Process for the preparation of pyrrolopyridine derivatives

Abstract

The present invention relates to a method for preparing a pyrrolopyridine derivative compound having an antiviral activity and a novel intermediate used therein. The preparation method of the present invention can reduce reaction steps through efficient process development, and can prepare a pyrrolopyridine derivative compound with high purity at a high yield, thus greatly reducing production costs, thereby saving economy, and being suitable for mass production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing a pyrrolopyridine derivative having an antiviral activity. BACKGROUND

[0002] Acquired immune deficiency syndrome (AIDS) is caused by infection with human immunodeficiency virus (HIV). In order to treat AIDS, enzyme inhibitors have been developed according to the mechanism of action of HIV. According to the mode of action, enzyme inhibitors are classified into nucleoside reverse transcriptase inhibitors (NRTI), protease inhibitors (PI), fusion inhibitors, and integrase inhibitors. Since there are problems such as side effects, drug interactions, drug resistance, etc. in reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors, development of integrase inhibitors is actively being conducted.

[0003] Integrase inhibitors are classified into catalytic site inhibitors and non-catalytic site inhibitors according to their mechanism. A representative example of catalytic site integrase inhibitors is raltegravir. Ziger Debyser et al. introduced the mechanism of non-catalytic site integrase inhibition (Frauke Christ, Zeger Debyser et al., Nature Chemical Biology, 2010, Vol. 6, 442), and a drug related thereto has not yet been successfully developed.

[0004] However, raltegravir, as a catalytic site integrase inhibitor, was also found to exhibit drug resistance. In the case of HIV, if the drug is discontinued, the drug taken is no longer effective because latent HIV is reactivated and drug resistance is generated, and thus development of a non-catalytic site integrase inhibitor as a drug capable of solving the problem of drug resistance is being attempted. In particular, a pyrrolopyridine derivative represented by the following Chemical Formula I is known as a non-catalytic site integrase inhibitor:

[0005] [Chemical Formula I]

[0006]

[0007] International Publication No. WO 2013 / 073875 does not directly disclose a compound of Chemical Formula I, but discloses a method for preparing a derivative containing a compound of Chemical Formula I. However, since many steps (a total of 16 steps) are required to obtain a derivative similar to the compound of Chemical Formula I, the above preparation method is not suitable for mass production.

[0008] In addition, International Publication No. WO 2018 / 174320 directly discloses a compound of Chemical Formula I and a method for preparing the same. However, since the method for preparing the same is performed as it is according to the method for preparing the same disclosed in International Publication No. WO 2013 / 073875, and all steps require column purification, the method for preparing the same is not suitable for mass production.

[0009] Accordingly, there is a need to develop a novel method for preparing a pyrrolopyridine derivative compound of Chemical Formula I in a high yield and high purity by improving the above inefficient method for preparing the same. SUMMARY

[0010] Technical problem

[0011] An object of the present application is to provide a method for preparing a pyrrolopyridine derivative, which is capable of preparing a pyrrolopyridine derivative in a high purity and a high yield, thereby reducing production costs and realizing an efficient process step suitable for mass production.

[0012] In addition, another object of the present application is to provide a novel intermediate for the above method for preparing the same.

[0013] Technical scheme

[0014] In one general aspect, the present application provides a method for preparing a pyrrolopyridine derivative represented by the following Chemical Formula I:

[0015] [Chemical Formula I]

[0016]

[0017] Specifically, the method for preparing the same according to the present application can include the following steps (S-1) to (S-5):

[0018] (S-1) a first step of preparing a compound represented by the following Chemical Formula 3 by cyclization of a compound represented by the following Chemical Formula 1 or a salt thereof with a butanone derivative represented by the following Chemical Formula 2;

[0019] (S-2) a second step of preparing a compound represented by the following Chemical Formula 4 by cyclization of the compound represented by Chemical Formula 3 with an acetylacetonate derivative;

[0020] (S-3) a third step of preparing a compound represented by the following Chemical Formula 5 by chiral reduction with the compound represented by Chemical Formula 4;

[0021] (S-4) a fourth step of preparing a compound represented by the following Chemical Formula 6 by alkylation with the compound represented by Chemical Formula 5; and

[0022] (S-5) The fifth step of preparing a compound represented by the following Chemical Formula I from a compound represented by Chemical Formula 6 by hydrolysis:

[0023] [Chemical Formula 1]

[0024]

[0025] [Chemical Formula 2]

[0026]

[0027] [Chemical Formula 3]

[0028]

[0029] [Chemical Formula 4]

[0030]

[0031] [Chemical Formula 5]

[0032]

[0033] [Chemical Formula 6]

[0034]

[0035] [Chemical Formula I]

[0036]

[0037] In the above Chemical Formulas, X is Cl, Br, or I, and R is C 1-4 alkyl.

