TW202509022A - Method of preparing intermediates for synthesizing xanthine oxidase inhibitor - Google Patents

Abstract

The present disclosure relates to a method of preparing an intermediate for a synthesis of a xanthine oxidase inhibitor, and more specifically, to a method of efficiently preparing a compound of the following Chemical Formula 3 through a work-up process using ammonia water and citric acid: In the above Chemical Formula 3, R1, R2, R3, R4, and R5 are as defined in the specification.

Description

Method for preparing intermediates for synthesizing xanthine oxidase inhibitors

The present disclosure relates to a method for preparing an intermediate for synthesizing a xanthine oxidase inhibitor, and more particularly, to a method for efficiently preparing a compound of the following chemical formula 3 by a work-up procedure using aqueous ammonia and citric acid:

[Chemical formula 3]

In the above Chemical Formula 3, R1, R2, R3, R4 and R5 are as defined herein.

Xanthine oxidase is an enzyme that converts hypoxanthine into xanthine and converts the resulting xanthine into uric acid. Uricase is present in most mammals, but not in humans and chimpanzees, so uric acid is known to be the final product of purine metabolism (SP Bruce, Ann. Pharm., 2006, 40, 2187~2194). High concentrations of uric acid in the blood can cause a variety of diseases, and a representative example is gout.

As mentioned above, gout is a disease caused by high concentrations of uric acid in the body, and refers to a condition in which uric acid crystals accumulate in joint cartilage, ligaments, and surrounding tissues, causing severe inflammation and pain. Gout is an 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 novel xanthine oxidase inhibitors, and Korean Patent Publication No. 10-2011-0037883 discloses a novel compound of the following chemical formula effective as a xanthine oxidase inhibitor:

In Korean Patent Publication No. 10-2011-0037883, a conventional preparation process of 5-bromo-3-cyano-1-isopropyl-indole is described. 5-bromo-3-cyano-1-isopropyl-indole is an intermediate of the xanthine oxidase inhibitor CsCO ₃ , which is inconvenient to use due to its low economic efficiency and high usage density, and therefore a substitute is needed. In addition, since there is no established purification method, the organic layer obtained after the reaction and work-up process is concentrated and immediately subjected to the next reaction. In this case, there arises a problem that 5-bromo-3-cyano-1H-indole contained in the reaction mixture without being purified or as a causative agent generates impurities in the next reaction and adversely affects the quality of the product.

Furthermore, the conventional preparation process of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester 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, resulting in an influence on the raw material drug, and thus improvement in quality and yield is required.

To address the above issues, Korean Patent Publication No. 10-2023-0006408 discloses a preparation method using low-cost starting materials and ligands, as well as a chelating extraction purification technology.

In the above preparation method, the post-treatment process after the reaction of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester is completed is disclosed in the following schematic diagram. Respond to IPC ↓ First post-processing 10% citric acid, 6N HCl (pH 2 to 3) ↓ Layer separation (water layer discard) ↓ Second post-processing 5% Disodium EDTA ↓ Layer separation (water layer discard) ↓ 3rd post-processing 5% Disodium EDTA ↓ Layer separation (water layer discard) ↓ 4th post-processing _H2O ↓ Layer separation (water layer discard) ↓ Evaporation

In the above preparation method, although the copper catalyst citric acid and chelating agent (e.g., EDTA) for CN coupling reaction are used and the pH is adjusted with HCl, the Cu removal rate for the purpose of post-treatment is unstable and several post-treatment steps are repeated, so the process efficiency is low, and there is a problem of sudden generation of a large amount of carbon dioxide during the injection of HCl, which may pose a safety risk. Prior Art Patent Documents

Korean Patent Application Early Publication No. 10-2011-0037883

Korean Patent Application Early Publication No. 10-2023-0006408

Technical issues

Therefore, the technical subject of the present disclosure provides an improved novel preparation method, which can reproducibly purify the copper catalyst and minimize the number of post-treatment repetitions without pH control to prepare the compound of the following chemical formula 3, which is a key intermediate for the synthesis of xanthine oxidase inhibitors:

[Chemical formula 3]

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

The present disclosure in order to achieve the above object provides a method for preparing a compound of the following chemical formula 3, the method comprising:

