Intermediate compound used in preparing heterocycle derivative, method for preparing same, 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, Cl-6alkyl, Cl-6alkoxy- Cl-6alkyl, Cl-6alkylcarbonyl- Cl-6alkyl, C2-

[0017] 7-alkenyl, amino, or amino C1-6 alkyl,

[0018] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I,

[0019] 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.

[0020] <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.

[0021] <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 the compound represented by Chemical Formula 1 with brucine. In the present invention, brucine refers to a compound whose IUPAC name is 2,3-Dimethoxystrychnidin-10-one. In one embodiment, the compound represented by Chemical Formula 1 and brucine can be reacted in the presence of methanol (MeOH), ethanol (EtOH), propanol (propano 1, PrOH), isopropanol (i-PrOH), methyl chloride (MC), acetonitrile (ACN), chloroform or a mixture thereof, and preferably in the presence of methanol, methyl chloride or acetonitrile. 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 brucine at 15 to 100 °C. In one embodiment, the compound represented by Chemical Formula 1 and brucine 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 brucine can be mixed at an equivalent ratio of 1:0.85 to 1:1.25. For example, the compound represented by Chemical Formula 1 and brucine can be mixed at an equivalent ratio of 1:0.9 to 1:1.2. For example, the compound represented by Chemical Formula 1 and brucine can be mixed at an equivalent ratio of 1:1 to 1:1.1. For example, the compound represented by Chemical Formula 1 and brucine can be mixed at an equivalent ratio of 1:1.05.In one embodiment, in the step of preparing a compound represented by Chemical Formula 2 by reacting a compound represented by Chemical Formula 1 with brucine in the presence of methanol, ethanol, propanol, isopropanol, methyl chloride, acetonitrile, chloroform or a mixture thereof, methanol, ethanol, propanol, isopropanol, methyl chloride, acetonitrile, chloroform or a mixture thereof may 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, methyl chloride, acetonitrile, chloroform or a mixture thereof may 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, methyl chloride, acetonitrile, chloroform or a mixture thereof can be mixed in an amount of 1 to 70 times the weight of the compound represented by Chemical Formula 1. For example, methanol, ethanol, propanol, isopropanol, methyl chloride, acetonitrile, chloroform 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 reacting the compound represented by Chemical Formula 1 and brucine in methanol to prepare the compound represented by Chemical Formula 2, methanol can be mixed in an amount of 5 to 50 times the weight of the compound represented by Chemical Formula 1. For example, methanol can be mixed in an amount of 20 to 40 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 with brucine in the presence of methyl chloride, methyl chloride may be mixed in a volume 5 to 50 times the weight of the compound represented by Chemical Formula 1. For example, methyl chloride may be mixed in a volume 20 to 40 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 brucine in acetonitrile, acetonitrile may be mixed in a volume of 10 to 150 times the weight of the compound represented by Chemical Formula 1. For example, acetonitrile may be mixed in a volume of 80 to 120 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> <Chemical Formula 2-1> In one embodiment, the step of reacting a compound represented by Chemical Formula 1-1 with brucine in methanol, methyl chloride or acetonitrile to produce a compound represented by Chemical Formula 2-1 can be represented by the following Reaction Scheme 1.

[0023] [Reaction Formula 1] In one embodiment, a compound represented by Chemical Formula 1-1 and brucine can be reacted in methanol to produce a compound represented by Chemical Formula 2-1. At this time, the compound represented by Chemical Formula 1 and brucine can be mixed in an equivalent ratio of 1:1.05, and methanol can be mixed in an equivalent ratio of 1:1.05.