[0038] According to the preparation method disclosed in International Publication No. WO 2013 / 073875 and International Publication No. WO 2018 / 174320, the compound represented by the above Chemical Formula I passes through a total of 16 steps, which is not suitable for mass production. However, the preparation method of the present application enables the compound represented by Chemical Formula I to be prepared through only a total of 5 steps (S-1) to (S-5), which can be applied to mass production.

[0039] In addition, all of the compounds represented by Chemical Formulas 3 to 6 prepared in steps (S-1) to (S-4) are useful intermediates for preparing the pyrrolopyridine derivative compound represented by Chemical Formula I.

[0040] Hereinafter, each of steps (S-1) to (S-5) is described, respectively.

[0041] Step (S-1)

[0042] In the present invention, step (S-1) is to prepare a pyrrole ring derivative compound represented by Chemical Formula 3 by cyclization of a pyrazole derivative compound represented by Chemical Formula 1 or a salt thereof with a butanone derivative represented by Chemical Formula 2 (Reaction Scheme 1):

[0043] [Reaction Scheme 1]

[0044]

[0045] In the above reaction scheme, X is Cl, Br, or I, and R is C 1-4 alkyl.

[0046] According to an embodiment of the present invention, the reaction can be performed by cyclization of (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride with a butanone derivative (e.g., 3-chlorobutan-2-one) and a 3-(4-chlorophenyl)-3-oxopropanenitrile compound.

[0047] In the above reaction, an organic solvent commonly used in cyclization can be used. For example, the solvent can be methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, 1,4-dioxane, acetone, or a mixture thereof. Specifically, ethanol can be used, but is not limited thereto.

[0048] Further, the reaction can be performed at 30 to 60°C, more specifically at 35 to 45°C, but is not limited thereto.

[0049] After the reaction, one or more steps of isolating or purifying the product can be additionally performed, but is not limited thereto. For example, in an embodiment of the present invention, a high-purity product is obtained by stirring the reaction product in an organic solvent, toluene.

[0050] Step (S-2)

[0051] In the present invention, step (S-2) is to prepare a pyrrolopyridine derivative compound represented by Chemical Formula 4 by cyclization using a pyrrole derivative compound represented by Chemical Formula 3 as a starting material (Reaction Scheme 2):

[0052] [Reaction Scheme 2]

[0053]

[0054] In the above reaction scheme, R is C 1-4 alkyl.

[0055] According to an embodiment of the present invention, in the reaction, the compound represented by Chemical Formula 4 can be prepared by reaction with ethyl acetoacetate. Here, R is ethyl.

[0056] The acid used in the reaction can be hydrochloric acid, acetyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or a mixture thereof. Specifically, hydrochloric acid can be used, but is not limited thereto.

[0057] Further, in the above reaction, an organic solvent commonly used in the cyclization can be used. Here, as the organic solvent, ethanol, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, or a mixture thereof can be used. Specifically, acetonitrile can be used, but is not limited thereto.

[0058] Further, the reaction can be performed at 40 to 80°C, more specifically at 60 to 65°C, but is not limited thereto.

[0059] Step (S-3)

[0060] In the present application, step (S-3) is to prepare a pyrrolopyridine derivative compound having a chiral alcohol structure represented by Chemical Formula 5 by chiral reduction of the ketone group of a pyrrolopyridine derivative compound represented by Chemical Formula 4 (Reaction Scheme 3):

[0061] [Reaction Scheme 3]

[0062]

[0063] In the above reaction scheme, R is C 1-4 alkyl.

[0064] According to an embodiment of the present application, chiral reduction can be performed using a combination of (R)-(+)-2-methyl-CBS-oxazaborolidine and catechol borane.

