Intermediate compound used in preparing heterocycle derivative, method for preparing intermediate compound, and method for preparing heterocycle derivative using same

Abstract

The present invention relates to: an intermediate compound used in preparing a heterocycle derivative; a method for preparing same; and a method for preparing a heterocycle derivative using same.

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003]

Technical Field

[0004]

Background Technology

[0005] STAT (signal transducer and activator of transcription) proteins are transcription factors that transmit signals from various cytokines and growth factors outside the cell to the nucleus. A total of seven subtypes (subtypes: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) have been reported to date. In particular, STAT3 protein is known to play a key role in the IL-6 and EGF signal transduction systems. It has also been reported that STAT3 protein is continuously activated in patients with solid tumors such as those occurring in the prostate, stomach, breast, lung, pancreas, kidney, uterus, ovary, and head and neck, as well as in patients with hematological cancers such as acute and chronic leukemia and multiple myeloma. In many studies, since apoptosis induced by anti-sensing STAT3 has been observed in various cancer cell lines, STAT3 is considered a very promising new anticancer target. In addition, the present inventors recently confirmed that the compound of the following chemical formula I has an excellent activity inhibitory effect on the STAT3 protein and can be usefully used in the treatment of cancer.

[0006] <Chemical Formula 1> Since the compound of Chemical Formula I is an optically active drug, a process for optically isolating a specific form is essential during the manufacturing process. In particular, for mass production, a manufacturing method that reduces costs, number of processes, and process time while maintaining stable, excellent yield and optical purity is required.

[0007]

Prior Art Documents

[0008]

Patent Document

[0009] (Patent Document 1) Korean Patent Publication No. 10-2017-0081708

[0010]

Contents of the invention

[0011] [Technical Problem] The present invention provides a method for producing a compound of formula I or a solvate thereof with a stable and excellent yield and optical purity. The present invention provides an intermediate compound used in producing a compound of formula I or a solvate thereof and a method for producing the same.

[0012]

Technical Solution

[0013] <Chemical Formula 1> In chemical formula 1, chemical formula 2, chemical formula la, chemical formula 3 and chemical formula I

[0014] Ri is - S(=O)(=Ra)Rb,

[0015] Ra is 0 or loss,

[0016] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl,

[0017] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I,

[0018] R2 and R3 are each independently F, Br, Cl or I. In the present invention, the compound represented by chemical formula 1 means a mixture including a compound represented by chemical formula la and a compound represented by chemical formula lb.

[0019] <chemical formula la> <chemical formula lb> In the present invention, the compound represented by chemical formula 2 means a mixture including a compound represented by chemical formula 2a and a compound represented by chemical formula 2b.

[0020] <Chemical Formula 2a> <Chemical Formula 2b> In one embodiment, the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1 may include a step of reacting a compound represented by Chemical Formula 1 with quinidine. In the present invention, quinidine refers to a compound having an IUPAC name of (S)-(6-methoxyquinolin-4-yl)((IS,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanol. In one embodiment, the compound represented by Chemical Formula 1 and quinidine may be reacted with methanol (methanol,

[0021] The reaction can be carried out under MeOH), ethanol (ethanol, ETOH), propanol (propano 1, PrOH), isopropanol (isopropanol, i-PrOH), butanol (butanol, BuOH) or a mixture thereof, and most preferably, the reaction can be carried out under methanol or ethanol. In one embodiment, the step of preparing the compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1 can include the step of reacting the compound represented by Chemical Formula 1 with quinidine at 0 to 90 °C. In one embodiment, the compound represented by Chemical Formula 1 and quinidine can be mixed in an equivalent ratio of 1:0.8 to 1:1.3. For example, the compound represented by Chemical Formula 1 and quinidine can be mixed in an equivalent ratio of 1:0, 85 to 1:1.25. For example, the compound represented by Chemical Formula 1 and quinidine can be mixed in an equivalent ratio of 1:0.9 to 1:1.2. For example, the compound represented by Chemical Formula 1 and quinidine can be mixed in an equivalent ratio of 1:1 to 1:1.1. For example, the compound represented by Chemical Formula 1 and quinidine can be mixed in an equivalent ratio of 1:1.05. In one embodiment, in the step of preparing the compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 1 and quinidine in the presence of methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof, the methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof can be mixed in a volume of 1 to 100 times the weight of the compound represented by Chemical Formula 1. For example, methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof can be mixed in a volume of 1 to 80 times the weight of the compound represented by Chemical Formula 1. For example, methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof can be mixed in a volume of 1 to 70 times the weight of the compound represented by Chemical Formula 1.For example, methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof can be mixed in an amount of 1 to 60 times the weight of the compound represented by Chemical Formula 1. In one embodiment, in the step of preparing a compound represented by Chemical Formula 2 by reacting a compound represented by Chemical Formula 1 and quinidine in the presence of methanol, methanol can be mixed in an amount of 1 to 40 times the weight of the compound represented by Chemical Formula 1. For example, methanol can be mixed in an amount of 2 to 35 times the weight of the compound represented by Chemical Formula 1. For example, methanol can be mixed in an amount of 3 to 30 times the weight of the compound represented by Chemical Formula 1. For example, methanol can be mixed in an amount of 4 to 30 times the weight of the compound represented by Chemical Formula 1. For example, methanol can be mixed in an amount of 5 to 30 times the weight of the compound represented by Chemical Formula 1. In one embodiment, in the step of preparing a compound represented by Chemical Formula 2 by reacting a compound represented by Chemical Formula 1 and quinidine under ethanol, ethanol may be mixed in an amount of 3 to 60 times the weight of the compound represented by Chemical Formula 1. For example, ethanol may be mixed in an amount of 5 to 55 times the weight of the compound represented by Chemical Formula 1. For example, ethanol may be mixed in an amount of 10 to 50 times the weight of the compound represented by Chemical Formula 1. For example, ethanol may be mixed in an amount of 15 to 50 times the weight of the compound represented by Chemical Formula 1. For example, ethanol may be mixed in an amount of 20 to 50 times the weight of the compound represented by Chemical Formula 1. In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 1-1, and the compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1.

[0022] <Chemical Formula 1-1> In one embodiment, the step of preparing a compound represented by Chemical Formula 2-1 by reacting a compound represented by Chemical Formula 1-1 with quinidine in methanol or ethanol can be represented by the following reaction scheme 1.

