TW202200558A - Cocrystal of dihydroquinolinone compound - Google Patents

Abstract

The present invention provides: a novel active pharmaceutical ingredient form of 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (compound A); a medication containing same; and a production method thereof. The present invention pertains to a cocrystal of compound A and a coformer, or to a cocrystal solvate thereof.

Description

Cocrystals of Dihydroquinolinone Compounds

The present invention relates to a kind of 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- A co-crystal of 8-fluoro-3,4-dihydroquinolin-2(1H)-one or a co-crystal solvate thereof, a pharmaceutical composition containing the same, and a method for producing the same.

In the development of pharmaceuticals, seek a compound that not only has the efficacy of the pharmaceutical compound itself, but also has physical properties (such as solubility, bioavailability, pharmacokinetics, or stability) that can be used as pharmaceuticals even through the formulation process. the form of the API. As one of the forms of such APIs, a co-crystal formed by incorporating an active molecule and a second component (also referred to as a "coformer" in this specification) into a crystal structure is generally known. . The formation of co-crystals is useful, for example, for the formulation of poorly water-soluble active molecules, but it is necessary to explore co-crystal formers specific to the active molecules and find co-crystals that maintain or improve their usefulness as medicines.

所表示之5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羥基哌啶-4-基]甲氧基}-8-氟-3,4-二氫喹啉-2(1H)-酮(於本說明書中，亦稱為「化合物A」)作為對結核菌、多重抗藥性結核菌及/或非結核性分枝桿菌具有抗菌作用之化合物而眾所周知(專利文獻1)。關於化合物A，迄今尚未發現醫藥上有用之共結晶。 [先前技術文獻] [專利文獻]Formula: [Chemical 1]

5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8- Fluoro-3,4-dihydroquinolin-2(1H)-one (also referred to as "Compound A" in this specification) as an anti-TB, multidrug-resistant Mycobacterium tuberculosis and/or nontuberculous mycobacteria A compound having an antibacterial action is well known (Patent Document 1). Regarding Compound A, no pharmaceutically useful co-crystals have been found so far. [Prior Art Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2016/031255

[Problems to be Solved by Invention]

One of the problems to be solved by the present invention is to provide a 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine-4- A new form of API, medicines containing the same, and methods for producing the same. [Technical means to solve problems]

The inventors of the present invention have made diligent studies to solve the above-mentioned problems, and as a result, they have found a novel co-crystal form of Compound A, thereby completing the present invention. [Effect of invention]

The co-crystal of Compound A or its co-crystal solvate can more stably and efficiently supply medicines having antibacterial activity against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and/or non-tuberculous mycobacteria. In addition, the co-crystal of Compound A or its co-crystal solvate can improve the absorption of Compound A in vivo and increase the bioavailability.

Several specific aspects are exemplified below. [Item 1] A co-crystal or a co-crystal solvate thereof, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine Co-crystals of pyridin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and co-crystal formers.

[Item 2] The co-crystal or its co-crystal solvate according to item 1, wherein the co-crystal former is a nonvolatile organic acid.

[Item 3] The co-crystal or its co-crystal solvate as described in item 2, wherein the non-volatile organic acid is at least one of ortho, meta or para positions can be selected from the group consisting of hydroxyl, amino and carboxyl groups Base-substituted benzoic acid.

[Item 4] The co-crystal or its co-crystal solvate as described in item 3, wherein the benzoic acid is gentisic acid or salicylic acid.

[Item 5] The co-crystal or its co-crystal solvate as described in item 2, wherein the nonvolatile organic acid is a carboxylic acid.

[Item 6] The co-crystal or a co-crystal solvate thereof as described in any one of Items 1 to 5, wherein in a powder X-ray diffraction pattern obtained using CuKα rays as an X-ray source, at a position selected from the diffraction angle (2θ) )9.7°±0.2°, 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 22.8°±0.2°, 25.0°±0.2°, 25.9 At least 3 places in the group consisting of °±0.2° and 26.9°±0.2° contain diffraction peaks.

[Item 7] The co-crystal or its co-crystal solvate according to item 6, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 11.4°±0.2°, 18.7° Diffraction peaks are included at °±0.2°, 19.3°±0.2° and 25.9°±0.2°.

[Item 8] The co-crystal or its co-crystal solvate according to item 6, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 9.7°±0.2°, 11.4° Diffraction peaks are included at °±0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 21.1°±0.2° and 25.9°±0.2°.

[Item 9] The co-crystal or a co-crystal solvate thereof as described in any one of Items 1 to 5, wherein in a powder X-ray diffraction pattern obtained using CuKα rays as an X-ray source, at a position selected from the diffraction angle (2θ) )3.9°±0.2°, 7.8°±0.2°, 11.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 20.0°±0.2°, 24.8°±0.2° and 25.8 At least 3 places in the group formed by °±0.2° contain diffraction peaks.

[Item 10] The co-crystal or its co-crystal solvate as described in Item 9, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 14.1°±0.2°, 20.0° Diffraction peaks are included at °±0.2° and 24.8°±0.2°.

[Item 11] The co-crystal or its co-crystal solvate according to item 9, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 3.9°±0.2°, 7.8° Diffraction peaks are included at °±0.2°, 11.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 20.0°±0.2° and 24.8°±0.2°.

[Item 12] The co-crystal or a co-crystal solvate thereof as described in any one of Items 1 to 5, wherein in a powder X-ray diffraction pattern obtained using CuKα rays as an X-ray source, at a position selected from the diffraction angle (2θ) )9.9°±0.2°, 11.4°±0.2°, 16.2°±0.2°, 18.8°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 19.8°±0.2°, 23.8°±0.2°, 24.9 At least 3 places in the group consisting of °±0.2°, 25.3°±0.2°, 26.1°±0.2° and 27.3°±0.2° contain diffraction peaks.

[Item 13] The co-crystal or its co-crystal solvate according to item 12, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 11.4°±0.2°, 18.8° Diffraction peaks are included at °±0.2°, 19.0°±0.2° and 26.1°±0.2°.

[Item 14] The co-crystal or its co-crystal solvate according to item 12, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 9.9°±0.2°, 11.4° Diffraction peaks are included at °±0.2°, 16.2°±0.2°, 18.8°±0.2°, 19.0°±0.2°, 23.8°±0.2° and 26.1°±0.2°.

[Item 15] The co-crystal or a co-crystal solvate thereof as described in any one of Items 1 to 5, wherein in a powder X-ray diffraction pattern obtained using CuKα rays as an X-ray source, at a position selected from the diffraction angle (2θ) )12.1°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 17.7°±0.2°, 23.4°±0.2°, 23.6°±0.2°, 24.8°±0.2°, 25.4°±0.2° and 26.7 At least 3 places in the group formed by °±0.2° contain diffraction peaks.

[Item 16] The co-crystal or its co-crystal solvate according to item 15, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 12.1°±0.2°, 15.1° Diffraction peaks are included at °±0.2° and 15.4°±0.2°.

[Item 17] The co-crystal or its co-crystal solvate according to item 15, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, the diffraction angles (2θ) are 12.1°±0.2°, 15.1° Diffraction peaks are included at °±0.2°, 15.4°±0.2°, 17.7°±0.2°, 23.6°±0.2°, 24.8°±0.2° and 25.4°±0.2°.

[Item 18] The co-crystal solvate as described in any one of Items 1 to 17, which is a hydrate, such as 0.5 hydrate, monohydrate or dihydrate.

表示。[Item 19] A compound or a solvate thereof, wherein the compound is of the formula: [Chem. 2]

Express.

表示。[Item 20] A compound or a solvate thereof, wherein the compound is of the formula: [Chem. 3]

Express.

[Item 21] A co-crystal or a co-crystal solvate thereof, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine Co-crystallization of pyridin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and 2,5-dihydroxybenzoic acid.

[Item 22] A co-crystal or a co-crystal solvate thereof, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine Co-crystallization of pyridin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(lH)-one with salicylic acid (ie, 2-hydroxybenzoic acid).

[Item 23] The solvate according to any one of Items 19 to 22, which is a hydrate, such as 0.5 hydrate, monohydrate or dihydrate.

[Item 24] The compound or solvate thereof according to any one of items 1 to 23, wherein the compound is a substantially pure crystal.