[0024] 1-1 can be mixed in a volume 32 times the weight of the compound represented by formula 1. In one embodiment, a step of recovering brucine may be further included after the step of preparing a compound represented by formula 2 using the compound represented by formula 1. In one embodiment, a step of recovering a compound represented by formula 1 may be further included after the step of preparing a compound represented by formula 2 using the compound represented by formula 1. In one embodiment, a step of recovering brucine and the compound represented by formula 1 may be further included after the step of preparing a compound represented by formula 2 using the compound represented by formula 1. In one embodiment, a step of recovering brucine may be further included between the step of preparing a compound represented by formula 2 using the compound represented by formula 1 and the step of preparing a compound represented by formula 1a using the compound represented by formula 2. 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 1 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 1 using the compound represented by Chemical Formula 2, a step of recovering brucine and the compound represented by Chemical Formula 1 may be further included. In one embodiment, the method may include a step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; a step of recovering a compound represented by Chemical Formula 1; a step of recovering brucine; and a step of preparing a compound represented by Chemical Formula 1 using a 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 the compound represented by Chemical Formula 1; recovering brucine; 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 steps of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; recovering the compound represented by Chemical Formula 1; and recovering brucine may be performed repeatedly. In one embodiment, after the steps of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; recovering the compound represented by Chemical Formula 1; and recovering brucine are repeatedly performed, the steps of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; recovering the compound represented by Chemical Formula 1; and recovering brucine may be performed, and the steps of 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 may be performed. In one embodiment, the steps of preparing a compound represented by Chemical Formula 2 using the compound represented by Chemical Formula 1; The steps of recovering a compound represented by Chemical Formula 1; and recovering brucine may be performed repeatedly two or more times. For example, the steps may be performed repeatedly three or more times. In one embodiment, the steps of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering a compound represented by Chemical Formula 1; and recovering brucine may be performed repeatedly five or fewer times. For example, the steps may be performed repeatedly four or fewer times. In one embodiment, the steps of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; recovering a compound represented by Chemical Formula 1; and recovering brucine may be performed repeatedly one or more times and five or fewer times. For example, the steps may be performed repeatedly one or more times and three or fewer times.For example, it can be performed repeatedly one or more times and two or less times. In one embodiment, the step of recovering the compound represented by Chemical Formula 1 can be performed through a desalting process and a racemization process. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed by adding an acid. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed by adding hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid, and preferably can be performed by adding hydrochloric acid. In one embodiment, the hydrochloric acid used in the desalting process can have a concentration of 0.1N to 15N. For example, the hydrochloric acid used in the desalting process can have a concentration of 0.5N to 15N. For example, the hydrochloric acid used in the desalting process can have a concentration of 1N to 11N. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed under water, methanol, ethanol, propanol, isopropanol, or a mixture thereof, and preferably under water. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed by adding hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or phosphoric acid under water, methanol, ethanol, propanol, isopropanol, or a mixture thereof. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed by adding hydrochloric acid under water, methanol, ethanol, propanol, isopropanol, or a mixture thereof. In one embodiment, the desalting process for recovering the compound represented by Chemical Formula 1 can be performed by adding hydrochloric acid under water, methanol, ethanol, propanol, isopropanol, or a mixture thereof. In one embodiment, the desalination process to recover the compound represented by Chemical Formula 1 can be performed under water by adding hydrochloric acid.In one embodiment, the racemization process for recovering the compound represented by Formula 1 can be carried out by adding a base under a solvent and then adding an acid. In one embodiment, the solvent used in the racemization process may be methanol, ethanol, propanol, isopropanol, tetrahydrofuran, water, or a mixture thereof, and preferably may be water, methanol, or a mixture of tetrahydrofuran and water. In one embodiment, the base used in the racemization process may be sodium hydroxide (NaOH), lithium hydroxide (LiOH), or 1,8-diazabicyclo[5.4.0]undec-7-ene (1,8-diazabicyclo[5.4.0]undec-7-ene, DBU). In one embodiment, the compound represented by Formula 1b and the base in the racemization process can be mixed in an equivalent ratio of 1:1 to 1:20. For example, the compound represented by Formula 1b and the base can be mixed in an equivalent ratio of 1:1 to 1:15. For example, the compound represented by Formula 1b and the base can be mixed in an equivalent ratio of 1:1 to 1:10. In one embodiment, in the racemization process, the solvent can be mixed in a volume 1 to 10 times the weight of the compound represented by Formula 1b. For example, the solvent can be mixed in a volume 2.5 to 7 times the weight of the compound represented by Formula 1b. In one implementation example, the racemization process