[0065] Further, according to another embodiment of the present application, chiral reduction can be performed using a combination of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer and (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine.

[0066] In the above reaction, an organic solvent commonly used in chiral reduction can be used. For example, the organic solvent can be toluene, acetonitrile, or a mixture thereof, but is not limited thereto.

[0067] Further, the reaction can be performed at -10 to 10°C, more specifically at -5 to 5°C, but is not limited thereto.

[0068] Step (S-4)

[0069] In the present application, step (S-4) is to prepare a pyrrolopyridine derivative compound represented by Chemical Formula 6 by alkylation of a chiral alcohol in a pyrrolopyridine derivative compound represented by Chemical Formula 5 (Reaction Scheme 4):

[0070] [Reaction Scheme 4]

[0071]

[0072] In the above reaction scheme, R is C 1-4 alkyl.

[0073] According to an embodiment of the present application, the alkylation can be performed using tert-butyl acetate. Herein, the reaction can be performed in the presence of perchloric acid, but is not limited thereto.

[0074] According to another embodiment of the present application, the alkylation can be performed using isobutylene. Herein, the reaction can also be performed in the presence of perchloric acid, but is not limited thereto.

[0075] In the above reaction, an organic solvent commonly used in alkylation can be used. For example, as the organic solvent, a halogenated solution, particularly, a dichloromethane solution can be used. However, examples of the organic solvent are not limited thereto.

[0076] Further, the reaction can be performed at -5 to 30°C, more specifically, at -5 to 20°C, but is not limited thereto.

[0077] Step (S-5)

[0078] In the present application, step (S-5) is to prepare a carboxylic acid compound represented by Chemical Formula I by hydrolysis of an ester compound represented by Chemical Formula 6 (Reaction Scheme 5):

[0079] [Reaction Scheme 5]

[0080]

[0081] In the above reaction scheme, R is C 1-4 alkyl.

[0082] According to an embodiment of the present application, the hydrolysis can be alkaline hydrolysis. The base used in the reaction can be lithium hydroxide, sodium hydroxide or potassium hydroxide, and can be specifically sodium hydroxide. However, examples of the base are not limited thereto.

[0083] In the above reaction, an organic solvent commonly used in hydrolysis can be used. Herein, as the organic solvent, tetrahydrofuran, methanol, ethanol, isopropanol, an aqueous solution or a mixture thereof can be used. Specifically, a mixture of tetrahydrofuran and methanol can be used, but is not limited thereto.

[0084] Further, the reaction can be performed at 20 to 80°C, more specifically, at 40 to 50°C, but is not limited thereto.

[0085] Advantageous effects

[0086] The preparation method of the present application can reduce reaction steps through efficient process development, thereby preparing the pyrrolopyridine derivative compound with high purity and high yield, thus greatly reducing production cost, saving economy, and being suitable for large-scale production. DETAILED DESCRIPTION

[0087] Hereinafter, preferred examples are provided to help understand the present application. However, the following examples are provided only to make it easier to understand the present application, and the scope of the present application is not limited by these examples.

[0088] Embodiment

[0089] In the examples of the present application, a pyrrolopyridine derivative compound represented by Chemical Formula I was prepared according to the following Reaction Scheme I:

[0090] [Reaction Scheme I]

[0091]

[0092] Example 1: Preparation of (2-amino-4,4-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrol-3-yl)(4-chlorophenyl)methanone

[0093]

[0094] (1-methyl-1H-pyrazol-4-yl)methylamine hydrochloride (10 g, 67.76 mmol) was diluted in 135 mL of ethanol, then diisopropylethylamine (29.5 mL, 169.37 mmol) and 4-chlorobenzoyl acetonitrile (13.38 g, 74.52 mmol) were added, and the reaction solution was stirred while the temperature was raised to 35 to 40°C. 3-chlorobutan-2-one (10.3 mL 101.62 mmol) was slowly added dropwise over 30 minutes, and the mixture was stirred for 3 hours while maintaining the temperature at 35 to 40°C. After the reaction was completed, the mixture was cooled to 10°C, 400 mL of water was added dropwise thereto, and then stirred for 30 minutes. The crystals precipitated were filtered, the resulting solid was diluted with 200 mL of toluene, and then stirred at 40°C for 30 minutes. The mixture was slowly cooled to 15°C and stirred for 30 minutes, then filtered and dried under reduced pressure, thereby obtaining the desired product (17.98 g, 77%).