[0023] [Reaction Formula 1] In one embodiment, the step of reacting a compound represented by Chemical Formula 1-1 and quinidine in methanol to prepare a compound represented by Chemical Formula 2-1 may be performed by mixing the compound represented by Chemical Formula 1-1 and quinidine in an equivalent ratio of 1:1.1 and mixing methanol in a volume 5 times the weight of the compound represented by Chemical Formula 1-1. In one embodiment, the step of recovering quinidine after the step of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1 may further include a step of recovering a compound represented by Chemical Formula 1. In one embodiment, the step of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1 may further include a step of recovering a compound represented by Chemical Formula 1. In one embodiment, the step of recovering quinidine and the compound represented by Chemical Formula 1 may further include a step of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1. In one embodiment, between the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1 and the step of preparing a compound represented by Chemical Formula 1a using the compound represented by Chemical Formula 2, a step of recovering quinidine may be further included. In one embodiment, between the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1 and the step of preparing a compound represented by Chemical Formula 1a using the compound represented by Chemical Formula 2, a step of recovering the compound represented by Chemical Formula 1 may be further included. In one embodiment, between the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1 and the step of preparing a compound represented by Chemical Formula 1a using the compound represented by Chemical Formula 2, a step of recovering quinidine and the compound represented by Chemical Formula 1 may be further included.In one embodiment, the method may include: preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering quinidine; recovering a compound represented by Chemical Formula 1; and preparing a compound represented by Chemical Formula la using the compound represented by Chemical Formula 2. In one embodiment, the method may include: preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering quinidine; recovering a compound represented by Chemical Formula 1; preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; and preparing a compound represented by Chemical Formula la using the compound represented by Chemical Formula 2. In one embodiment, the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering quinidine; and recovering a compound represented by Chemical Formula 1 may be performed repeatedly. In one embodiment, the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering quinidine; And after the step of recovering the compound represented by Chemical Formula 1 is repeatedly performed, the step of preparing the compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1 and the step of preparing the compound represented by Chemical Formula 1a using the compound represented by Chemical Formula 2 may be performed. In one embodiment, the step of preparing the compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; the step of recovering quinidine; and the step of recovering the compound represented by Chemical Formula 1 may be repeatedly performed two or more times. For example, the step may be repeatedly performed three or more times. For example, the step may be repeatedly performed four or more times. For example, the step may be repeatedly performed five or more times. For example, the step may be repeatedly performed six or more times.In one embodiment, the steps of preparing a compound represented by Formula 2 using a compound represented by Formula 1; recovering quinidine; and recovering the compound represented by Formula 1 may be repeated 10 times or less. For example, it may be repeated 9 times or less. For example, it may be repeated 8 times or less. For example, it may be repeated 7 times or less. In one embodiment, the steps of preparing a compound represented by Formula 2 using a compound represented by Formula 1; recovering quinidine; and recovering the compound represented by Formula 1 may be repeated at least 1 time and 10 times or less. For example, it may be repeated at least 1 time and 8 times or less. For example, it may be repeated at least 1 time and 6 times or less. For example, it may be repeated at least 1 time and 5 times or less. For example, it may be repeated at least 2 times and 10 times or less. For example, it may be repeated at least 2 times and 8 times or less. For example, it may be repeated at least 2 times and 6 times or less. For example, it may be repeated at least 2 times and 5 times or less. In one embodiment, the step of recovering quinidine may be carried out by adding 1,8-diazabicyclo[5.4.0]undec-7-ene (1,8-(pent3231but07010[5.4.1111(160-7-6116, DBU)). In one embodiment, the step of recovering quinidine may be carried out under methanol, ethanol, propanol, isopropanol, or a mixture thereof, and most preferably under methanol. In one embodiment, the step of recovering quinidine may be carried out by adding DBU under methanol, ethanol, propanol, isopropanol, or a mixture thereof. In one embodiment, the step of recovering quinidine may be carried out by adding DBU to a compound represented by Formula 2b under methanol, ethanol, propanol, isopropanol, or a mixture thereof.In one embodiment, the step of recovering quinidine may be performed to obtain a compound represented by Chemical Formula 1 and quinidine. In one embodiment, the step of recovering quinidine may be performed by adding DBU to a compound represented by Chemical Formula 2b in the presence of methanol, ethanol, propanol, isopropanol or a mixture thereof, thereby obtaining a compound represented by Chemical Formula 1 and quinidine. In one embodiment, the step of recovering the compound represented by Chemical Formula 1 may be performed by adding an acid. In one embodiment, the step of recovering the compound represented by Chemical Formula 1 may be performed by adding an acid to the compound represented by Chemical Formula 1 in a dissolved state. In one embodiment, the step of recovering the compound represented by Chemical Formula 1 can be performed by adding hydrochloric acid (HC1), sulfuric acid, acetic acid, or trifluoroacetic acid, and preferably, can be performed by adding hydrochloric acid. In one embodiment, by performing the step of recovering the compound represented by Chemical Formula 1, the compound represented by Chemical Formula 1 in a dissolved state can be obtained as a solid. In one embodiment, by performing the step of recovering the compound represented by Chemical Formula 1, the compound represented by Chemical Formula 1 in a solid state can be obtained from the compound represented by Chemical Formula 1 in a dissolved state. In one embodiment, the step of recovering the compound represented by Chemical Formula 1 can be performed by adding an acid to the compound represented by Chemical Formula 1 in a dissolved state, thereby obtaining the compound represented by Chemical Formula 1 in a solid state.In the method for preparing a compound of formula I or a solvate thereof according to the present invention, the compound of formula I or a solvate thereof can be prepared in a high yield due to repetition of the synthesis process and the recovery process as described above, and the compound of formula I or a solvate thereof can be prepared economically by reducing the manufacturing cost. In one embodiment, the step of preparing a compound of formula I or a solvate thereof using the compound of formula 2 may be a desalting process. In one embodiment, the step of preparing a compound of formula I or a solvate thereof using the compound of formula 2 may be performed by adding an acid. In one embodiment, the step of preparing a compound of formula I or a solvate thereof using the compound of formula 2 may be performed by adding hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid, and preferably, by adding hydrochloric acid. In one embodiment, the step of preparing the compound represented by the formula (la) using the compound represented by the formula (2) can be performed in the presence of methanol, ethanol, propanol, isopropanol or a mixture thereof, and preferably can be performed in the presence of methanol. In one embodiment, the step of preparing the compound represented by the formula (la) using the compound represented by the formula (2) can be performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid in the presence of methanol, ethanol, propanol, isopropanol or a mixture thereof. In one embodiment, the step of preparing the compound represented by the formula (la) using the compound represented by the formula (2) can be performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid in the presence of methanol. In one embodiment, the step of preparing the compound represented by the formula (la) using the compound represented by the formula (2) can be performed by adding hydrochloric acid in the presence of methanol, ethanol, propanol, isopropanol or a mixture thereof.In one embodiment, in the step of preparing a compound represented by Chemical Formula Ia using a compound represented by Chemical Formula 2, methanol, ethanol, propanol, isopropanol or a mixture thereof may be mixed in an amount of 1 to 20 times the weight of the compound represented by Chemical Formula 2. For example, methanol, ethanol, propanol, isopropanol or a mixture thereof may be mixed in an amount of 1 to 15 times the weight of the compound represented by Chemical Formula 2. For example, methanol, ethanol, propanol, isopropanol or a mixture thereof may be mixed in an amount of 1 to 10 times the weight of the compound represented by Chemical Formula 2. In one embodiment, in the step of preparing a compound represented by Chemical Formula Ia using a compound represented by Chemical Formula 2, methanol may be mixed in an amount of 3 to 10 times the weight of the compound represented by Chemical Formula 2. For example, methanol may be mixed in an amount of 4 to 8 times the weight of the compound represented by Chemical Formula 2. For example, methanol can be mixed in a volume of 4 to 6 times the weight of the compound represented by Chemical Formula 2. In one embodiment, in the step of preparing the compound represented by Chemical Formula Ia using the compound represented by Chemical Formula 2, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid can be at a concentration of 1 N to 20 N. For example, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid can be at a concentration of 1 N to 10 N. For example, hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid can be at a concentration of 1 N to 5 N. In one embodiment, in the step of preparing the compound represented by Chemical Formula Ia using the compound represented by Chemical Formula 2, hydrochloric acid can be at a concentration of 1 N to 5 N. For example, hydrochloric acid can be at a concentration of 1 N to 4 N. For example, hydrochloric acid can be at a concentration of 1 N to 3 N. For example, hydrochloric acid can have a concentration of 1N to 2N.In one embodiment, in the step of preparing a compound represented by Chemical Formula 1a using a compound represented by Chemical Formula 2, hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid may be mixed in a volume of 1 to 100 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid may be mixed in a volume of 1 to 80 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid may be mixed in a volume of 1 to 70 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid may be mixed in a volume of 1 to 60 times the weight of the compound represented by Chemical Formula 2. In one embodiment, in the step of preparing a compound represented by Chemical Formula Ia using a compound represented by Chemical Formula 2, hydrochloric acid may be mixed in an amount of 1 to 60 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid may be mixed in an amount of 3 to 55 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid may be mixed in an amount of 5 to 50 times the weight of the compound represented by Chemical Formula 2. For example, hydrochloric acid may be mixed in an amount of 10 to 50 times the weight of the compound represented by Chemical Formula 2. In one embodiment, in the step of preparing a compound represented by Chemical Formula Ia using a compound represented by Chemical Formula 2, hydrochloric acid having a concentration of 1N to 2N may be mixed in an amount of 5 to 50 times the weight of the compound represented by Chemical Formula 2. Preferably, hydrochloric acid having a concentration of 2N may be mixed in an amount of 10 to 50 times the weight of the compound represented by Chemical Formula 2. In one embodiment, the step of preparing a compound represented by the chemical formula la using a compound represented by the chemical formula 2 can be performed at 0 to 40°C.In one embodiment, the compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1, and the compound represented by Chemical Formula la may be a compound represented by Chemical Formula la-1.