can be carried out by adding sodium hydroxide to the compound of Formula 1b-1 under water and then adding hydrochloric acid. At this time, the compound represented by Formula 1b-1 and sodium hydroxide can be mixed in an equivalent ratio of 1:3, and water can be mixed in a volume 2.5 times the weight of the compound represented by Formula 1b-1. In one embodiment, the acid used in the racemization process may be hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or phosphoric acid, and preferably may be hydrochloric acid. In one embodiment, the hydrochloric acid used in the racemization process may have a concentration of 1N to 6N.In one embodiment, the step of recovering brucine may be performed by adding a base. In one embodiment, the base may be sodium hydroxide. In one embodiment, the step of recovering brucine may be performed by adjusting the pH of the filtrate after recovering the compound represented by Chemical Formula 1-1 to 9 or higher with a sodium hydroxide solution, filtering and vacuum-drying the obtained solid. In the method for preparing a compound of Chemical Formula I or a solvate thereof according to the present invention, the compound of Chemical Formula I or a solvate thereof may be prepared in a high yield due to the repetition of the synthesis process and the recovery process as described above, and the compound of Chemical Formula I or a solvate thereof may be prepared economically by reducing the manufacturing cost. In one embodiment, the step of preparing a compound represented by Chemical Formula I using a compound represented by Chemical Formula 2 may be a desalting process. In one embodiment, the step of preparing a compound represented by Chemical Formula I using a compound represented by Chemical Formula 2 may be performed by adding an acid. In one embodiment, the step of preparing a compound represented by the formula Ia using a compound represented by the formula 2 can be performed by adding hydrochloric acid (HC1), sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid, and preferably, hydrochloric acid can be performed. In one embodiment, in the step of preparing a compound represented by the formula Ia using a compound represented by the formula 2, the hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid can be at a concentration of 0.1 N to 20 N. For example, the hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid can be at a concentration of 0.1 N to 15 N.In one embodiment, in the step of preparing a compound represented by the formula la using a compound represented by the formula 2, the hydrochloric acid may have a concentration of 0.1 N to 15 N. For example, the hydrochloric acid may have a concentration of 0.5 N to 15 N. Preferably, the hydrochloric acid may have a concentration of 1 N to 11 N. In one embodiment, the step of preparing a compound represented by the formula la using a compound represented by the formula 2 may be performed under water, methanol, ethanol, propanol, isopropanol, dichloromethane or a mixture thereof, and preferably may be performed under water or dichloromethane. In one embodiment, the step of preparing a compound represented by the formula la using a compound represented by the formula 2 may be performed by adding hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid under water, methanol, ethanol, propanol, isopropanol, dichloromethane or a mixture thereof. In one embodiment, the step of preparing a compound represented by formula la using a compound represented by formula 2 can be performed by adding hydrochloric acid in the presence of water, methanol, ethanol, propanol, isopropanol, dichloromethane or a mixture thereof. In one embodiment, the step of preparing a compound represented by formula la using a compound represented by formula 2 can be performed by adding hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or phosphoric acid in the presence of water, dichloromethane or a mixture thereof. In one embodiment, the step of preparing a compound represented by formula la using a compound represented by formula 2 can be performed by adding hydrochloric acid in the presence of water, dichloromethane or a mixture thereof. In one embodiment, in the step of preparing a compound represented by formula la using a compound represented by formula 2, water can be mixed in a volume that is 10 to 20 times the weight of the compound represented by formula 2.In one embodiment, in the step of preparing a compound represented by the formula la using a compound represented by the formula 2, dichloromethane may be mixed in an amount of 10 to 20 times the weight of the compound represented by the formula 2. In one embodiment, in the step of preparing a compound represented by the formula la using a compound represented by the formula 2, hydrochloric acid may be mixed in an amount of 10 to 120 times the weight of the compound represented by the formula 2. In one embodiment, in the step of preparing a compound represented by the formula la using a compound represented by the formula 2, hydrochloric acid having a concentration of 1 N to 2 N may be mixed in an amount of 80 to 120 times the weight of the compound represented by the formula 2. In one embodiment, in the step of preparing a compound represented by the formula la using a compound represented by the formula 2, hydrochloric acid having a concentration of 10 N to 11 N may be mixed in an amount of 10 to 20 times the weight of the compound represented by the formula 2. In one embodiment, the step of preparing a compound represented by chemical formula la using a compound represented by chemical formula 2 may be performed at 10 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. <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 adding a solid obtained by cooling the compound represented by the formula 2-1 to 25 to 30 °C, filtering it, and ACN, heating it to 80 to 85 °C, stirring it for 4 to 5 hours, cooling it to 25 to 30 °C, and filtering it, repeating the steps twice more. In addition, the step of desalting the compound represented by Chemical Formula 2a-1 may be performed by reacting the compound represented by Chemical Formula 2a-1, water in an amount 15 times the weight of the compound, and hydrochloric acid in a concentration of 10N to 11N in an amount 15 times the weight of the compound, at 20 to 30 °C, filtering, and vacuum drying.