In an organic solvent, a copper catalyst, a base and a ligand are used to carry out a C-N coupling reaction of the compound of Chemical Formula 1 and the compound of Chemical Formula 2; and

The compound of Formula 3 is purified using 10 to 20 wt.% aqueous ammonia (NH ₄ OH) or 10 to 20 wt.% aqueous ammonium chloride (NH ₄ Cl) 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 phenyl;

R3 is hydrogen; C ₁ -C ₇ alkyl which is unsubstituted or substituted with one or more substituents selected from halogen, C ₃ -C ₇ cycloalkyl and O-R6; C ₃ -C ₇ cycloalkyl; or , wherein R6 represents a C ₁ -C ₄ alkyl group, W represents O or S, R7 represents hydrogen or a C ₁ -C ₄ alkyl group, and n is an integer from 0 to 3;

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

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

According to the preparation method disclosed herein, the residual amount of the copper catalyst in the prepared compound of Chemical Formula 3 can be reproducibly maintained at less than 50 ppm. According to the preparation method disclosed herein, by reducing the number of repetitions of the post-treatment procedure to three times, the process time and the amount of waste liquid generated are reduced, thereby improving the preparation efficiency. In addition, according to the preparation method disclosed herein, the process safety can be improved by omitting the pH control step and blocking the rapid generation of carbon dioxide. Best Mode

In the following text, the present disclosure will be described in more detail.

According to the specific examples of the present disclosure, the ligand can 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 the specific examples of the present invention, the ligand can be N,N-dimethylethylamine. The amount of the ligand used can be 0.2 to 1.0 equivalents, or preferably 0.4 equivalents, based on the weight of the compound of Chemical Formula 1.

According to the specific examples of the present disclosure, the organic solvent can be selected from the group consisting of toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and mixtures thereof, but is not limited thereto. According to the specific examples of the present invention, the organic solvent can be toluene. Based on the weight of the compound of Chemical Formula 1, the amount of the organic solvent used can be 4 times (ml/g) to 8 times (ml/g), preferably 4 times (ml/g) to 6 times (ml/g).

According to a specific embodiment of the present invention, the copper catalyst can 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 a specific embodiment of the present invention, the copper catalyst can be CuI. Based on the weight of the compound of Chemical Formula 1, the amount of the copper catalyst used can be 0.1 equivalent to 0.5 equivalent, preferably 0.1 equivalent to 0.3 equivalent, or more preferably 0.2 equivalent.

According to a specific embodiment of the present invention, the base can be selected from the group consisting of potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), tripotassium phosphate (K ₃ PO ₄ ), triethylamine, sodium tertiary butoxide and a mixture thereof, but is not limited thereto. According to a specific embodiment of the present invention, the base can be potassium carbonate. Based on the weight of the compound of Chemical Formula 1, the amount of the base used can be 1 to 4 equivalents, preferably 1 to 3 equivalents, or more preferably 2 equivalents.

According to a specific example of the present disclosure, 12 to 16 wt.% of aqueous ammonia (NH ₄ OH) may be used. According to a specific example of the present invention, 15 wt.% of aqueous ammonia (NH ₄ OH) may be used. According to a specific example of the present invention, 10 to 20 wt.% of ammonium chloride (NH ₄ Cl) may be used.

According to a specific embodiment of the present disclosure, 5 to 15 wt.% of citric acid can be used. According to a specific embodiment of the present invention, 7 to 12 wt.% of citric acid can be used. According to a specific embodiment of the present invention, 10 wt.% of citric acid can be used.

According to the specific example of the present disclosure, the step of purifying the compound of Chemical Formula 3 using purified water may be further included.

According to specific embodiments of the present disclosure, in the above 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 the specific examples of the present disclosure, unlike the removal efficiency in the related art with a large deviation, the residual amount of the copper catalyst in the prepared compound of Chemical Formula 3 can be stably maintained at less than 50 ppm, and is therefore reproducible. More specifically, when using ammonia NH ₄ OH, the residual amount can be stably maintained at less than 1 ppm, or when using an aqueous solution of ammonium chloride (NH ₄ Cl), the residual amount can be stably maintained at less than 50 ppm.