[Item 25] A method for producing a co-crystal or a co-crystal solvate, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4- A co-crystallization of dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and a co-crystal former, the manufacturing method comprising the following steps: (1) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8 - Fluoro-3,4-dihydroquinolin-2(1H)-one and the co-crystal former are mixed in a solvent; and (2) The solid precipitated in the above-mentioned step (1) is collected by filtration to obtain the above-mentioned co-crystal or a co-crystal solvate thereof.

[Item 26] A method for producing a co-crystal or a co-crystal solvate, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4- A co-crystallization of dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and a co-crystal former, the manufacturing method comprising the following steps: (1) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8 - Fluoro-3,4-dihydroquinolin-2(1H)-one and co-crystal former are mixed in a good solvent; and (2) A poor solvent is added to the mixture obtained in the above step (1).

[Item 27] The method according to item 26, wherein the good solvent is tetrahydrofuran, acetone or methanol, and the poor solvent is hexane or water.

[Item 28] A pharmaceutical composition comprising the compound described in any one of items 1 to 24, or a co-crystal or a co-crystal solvate thereof, and a pharmaceutically acceptable carrier.

[Item 29] An agent for diagnosing, preventing and/or treating tuberculosis, comprising the compound described in any one of items 1 to 24 or a co-crystal or a co-crystal solvate thereof.

[Item 30] The compound according to any one of items 1 to 24, or the co-crystal or a co-crystal solvate thereof, for the diagnosis, prevention and/or treatment of tuberculosis.

[Item 31] A use of the compound described in any one of items 1 to 24, or a co-crystal or a co-crystal solvate thereof, for the manufacture of a diagnostic, prophylactic and/or therapeutic drug for tuberculosis.

[Item 32] A method for diagnosing, preventing and/or treating tuberculosis in a subject, wherein the subject needs an effective dose of the compound or co-crystal or a co-crystal solvate thereof as described in any one of items 1 to 24, the The method is to administer to the subject an effective dose of a compound as recited in any one of items 1 to 24, or a co-crystal or a co-crystal solvate thereof.

In this specification, "co-crystal" refers to a crystalline substance composed of compound A and any second component ("coformer") existing in the same crystal lattice at any molar ratio, and a solvate. make a difference. Co-crystals can exist in a plurality of crystal forms (also referred to in this specification as "polymorphs"). Compound A that forms a co-crystal may be in any crystalline form or a mixture of these, and may also be amorphous. In this specification, the co-crystal is described according to the type of the co-crystal former. For example, the so-called "2,5DHBA co-crystal" refers to the co-crystal of Compound A and 2,5DHBA and any polymorphs thereof, and the so-called "salicylic acid co-crystal" refers to the co-crystal of Compound A and salicylic acid and any of its polymorphs. polymorph. For example, the 2,5DHBA co-crystal includes type I crystal and type II crystal.

As the crystal form of the co-crystal, for example, a type I co-crystal (co-crystal (I-type crystal)) or a II-type co-crystal (co-crystal (II-type crystal)) can be mentioned. In a certain aspect, the co-crystal is a substantially pure type I co-crystal, that is, a type I co-crystal that does not substantially contain any other crystalline form. Here, the I-type co-crystal that does not substantially contain any other crystal form may be, for example, less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight , less than 0.5% by weight, including any other crystal forms, such as type I co-crystals of type II co-crystals. In another aspect, the co-crystals are substantially pure type II co-crystals, ie, type II co-crystals that do not substantially contain any other crystalline form. Here, the type II co-crystal that does not substantially contain any other crystal form may be, for example, less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight , Less than 0.5% by weight, including any other crystal forms, such as type II co-crystals of type I co-crystals.

In this specification, "co-crystal formers" are non-ionized molecules that can form co-crystals with Compound A. Specifically, for example, an organic acid, an amino acid, an amine, and an amide can be mentioned, and a nonvolatile organic acid or an amino acid is preferable. The molar ratio of Compound A and the co-crystal former can take any value according to the co-crystal former, for example, 1:0.5-1:2.5, 1:0.8-1:2, preferably 1:0.9-1:1.5, More preferably, it is 1:1. In a certain aspect, the co-crystal former can also be eluted from the crystal lattice of the co-crystal under specific conditions, whereby Compound A becomes a supersaturated state, which improves the solubility. In this case, the co-crystal former is preferably water-soluble. In another aspect, the eutectic former is a solid molecule at normal temperature (15°C-25°C) and normal pressure.

In this specification, the "organic acid" is not particularly limited as long as it is an organic compound showing acidity that can form a co-crystal with the compound A, and examples thereof include carboxylic acids and phenols. The "carboxylic acid" is not particularly limited as long as it is an organic compound having at least one carboxyl group (-COOH) that can form a co-crystal with the compound A, for example, a chain carboxylic acid, an aromatic carboxylic acid, a heterocyclic carboxylic acid acid.

In this specification, the "non-volatile organic acid" is not particularly limited as long as it is an organic acid that can form a co-crystal with compound A, for example, an organic acid that is not easily volatilized at normal temperature (15°C to 25°C) under normal pressure. acid. In one aspect, the non-volatile organic acid is a water-soluble organic acid. Preferred are carboxylic acids. More preferably, at least one of the ortho, meta or para positions of the benzoic acid compound may be substituted with a group selected from the group consisting of hydroxyl, amino and carboxyl. More preferably, it is 2,5-dihydroxybenzoic acid or salicylic acid.

In this specification, "amino acid" is not particularly limited as long as it is an organic compound having two functional groups of amino group and carboxyl group, and includes natural amino acid and non-natural amino acid.

In this specification, "amine" is not particularly limited as long as it is a compound in which the hydrogen atom of ammonia is substituted with a hydrocarbon group or an aryl group, and includes aliphatic amines and aromatic amines.

In the present specification, "amide" is not particularly limited as long as it is a compound obtained by dehydration condensation of oxoacid and ammonia or primary or secondary amine, and examples thereof include carboxyamide.

Examples of the co-crystal formers include, but are not limited to, the compounds exemplified below. [Table 1] Examples of eutectic formers carboxylic acid Fumaric acid, succinic acid, tartaric acid, malic acid, glutaric acid, citric acid, maleic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 3,5-dihydroxyl Benzoic acid, salicylic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 4-aminosalicylic acid, 2-amino-5-hydroxybenzoic acid, hippuric acid, nicotinic acid, phthalic acid amino acid Proline, lysine, tyrosine, histidine amine Meglumine, Tromethamine Amide Nicotinamide other Vanillin, Urea, Ascorbic Acid, Pyridoxine, Saccharin, Hydroquinone

The co-crystal of Compound A can also exist in the form of a solvate formed by the co-crystal and solvent molecules in any molar ratio (in this specification, also referred to as "co-crystal solvate"). As such a solvate, a hydrate, an ethanolate, and a THF compound are mentioned, for example. For example, the co-crystal of Compound A can exist in the form of a solvate with 0.5-2 molecules of solvent relative to the molecule of Compound A1, such as 0.5-hydrate, 1-hydrate, 1.5-hydrate and 2-hydrate.

In this specification, the following abbreviations may be used. Coformer: Cocrystal former 2,5DHBA: 2,5-Dihydroxybenzoic acid (gentisic acid) THF: Tetrahydrofuran HPMC: Hypromellose (Hydroxypropylmethylcellulose) NMR: Nuclear Magnetic Resonance UHPLC: Ultra High Performance Liquid Chromatography LC/MS/MS: Liquid Chromatography Mass Spectrometry PXRD: Powder X-ray Diffraction TG/DTA: Differential Calorimetry Simultaneous Determination C _max : Maximum Plasma Concentration AUC: Area Under the Drug Concentration Time Curve JP1: Japanese Pharmacopoeia dissolution test liquid 1 JP2: Japanese Pharmacopoeia dissolution test liquid 2

[Production method] Hereinafter, the method for producing Compound A will be illustrated. The compound obtained in each step can be appropriately isolated and purified by well-known methods commonly used in this field, such as distillation, recrystallization, column chromatography, or the like, or it can be proceeded to the next step without isolation or purification. . In addition, the reagents used in each step are commercially available, and can also be produced according to methods known to those skilled in the art.