[0026] <Chemical Formula 2a-l> In one embodiment, the step of preparing a compound represented by formula I or a solvate thereof using a compound represented by formula la and a 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 a compound represented by formula I or a solvate thereof using a compound represented by formula la and a 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 a compound represented by formula I or a solvate thereof using a compound represented by formula la and a 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 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.

[0027] <Chemical formula la-1>

[0028] <

[0029] <Chemical Formula 1-1> 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 la-1 and a compound represented by chemical formula 3-1 can be represented by the following reaction scheme 3.

[0030] [Reaction Formula 3] In one embodiment, the step of preparing a compound represented by Formula I or a solvate thereof using a compound represented by Formula la and a compound represented by Formula 3 may further include a step of preparing a solvate of a compound represented by Formula I using a compound represented by 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 may be performed by adding tetrahydrofuran (THF) and water. In one embodiment, the compound represented by Formula I may be a compound represented by Formula 1-1.

[0031] <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. [Reaction Scheme 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.

[0032] [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.

[0033] <Chemical Formula 4>

[0034] <Chemical Formula 5>

[0035] 0B

[0036] EtO'、'"'"'。

[0037] <Chemical Formula 6> 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 performed 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 can be dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile (ACN), toluene (Tol), or a mixture thereof, and preferably dimethylformamide. In one embodiment, the base can 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 Formula 6] '※ Factory 9B 〈Cold-sauce QEi f-se'"'

[0039] HO*”' "'bird'" Cl * E。 ■'、three DMF EtO"'、—。'〜。 1In one embodiment, the step of preparing a compound represented by Chemical Formula 7 using a compound represented by Chemical Formula 6 may 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 may 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 may be improved. In one embodiment, trifluoroacetic acid and dichloromethane may be mixed in a volume ratio of 1:1 to 5:1. For example, trifluoroacetic acid and dichloromethane may 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. 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. In one embodiment, the step of preparing a compound represented by Chemical Formula 1 using a compound represented by Chemical Formula 8 can be performed by adding methyl thioglycolate and cesium carbonate (CS2CO3) in dimethylformamide. In one embodiment, the methyl thioglycolate can be introduced in portions. 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 pH 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.

[0041] [Reaction Formula 1 The present invention provides an intermediate compound for the preparation of a compound represented by the following chemical formula 2, a compound represented by the following chemical formula I, or a solvate thereof:

[0042] <Chemical Formula 2> In chemical formula 2

[0043] Ri is - S(=O)(=Ra)Rb,

[0044] Ra is 0 or loss,

[0045] Rb is H, C1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, C1-6 alkylcarbonyl- C1-6 alkyl, C2 -

[0046] 7-alkenyl, amino, or amino C1-6 alkyl,

[0047] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I. In one embodiment, the intermediate compound represented by Chemical Formula 2 may be a compound represented by Chemical Formula 2-1.

[0048] <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:

[0049] <Chemical Formula 1> In chemical formula 1 and chemical formula 2

[0050] Ri is - S(=O)(=Ra)Rb,

[0051] Ra is 0 or loss,

[0052] 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,

[0053] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I. The present invention provides the 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 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.

[0054] <Chemical Formula 1-1> The method for preparing the compound represented by the above chemical formula 2 is substantially the same as that described for the step for preparing the compound represented by the chemical formula 2 among the methods for preparing the compound of the chemical formula I or a solvate thereof, and therefore, redundant detailed descriptions are omitted. For example, the compound represented by the above chemical formula 2-1 can be prepared according to the above reaction scheme 1.