[0024] <Chemical Formula 2-1> In one embodiment, the step of preparing a compound represented by chemical formula la-1 using a compound represented by chemical formula 2-1 can be represented by the following reaction scheme 2.

[0025] [Reaction Formula 2] In one embodiment, the step of preparing a compound represented by the formula la-1 using the compound represented by the formula 2-1 may include the step of obtaining a compound represented by the formula 2a-1 using the compound represented by the formula 2-1 and the step of preparing a compound represented by the formula la-1 through a desalting process of the compound. Here, the step of obtaining a compound represented by the formula 2a-1 using the compound represented by the formula 2-1 may be performed by washing and filtering the compound represented by the formula 2a-1 with a volume of methanol twice the weight of the compound. In addition, the step of preparing a compound represented by the formula 2a-1 through the desalting process of the compound represented by the formula 2a-1 may be performed by reacting the compound represented by the formula 2a-1 with a volume of methanol five times the weight of the compound and a volume of 2N hydrochloric acid 50 times the weight of the compound at 20 to 30 °C, filtering, and drying under vacuum.

[0026] <Chemical Formula 2a-l> In one embodiment, the step of preparing the compound represented by formula I or a solvate thereof using the compound represented by formula la and the compound represented by formula 3 can be performed through an amidation reaction. In one embodiment, the amidation reaction can be performed through various methods known in the art. In one embodiment, the step of preparing the compound represented by formula I or a solvate thereof using the compound represented by formula la and the compound represented by formula 3 can be performed by adding chlorophosphoric acid (POCh) in the presence of pyridine. In this case, the purity can be improved. In one embodiment, the step of preparing the compound represented by formula I or a solvate thereof using the compound represented by formula la and the compound represented by formula 3 can be performed at -10 to 30°C. Preferably, it can be performed at -10 to 20°C. In one embodiment, the compound represented by the chemical formula la may be a compound represented by the chemical formula la-1, the compound represented by the chemical formula 3 may be a compound represented by the chemical formula 3-1, and the compound represented by the chemical formula I may be a compound represented by the chemical formula 1-1.

[0027] <Chemical formula la-l>

[0028] <Chemical formula Il> In one embodiment, the step of preparing a compound represented by Chemical Formula 1-1 or a solvate thereof using a compound represented by Chemical Formula 1-1 and a compound represented by Chemical Formula 3-1 can be represented by the following Reaction Scheme 3. [Reaction Scheme 3] In one embodiment, the step of preparing a compound represented by chemical formula 1-1 using a compound represented by chemical formula la-1 and a compound represented by chemical formula 3-1 may be performed by mixing the compound represented by chemical formula la-1 and the compound represented by chemical formula 3-1 in an equivalent ratio of 1:1.2, adding pyridine in an amount of 10 times the weight of the compound represented by chemical formula la-1 and water in an amount of 0.06 times the weight of the compound represented by chemical formula la-1, cooling, and then adding POCls in three portions in amounts of 0.5 equivalents each based on the weight of the compound represented by chemical formula la-1. In one embodiment, the step of preparing a compound represented by chemical formula I or a solvate thereof using a compound represented by chemical formula la and a compound represented by chemical formula 3 may further include a step of preparing a solvate of the compound represented by chemical formula I using the compound represented by chemical formula I. In one embodiment, the step of preparing a solvate of a compound represented by Formula I using a compound represented by Formula I can be performed by adding tetrahydrofuran (THF) and water. In one embodiment, the compound represented by Formula I can be a compound represented by Formula 1-1.