(Manufacturing method 1) Synthesis of 4-Chloro-2,6-difluoroaniline and 4-methylbenzenesulfonate Regarding 4-chloro-2,6-difluoroaniline and 4-methylbenzenesulfonate, 2,6-difluoroaniline can be reacted in a solvent in the presence of a chlorinating agent and an alkylthiourea manufacture. As the chlorinating agent, N-chlorosuccinimide and trichloroisocyanuric acid may, for example, be mentioned. As an alkyl thiourea, 1, 3- dimethyl thiourea is mentioned. As a solvent, acetonitrile, ethyl acetate, and the mixture of these are mentioned. The reaction temperature is, for example, room temperature. The reaction time is, for example, 30 minutes to 6 hours, preferably 1 to 2 hours.

(Manufacturing method 2) Synthesis of 1-ethyl-1-(2-methylallyl)-4-oxopiperidine-1-onium iodide As for 1-ethyl-1-(2-methylallyl)-4-oxopiperidine-1-onium iodide, isobutenyl chloride can be mixed with 1- It is produced by reacting ethyl-4-piperidone. As an iodinating agent, sodium iodide is mentioned. As the solvent, acetone may, for example, be mentioned. The reaction temperature is, for example, room temperature to 50°C. The reaction time is, for example, 3 to 20 hours, preferably 5 to 13 hours.

(Manufacturing method 3) Synthesis of 1-(4-Chloro-2,6-difluorophenyl)piperidin-4-one About 1-(4-chloro-2,6-difluorophenyl)piperidin-4-one, it can be obtained from 4-chloro-2,6-difluoroaniline・4-methylbenzenesulfonate by base After treatment to obtain 4-chloro-2,6-difluoroaniline, in the presence of alkylthiourea, it is combined with 1-ethyl-1-(2-methylallyl)-4 in a solvent -Oxopiperidine-1-onium iodide is produced by reacting. As a base, sodium hydroxide is mentioned. As an alkyl thiourea, 1, 3- dimethyl thiourea is mentioned. As a solvent, water is mentioned, for example. In the reaction for obtaining 4-chloro-2,6-difluoroaniline, the reaction temperature is, for example, room temperature. The reaction time is, for example, 30 minutes to 3 hours, preferably 1 hour. In the reaction with 1-ethyl-1-(2-methylallyl)-4-oxopiperidine-1-onium iodide, the reaction temperature is, for example, the reflux temperature. The reaction time is, for example, 5 to 12 hours, preferably 10 hours.

(Manufacturing method 4) Synthesis of (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol (1) 4-[(tert-butyl group can be produced by reacting 1-(4-chloro-2,6-difluorophenyl)piperidin-4-one in a solvent in the presence of a silylating agent and a base Dimethylsilyl)oxy]-1-(4-chloro-2,6-difluorophenyl)-1,2,3,6-tetrahydropyridine. As a silanizing agent, tert-butyldimethylchlorosilane is mentioned, for example. As a base, triethylamine is mentioned, for example. As a solvent, acetonitrile is mentioned, for example. The reaction temperature is, for example, the reflux temperature. The reaction time is, for example, 1 to 5 hours, preferably 2 hours. (2) 4-[(tert-butyldimethylsilyl)oxy]-1-(4-chloro-2,6-difluorophenyl)-1,2, obtained in (1), In the presence of additives, 3,6-tetrahydropyridine undergoes asymmetric epoxidation with D-EPOXONE in a solvent to produce (1R,6R)-[(tert-butyldimethylsilyl)oxy] -3-(4-Chloro-2,6-difluorophenyl)-7-oxa-3-azabicyclo[4.1.0]heptane. As an additive, for example, disodium edetate, potassium carbonate, hydrogen peroxide solution, and these mixtures can be mentioned. As the solvent, for example, toluene, propanol, acetonitrile, and a mixture thereof may be mentioned. The reaction temperature is, for example, 0 to 20°C, preferably 5 to 15°C. The reaction time is, for example, 2 to 10 hours, preferably 5 hours. (3) (1R,6R)-[(tert-butyldimethylsilyl)oxy]-3-(4-chloro-2,6-difluorophenyl)- 7-oxa-3-azabicyclo[4.1.0]heptane reacts in a solvent in the presence of a dipole generator and a base to produce (3R,4R)-6-(4-chloro-2, 6-Difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol. As a dipole-generating agent, for example, trimethyl thionous iodide may be mentioned. As a base, potassium hydroxide is mentioned, for example. As the solvent, for example, dimethylsulfoxide can be mentioned. The reaction temperature is, for example, room temperature. The reaction time is, for example, 1 to 5 hours, preferably 3 hours.

(Manufacturing method 5) 5-{[(3R,4R)-1-(4-Chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3 Synthesis of ,4-dihydroquinolin-2(1H)-one (Compound A) About 5-{[(3R,4R)-1-(4-Chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro- 3,4-Dihydroquinolin-2(1H)-one, which can make (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro [2.5] Octan-4-ol is produced by reacting with 8-fluoro-5-hydroxy-3,4-dihydroquinolin-2(1H)-one in a solvent in the presence of a base. As a base, potassium carbonate is mentioned, for example. As a solvent, propanol, water, and a mixture of these are mentioned, for example. The reaction temperature is, for example, the reflux temperature. The reaction time is, for example, 1 to 5 hours, preferably 3 hours.

(Manufacturing method 6) Synthesis of (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol (another method) (1) In the presence of catalysts and additives, 2-methyl-2-vinyl oxirane reacts with 1,3-bis(hexafluoro-α-hydroxyisopropyl)benzene to generate vinyl epoxy After the transfer reaction, it reacts with 4-chloro-2,6-difluoroaniline, 4-methylbenzenesulfonate and paraformaldehyde to produce [1-(4-chloro-2,6-difluorobenzene]. base)-1,2,3,6-tetrahydropyridin-4-yl]methanol. (1-1) Conditions for vinyl epoxide transfer reaction As a catalyst, a palladium catalyst is mentioned, for example, Preferably it is tetrakis (triphenylphosphine) palladium. As an additive, triphenylphosphine is mentioned, for example. As a solvent, toluene, 1, 2- dimethoxyethane, and these mixtures are mentioned, for example. The reaction temperature is, for example, room temperature. The reaction time is, for example, 30 minutes to 2 hours, preferably one and a half hours. (1-2) Reaction conditions with 4-chloro-2,6-difluoroaniline and 4-methylbenzenesulfonate As a solvent, toluene is mentioned, for example. The reaction temperature is, for example, room temperature. The reaction time is, for example, 1 to 4 hours, preferably two and a half hours.

(2) [1-(4-Chloro-2,6-difluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl]methanol obtained in (1) was added to peroxide After reacting in a solvent in the presence of and additives, and then treating in the presence of a base and additives, [(1R,6R)-3-(4-chloro-2,6-difluorophenyl)-7- Oxa-3-azabicyclo[4.1.0]heptan-6-yl]methanol. (2-1) Reaction conditions with peroxide As a peroxide, cumene hydroperoxide is mentioned, for example. As additives, for example, zeolite, (D)-(-)-isopropyl tartrate, titanium tetraisopropoxide, and mixtures thereof can be exemplified. As the solvent, for example, toluene, dimethylsulfite, and a mixture of these may be mentioned. The reaction temperature is, for example, 0°C or lower to room temperature. The reaction time is, for example, 1 to 5 hours, preferably 3 hours. (2-2) Alkali treatment conditions Examples of the base include triethylamine, 4-dimethylaminopyridine, and a mixture of these. As an additive, phthalic anhydride is mentioned, for example. As a solvent, ethyl acetate is mentioned, for example. The reaction temperature is, for example, room temperature. The reaction time is, for example, 30 minutes to 2 hours, preferably 1 hour.

(3) [(1R,6R)-3-(4-chloro-2,6-difluorophenyl)-7-oxa-3-azabicyclo[4.1.0] obtained in (2) Heptan-6-yl]methanol reacts in a solvent in the presence of tosyl chloride and a base, and then removes it to produce (S)-1-(4-chloro-2,6-difluorophenyl) )-4-methylenepiperidin-3-ol. (3-1) Tosylation conditions As the base, for example, triethylamine, trimethylamine hydrochloride, and a mixture thereof can be exemplified. As a solvent, toluene is mentioned, for example. The reaction temperature is, for example, room temperature. The reaction time is, for example, 30 minutes to 3 hours, preferably one and a half hours. (3-2) Removal conditions As additives, for example, sodium iodide, ascorbic acid and mixtures of these can be used. As a solvent, for example, acetonitrile, water, and the mixture of these are mentioned. The reaction temperature is, for example, room temperature to 80°C. The reaction time is, for example, 1 to 4 hours, preferably 3 hours.