[0055] (1) The present invention provides a method for preparing a compound represented by Chemical Formula I or a solvate thereof, comprising the following steps: a step of preparing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1; a step of preparing a compound represented by Chemical Formula I using a compound represented by Chemical Formula 2; and a step of preparing a compound represented by Chemical Formula I or a solvate thereof using a compound represented by Chemical Formula I and a compound represented by Chemical Formula 3.

[0056] <Chemical Formula 1> In chemical formula 1, chemical formula 2, chemical formula la, chemical formula 3 and chemical formula I

[0057] Ri is - S(=O)(=Ra)Rb,

[0058] Ra is 0 or loss,

[0059] Rb is H, Cl-6alkyl, Cl-6alkoxy-Cl-6alkyl, Cl-6alkylcarbonyl-Cl-6alkyl, C2-7alkenyl, amino, or amino C1-6alkyl,

[0060] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I,

[0061] R2 and R3 are each independently F, Br, Cl or I.

[0062] (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 brucine.

[0063] (3) In (1) or (2), 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 brucine in methanol, ethanol, propanol, isopropanol, methyl chloride, acetonitrile, chloroform, or a mixture thereof.

[0064] (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 brucine at 15 to 100°C.

[0065] (5) In any one of (2) to (4), the compound represented by chemical formula 1 and brucine may be mixed in an equivalent ratio of 1:0.8 to 1:1.3.

[0066] (6) In any one of (3) to (5), methanol or methyl chloride may be mixed in a volume of 5 to 50 times the weight of the compound represented by chemical formula 1.

[0067] (7) In any one of (3) to (6), acetonitrile may be mixed in a volume of 10 to 150 times the weight of the compound represented by chemical formula 1.

[0068] (8) In any one of (1) to (7), a step of recovering the compound represented by the formula 1 and a step of recovering brucine may be additionally included between the step of preparing the compound represented by the formula 2 using the compound represented by the formula 1 and the step of preparing the compound represented by the formula 1a using the compound represented by the formula 2.

[0069] (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 the compound represented by chemical formula 1, and the step of recovering brucine may be repeated.

[0070] (10) In (9), repetition may be performed 2 to 5 times.

[0071] (11) In any one of (8) to (10), the step of recovering the compound represented by chemical formula 1 may be performed through a desalting process and a racemization process.

[0072] (12) In any one of (1) to (11), the step of preparing a compound represented by the chemical formula la using a compound represented by the chemical formula 2 may be performed by adding hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or phosphoric acid.

[0073] (13) In any one of (1) to (12), 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 be performed through an amidation reaction.

[0074] (14) In any one of (1) to (13), 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:

[0075] <Chemical Formula 1-1>

[0076] <Chemical Formula 2-1>

[0077] (15) In (14), the compound represented by Chemical Formula 1-1 may 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.

[0078] <Chemical Formula 4>

[0079] <Chemical Formula 5>

[0080] <

[0081] <Chemical Formula 7>

[0082] <Chemical Formula 8>

[0083] (16) In (14) or (15), the step of preparing a compound represented by the chemical formula la-1 using the compound represented by the chemical formula 2-1 may include a step of obtaining a compound represented by the chemical formula 2a-1 using the compound represented by the chemical formula 2-1, and a step of preparing a compound represented by the chemical formula la-1 through a desalting process of the compound. Here, the step of obtaining a compound represented by the chemical formula 2a-1 using the compound represented by the chemical formula 2-1 may be performed by adding a solid obtained by cooling the compound represented by the chemical formula 2-1 to 25 to 30 °C, filtering it, and raising the temperature to 80 to 85 °C, stirring for 4 to 5 hours, cooling it to 25 to 30 °C, and filtering it, repeating the steps twice more. In addition, the step of desalting the compound represented by Chemical Formula 2a-1 may be performed by reacting the compound represented by Chemical Formula 2a-1, water in an amount 15 times the weight of the compound, and hydrochloric acid in a concentration of 10N to 11N in an amount 15 times the weight of the compound, at 20 to 30°C, filtering, and vacuum drying.