[0029] <Chemical Formula 1-1> In one embodiment, the step of preparing a salt of a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 1-1 can be represented by the following reaction scheme 4.

[0030] [Reaction Formula 4] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 1-1, the compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1, the compound represented by Chemical Formula la may be a compound represented by Chemical Formula la-1, the compound represented by Chemical Formula 3 may be a compound represented by Chemical Formula 3-1, and the compound represented by Chemical Formula I may be a compound represented by Chemical Formula 1-1. In one embodiment, a method for preparing a compound represented by Chemical Formula 1-1 or a solvate thereof according to the present invention may be performed according to the following Reaction Scheme 5.

[0031] [Reaction Formula 5] In one embodiment, a compound represented by Chemical Formula 1-1 can be prepared by a method comprising the following steps: preparing a compound represented by Chemical Formula 6 using a compound represented by Chemical Formula 4 and a compound represented by Chemical Formula 5; preparing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6; preparing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7; and preparing a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 8.

[0032] <Chemical Formula 4>

[0033] <Chemical Formula 5>

[0034] Q

[0035] — Iw o

[0036] 『••'으 Y뉴' V •••서

[0037] In one embodiment, the step of preparing a compound represented by Chemical Formula 6 using a compound represented by Chemical Formula 4 and a compound represented by Chemical Formula 5 can be carried out by treating the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 with a base in an organic solvent. In one embodiment, the organic solvent may be dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran, 2 - methyltetrahydrofuran, acetonitrile (ACN), toluene (Tol), or a mixture thereof, and most preferably may be dimethylformamide. In one embodiment, the base may be potassium hydroxide (KOH), potassium carbonate (K2CO3), or cesium carbonate (Cs2CO3). In one embodiment, the step of preparing a compound represented by Chemical Formula 6 using a compound represented by Chemical Formula 4 and a compound represented by Chemical Formula 5 can be represented by the following Reaction Scheme 6.

[0038] [Reaction Scheme 6] In one embodiment, the step of preparing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6 can be performed by adding sodium methanesulfinate (MeSO2Na) in the presence of trifluoroacetic acid (TFA) and dichloromethane (DCM). In one embodiment, the step of preparing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6 can be performed by adding the compound represented by Chemical Formula 6 to a solution in which trifluoroacetic acid and dichloromethane are mixed. In this case, production efficiency can be improved. In one embodiment, trifluoroacetic acid and dichloromethane can be mixed in a volume ratio of 1:1 to 5:1. For example, trifluoroacetic acid and dichloromethane can be mixed in a volume ratio of 1:1 to 4:1. For example, trifluoroacetic acid and dichloromethane can be mixed in a volume ratio of 1:1 to 3:1. For example, trifluoroacetic acid and dichloromethane can be mixed in a volume ratio of 2:1. In one embodiment, the step of preparing a compound represented by chemical formula 7 using a compound represented by chemical formula 6 can be represented by the following reaction scheme 7. [Reaction scheme 7] In one embodiment, the step of preparing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6 may include a step of crystallizing with methanol. In this case, yield, quality, and production efficiency may be improved. In one embodiment, the step of preparing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7 may be performed by adding ceric ammonium nitrate (CAN) in a solvent. In one embodiment, in the step of preparing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7, the solvent may be water, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, or a mixture thereof, and preferably, ethanol. In one embodiment, the step of preparing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7 can be a relatively simple process in which a large amount of a compound represented by Chemical Formula 8 is prepared in excellent yield by adding ceric ammonium nitrate (CAN) in ethanol. In one embodiment, the step of preparing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7 can be represented by the following Reaction Scheme 8.

[0039] [Reaction Formula 8] In one embodiment, the step of preparing a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 8 can be performed by adding methyl thioglycolate and cesium carbonate (CS2CO3) under dimethylformamide. In one embodiment, the methyl thioglycolate can be added in portions. For example, 1.5 equivalents of methyl thioglycolate per 1 equivalent of the compound represented by Chemical Formula 8 can be slowly added dropwise, the reaction solution can be heated, 0.5 equivalents of methyl thioglycolate can be added after 1 hour, and 0.5 equivalents of methyl thioglycolate can be added once more at 30-minute intervals. In this case, the yield can be improved. In one embodiment, the step of preparing a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 8 can include a step of crystallizing at a pH of 2 to 3 and 15 to 25 °C. In this case, the yield can be improved. In one embodiment, the step of preparing a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 8 can be represented by the following reaction scheme 9.

[0040] [Reaction Formula 9] In one embodiment, the method for preparing a compound represented by Chemical Formula 1-1 according to the present invention can be performed according to the following Reaction Scheme 10. [Reaction Scheme 1 The present invention provides an intermediate compound for the preparation of a compound represented by the following chemical formula 2, or a solvate thereof, represented by the following chemical formula I:

[0041] <Chemical Formula 2> In chemical formula 2

[0042] Ri is - S(=O)(=Ra)Rb,

[0043] Ra is 0 or loss,

[0044] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl,

[0045] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I. The present invention provides a use of an intermediate compound represented by Chemical Formula 2 for the preparation of a compound represented by Chemical Formula I or a solvate thereof. In one embodiment, the intermediate compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1.