(4) The ring of (S)-1-(4-chloro-2,6-difluorophenyl)-4-methylenepiperidin-3-ol obtained in (3) and perbenzoic acid Oxidation reaction can produce (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol. As perbenzoic acid, m-chloroperbenzoic acid is mentioned, for example. As a solvent, ethyl acetate, water, and a mixture of these are mentioned, for example. The reaction temperature is, for example, 10°C or lower. The reaction time is, for example, 1 to 4 hours, preferably 3 hours.

(Manufacturing method 7) Synthesis of 8-Fluoro-5-hydroxy-3,4-dihydroquinolin-2(1H)-one (Manufacturing method 7-1) Synthesis of N-(2,5-difluorophenyl)-3-phenylacrylamidoamide N-(2,5-Difluorophenyl)- 3-Phenylpropenamide. As a palladium catalyst, for example, 5% palladium carbon can be mentioned. As a solvent, ethyl acetate is mentioned, for example. The reaction temperature is, for example, 0°C or lower. The reaction time is, for example, 30 minutes to 2 hours, preferably 1 hour.

(Manufacturing method 7-2) Synthesis of 5,8-difluoroquinolin-2(1H)-one 5,8-Difluoroquinolin-2(1H)-one can be produced by reacting N-(2,5-difluorophenyl)-3-phenylpropenamide in the presence of aluminum chloride. As additives, for example, sodium chloride, potassium chloride and mixtures of these can be used. The reaction temperature is, for example, 100 to 130°C, preferably 120°C. The reaction time is, for example, 30 minutes to 3 hours, preferably 1 hour.

(Manufacturing method 7-3) Synthesis of 2-chloro-5,8-difluoroquinoline 2-Chloro-5,8-difluoroquinoline can be produced by reacting 5,8-difluoroquinolin-2(1H)-one with thionyl chloride in a solvent. As a solvent, N,N- dimethylformamide is mentioned, for example. The reaction temperature is, for example, 60 to 80°C, preferably 70°C. The reaction time is, for example, 30 minutes to 3 hours, preferably 1 hour.

(Manufacturing method 7-4) Synthesis of 8-Fluoro-2,5-dimethoxyquinoline 8-Fluoro-2,5-dimethoxyquinoline can be produced by reacting 2-chloro-5,8-difluoroquinoline with methanol in a solvent in the presence of a base. As a base, potassium tertiary butoxide is mentioned, for example. As a solvent, N,N- dimethylacetamide is mentioned, for example. The reaction temperature is, for example, 60 to 80°C, preferably 70°C. The reaction time is, for example, 30 minutes to 3 hours, preferably 1 hour.

(Manufacturing method 7-5) Synthesis of 8-Fluoro-5-hydroxyquinolin-2(1H)-one 8-Fluoro-5-hydroxyquinolin-2(1H)-one can be produced by reacting 8-fluoro-2,5-dimethoxyquinoline in the presence of an acid. As an acid, for example, acetic acid, hydrobromic acid, and these mixtures can be mentioned. The reaction temperature is, for example, the reflux temperature. The reaction time is, for example, 6 to 18 hours, preferably 14 hours.

(Manufacturing method 7-6) Synthesis of 8-Fluoro-2-oxo-1,2-dihydroquinolin-5-yl acetate 8-Fluoro-2-oxo-1,2-dihydroquinoline-5 can be produced by reacting 8-fluoro-5-hydroxyquinolin-2(1H)-one with acetic anhydride in the presence of an acid - base ester. As an acid, concentrated sulfuric acid is mentioned, for example. The reaction temperature is, for example, 100 to 130°C, preferably 120°C. The reaction time is, for example, 1 to 4 hours, preferably 2 hours.

(Manufacturing method 7-7) Synthesis of 8-fluoro-2-oxy-1,2,3,4-tetrahydroquinolin-5-yl acetate Acetate 8-fluoro-2-oxo-1,2-dihydroquinolin-5-yl ester is subjected to a reduction reaction in a solvent in the presence of a hydrogen atmosphere and a palladium catalyst to produce acetic acid 8-fluoro- 2-Pendant oxy-1,2,3,4-tetrahydroquinolin-5-yl ester. As a palladium catalyst, 10% palladium carbon is mentioned, for example. As a solvent, acetic acid is mentioned, for example. The reaction temperature is, for example, 60 to 80°C, preferably 70°C. The reaction time is, for example, 6 to 10 hours, preferably 8 hours.

(Manufacturing method 7-8) Synthesis of 8-Fluoro-5-hydroxy-3,4-dihydroquinolin-2(1H)-one 8-Fluoro-5-hydroxy- 3,4-Dihydroquinolin-2(1H)-one. As an acid, concentrated hydrochloric acid is mentioned, for example. As a solvent, methanol is mentioned, for example. The reaction temperature is, for example, the reflux temperature. The reaction time is, for example, 30 minutes.

(Manufacturing method 8) Synthesis of 8-fluoro-5-hydroxyquinolin-2(1H)-one (another method) (Manufacturing method 8-1) Synthesis of 2,5-bis(benzyloxy)-8-fluoroquinoline 2,5-bis(benzyloxy)-8-fluoroquinoline can be produced by reacting 2-chloro-5,8-difluoroquinoline with benzyl alcohol in a solvent in the presence of a base. As a base, potassium tertiary butoxide is mentioned, for example. As a solvent, N,N- dimethylformamide is mentioned, for example. The reaction temperature is, for example, 30 to 80°C, preferably 70°C. The reaction time is, for example, 1 to 4 hours, preferably 2 hours.

(Manufacturing method 8-2) Synthesis of 8-Fluoro-5-hydroxyquinolin-2(1H)-one 8-Fluoro-5-hydroxyquinolin-2(1H)-one can be produced by reacting 2,5-bis(benzyloxy)-8-fluoroquinoline in the presence of a palladium catalyst and an acid under a hydrogen atmosphere . As a palladium catalyst, for example, 5% palladium carbon can be mentioned. As an acid, acetic acid is mentioned, for example. The reaction temperature is, for example, 60 to 80°C, preferably 70°C. The reaction time is, for example, 1 to 4 hours, preferably 2 hours.

[Production method of polymorphic form of compound A] The compound A obtained by the above-mentioned production method was stirred at 60-80° C. in the presence of acetic acid and/or potassium acetate until the crystals were dissolved, followed by hot filtration, and then slowly cooled and heated to 30° C. The acetic acid compound of Compound A can be obtained by aging at a temperature below ℃ for more than 1 hour, and then vacuum drying or air drying can be carried out to produce a Type I crystal of Compound A. Moreover, after stirring compound A at room temperature - a reflux temperature in a solvent, it cools and matures, and blow-drying can manufacture the type-II crystal of compound A by this.

[Production method of co-crystal of compound A or its co-crystal solvate] Compound A obtained above and the co-crystal former are mixed at room temperature and appropriately in a solvent, a solid is precipitated, and the obtained solid is filtered to obtain a co-crystal of Compound A or a co-crystal solvate thereof. . (Crush method) The compound A and the co-crystal former obtained above are mixed at room temperature in a molar ratio of 1:0.5 to 1:20, and a solvent is added or pulverized without adding a solvent, whereby the compound A can be obtained. A co-crystal or a co-crystal solvate thereof. The molar ratio of Compound A and the co-crystal former is preferably 1:1 or 1:2, more preferably 1:1. As a solvent, water is mentioned, for example. The pulverization is not particularly limited as long as it is a method used in this field, and examples thereof include mechanical pulverization and ball mill pulverization.

(melting method (thermal analysis method)) The co-crystal of Compound A or its co-crystal solvate can be confirmed by simultaneous differential calorimetric determination of the physical mixture of Compound A and the co-crystal former.