[0084] <Chemical Formula 2a-l>

[0085] (17) The present invention provides 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:

[0086] <Chemical Formula 2> In chemical formula 2

[0087] Ri is - S(=O)(=Ra)Rb,

[0088] Ra is 0 or loss,

[0089] 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,

[0090] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I.

[0091] (18) In (17), the compound represented by chemical formula 2 may be a compound represented by the following chemical formula 2-1:

[0092] <Chemical Formula 2-1>

[0093] (19) The present invention provides a method for producing an intermediate compound according to (16), which comprises a step of producing a compound represented by Chemical Formula 2 using a compound represented by Chemical Formula 1:

[0094] <Chemical Formula 1> In chemical formula 1 and chemical formula 2

[0095] Ri is - S(=O)(=Ra)Rb,

[0096] Ra is 0 or loss,

[0097] 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,

[0098] At least one of Ra or Rb may be independently substituted with F, Br, Cl or I.

[0099]

Effect of the invention

[0100]

Form for Embodiment of the Invention

[0101] 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) ,

[0102] 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)

[0103] (Step 2) Synthesis of 7-chloro-6-methyl-4-(methylsulfonyl)chroman (formula 7)

[0104] 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)

[0105] (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%). ppm 2.23-2.33 (m, IH) , 2.53— 2.63(m, IH) , 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);

[0106] 7.98(s, IH), 10.19(s, IH) (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%). iH NMR (500 MHz, DMS0-d6) 5 ppm 2.27-2.36(m, 1H) , 2.58— 2.64(m, 1H) , 3.16(s, 3H), 4.28- 4.34(m, IH) , 4.43- 4.50(m, IH) , 4.81(br d, _A3.91Hz, IH) , 7.53(s, IH) , 8.05(d, _A5.37Hz, 2H) , 13.36(br s, IH)

[0107] (Step 5) (4aR,4aiR,5aS,8aS,8aiS,15aS)- 10,11-Dimethoxy- 14 -oxo-

[0108] Synthesis of 4a,4ai,5,5a,6,7,8,8ai,15,15a-decahydro-2H,14H-4,6-methanoindro[3,2,l-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-6-ium 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromen-7-carboxylate (Formula 2-1) (1)

[0109] (a) The compound of chemical formula 1-1 (l.Oeq, 100 g), brucine (1.05eq, 132.59 g), and MeOH (32 vol, 3200 ml) obtained in the above step 4 were added to the reactor. The reaction solution was heated to 60 to 70 °C, stirred for 7 to 8 hours, cooled to 25 5 °C, and completely concentrated. ACN (5 vol, 500 ml) was added, and concentrated once more to obtain the title compound.

[0110] (b) ACN (40 vol, 4000 ml) was added to the concentrated residue, the temperature was raised to 80–85°C, and the mixture was stirred for 4–5 hours. After cooling to 25–30°C, the mixture was filtered. After repeating the process of (b) twice more, the solid was vacuum-dried to obtain a compound of chemical formula 2a-1 (yield 28.2%, chiral purity 99.2%).

[0111] (c) The solid obtained by concentrating the filtrate in the reactor (100 g, l.Oeq), water (15 vol, 1500 ml), and c-HCl (15 vol, 1500 ml) were added. After reaction at 20 to 30°C for 28 to 30 hours, the mixture was filtered and vacuum-dried to recover the compound of chemical formula lb-1. The compound of chemical formula lb-1 (leg, 100 g) recovered in the reactor was added, and a solution made of NaOH (3 eq, 76.84 g) and water (2.5 vol, 250 ml) was added, and stirred at 25 to 35°C for 5 to 6 hours. The pH was adjusted to 1 to 2 with 6N HCl solution, and the obtained solid was filtered and vacuum-dried to recover the compound of chemical formula 1-1 obtained in step 4 (yield 68 to 70%).