[0046] <Chemical Formula 2-1> In one embodiment, the intermediate compound represented by Chemical Formula 2-1 may be used for preparing a compound represented by Chemical Formula 1-1 or a solvate thereof. In the present invention, the compound represented by Chemical Formula 2 is a stable substance and can be easily obtained as a solid without a separate purification process. Since the compound represented by Chemical Formula 2 has excellent stability, it can be stably and easily used for preparing a compound of Chemical Formula I or a solvate thereof. In addition, the compound represented by Chemical Formula 2 according to the present invention has a good chiral resolution effect. That is, the compound represented by Chemical Formula 1 can be easily chiral resolved. The present invention provides a method for preparing an intermediate compound for preparing a compound represented by Chemical Formula I or a solvate thereof, comprising the step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1:

[0047] <Chemical Formula 1> <Chemical Formula 2> In chemical formula 1 and chemical formula 2

[0048] Ri is - S(=O)(=Ra)Rb,

[0049] Ra is 0 or loss,

[0050] Rb is H, C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylcarbonyl-C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl,

[0051] At least one of Ra or Rb may each independently be substituted with F, Br, Cl, or I. In one embodiment, the compound represented by Formula 1 may be the compound represented by Formula 1-1, and the compound represented by Formula 2 may be the compound represented by Formula 2-1.

[0052] <Formula 1-1> The method for preparing the compound represented by Formula 2 is substantially the same as that described for the step of preparing the compound represented by Formula 2 in the method for preparing the compound represented by Formula I or its solvate, so overlapping detailed descriptions are omitted. For example, the compound represented by Formula 2-1 may be prepared according to Scheme 1.

[0053] (1) The present invention provides a method for preparing a compound represented by Formula I or its solvate, comprising the following steps: preparing a compound represented by Formula 2 using the compound represented by Formula 1; preparing a compound represented by Formula la using the compound represented by Formula 2; and preparing a compound represented by Formula I or its solvate using the compound represented by Formula la and the compound represented by Formula 3.

[0054] <Formula 1> 소 스、 흐、 ~서 ※슨* •- •그 P

[0055] 0 ( 스…—《

[0056] ※、。•'人、、:;易''''s' bn

[0057] <Formula 2>

[0058] <Formula 3> In chemical formula 1, chemical formula 2, chemical formula la, chemical formula 3 and chemical formula I

[0059] Ri is - S(=O)(=Ra)Rb,

[0060] Ra is 0 or loss,

[0061] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl,

[0062] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I,

[0063] R2 and R3 are each independently F, Br, Cl or I.

[0064] (2) In (1), the step of preparing a compound represented by chemical formula 2 using a compound represented by chemical formula 1 may include a step of reacting the compound represented by chemical formula 1 with quinidine.

[0065] (3) In (1) or (2), the chemical formula is prepared by using a compound represented by chemical formula 1.

[0066] The step of preparing the compound represented by 2 may include a step of reacting the compound represented by chemical formula 1 with quinidine in the presence of methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof.

[0067] (4) In any one of (1) to (3), the step of preparing a compound represented by chemical formula 2 using a compound represented by chemical formula 1 may include a step of reacting the compound represented by chemical formula 1 with quinidine at 0 to 90°C.

[0068] (5) In any one of (2) to (4), the compound represented by chemical formula 1 and quinidine can be mixed in an equivalent ratio of 1:0.8 to 1:1.3.

[0069] (6) In any one of (3) to (5), methanol can be mixed in a volume of 1 to 40 times the weight of the compound represented by chemical formula 1.

[0070] (7) In any one of (3) to (6), ethanol can be mixed in a volume of 3 to 60 times the weight of the compound represented by chemical formula 1.

[0071] (8) In any one of (1) to (7), a step of recovering quinidine and a step of recovering the compound represented by formula 1 may be additionally included between the step of preparing a compound represented by formula 2 using a compound represented by formula 1 and the step of preparing a compound represented by formula 1a using a compound represented by formula 2.

[0072] (9) In (8), the step of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1, the step of recovering quinidine, and the step of recovering the compound represented by chemical formula 1 can be repeated.

[0073] (10) In (9), repetition can be performed 2 to 10 times.

[0074] (11) In any one of (8) to (10), the step of recovering quinidine can be performed by adding 1,8-diazabicyclo[5.4.iundec-7-ene.

[0075] (12) In any one of (8) to (11), the step of recovering the compound represented by chemical formula 1 can be performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.

[0076] (13) In any one of (1) to (12), the step of preparing a compound represented by the chemical formula la using a compound represented by the chemical formula 2 can be performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.

[0077] (14) In any one of (1) to (13), the step of preparing a compound represented by chemical formula I or a solvate thereof using a compound represented by chemical formula la and a compound represented by chemical formula 3 can be performed through an amidation reaction.

[0078] (15) In any one of (1) to (14), the compound represented by chemical formula 1 may be a compound represented by chemical formula 1-1, the compound represented by chemical formula 2 may be a compound represented by chemical formula 2-1, the compound represented by chemical formula la may be a compound represented by chemical formula la-1, the compound represented by chemical formula 3 may be a compound represented by chemical formula 3-1, and the compound represented by chemical formula I may be a compound represented by chemical formula 1-1.

[0079] <Chemical Formula 1-1>

[0080] <Chemical formula la-l>

[0081] <Chemical formula Il>

[0082] (16) In (15), the compound represented by Chemical Formula 1-1 can be produced by a method including a step of producing a compound represented by Chemical Formula 6 using a compound represented by Chemical Formula 4 and a compound represented by Chemical Formula 5; a step of producing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6; a step of producing a compound represented by Chemical Formula 8 using a compound represented by Chemical Formula 7; and a step of producing a compound represented by Chemical Formula 1-1 using a compound represented by Chemical Formula 8.

[0083] <Formula 4>

[0084] : r ''으厂"

[0085] HQ'" ''''■''서' S지

[0086] <Formula 5>

[0087] <Formula 6> <

[0088] <Formula 8>

[0089] (17) In (15) or (16), the step of preparing the compound represented by Formula la-1 using the compound represented by Formula 2-1 may include obtaining the compound represented by Formula 2a-1 using the compound represented by Formula 2-1 and preparing the compound represented by Formula la-1 through the desalting process of the compound. Here, the step of obtaining the compound represented by Formula 2a-1 using the compound represented by Formula 2-1 may be carried out by washing and filtering the compound represented by Formula 2-1 and methanol having a volume twice that of the weight of the compound. In addition, the step of preparing the compound represented by Formula la-1 through the desalting process of the compound represented by Formula 2a-1 may be carried out by reacting the compound represented by Formula 2a-1 with methanol having a volume five times that of the weight of the compound and 2N hydrochloric acid having a volume of 50 times at 20 to 30 °C, filtering, and drying under vacuum.

[0090] <Formula 2a-l>

[0091] (18) The present invention provides an intermediate compound for preparing a compound represented by Formula I or a solvate thereof, represented by the following Formula 2:

[0092] <Formula 2> In Formula 2

[0093] Ri is - S(=O)(=Ra)Rb,

[0094] Ra is 0 or loss,

[0095] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl,

[0096] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I.