(Crystallization method) After dissolving the mixture of compound A and co-crystal former obtained above in a molar ratio of 1:1 to 1:200 in a good solvent at room temperature, a small amount of the poor solvent is gradually added dropwise to obtain a co-crystal of compound A. or its co-crystalline solvate. The molar ratio of Compound A and the co-crystal former is preferably 1:2 to 1:150, more preferably 1:5, 1:10, 1:20, 1:50, or 1:100. As a good solvent, THF, acetone, methanol, and acetic acid are mentioned, for example. Preferred are THF, acetone or methanol. The addition amount (volume) is, for example, 0.1 to 10% (w/v), preferably 0.5 to 5% (w/v), relative to Compound A (weight). As a poor solvent, hexane, water, and diethyl ether are mentioned, for example. Preferred are hexane and water. The addition amount (volume) is, for example, 0.01 to 15% (w/v), preferably 0.01 to 12% (w/v), more preferably 0.03 to 10% (w/v) based on the compound A (weight). ), more preferably 0.1 to 5% (w/v). As a combination of a good solvent and a poor solvent, the arbitrary combination of any of the above can be mentioned. The combination of good solvent/poor solvent is preferably a combination of THF/hexane, a combination of methanol/water or a combination of acetone/water, more preferably a combination of methanol/water or a combination of acetone/water.

所表示之化合物(即，5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羥基哌啶-4-基]甲氧基}-8-氟-3,4-二氫喹啉-2(1H)-酮 2,5-二羥基苯甲酸)、或式： [化5]

所表示之化合物(即，5-{[(3R,4R)-1-(4-氯-2,6-二氟苯基)-3,4-二羥基哌啶-4-基]甲氧基}-8-氟-3,4-二氫喹啉-2(1H)-酮 2-羥基苯甲酸)。較佳為，化合物A與2,5-二羥基苯甲酸或水楊酸亦可以1：0.5～2.5、例如1：1之莫耳比形成共結晶。 如上所述，該等共結晶可以溶劑合物之形式存在，例如可為水合物，具體而言，可為0.5水合物、1水合物或2水合物。[Co-crystal] In one aspect, the co-crystal of Compound A is a co-crystal of Compound A and 2,5-dihydroxybenzoic acid or salicylic acid (ie, 2-hydroxybenzoic acid). That is, the formula: [Chem.4]

The compound represented (ie, 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy }-8-Fluoro-3,4-dihydroquinolin-2(1H)-one 2,5-dihydroxybenzoic acid), or formula: [Chem. 5]

The compound represented (ie, 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy }-8-Fluoro-3,4-dihydroquinolin-2(1H)-one 2-hydroxybenzoic acid). Preferably, Compound A and 2,5-dihydroxybenzoic acid or salicylic acid can also form a co-crystal in a molar ratio of 1:0.5-2.5, for example, 1:1. As mentioned above, these co-crystals may exist in the form of solvates, such as hydrates, specifically, 0.5 hydrates, monohydrates or dihydrates.

In a certain aspect, the co-crystallization of Compound A can be shown in the powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, and can be displayed at a diffraction angle (2θ) of 9.7°±0.2°, 11.4°± 0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 22.8°±0.2°, 25.0°±0.2°, 25.9°±0.2° and 26.9°±0.2° At least 3, 4, 5, 6, 7, 8 or 9 PXRD patterns of diffraction peaks (2,5DHBA co-crystal (I-type crystal)) in the formed group. For example, the co-crystals may show PXRD patterns (2,5DHBA co-crystals ( Type I crystal)). Furthermore, for example, co-crystals can be exhibited at diffraction angles (2θ) of 9.7°±0.2°, 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 21.1°±0.2° and PXRD pattern containing diffraction peaks at 25.9°±0.2° (2,5DHBA co-crystal (type I)). In another aspect, the co-crystallization can be shown in the powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, and can be displayed at a diffraction angle (2θ) of 3.9°±0.2°, 7.8°±0.2° , 11.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 20.0°±0.2°, 24.8°±0.2° and 25.8°±0.2° at least 3 PXRD pattern (2,5DHBA co-crystal (type II)) containing diffraction peaks at 1, 4, 5, 6, 7, 8, or 9. For example, the co-crystal may show a PXRD pattern (2,5DHBA co-crystal (type II)) containing diffraction peaks at diffraction angles (2θ) of 14.1°±0.2°, 20.0°±0.2°, and 24.8°±0.2°. Further, for example, co-crystals can be exhibited at diffraction angles (2θ) of 3.9°±0.2°, 7.8°±0.2°, 11.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 20.0°±0.2° and PXRD pattern containing diffraction peaks at 24.8°±0.2° (2,5DHBA co-crystal (type II)). In yet another aspect, the co-crystallization can be displayed in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, and can be displayed at a diffraction angle (2θ) of 9.9°±0.2°, 11.4°±0.2° , 16.2°±0.2°, 18.8°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 19.8°±0.2°, 23.8°±0.2°, 24.9°±0.2°, 25.3°±0.2°, 26.1 PXRD patterns containing diffraction peaks at least 3, 4, 5, 6, 7, 8 or 9 in the group consisting of °±0.2° and 27.3°±0.2° (salicylic acid co-crystal) . For example, co-crystals can show PXRD patterns containing diffraction peaks at diffraction angles (2θ) 11.4°±0.2°, 18.8°±0.2°, 19.0°±0.2°, and 26.1°±0.2° (salicylic acid co-crystals) . Further, for example, co-crystals can be exhibited at diffraction angles (2θ) of 9.9°±0.2°, 11.4°±0.2°, 16.2°±0.2°, 18.8°±0.2°, 19.0°±0.2°, 23.8°±0.2° and PXRD pattern containing diffraction peaks at 26.1°±0.2° (salicylic acid co-crystal). In yet another aspect, the co-crystallization can be shown in a powder X-ray diffraction pattern obtained by using CuKα rays as an X-ray source, and can be displayed at a diffraction angle (2θ) of 12.1°±0.2°, 15.1°±0.2° , 15.4°±0.2°, 17.7°±0.2°, 23.4°±0.2°, 23.6°±0.2°, 24.8°±0.2°, 25.4°±0.2° and 26.7°±0.2° at least 3 PXRD patterns containing diffraction peaks at 1, 4, 5, 6, 7, 8, or 9 (2,5DHBA co-crystallized 0.5 hydrate). For example, a co-crystal may exhibit a PXRD pattern (2,5DHBA co-crystal 0.5 hydrate) comprising diffraction peaks at diffraction angles (2θ) of 12.1°±0.2°, 15.1°±0.2°, and 15.4°±0.2°. Further, for example, co-crystals can be exhibited at diffraction angles (2θ) of 12.1°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 17.7°±0.2°, 23.6°±0.2°, 24.8°±0.2° and PXRD pattern containing diffraction peaks at 25.4°±0.2° (2,5DHBA co-crystal 0.5hydrate). The ±0.2° in the above-mentioned diffraction angle (2θ) is an error that may occur due to measurement equipment and measurement conditions, etc., and the error of the diffraction angle is included in the scope of the present invention as an allowable range.

In a certain aspect, the 2,5DHBA co-crystal (type I crystal) can show a melting point of 155-166° C. in the differential thermal gravimetric simultaneous measurement. Here, the initial temperature can be displayed as 157°C, and the peak top temperature can be displayed as 160°C. For example, the 2,5DHBA co-crystal (type I crystal) shows the TG/DTA curve of FIG. 13 . In a certain aspect, the 2,5DHBA co-crystal (type II crystal) can show a melting point of 140-150° C. in the differential thermal gravimetric simultaneous measurement. Here, the initial temperature may show 145°C, and the peak top temperature may show 147°C. After that, the exothermic peak at 150°C ± 1°C may show recrystallization to type I co-crystal. For example, 2,5DHBA co-crystal (type II crystal) shows the TG/DTA curve of FIG. 12 . The 2,5DHBA co-crystal (type II crystal) can also be transformed into the type I co-crystal by any transformation conditions, such as heating at 100-145°C. In a certain aspect, the salicylic acid co-crystal can exhibit a melting point of 150-170° C. in a simultaneous differential calorimetric determination. Here, the initial temperature may show 161°C, and the peak top temperature may show 163°C. For example, salicylic acid co-crystals show the TG/DTA curve of Figure 23.

