C ₁ -C ₇ alkyl, or C ₃ -C ₇ cycloalkyl. A manufacturing method according to claim 1, characterized in that the organic solvent is selected from the group consisting of toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and mixtures thereof. A manufacturing method according to claim 2, characterized in that the organic solvent is toluene. A manufacturing method according to claim 1, characterized in that the copper catalyst is selected from the group consisting of CuI, Cu(OAc) ₂ , Cu, Cu ₂ O, CuO and mixtures thereof. A manufacturing method according to claim 4, characterized in that the copper catalyst is CuI. A manufacturing method according to claim 1, characterized in that the base is selected from the group consisting of potassium carbonate, cesium carbonate, tribasic potassium phosphate, triethylamine, sodium tert-butoxide and mixtures thereof. A manufacturing method according to claim 1, characterized in that the base is potassium carbonate. A manufacturing method characterized in that in claim 1, 12 to 16 wt% of ammonia water (NH ₄ OH) or 12 to 16 wt% of ammonium chloride (NH ₄ Cl) aqueous solution is used. A manufacturing method characterized in that in claim 1, 5 to 15 wt% of citric acid is used. A manufacturing method characterized in that, in claim 1, it further comprises a step of purifying the compound of formula 3 using purified water. A manufacturing method according to any one of claims 1 to 10, characterized in that X is Br, R1 is CN, R2 is hydrogen, R3 is isopropyl, R4 is hydrogen, and R5 is ethoxycarbonyl (-C(O)OEt).