According to a specific example of the present invention, the amount of waste liquid generated in the preparation method is reduced and the rapid generation of carbon dioxide is blocked, thereby improving the stability of the process.

Hereinafter, the present disclosure will be described in more detail through embodiments. However, the following embodiments are merely illustrative to facilitate understanding of the present disclosure, and the scope of the present disclosure is not limited thereto.

5-Bromo-3-cyano-1-isopropyl-indole (100.0 g), ethyl 1H-pyrazole-4-carboxylate (58.6 g), K ₂ CO ₃ (105.1 g) and toluene (400 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (14.5 g) and N,N-dimethylethylenediamine (DMEDA) (13.4 g) were further added, heated, and purged with N ₂ until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., 15 wt.% aqueous ammonia NH ₄ OH (400 ml) and ethyl acetate (EtOAc) (400 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (400 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (400 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (500 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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), ethyl 1H-pyrazole-4-carboxylate (234.3 g), K ₂ CO ₃ (420.2 g) and toluene (1,600 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (57.9 g) and N,N-dimethylethylenediamine (DMEDA) (53.6 g) were added, heated, and purged with N ₂ until the internal temperature reached 45 to 50°C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40°C, 15 wt.% aqueous ammonia NH ₄ OH (1,600 ml) and ethyl acetate (EtOAc) (1,600 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (1,600 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (1,600 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (2,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then washed with IPA (1,600 ml) and dried to give 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), ethyl 1H-pyrazole-4-carboxylate (937.3 g), K ₂ CO ₃ (1,680.8 g) and toluene (6,400 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (231.6 g) and N,N-dimethylethylenediamine (DMEDA) (214.4 g) were added, heated, and purged with N ₂ until the internal temperature reached 45 to 50°C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40°C, 15 wt.% aqueous ammonia NH ₄ OH (6,400 ml) and ethyl acetate (EtOAc) (6,400 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (6,400 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (6,400 ml) was added, stirred and allowed to stand for 30 minutes to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (8,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then washed with IPA (6,400 ml) and dried to give 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) obtained in Comparative Example 1-2, toluene (175 ml), EtOAc (175 ml) and 15 wt.% aqueous ammonia (175 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (175 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (175 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, IPA (220 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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

1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (Cu content: less than 1 ppm/40 g) obtained in Example 4, toluene (140 ml), EtOAc (140 ml) and 15 wt.% aqueous ammonia (140 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (140 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (140 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, IPA (176 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then washed with IPA (140 ml) and dried to give 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), ethyl 1H-pyrazole-4-carboxylate (937.3 g), K ₂ CO ₃ (1,680.8 g) and toluene (6,400 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (231.6 g) and N,N-dimethylethylenediamine (DMEDA) (214.4 g) were added, heated, and purged with N ₂ until the internal temperature reached 45 to 50°C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40°C, 10 wt.% ammonium chloride (NH ₄ Cl) (6,400 ml) and ethyl acetate (EtOAc) (6,400 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 10 wt.% citric acid (6,400 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (6,400 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (8,000 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then washed with IPA (6,400 ml) and dried to give 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), ethyl 1H-pyrazole-4-carboxylate (129 kg), K ₂ CO ₃ (231 kg), and toluene (880 L) were added, stirred, and N ₂ purged for about 30 minutes. CuI (32 kg) and DMEDA (30 kg) were further added, heated, and N ₂ purged was continued until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., 10 wt.% citric acid (880 L) and EtOAc (880 L) were added, and then 6N HCl was slowly added until pH = 2 to 3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 5 wt.% EDTA (880 L), the process of removing the aqueous layer by stirring and standing for 30 minutes each was repeated twice. Finally, after adding purified water (880 L), the aqueous layer was removed by stirring and standing for 30 minutes each. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (880 L) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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 procedure 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), ethyl 1H-pyrazole-4-carboxylate (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were further added, heated, and purged with N ₂ until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., 10 wt.% citric acid (80 ml) and EtOAc (80 ml) were added, and then 6N HCl was slowly added until pH = 2 to 3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 5 wt.% EDTA (80 ml), the procedure of removing the aqueous layer by stirring and standing for 30 minutes each was repeated twice. Finally, after adding purified water (80 ml), the aqueous layer was removed by stirring and standing for 30 minutes each. After the organic layer thus obtained was distilled as much as possible, isopropyl alcohol (IPA) (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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) Comparison of Examples 3-1 and 3-2