[Preparation/Pharmaceutical composition] The co-crystal of Compound A can be formulated together with at least one or more pharmaceutically acceptable carriers according to well-known methods generally used in this field. The content of Compound A in the preparation (also referred to as "pharmaceutical composition" in this specification) varies according to the dosage form, dosage and other conditions, for example, it is 1-50% by weight of the whole preparation or the core tablet , preferably 1.5-35% by weight of the whole preparation or the core tablet. In addition, the content of the co-crystal in the formulation is, for example, 1 to 70% by weight of the entire formulation or the core tablet, preferably 1.5 to 50% by weight of the entire formulation or the core tablet. Co-crystals of Compound A can be administered to humans (including adults and children) and mammals (subjects) other than humans. The dose (effective dose) varies depending on the subject to be administered, the symptoms, the dosage form, the route of administration, etc. For example, regarding the dose in the case of oral administration to a human adult patient (body weight 65 kg), For compound A, it is usually in the range of about 1 mg to 100 mg per time, preferably in the range of about 3 mg to 60 mg per time. In addition, the co-crystal is, for example, in the range of about 1 mg to 150 mg per time, preferably in the range of about 3 mg to 80 mg per time.

Examples of the "pharmaceutically acceptable carrier" include components such as water-soluble coating agents, surfactants, excipients, disintegrants, binders, slip agents, and lubricants commonly used in this field. In a certain aspect, the pharmaceutically acceptable carrier may also contain a water-soluble coating agent or a surfactant to prevent the crystallization of Compound A after it reaches supersaturation, thereby promoting dissolution. Examples of the water-soluble coating agent include water-soluble polymers, and specific examples include hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, and hypromellose phthalate. Formate or hypromellose acetate succinate, preferably hydroxypropyl methylcellulose.

As a formulation method of the cocrystal of compound A, wet granulation method, dry granulation method, and direct tableting method are mentioned, for example.

As the dosage form of the pharmaceutical composition containing the co-crystal of Compound A, oral preparations such as lozenges (including film-coated tablets), capsules, granules, powders, and buccal preparations can be exemplified. Film-coated tablets or capsules are preferred. In one aspect, the film-coated tablet may also be one that does not contain a non-cellulosic plasticizer (eg, polyethylene glycol) in order to avoid crystalline transformation. In another aspect, the film-coated tablet may also include hydroxypropyl methylcellulose. [Example]

Hereinafter, although an Example and a test example are given and this invention is demonstrated in detail, this invention is not limited to these. The analysis equipment used in the examples and the like, the measurement conditions of the measurement equipment, and the like are shown below.

(Powder X-ray Diffraction Device) Device name: X'Pert PRO MPD Manufacturer: Spectris Co., Ltd. Measurement method: transmission method Radiation source: CuKα radiation (λ=1.5418 Å) Current: 40 mA Voltage: 45kV Measuring range: 3～39.999° Stride: 0.0167113° Scanning speed: 0.334225°/sec

(X-ray diffraction-differential scanning calorimeter synchronous measurement device) X-ray diffraction-differential scanning calorimetry simultaneous measurement was performed under the conditions described below, and PXRD was performed using XRD-DSC (X-ray diffraction-Differential scanning calorimetry, X-ray diffraction-differential scanning calorimetry) software Display of the connection between data and differential scanning calorimetry data. Device name: RINT2000, XRD-DSC II Manufacturer: Rigaku Co., Ltd. Measurement method: reflection method Radiation source: CuKα radiation (λ=1.5418 Å) Current: 40 mA Voltage: 40kV Measuring range: 3～40° Scanning speed: 10°/min Sampling width: 0.02° Heating rate: 1℃/min

(Single crystal structure analysis) The collection of single crystal X-ray diffraction data was performed using XtaLAB Synergy R, DW system, HyPix diffractometer. The measurement temperature was set to 100 K, and the X-ray source used CuKα rays (λ=1.5418 Å). Data collection and processing were performed using the CrysAlisPro (Rigaku, V1.171.40.67a, 2019) program. The structure was determined by direct method by SHELXT (Sheldrick, G. M.: SHELXT-Integrated space-group and crystal-structure determination. Acta Cryst. A71 (2015) 3-8.1). Non-hydrogen atoms are refined anisotropically, while hydrogen atoms are refined isotropically. Calculations were performed by the Crystal Structure crystallographic software package and SHELXL (Sheldrick, G. M.: Crystal structure refinement with SHELXL. Acta. Cryst. C71 (2015) 3-8.).

(Synchronous measurement of differential calorimetry) TG/DTA was measured using a thermal analyzer TG/DTA7200 manufactured by Seiko Electronics Nanotechnology Co., Ltd. Put 3-10 mg of the sample into an aluminum pot, and heat it from room temperature to 180, 200, 250 or 300 °C at a heating rate of 5 °C/min or 10 °C/min under a dry nitrogen atmosphere. The determination was carried out in a reference pan using alpha-alumina as the reference substance, or in an empty pan (without reference substance).

(Ultra-performance liquid chromatography assay) UHPLC was performed using an Agilent 1290 Infinity LC System from Agilent Technologies. (Liquid chromatography mass spectrometry) MS/MS (tandem mass spectrometry, tandem mass spectrometry) was measured using the TSQ Vantage system of Edwards Co., Ltd., and HPLC (high performance liquid chromatography, high performance liquid chromatography) was measured using the Shimadzu Nexera system of Shimadzu Corporation to measure.

(Particle Size Measurement) The particle size was measured using a laser diffraction particle size distribution analyzer SALD-3100 of Shimadzu Corporation. Into a batch tank, 15 mL of water or a saturated aqueous solution of the co-crystal former was added, and into it, the following substance was added to measure 5 mg of Compound A or a co-crystal in 300 μL of water or a saturated aqueous solution of the co-crystal former. It is obtained by suspension and sound vibration dispersion.

(Raman Spectroscopy) LF (Low Frequency, low frequency)-Raman measurement (THz (terahertz, megahertz)-Raman measurement) Megahertz Raman spectroscopy device: Coherent's low-frequency Raman module (XLF-MICRO Microscope THz -Raman Unit) in combination with a micro-Raman spectrophotometer (Raman WorkStation-785) from Kaiser Corporation. Device name: Raman WorkStation-785 and XLF-MICRO Microscope THz-Raman Unit Manufacturer: Kaiser, Coherent Excitation wavelength: 808 nm Measurement range: -200 to 1500 cm ^-1

[Reference Example] (Reference Example 1) Synthesis of 1-(2,6-dichlorobenzyl)-1-methyl-4-oxopiperidine-1-onium bromide Acetone (70 L ), 2,6-dichlorobenzyl bromide (14.00 kg), 1-methyl-4-piperidone (7.26 kg), and stirred under reflux for 5 hours. The precipitated crystals were separated, washed with acetone (70 L), and air-dried at 50°C for 20 hours to obtain the title compound (18.82 kg) (91% yield) as a white to slightly yellow solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 2.48-2.61 (2H, m), 2.88-3.04 (2H, m), 3.45 (3H, s), 3.85-3.98 (2H, m), 3.98-4.12 (2H , m), 4.99 (2H, s), 7.58-7.74 (3H, m).

(Reference Example 2) Synthesis of 1-(4-chloro-2,6-difluorophenyl)piperidin-4-one Water (35 mL) and 4-chloro-2,6-difluoro were added to a reaction vessel Aniline・4-methylbenzenesulfonate (5 g), and 5 mol/L sodium hydroxide aqueous solution (3.28 mL) was slowly poured in. After the inflow was completed, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were separated and washed with water (25 mL) to obtain 4-chloro-2,6-difluoroaniline as a white to gray solid. To the obtained solid were added 2-propanol (15 mL), water (15 mL), 1-(2,6-dichlorobenzyl)-1-methyl-4-oxopiperidine-1-onium Bromide (7.57 g), 1,3-dimethylthiourea (0.085 g), and stirred at reflux for 10 hours. Toluene (15 mL) and sodium chloride (0.375 g) were added for liquid separation. Toluene (15 mL) was added to the aqueous layer for extraction. The organic layers were concentrated under reduced pressure, 2-propanol (7.5 mL) was added to the residue, and the mixture was stirred at -10°C or lower for 1 hour. The precipitated crystals were separated, washed with 2-propanol (5 mL), and air-dried at 35°C for more than 12 hours to obtain the title compound (1.27 g) (34% yield) as a white to slightly yellow solid. Rate). ¹ HNMR (CDCl ₃ ) δ ppm: 2.58 (4H, t, J = 6.0 Hz), 3.46 (4H, t, J = 6.0 Hz), 6.86-6.98 (2H, m).