[0112] (d) The pH of the filtrate was adjusted to 9 or higher with NaOH solution, and the obtained solid was filtered and vacuum-dried to recover brucine (yield 32%). The processes of (a) and (b) were repeated once more. iH NMR (500 MHz, DMS0-d6) 5 ppm 1.27- 1.31 (m, 1H), 1.40 (br d, ^14.17 Hz,

[0113] 1H), 1.82-1.90(m, 2H) , 2.26- 2.37(m, 2H) , 2.52- 2.63(m, 2H) , 2.80- 2.97(m, 3H) , 3.09-3.21(m, 5H) , 3.24- 3.29(m, 1H) ,3.68- 3.80(m, 7H) , 3.84(d, ^10.75Hz, 1H) , 4.07(br d, _A6.35Hz, 2H) , 4.13(br s, 1H) , 4.27- 4.34(m, 2H) , 4.41- 4.49(m, 1H) , 4.79(br d, _A3.91Hz, 1H) , 6.00(m, 1H) , 7.04(s, 1H) , 7.47(s, 1H) , 7.64(s, 1H) , 7.87(s, 1H), 7.98(s, 1H)

[0114] (Step 5) (4aR,4aiR,5aS,8aS,8aiS,15aS)- 10,11-Dimethoxy- 14 -oxo-

[0115] Synthesis of 4a,4ai,5,5a,6,7,8,8ai,15,15a-decahydro-2H,14H-4,6-methanoindro[3,2,l-ii]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-6-ium 4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromen-7-carboxylate (Formula 2-1) (2)

[0116] (a) The compound of chemical formula 1-1 (l.Oeq, 100 g), brucine (l.OOeq, 126 g), and MeOH (32 vol, 3200 ml) obtained in the above step 4 were added to the reactor. The reaction solution was heated to 60 to 70°C, stirred for 3 to 4 hours, cooled to 25 5°C, completely concentrated, and then dried in vacuo to obtain the title compound.

[0117] (b) DCM (11.5 vol, 1150 ml) was added to the above dried material and dissolved, then ethyl ether (4.6 vol, 460 ml) was slowly added to precipitate crystals and stirred for 1 hour. The crystals were filtered, and the filtrate was concentrated and dried in vacuo. ACN (80 vol, 8000 ml) was added to the concentrated residue, the temperature was increased to 100–110°C, and stirred for 3–4 hours. After cooling to 35–38°C, it was filtered and washed with ACN (2.5 vol). The solid was dried in vacuo to obtain a compound represented by chemical formula 2a-1 (yield 41%, chiral purity 99.4%). iH NMR (500 MHz, DMS0-d6) 5 ppm 1.27–1.31 (m, 1H), 1.40 (br d, ^14.17 Hz,

[0118] 1H), 1.82-1.90(m, 2H) , 2.26- 2.37(m, 2H) , 2.52- 2.63(m, 2H) , 2.80- 2.97(m, 3H) , 3.09-3.21(m, 5H) , 3.24- 3.29(m, 1H) ,3.68- 3.80(m, 7H) , 3.84(d, ^10.75Hz, 1H) ,

[0119] 4.07(br d, _A6.35Hz, 2H) , 4.13(br s, 1H) , 4.27- 4.34(m, 2H) , 4.41- 4.49(m, 1H) , 4.79(br d, _A3.91Hz, 1H) , 6.00(m, 1H) , 7.04(s, 1H) , 7.47(s, 1H) , 7.64(s, 1H) , 7.87(s, 1H), 7.98(s, 1H)

[0120] (Step 6) Synthesis of (S)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid (formula la-1) (1) The compound of formula 2a-1 (50 g, l.Oeq), water (15 vol, 750 ml), and c-HCl (15 vol, 750 ml) obtained in Step 5 were added to a reactor. After reaction at 20 to 30 °C for 28 to 30 hours, the mixture was filtered and dried under vacuum to obtain the title compound (yield 86%, purity 96.6%, chiral purity 99.2%, total yield of Steps 5(1) and 6(1) 24.25%). Water (5 vol, 250 ml) was used as the washing solution at this time. iH NMR (500 MHz, DMS0-d6) 5 ppm 2.28-2.37(m, 1H) , 2.54— 2.70(m, 1H) , 3.16(s, 3H), 4.29-4.35(m, IH) , 4.48(td, ^11.48, 2.44Hz, IH) , 4.81(br d, _A4.40Hz, IH) , 7.54(s, IH), 8.06(s, 2H) , 13.33(br s, IH)