[0095] 1 H-NMR 400Hz (DMSO-d6): 7.58 (s, 1H), 7.45-7.43 (m, 2H), 7.35-7.33 (m, 3H), 7.18 (s, 2H), 4.80 (s, 2H), 3.78 (s, 3H), 1.99 (s, 3H), 1.36 (s, 3H);

[0096] LCMS: m / z 343.1 [M+1].

[0097] Example 2: Preparation of ethyl 2-(4-(4-chlorophenyl)-2,3,4-trimethyl-1-((1-methyl-1H- pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate

[0098]

[0099] The (2-amino-4,4-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrol-3-yl)(4- chlorophenyl)methanone (17.6 g, 51.34 mmol) prepared in Example 1 was diluted in 103 mL of acetonitrile, and then ethyl acetoacetate (10.81 mL, 77.00 mmol) was added under nitrogen. While stirring the reaction solution, 4M-hydrochloric acid dioxane solution (38.5 mL, 154.01 mmol) was added dropwise thereto, and then stirred at 62 to 65°C for 20 hours or more, and completion of the reaction was confirmed by HPLC. The reaction solution was concentrated, the reaction solution was diluted with 528 mL of ethyl acetate and 352 mL of saturated aqueous sodium bicarbonate solution at 0°C, and then stirred for 10 minutes, and then the organic layer was extracted at room temperature. The separated organic layer was washed with 352 mL of saturated aqueous sodium bicarbonate solution twice, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain the desired product (10.2 g, 42.7%).

[0100] 1 H-NMR 400Hz (CDCI3): 7.43-7.37 (m, 3H), 7.26-7.22 (m, 3H), 5.34 (s, 2H), 3.86-3.83 (m, 5H), 2.69 (s, 3H), 2.32 (s, 3H), 1.63 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H);

[0101] LCMS: m / z 465.1 [M+1].

[0102] Example 3-1: Preparation of ethyl (S)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H- pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate

[0103]

[0104] The ethyl 2-(4-(4-chlorophenyl)-2,3,4-trimethyl-l-((l-methyl-lH-pyrazol-4-yl)methyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (6.67 g, 14.35 mmol) prepared in Example 2 was diluted in 48 mL of toluene, then (R)-(+)-2-methyl-CBS-oxazaborolidine (1 M solution in toluene, 5.75 mL, 5.74 mmol) was added under nitrogen. The reaction mixture was cooled to -50 °C, then catecholborane (1 M solution in tetrahydrofuran, 43.04 mL, 43.04 mmol) was added slowly dropwise over 25 minutes and stirred at -10 to -5 °C for 8 hours. After completion of the reaction, 267 mL of heptane was added and stirred. The formed solid was stirred for 10 minutes, then filtered. The obtained solid was dissolved in 100 mL of methanol, stirred for 15 minutes, and concentrated. The concentrated residue was dissolved in 200 mL of ethyl acetate and cooled to 5 to 10 °C, then 66 mL of an aqueous sodium carbonate solution was added dropwise, then stirred for 30 minutes. The separated aqueous layer was extracted with 176 mL of ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired product (2.2 g, 32.8%, ee: 97%).

[0105] 1 H-NMR 400Hz (DMSO-d6): 7.55-7.52 (m, 3H), 7.33-7.28 (m, 3H), 5.70 (d, J = 3.6 Hz, 1H), 5.31-5.18 (m, 2H), 4.98 (d, J = 3.6 Hz, 1H), 4.08-3.97 (m, 2H), 3.74 (s, 3H), 2.56 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H), 1.10 (t, J = 6.8 Hz, 3H);

[0106] LCMS: m / z 467.1 [M+1].

[0107] Example 3-2: Preparation of (S)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-l-((l-methyl- lH-pyrazol-4-yl)methyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (IV)

[0108]

[0109] Ethyl 2-(4-(4-chlorophenyl)-2,3,4-trimethyl-l-((l-methyl-lH-pyrazol-4-yl)methyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (11.71 g, 25.19 mmol) prepared in Example 2 was diluted in 84 mL of acetonitrile, triethylamine (7.02 mL, 50.4 mmol) was added under nitrogen and then stirred for 10 minutes. After the reaction temperature was lowered to -5°C or lower, formic acid (2.85 mL, 75.6 mmol) was slowly added dropwise.