[0097] (19) In (18), the compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1 below. <Chemical Formula 2-1>

[0098] (20) The present invention provides a method for producing an intermediate compound according to (17), which comprises a step of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1.

[0099] <Chemical Formula 1> In chemical formula 1 and chemical formula 2

[0100] Ri is - S(=O)(=Ra)Rb,

[0101] Ra is 0 or loss,

[0102] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino Cl-6 alkyl,

[0103] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I.

[0104]

Effect of the invention

[0105]

Form for Embodiment of the Invention

[0106] (Step 1) Synthesis of 2-chloro-4-(3,3-diethoxypropoxy)-1-methylbenzene (Formula 6)

[0107] 3-Chloro-4-methylphenol (formula 4) (l.Oeq, 100 g), Cs2C03 (l.Oeq, 228.52 g) and 3-chloro-1,1-diethoxypropane (formula 5) (1.2eq, 140.26 g) were added to DMF (lOvol, 1000 ml). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction was terminated when 3-chloro-4-methylphenol < 1.0%, and MTBE (10 vol, 1000 ml) and water (15 vol, 1500 ml) were added, extracted, and the aqueous layer was re-extracted with MTBE (5 vol, 500 ml). The organic layer was washed with brine (15 vol, 1500 ml), dehydrated with Na2S04 (2 times, 200 g), filtered, concentrated, and dried to obtain the title compound (purity 93.68%, in-situ). iH NMR (500 MHz, DMS0-d6) 5 ppm _A6.84Hz, 6H) , 1.97-2.01 (m, 2H) ,

[0108] 2.29 (s, 3H), 3.40-3.53 (m, 2H) , 3.58-3.68 (m, 2H) , 4.03(t, _A6.35Hz, 2H) , 4.72(t, _A5.62Hz, IH) , 6.84- 6.91(m, IH) , 7.01- 7.06(m, IH), 7.28 (d, 8.30 Hz, IH)

[0109] (Step 2) Synthesis of 7-chloro-6-methyl-4-(methylsulfonyl)chroman (formula 7)

[0110] TFA (3 vol, 600 ml) was added to DCM (8 vol, 1600 ml) and cooled to 0 to 10°C. The compound of formula 6 (l.Oeq, 200 g) obtained in step 1 was dissolved in DCM (2 vol, 200 ml), and slowly added dropwise to the DCM solution containing TFA while maintaining the temperature, and stirred for 10 minutes. MeSO2Na (1.5 eq, 112.27 g) was slowly added while paying attention to exotherm, and the mixture was stirred for an additional hour at 10 to 20°C. When the reaction was complete, water (8 vol, 1600 ml) was added, the layers were separated, and the aqueous layer was extracted once more with DCM (2 vol, 400 ml). The organic layers were collected again, washed with water (8 vol, 1600 ml), and sat. NaHCOs (5 vol, 1000 ml) was added to adjust the pH to 8–9, and the organic layer was washed with water (8 vol, 1600 ml). After dehydration by adding Na2S04 (2 times, 400 g), it was filtered, and the washing liquid was DCM (2 vol, 400 ml). The organic layer was concentrated. For purification, MeOH (lOvol, 2000 ml) was added, refluxed, stirred for 2–3 hours, slowly cooled to 20–30°C, stirred for 0.5–1 hour, filtered (washing liquid MeOH (2 vol, 400 ml)), and dried in vacuo to obtain the title compound (overall yield of steps 1 and 2: 50.47%, purity: 98.08%). iH NMR (500 MHz, DMS0-d6) 5 ppm 2.17-2.24(m, 1H) , 2.25(s, 3H) , 2.53— 2.55(m, 1H), 3.12(s, 3H), 4.23 (dt, ^11.11, 3.24Hz, IH) , 4.30- 4.40(m, IH) , 4.59(br d, •A4.89Hz, IH), 6.97(s, IH) , 7.34(s, IH)

[0111] (Step 3) Synthesis of 7-chloro-4-(methylsulfonyl)chroman-6-carbaldehyde (formula 8) The compound of formula 7 (l.Oeq, 90 g) obtained in step 2 and CAN (5.15eq, 974.53 g) were added to EtOH (7 vol, 630 ml). The reaction solution was heated to 40 to 50°C and stirred for 4 hours. When the reaction was complete (the compound of formula 7 obtained in step 2 <3%), the inside of the reactor was cooled to 25 5°C. Water (20 vol, 1800 ml) was added, stirred at the same temperature for 1 hour, filtered, and dried in vacuum to obtain the title compound (yield 86.79%, purity 96.66%). iH NMR (500 MHz, DMS0-d6) 5 ppm 2.23-2.33 (m, 1H) , 2.53— 2.63(m, 1H) , 3.17(s, 3H), 4.38- 4.43(m, IH) , 4.45- 4.51(m, IH) , 4.78(br d, _A4.89Hz, IH) , 7.18(s, IH) , 7.98(s, IH), 10.19(s, IH)

[0112] (Step 4) Synthesis of 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid (Formula 1-1) The compound of formula 8 (leq, 80 g) obtained in Step 3 and Cs2C03 (3 eq, 284.64 g) were added to DMF (8 vol, 640 ml), and methyl thioglycolate (1.5 eq, 46.6 g) was dissolved in DMF (2 vol, 160 ml) and slowly added dropwise to the reaction solution. The reaction solution was heated to 70–80°C, and after 1 hour of heating, methyl thioglycolate (0.5 eq, 15.45 g) was slowly added dropwise, and methyl thioglycolate (0.5 eq, 15.45 g) was added once more at 30-minute intervals. When the reaction was complete, the reaction solution was cooled to 20–30°C, and water (20 vol, 1600 ml) and DCM (20 vol, 1600 ml) were added and extracted. The extracted aqueous layer was washed by adding DCM (20 vol, 1600 ml), and the reaction solution was cooled to 15–25°C and the pH was adjusted to 2–3 with 4 N HC1. The mixture was stirred at the same temperature for 1 hour and filtered. The title compound was obtained by washing once with EtOH (1 vol, 80 ml) and three times with hexane (3 vol, 240 ml), and drying the filtered solid in vacuo (yield 92.95%, purity 96.70%). ppm 2.27-2.36(m, IH) , 2.58— 2.64(m, IH) , 3.16(s, 3H), 4.28- 4.34(m, 1H) , 4.43- 4.50(m, 1H) , 4.81(br d, _A3.91Hz, 1H) , 7.53(s, 1H) , 8.05(d, _A5.37Hz, 2H) , 13.36(br s, 1H)

[0113] (Step 5) Synthesis of (1S,2R,4S,5R)-2-((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidine-1-ium 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylate (Formula 2-1)

[0114] (a) The compound of formula 1-1 (l.Oeq, 80 g), quinidine (l.leq, 91.40 g), and MeOH (5 vol, 400 ml) obtained in the above step 4 were charged into the reactor. The reaction solution was heated to 60 5°C and stirred for 30 minutes, then cooled to 25 5°C and stirred for 3 hours to obtain the title compound. Thereafter, the solution was filtered (washed with cold MeOH (2 vol, 160 ml)) and dried under vacuum to obtain the compound of formula 2a-1.