[0121] (Step 6) Synthesis of (S)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxylic acid (formula la-1) (2) The compound of formula 2a-1 obtained in step 5 (50 g, l.Oeq), DCM (12 vol, 600 ml) and IM HCKlOOvol, 5000 ml) were added to the reactor. After reaction at 20 to 30°C for 15 hours, the product was filtered and washed with water (18 vol), EtOH (6 vol) and hexane (18 vol), and the wet mass was checked by NMR to confirm the removal of brucine. If brucine was not completely removed, the above process was repeated. The solid was vacuum-dried to obtain the title compound (yield 78%, purity 99.64%, overall yield of steps 5(2) and 6(2) 31.98%). ppm 2.28-2.37(m, 1H) , 2.54— 2.70(m, 1H) , 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)

[0122] (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 obtained in the above Preparation Example (1.2 eq, 44.1 g), pyridine (lOvol, 450 ml) and water (0.06 vol, 27 ml) were charged and cooled to 0 5°C. POC13 (0.5 eq, 11.0 g) was charged 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%). ppm 2.30-2.38(m, 1H) , 2.59— 2.66(m, 1H) , 3.16(s,

[0123] 3H), 4.30- 4.34(m, 1H), 4.45- 4.52(m, 1H), 4.81(br d, 3.91, 1H), 7.26(m, 2H), 7.31(s, 1H), 7.52(m, 2H), 7.58(s, 1H) , 7.66(s, 1H) , 8.06(s, 1H) , 8.31(s, 1H) ,

[0124] 10.93(s, 1H)

[0125] (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.

[0126] 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

【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> 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. 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 the compound represented by chemical formula 1 with brucine.

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 the compound represented by chemical formula 1 with brucine in the presence of methanol, ethanol, propanol, isopropanol, methyl chloride, acetonitrile, chloroform 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 brucine at 15 to 100°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 brucine are mixed in an equivalent ratio of 1:0.8 to 1:1.

3.

6. In claim 3, methanol or methyl chloride is present in an amount of 5 wt. % relative to the weight of the compound represented by chemical formula 1. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein the compound is mixed in a volume 50 times greater than that of the solvent. 【

7. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 3, acetonitrile is mixed in a volume of 10 to 150 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, further comprising a step of recovering the compound represented by formula 1 and a step of recovering brucine 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 the compound represented by chemical formula 1, and recovering brucine are repeated in claim 8.

10. A method for producing a compound represented by chemical formula I or a solvate thereof, wherein in claim 9, the repetition is performed 2 to 5 times.

11. 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 through a desalting process and a racemization process.

12. 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, trifluoroacetic acid or phosphoric 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 I or a solvate thereof using a compound represented by chemical formula la and a compound represented by chemical formula 3 in claim 1 is performed through an amidation reaction.

14. In claim 1, the compound represented by chemical formula 1 is a compound represented by chemical formula 1-1, the compound represented by chemical formula 2 is a compound represented by chemical formula 2-1, the compound represented by chemical formula la is a compound represented by chemical formula la-1, the compound represented by chemical formula 3 is a compound represented by chemical formula 3-1, and the compound represented by chemical formula I is a compound represented by chemical formula 1-1, a method for producing a compound represented by chemical formula I or a solvate thereof: <Chemical Formula 1-1> <화학식 la-l> <화학식 3-1> 【

15. In claim 14, a method for producing a compound represented by chemical formula I or a solvate thereof, wherein the compound represented by chemical formula 1-1 is produced by a method including the steps 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; the step of producing a compound represented by chemical formula 7 using a compound represented by chemical formula 6; the step of producing a compound represented by chemical formula 8 using a compound represented by chemical formula 7; and the step of producing a compound represented by chemical formula 1-1 using a compound represented by chemical formula 8: <화학식 4> <Chemical Formula 5> OEt Eto" 、'''"''。 <Chemical Formula 6> < <화학식 8>

16. An intermediate compound for producing 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. 【

17. In claim 16, the compound represented by chemical formula 2 is a compound represented by chemical formula 2-1 below, an intermediate compound for producing a compound represented by chemical formula I or a solvate thereof: <화학식 2-1> 【

18. A method for producing an intermediate compound according to claim 16, 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, 60 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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