[Examples] (Example 1) Synthesis of N-(2,5-difluorophenyl)-3-phenylpropenamide To the reaction vessel was added 1,4-difluoro-2-nitrobenzene (75.0 g), ethyl acetate (375 mL), 5% palladium on carbon (4.0 g), and stirred at 25-60° C. for 4 hours under a hydrogen atmosphere. The solid was removed by filtration, water (375 mL), sodium bicarbonate (59.4 g) were added to the filtrate, and cinnamon chloride (86.0 g) was slowly flowed in at a temperature not exceeding 0°C. After the inflow was completed, stirring was performed for 1 hour. The liquid was separated, and the organic layer was washed twice with water (375 mL). The organic layer was concentrated under reduced pressure, and toluene (375 mL) was added to the residue for recrystallization to obtain the title compound (100.0 g) (81% yield) as a white solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 6.96-7.02 (1H,m), 7.13 (1H, d, J = 15.6 Hz), 7.31-7.39 (1H, m), 7.42-7.50 (3H, m), 7.61-7.66 (3H, m), 8.09-8.16 (1H, m), 10.1 (1H, s).

(Example 2) Synthesis of 5,8-difluoroquinolin-2(1H)-one To a reaction vessel were added sodium chloride (36.0 g), potassium chloride (36.0 g), and aluminum chloride (238.0 g) , and heated until the contents melted. With stirring, N-(2,5-difluorophenyl)-3-phenylacrylamide (103 g) was gradually added, and after completion of the addition, the mixture was stirred at 120° C. for 1 hour. The reaction solution was poured into ice water (2 L) little by little. After the inflow was completed, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to obtain the title compound (75.5 g) as a pale red solid (104% yield). ¹ HNMR (DMSO-d ₆ ) δ ppm: 6.63 (1H, d, J = 9.9 Hz), 7.02 (1H, dtd, J = 12.9 Hz, 9.2 Hz, 3.6 Hz), 7.40-7.48 (1H, m), 8.00 (1H, dd, J = 9.9 Hz, 1.2 Hz), 12.0 (1H, s).

(Example 3) Synthesis of 2-chloro-5,8-difluoroquinoline 5,8-difluoroquinolin-2(1H)-one (69.9 g), N,N-dimethylformaldehyde were added to the reaction vessel formamide (350 mL), and cooled to around 0 °C. Thion chloride (115.0 g) was slowly flowed in. After flowing in, the mixture was stirred at around 70°C for 1 hour. A mixed solution (700 mL) of acetone/water (2/1) was added to precipitate crystals, and 25% aqueous sodium hydroxide solution (340 mL) was added for neutralization. After aging at 40°C for 1 hour and then at 0°C for 1 hour, the precipitated crystals were collected by filtration and washed with water to obtain the title compound (63.0 g) (81% yield) as a brown solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 7.52 (1H, dtd, J = 12.9 Hz, 9.3 Hz, 3.6 Hz), 7.69-7.76 (1H, m), 7.80 (1H, d, J = 8.7 Hz), 8.58 (1H, dd, J = 9.0 Hz, 1.5 Hz).

(Example 4) Synthesis of 8-fluoro-2,5-dimethoxyquinoline Potassium tert-butoxide (14.1 g) and N,N-dimethylacetamide (50 mL) were added to the reaction vessel , methanol (1.3 g), and cooled to below 10°C. 2-Chloro-5,8-difluoroquinoline (10.0 g) was slowly added at a temperature not exceeding 30°C. Stir at around 70°C for 1 hour. After cooling to around 20°C, a mixed solution (100 mL) of water/methanol (1.5/1) was poured to precipitate crystals, water (30 mL) was added, and the mixture was stirred at 20 to 40°C for 1 hour. Further, after aging at around 0°C for 1 hour, the precipitated crystals were collected by filtration and washed with a mixed solution of water/methanol (1/1) to obtain the title compound (7.7 g) (74%) as a brown solid Yield). ¹ HNMR (DMSO-d ₆ ) δ ppm: 3.95 (3H, s), 4.01 (3H, s), 6.84 (1H, dd, J = 8.7 Hz, 3.3 Hz), 7.05 (1H, d, J = 9.0 Hz) ), 7.44 (1H, dd, J = 11.1 Hz, 8.7 Hz), 8.38 (1H, dd, J = 9.0 Hz, 0.9 Hz).

(Example 5) Synthesis of 8-fluoro-5-hydroxyquinolin-2(1H)-one 8-fluoro-2,5-dimethoxyquinoline (100 g), acetic acid (300 g) were added to a reaction vessel mL), an aqueous hydrobromic acid solution (50%, 1.2 L), and the reaction solution was poured into water (3 L) under reflux for 14 hours, and aged at 70 to 100° C. for 1 hour. Thereafter, it was aged at room temperature for 1 hour, and the precipitated crystals were collected by filtration and washed with water to obtain the title compound (85.7 g) (99% yield) as a beige solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 6.46 (1H, d, J = 9.8 Hz), 6.52 (1H, dd, J = 8.8 Hz, 3.7 Hz), 7.21 (1H, dd, J = 10.9 Hz, 8.8 Hz), 8.02 (1H, dd, J = 9.8 Hz, 1.6 Hz), 10.33 (1H, brs), 11.60 (1H, brs).

(Example 6) Synthesis of 8-fluoro-2-oxo-1,2-dihydroquinolin-5-yl acetate 8-fluoro-5-hydroxyquinoline-2(1H) was added to the reaction vessel -ketone (2.0 g), acetic anhydride (12 mL), concentrated sulfuric acid (0.03 mL), and stirred at around 120°C for 2 hours. After cooling to around 0°C, the reaction solution was poured into water (20 mL). After the inflow is completed, aging is performed for 1 hour or more. The precipitate was collected by filtration and washed with water to obtain the title compound (2.13 g) (86% yield) as a white to beige solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 2.39 (3H, s), 6.60 (1H, d, J = 9.9 Hz), 6.96 (1H, dd, J = 8.7 Hz, 3.9 Hz), 7.45 (1H, dd , J = 10.5 Hz, 8.7 Hz), 7.90 (1H, dd, J = 9.9 Hz, 1.8 Hz), 11.9 (1H, s).

(Example 7) Synthesis of 8-fluoro-2-pendoxyl acetate-1,2,3,4-tetrahydroquinolin-5-yl ester 8-fluoro-2-pendoxyl acetate was added to the reaction vessel -1,2-Dihydroquinolin-5-yl ester (128 g), 10% palladium on carbon (12.8 g), acetic acid (1.0 L), and stirred at 70°C for 8 hours under a hydrogen atmosphere. The precipitate was removed by filtration, water (1.3 L) was added, and the mixture was heated to around 80°C. Cooled to around room temperature, and aged around 0°C for 1 hour. The precipitate was collected by filtration and washed with water to obtain the title compound (104 g) as a white to beige solid (80% yield). ¹ HNMR (DMSO-d ₆ ) δ ppm: 2.29 (3H, s), 2.45 (2H, dd, J = 8.1 Hz, 6.0 Hz), 2.73 (2H, dd, J = 8.1 Hz, 6.9 Hz), 6.75 ( 1H, dd, J = 9.0 Hz, 4.2 Hz), 7.12 (1H, t, J = 9.3 Hz), 10.2 (1H, s).

(Example 8) Synthesis of 8-fluoro-5-hydroxy-3,4-dihydroquinolin-2(1H)-one To the reaction vessel was added acetic acid 8-fluoro-2-oxy-1,2,2, 3,4-Tetrahydroquinolin-5-yl ester (51 g), methanol (255 mL), concentrated hydrochloric acid (306 g), and stirred at reflux for 30 minutes. It was cooled, and water (1.0 L) was poured in, and it aged at 30-40 degreeC for 1 hour or more. After cooling to around 0°C, the precipitated crystals were collected by filtration and washed with water to obtain the title compound (40.9 g) (98% yield) as a white to beige solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 2.42 (2H, dd, J = 7.8 Hz, 6.3 Hz), 2.79 (2H, t, J = 7.8 Hz), 6.40 (1H, dd, J = 9.0 Hz, 4.2 Hz), 6.85 (1H, t, J = 10.5 Hz), 9.45 (1H, s), 9.90 (1H, s).