[0115] (b) DBU (leq, 39 g) was added to the filtrate, the inside of the reactor was heated to 50–55°C, and stirred for 0.5 h. The reaction was completed when ee < 2.0% as confirmed by IPC (chiral HPLC). The reaction solution was cooled to 20 sq 5°C, stirred for 0.5–1.0 h, and the precipitated solid was filtered and vacuum-dried to recover quinidine.

[0116] (c) The inside of the reactor containing the filtrate was cooled to below 10°C. IN HC1 (5 vol, 400 ml) was added to adjust the pH to 1 to 2, and the inside of the reactor was maintained at 0 to 10°C, followed by stirring for 0.5 to 1 hour. The precipitated solid was filtered, washed with MeOH (2 vol), and vacuum-dried to recover the compound of chemical formula 1-1 obtained in step 4. Using the compound of chemical formula 1-1 and quinidine obtained in the above step 4 recovered in this way, (a) to (the process was repeated twice and then proceeded to process (a). (d) The compound of chemical formula 2a-1 (leq, 135 g) and EtOH (20 vol, 2700 ml) were added to the reactor, and the inside of the reactor was heated to 70 to 80°C. The inside of the reactor was stirred for 1 to 2 hours, cooled to 20 to 30°C, stirred for 1 hour, filtered (washed with EtOH (3 vol, 405 ml)), and vacuum-dried (yield 74.99%, ee 99.32%). iH NMR (500 MHz, DMS0-d6) 5 ppm 1H) , 1.72(m, 2H) , 1.87(m, 1H) ,

[0117] 2.22(m, IH), 2.30(m, IH) , 2.52- 2.64(m, 2H) , 3.08(m, IH) , 3.15(s, 3H) , 3.17(s, IH), 3.32(m, 2H), 3.47(m, IH) , 3.86(m, IH) , 4.00(m, 3H) , 4.24- 4.30(m, IH) , 4.40- 4.49(m, IH), 4.77(br d, _A4.58Hz, IH) , 5.15- 5.25(m, 2H) , 6.04- 6- 18(m, 2H) , 6.44(br s, IH) , 7.38- 7.44(m, 2H) , 7.58- 7.65(m, 2H) , 7.70(s, IH) , 7.94(s, IH) , 7.96(d, _A9.16Hz, IH) , 8.75(m, IH)

[0118] (Step 6) Synthesis of (S)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid (formula la-1) In a reactor, the compound of formula 2a-1 (l.Oeq, 120 g) obtained in step 5 and MeOH (5 vol, 600 ml) were added, and 2N HC1 (50 vol, 6000 ml) was added dropwise. The reaction solution was stirred for 1 hour while maintaining it at 20 to 30°C, and the IPC was checked. The reaction was terminated when quinidine < 1.0%. The resulting solid was filtered and washed sequentially with water (5 vol, 600 ml), cold EtOH (l vol, 120 ml), and heptane (3 vol, 360 ml). The filtered solid was vacuum dried to obtain the title compound (ee 99.50%, purity 99.86%, yield 91.6%, overall yield of steps 5 and 6 68.69%). ppm 2.28-2.37(m, IH) , 2.54— 2.70(m, IH) , 3.16(s, 3H), 4.29-4.35(m, 1H) , 4.48(td, ^11.48, 2.44Hz, 1H) , 4.81(br d, _A4.40Hz, 1H) , 7.54(s, 1H), 8.06(s, 2H) , 13.33(br s, 1H)

[0119] (Step 7) (S)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide (Formula 1-1) In a synthesis reactor, the compound of formula la-1 obtained in Step 6 (leq, 45 g), the compound of formula 3-1 obtained in the above Preparation Example (1.2 eq, 44.1 g), pyridine (lOvol, 450 ml) and water (0.06 vol, 27 ml) were added and cooled to 0 5°C. POC13 (0.5 eq, 11.0 g) was added in three portions, and the inside of the reactor was heated to 10 5°C and stirred for 1 hour. When the compound of chemical formula la-1 obtained in the above step 6 was <1.0%, the reaction was terminated, and 2N HC1 (20 vol, 900 ml) was slowly added dropwise at the same temperature for 2 hours. The reaction solution was heated to 20 to 30 °C, stirred for 1 hour, and then filtered (washed with water (lOvol, 450 ml)). The filtered solid was placed in the reactor, and water (10 vol, 450 ml) and 2N HC1 (10 vol, 450 ml) were added, stirred for 1 hour, filtered (washed with water (10 vol, 450 ml)), and dried under vacuum to obtain the title compound (yield 103.98%, purity 96.34%). iH NMR (500 MHz, DMS0-d6) 5 ppm 2.30-2.38(m, 1H) , 2.59— 2.66(m, 1H) , 3.16(s, 3H), 4.30- 4.34(m, IH) , 4.45- 4.52(m, IH) , 4.81(br d, g3.91, IH) , 7.26(m, 2H) , 7.31(s, IH), 7.52(m, 2H) , 7.58(s, IH) , 7.66(s, IH) , 8.06(s, IH) , 8.31(s, IH) , 10.93(s, IH)

[0120] (Step 8) Synthesis of THF solvate of (S)-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide In a reactor, the compound of formula 1-1 obtained in step 7 (l.Oeq, 80 g), THF (9 vol, 720 ml) and water (0.5 vol, 40 ml) were added and dissolved. The solution was filtered using a 0.65 um housing filter and washed using THF (Ivo 1, 80 ml). Water (20 vol, 1600 ml) was added to the reactor containing the filtered solution.