[0110] To another reactor was added dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.74 g, 1.2 mmol), (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (1.1 g, 3.0 mmol) and 27 mL of acetonitrile and stirred for about 10 minutes or more. While maintaining the internal temperature at 0 to 5°C, triethylamine (1.76 mL, 12.6 mmol) was added and stirred for 1 hour, and then added dropwise to the reaction solution. The reaction was carried out at an internal temperature of -5 to 5°C for 60 hours. After the completion of the reaction, 210 mL of ethyl acetate and 180 mL of purified water were added, and then the organic layer was extracted and washed twice with purified water. The separated organic layer was dried with anhydrous sodium sulfate and filtered with a carbon filter, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired product (9.64 g, 82%, ee: 99%).

[0111] 1 H-NMR 400Hz (DMSO-d6): 7.55-7.52 (m, 3H), 7.33-7.28 (m, 3H), 5.70 (d, J=3.6 Hz, 1H), 5.31-5.18 (m, 2H), 4.98 (d, J=3.6 Hz, 1H), 4.08-3.97 (m, 2H), 3.74 (s, 3H), 2.56 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H), 1.10 (t, J=6.8 Hz, 3H);

[0112] LCMS: m / z 467.1 [M+1].

[0113] Example 4-1: Preparation of (S)-ethyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6- trimethyl-l-((l-methyl-lH-pyrazol-4-yl)methyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)acetate (V)

[0114]

[0115] (S)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetic acid ethyl ester (16 g, 34.26 mmol) prepared in Example 3-1 was diluted in 68.5 mL of dichloromethane, and then 456 mL of tert-butyl acetate was added under nitrogen. The reaction solution was cooled to 0 to 5°C, and 70% perchloric acid (11.8 mL, 137.05 mmol) was slowly added dropwise over 1 hour, and then the temperature was gradually increased, and stirred at 20°C for 4 hours. The reaction solution was cooled to 0 to 5°C and diluted with 480 mL of dichloromethane and 960 mL of saturated aqueous sodium carbonate solution, and then stirred for 20 minutes to separate the organic layer. The separated organic layer was washed with 240 mL of water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired product (12.4 g, 69%, ee: 99%).

[0116] 1 H-NMR 400Hz (DMSO-d6): 7.61-7.53 (m, 3H), 7.42 (dd, J=8.2 Hz, J=2 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=8.2 Hz, J=2 Hz, 1H), 5.28-5.18 (m, 2H), 4.98 (s, 1H), 4.10-4.02 (m, 2H), 3.74 (s, 3H), 2.62 (s, 3H), 2.29 (s, 3H), 1.41 (s, 3H), 0.91 (s, 9H);

[0117] LCMS: m / z 523.2 [M+1].

[0118] Example 4-2: Preparation of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid ethyl ester (V)

[0119]

[0120] (S)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetic acid ethyl ester (7 g, 14.99 mmol) prepared in Example 3-1 was diluted in 8% isobutene solution in dichloromethane (158.1 mL, 300 mmol). The reaction mixture was cooled to -5 to 0°C, 70% perchloric acid (4.51 mL, 52.5 mmol) was added dropwise, and then stirred at 5 to 10°C for 24 hours. After completion of the reaction, 1N aqueous sodium hydroxide solution (55.5 mL, 57.7 mmol) was slowly added to the reaction solution at -5 to 0°C, and then stirred at room temperature for 10 minutes. The organic layer was washed with 50 mL of water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the desired product (6.46 g, 82%, ee: 99%).

[0121] 1 H-NMR 400Hz (DMSO-d6): 7.61-7.53 (m, 3H), 7.42 (dd, J=8.2 Hz, J=2 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=8.2 Hz, J=2 Hz, 1H), 5.28-5.18 (m, 2H), 4.98 (s, 1H), 4.10-4.02 (m, 2H), 3.74 (s, 3H), 2.62 (s, 3H), 2.29 (s, 3H), 1.41 (s, 3H), 0.91 (s, 9H);

[0122] LCMS: m / z 523.2 [M+1].