5-Bromo-3-cyano-1-isopropyl-indole (20.0 g), ethyl 1H-pyrazole-4-carboxylate (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were further added, heated, and purged with N ₂ until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., and 10 wt.% citric acid (80 ml) and EtOAc (80 ml) were added, and then 6N HCl was slowly added until pH = 2 to 3. After the addition was completed, the mixture was stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 5 wt.% aqueous ammonia (80 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, after adding purified water (80 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After the organic layer thus obtained was distilled as much as possible, isopropyl alcohol (IPA) (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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 procedure 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), ethyl 1H-pyrazole-4-carboxylate (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were further added, heated, and purged with N ₂ until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., 5 wt.% aqueous ammonia (80 ml) and EtOAc (80 ml) were added, stirred and allowed 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 each to remove the aqueous layer. Finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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 procedure 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), ethyl 1H-pyrazole-4-carboxylate (11.7 g), K ₂ CO ₃ (21.0 g) and toluene (80 ml) were added, stirred, and purged with N ₂ for about 30 minutes. CuI (2.9 g) and DMEDA (2.68 g) were further added, heated, and purged with N ₂ until the internal temperature reached 45 to 50° C. After confirming that the reaction was completed under reflux conditions, the mixture was cooled to 30 to 40° C., 5 wt.% aqueous ammonia (110 ml) and EtOAc (80 ml) were added, stirred and allowed to stand for 30 minutes each, and then the aqueous layer was removed. After adding 5 wt.% aqueous ammonia (80 ml), the mixture was stirred and allowed to stand for 30 minutes each to remove the aqueous layer. Finally, purified water (80 ml) was added, stirred and allowed to stand for 30 minutes each to remove the aqueous layer. After distilling the organic layer thus obtained as much as possible, isopropyl alcohol (IPA) (80 ml) was added, heated to completely dissolve, and then slowly cooled to recrystallize. The obtained solid was filtered, and then 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 residual Cu content in the 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester prepared in the Examples and Comparative Examples was measured and shown in Table 1.

Claims (11)

A method for preparing a compound of the following chemical formula 3 comprises: performing a CN coupling reaction of a compound of the chemical formula 1 and a compound of the chemical formula 2 using a copper catalyst, a base and a ligand containing N,N-dimethylethylenediamine in an organic solvent; and purifying the compound of the chemical formula 3 using 10 to 20 wt.% ammonia NH ₄ OH or 10 to 20 wt.% 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 phenyl, R3 is hydrogen, C ₁ -C ₇ alkyl which is unsubstituted or substituted with 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, and R5 is -C(O)OR8, wherein R8 is hydrogen, C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl. The preparation method of claim 1, wherein the organic solvent is selected from the group consisting of toluene, xylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and mixtures thereof. The preparation method of claim 2, wherein the organic solvent is toluene. The preparation method of claim 1, wherein the copper catalyst is selected from the group consisting of CuI, Cu(OAc) ₂ , Cu, Cu ₂ O, CuO and mixtures thereof. The preparation method of claim 4, wherein the copper catalyst is CuI. The preparation method of claim 1, wherein the base is selected from the group consisting of potassium carbonate, cesium carbonate, tripotassium phosphate, triethylamine, sodium tributoxide and mixtures thereof. The preparation method of claim 1, wherein the base is potassium carbonate. The preparation method of claim 1, wherein 12 to 16 wt.% of the aqueous ammonia (NH ₄ OH) or 12 to 16 wt.% of the aqueous ammonium chloride (NH ₄ Cl) solution is used. The preparation method of claim 1, wherein 5 to 15 wt.% of citric acid is used. The preparation method of claim 1 further comprises purifying the compound of Chemical Formula 3 using purified water. The preparation method of any one of claims 1 to 10, wherein X is Br, R1 is CN, R2 is hydrogen, R3 is isopropyl, R4 is hydrogen, and R5 is ethoxycarbonyl (-C(O)OEt).