[0121] After stirring at 20-30°C for 1 hour, it was filtered (washing solution was 30% THF in H2O (2 vol, 160 ml)). The filtered solid was vacuum-dried to confirm the L-form (XRD: L-form confirmation). The dried solid was placed in a reactor, THF (5 vol, 400 ml) was added, the temperature was raised to 60-70°C, and the mixture was stirred for 0.5-1 hour. After cooling the inside of the reactor to 20-30°C, it was stirred at that temperature for 3 hours and filtered. The title compound was obtained by washing with cooled THF (2 vol, 160 ml) and vacuum-drying (yield 80.06%, purity 99.93%). iH NMR (500 MHz, DMS0-d6) 5 ppm 1.72-1 ,79(THF) , 2.30— 2.38(m, 1H) , 2.62(br dd, ^15.14, 2.44Hz, IH) , 3.16(s, 3H) , 3.57-3 ,62(THF) , 4.30— 4.35(m, IH) , 4.48(td, •All.60, 2.69Hz, IH) , 4.81(br d, _A3.91Hz, IH) , 7.24- 7.28(m, 2H) , 7.31(s, IH) , 7.50-7.54(m, 2H), 7.58(s, IH), 7.66(s, IH), 8.07(s, IH), 8.30(s, IH), 10.92(s, IH) Although the above has been described with reference to preferred embodiments of the present invention, it will be understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention as set forth in the claims below.

Claims

49 【Scope of Claims】 【 Claim 11 A method for producing a compound represented by formula I or a solvate thereof, comprising: a step of producing a compound represented by formula 2 using a compound represented by formula 1; a step of producing a compound represented by formula la using a compound represented by formula 2; and a step of producing a compound represented by formula I or a solvate thereof using the compound represented by formula la and the compound represented by formula 3: <화학식 1> <화학식 la> <Chemical Formula 3> 50 In chemical formula 1, chemical formula 2, chemical formula la, chemical formula 3 and chemical formula I Ri is - S(=O)(=Ra)Rb, Ra is 0 or failure, Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl, At least one of Ra or Rb may be independently substituted with F, Br, Cl or I, R 2 and R3 are each independently F, Br, Cl or I. 【

2. In claim 1, the step of preparing the compound represented by chemical formula 2 using the compound represented by chemical formula 1 includes the step of reacting the compound represented by chemical formula 1 with quinidine. 51 A method for producing a compound represented by chemical formula I or a solvate thereof.

3. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the step of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1 in claim 1 comprises a step of reacting a compound represented by chemical formula 1 with quinidine in the presence of methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof. 【

4. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the step of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1 in claim 1 comprises a step of reacting a compound represented by chemical formula 1 with quinidine at 0 to 90 °C. 【

5. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 2, the compound represented by chemical formula 1 and quinidine are mixed in an equivalent ratio of 1:0.8 to 1:1.

3.

6. In claim 3, A method for producing a compound represented by chemical formula I or a solvate thereof, wherein methanol is mixed in an amount of 1 to 40 times the weight of the compound represented by chemical formula 1. 【

7. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 3, ethanol is mixed in a volume of 3 to 60 times the weight of the compound represented by chemical formula 1.

8. A method for producing a compound represented by formula I or a solvate thereof, wherein the method further comprises a step of recovering quinidine and a step of recovering the compound represented by formula 1 between the step of producing a compound represented by formula 2 using the compound represented by formula 1 and the step of producing a compound represented by formula la using the compound represented by formula 2. 【A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the steps of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1, recovering quinidine, and recovering the compound represented by chemical formula 1 in claim 8 are repeated.

10. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the repetition is performed 2 to 10 times in claim 9.

11. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 8, the step of recovering quinidine is performed by adding 1,8-diazabicyclo[5.4.iundec-7-ene.

12. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the step of recovering the compound represented by chemical formula 1 in claim 8 is performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.

13. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the step of producing a compound represented by chemical formula la using a compound represented by chemical formula 2 in claim 1 is performed by adding hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.

14. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 1, the step of producing a compound represented by chemical formula I or a solvate thereof using a compound represented by chemical formula la and a compound represented by chemical formula 3 is performed through an amidation reaction.

15. A method for producing a compound represented by formula I or a solvate thereof, wherein in claim 1, the compound represented by formula 1 is a compound represented by formula 1-1, the compound represented by formula 2 is a compound represented by formula 2-1, the compound represented by formula la is a compound represented by formula la-1, the compound represented by formula 3 is a compound represented by formula 3-1, and the compound represented by formula I is a compound represented by formula 1-1: <화학식 1-1> <Chemical Formula 2-1> 55 <화학식 3-1>

16. In claim 15, the compound represented by chemical formula 1-1 is prepared by using a compound represented by chemical formula 4 and a compound represented by chemical formula 5. A method for producing a compound represented by chemical formula I or a solvate thereof, which is produced by a method comprising: a step of producing a compound represented by chemical formula 6; a step of producing a compound represented by chemical formula 7 using the compound represented by chemical formula 6; a step of producing a compound represented by chemical formula 8 using the compound represented by chemical formula 7; and a step of producing a compound represented by chemical formula 1-1 using the compound represented by chemical formula 8: <화학식 4> <Chemical Formula 5> < <화학식 7> <Chemical Formula 8> 57

17. An intermediate compound for the production of a compound represented by the following chemical formula 2, a compound represented by the following chemical formula I, or a solvate thereof: <화학식 2> In chemical formula 2 Ri is - S(=O)(=Ra)Rb, Ra is 0 or failure, Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl, At least one of Ra or Rb may be independently substituted with F, Br, Cl or I. 【

18. In claim 17, the compound represented by chemical formula 2 is a compound represented by chemical formula 2-1 below, a compound represented by chemical formula I or a solvate thereof. 58 Intermediate compounds for manufacturing: <화학식 2-1> 【A method for producing an intermediate compound according to claim 17, comprising the step of producing a compound represented by chemical formula 2 using a compound represented by chemical formula 1: <화학식 1> In chemical formula 1 and chemical formula 2 Ri is - S(=O)(=Ra)Rb, 59 Ra is 0 or failure, Rb is H, Cl-6 alkyl, Cl-6 alkoxy- Cl-6 alkyl, Cl-6 alkylcarbonyl- Cl-6 alkyl, C2-7 alkenyl, amino, or amino C1-6 alkyl, At least one of Ra or Rb may be independently substituted with F, Br, Cl or I.

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