[0123] Example 5: Preparation of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid

[0124]

[0125] (S)-2-(tert-Butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate prepared in Example 4-1 (13.5 g, 25.8 mmol) was diluted in 108 mL of tetrahydrofuran and 27 mL of methanol. Sodium hydroxide (3.1 g, 77.4 mmol) was added, and then the mixture was stirred at 40 to 45°C for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and 120 mL of dichloromethane and 60 mL of purified water were added thereto. The mixture was cooled to 0 to 5°C, and the pH was adjusted to 4.5 to 5.0 with 2N aqueous hydrochloric acid solution. The organic layer was separated, washed with 60 mL of purified water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the obtained residue, 30 mL of acetonitrile was added, and then the mixture was stirred while cooling to 5 to 10°C for 3 hours. The precipitated crystals were filtered and dried under reduced pressure, thereby obtaining the desired product (9.25 g, 72%, ee: 99%) as a white solid.

[0126] 1 H-NMR 400Hz (DMSO-d6): 7.60 (dd, J=8.4Hz, J=2.4Hz, 1H), 7.56-7.53 (m, 2H), 7.46 (dd, J=8Hz, J=2.4Hz, 1H), 7.35 (s, 1H), 7.30 (dd, J=8.4Hz, J=2.4Hz, 1H), 5.28-5.19 (m, 2H), 4.93 (s, 1H), 3.74 (s, 3H), 2.63 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H), 0.89 (s, 9H);

[0127] LCMS: m / z 495.2 [M+1].

[0128] While the application has been shown and described with reference to certain preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details can be made therein without departing from the spirit and scope of the application. Therefore, the scope of the application should not be determined from the preferred embodiments but from the appended claims and their equivalents.

Claims

1. A method for preparing a compound represented by the following Chemical Formula I, comprising: (S-1) a first step of preparing a compound represented by the following Chemical Formula 3 by cyclization of a compound represented by the following Chemical Formula 1 or a salt thereof with a butanone derivative represented by the following Chemical Formula 2 and a 3-(4-chlorophenyl)-3-oxopropionitrile compound; (S-2) a second step of preparing a compound represented by the following Chemical Formula 4 by cyclization of the compound represented by Chemical Formula 3 with an acetylacetonate derivative; (S-3) a third step of preparing a compound represented by the following Chemical Formula 5 from the compound represented by Chemical Formula 4 by chiral reduction; (S-4) a fourth step of preparing a compound represented by the following Chemical Formula 6 from the compound represented by Chemical Formula 5 by alkylation; and (S-5) a fifth step of preparing a compound represented by the following Chemical Formula I from the compound represented by Chemical Formula 6 by hydrolysis: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula I] In the above Chemical Formulas, X is Cl, Br or I, and the salt of the compound represented by Chemical Formula 1 is a hydrochloride. R is C 1-4 alkyl.

2. The method of claim 1, wherein, X is Cl.

3. The method of claim 1, wherein, Step (S-1) further includes a process of isolating or purifying the precipitated compound represented by Chemical Formula 3.

4. The method of claim 1, wherein, Step (S-2) is a reaction with ethyl acetoacetate.

5. The method of claim 1, wherein, Step (S-3) is a reaction with (R)-(+)-2-methyl-CBS-oxazaborolidine and catechol borane.

6. The method of claim 1, wherein, Step (S-3) is a reaction with dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer and (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine.

7. The method of claim 1, wherein, Step (S-4) is a reaction with tert-butyl acetate or isobutene.

8. The method of claim 1, wherein, Step (S-4) is performed in the presence of perchloric acid.

9. The method of claim 8, wherein, Step (S-5) is basic hydrolysis.

10. The method of claim 1, wherein, 11. A compound represented by the following Chemical Formula 3 or a salt thereof: [Chemical Formula 3] 12. A compound represented by the following Chemical Formula 4 or a salt thereof: [Chemical Formula 4] 13. A compound represented by the following Chemical Formula 5 or a salt thereof: In the above formula, R is C 1-4 alkyl. [Chemical Formula 5] ​ In the above formula, R is C 1-4 alkyl.

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