(Example 9) Synthesis of 2,5-bis(benzyloxy)-8-fluoroquinoline To the reaction vessel were added potassium tert-butoxide (46.4 g), N,N-dimethylformamide (165 g) mL), benzyl alcohol (50.1 g), and slowly added 2-chloro-5,8-difluoroquinoline (33.0 g) at a temperature not exceeding 30°C. Stir at around 70°C for 2 hours. It was cooled to around 20°C, and a mixed solution (330 mL) of water/acetone (1/2) was added for crystallization, and water (165 mL) was added, and the mixture was aged at 20 to 40°C for 1 hour. After aging at 0°C for 1 hour, the precipitated crystals were collected by filtration and washed with a mixed solution of water/acetone (1/1) to obtain a brown solid. Acetone (330 mL) and activated carbon (3.3 g) were added, and the mixture was stirred under reflux for more than 30 minutes. The precipitate was filtered hot, and the filtrate was cooled to crystallize to obtain the title compound (44.2 g) (74% yield) as a pale brown solid. ¹ HNMR (CDCl ₃ ) δ ppm: 5.19 (2H, s), 5.58 (2H, s), 6.69 (1H, dd, J = 8.8 Hz, 3.6 Hz), 6.96 (1H, d, J = 9.2 Hz), 7.23 (1H, dd, J = 10.8 Hz, 2.0 Hz), 7.32-7.43 (6H, m), 7.48 (2H, d, J = 7.2 Hz), 7.55 (2H, d, J = 7.2 Hz), 8.46 ( 1H, dd, J = 9.2 Hz, 1.6 Hz).

(Example 10) Synthesis of 8-fluoro-5-hydroxyquinolin-2(1H)-one 2,5-bis(benzyloxy)-8-fluoroquinoline (35.6 g), 5 % palladium on carbon (3.5 g), acetic acid (245 mL), and stirred at around 70 °C for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration, and a part of the residue was concentrated. Water (350 mL) was added and heated, and then cooled to recrystallize. The aging was performed at 20-40°C for 1 hour, and the aging was performed at 0°C for 1 hour. The precipitate was collected by filtration and washed with water to obtain the title compound (14.0 g) (78% yield) as a light brown solid. ¹ HNMR: Refer to Example 5

(Example 11) Synthesis of 4-chloro-2,6-difluoroaniline and 4-methylbenzenesulfonate (1) Acetonitrile (140 L) and N-chlorosuccinimide were added to the reaction vessel (22.75 kg), 1,3-dimethylthiourea (0.32 kg), and 2,6-difluoroaniline (20.0 kg) were slowly flowed in. After the inflow was completed, the mixture was stirred at room temperature for 2 hours. P-toluenesulfonic acid monohydrate (32.41 kg) was put in, and it matured for 1 hour or more. The precipitated crystals were separated, washed with ethyl acetate (60 L), and air-dried at 60°C for 19 hours to obtain the title compound (44.66 kg) (85% yield) as a white to slightly yellow solid. . ¹ HNMR (DMSO-d ₆ ) δ ppm: 2.29 (3H, s), 6.33-6.80 (3H, brs), 7.03-7.19 (4H, m), 7.44-7.52 (2H, m).

(Example 12) Synthesis of 4-chloro-2,6-difluoroaniline and 4-methylbenzenesulfonate (2) To the reaction vessel were added acetonitrile (60 L), ethyl acetate (60 L), 2 , 6-difluoroaniline (20.0 kg), and slowly put into trichloroisocyanuric acid (12.60 kg). After the addition, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were removed by filtration, and washed with a mixed solution of acetonitrile (20 L)/ethyl acetate (20 L). P-toluenesulfonic acid monohydrate (32.41 kg) was put in, and it matured for 1 hour or more. The precipitated crystals were separated, washed with a mixed solution of acetonitrile (40 L)/ethyl acetate (20 L), and air-dried at 60°C for 19 hours to obtain the title compound as a white to slightly yellow solid ( 44.68 kg) (85% yield). ¹ HNMR: Reference Example 11

(Example 13) Synthesis of 1-ethyl-1-(2-methylallyl)-4-oxopiperidine-1-onium iodide Acetone (60 L) and isobutenyl chloride were added to the reaction vessel (18.42 kg), sodium iodide (28.15 kg), and stirred at room temperature for 5 hours. Water (200 L) was poured in and liquid separation was performed to obtain an organic layer (27 L). To the obtained organic layer were added acetone (140 L), 1-ethyl-4-piperidone (20.0 kg), and stirred at a temperature not exceeding 50°C for 8 hours. The precipitated crystals were separated, washed with acetone (200 L), and air-dried at 60°C for 11 hours to obtain the title compound (41.35 kg) (85% yield) as a white to slightly yellow solid. ¹ HNMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, t, J = 7.2 Hz), 1.98 (3H, s), 2.55-2.87 (4H, m), 3.56 (2H, q, J = 7.2 Hz) , 3.64-3.80 (4H, m), 4.10 (2H, s), 5.41 (1H, brs), 5.49-5.55 (1H, m).

(Example 14) Synthesis of 1-(4-chloro-2,6-difluorophenyl)piperidin-4-one Water (418 L) and 4-chloro-2,6-difluoro were added to the reaction vessel Aniline and 4-methylbenzenesulfonate (59.77 kg), and a 25% aqueous sodium hydroxide solution (31.33 kg) was slowly introduced. After the inflow was completed, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were separated and washed with water (299 L) to obtain 4-chloro-2,6-difluoroaniline as a white to gray solid. To the obtained solid were added 2-propanol (179 L), water (179 L), 1-ethyl-1-(2-methylallyl)-4-oxopiperidine-1-onium iodide compound (82.48 kg), 1,3-dimethylthiourea (1.02 kg), and stirred at reflux for 10 hours. It was cooled to around 0°C and aged for 1 hour or more. The precipitated crystals were separated, washed with a mixed solution of 2-propanol (20 L)/water (20 L), followed by washing with 2-propanol (20 L), and blowing at 35°C for 37 hours Dry to obtain the title compound (26.30 kg) as a white to slightly yellow solid (60% yield). ¹ HNMR: refer to Reference Example 2

(Example 15) Synthesis of (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol into a reaction vessel Add acetonitrile (48 L), 1-(4-chloro-2,6-difluorophenyl)piperidin-4-one (16.0 kg), tert-butyldimethylchlorosilane (11.3 kg), iodine Sodium chloride (11.2 kg) and triethylamine (8.24 kg) were added, and the mixture was stirred under reflux for 2 hours. A mixed solution of toluene (64 L) and water (64 L)/sodium bicarbonate (3.20 kg) was poured in, and liquid separation was performed. The organic layer was washed with water (64 L) and water (32 L). The organic layer was concentrated under reduced pressure, toluene (128 L) and silica gel 60N (1.60 kg) were added to the residue, and the mixture was stirred at room temperature for 30 minutes or more. The precipitate was removed by filtration and washed with toluene (16.7 kg) to obtain 4-[(tert-butyldimethylsilyl)oxy]-1-(4-chloro-2,6-difluorophenyl) )-1,2,3,6-tetrahydropyridine in toluene. Add a mixture of 1-propanol (58.9 kg), acetonitrile (74 L), water (99 L)/disodium EDTA (15.0 g)/potassium carbonate (27.0 kg), D-EPOXONE (2.52 kg) ), and slowly inflow 35% hydrogen peroxide solution (25.3 kg) at a temperature not exceeding 10 °C. After completion of the inflow, the mixture was stirred at 5 to 15°C for 5 hours. A mixture of water (131 L)/sodium thiosulfate pentahydrate (65.1 kg)/sodium carbonate (528 g) was slowly poured into the mixture at a temperature not exceeding 20°C, and stirred for more than 30 minutes. After standing, liquid separation was performed, and the organic layer was washed twice with a mixed solution of water (160 L)/sodium chloride (4 kg) to obtain (1R,6R)-[(tert-butyldimethylformaldehyde. silyl)oxy]-3-(4-chloro-2,6-difluorophenyl)-7-oxa-3-azabicyclo[4.1.0]heptane in toluene/1-propanol/ Acetonitrile mixture. Dimethylthionite (88.0 kg), trimethylthionite (15.8 kg), and 48% potassium hydroxide aqueous solution (8.38 kg) were added, followed by stirring at room temperature for 3 hours. Water (160 L) was poured in and liquid separation was performed. The organic layer was washed with a mixed solution of water (160 L)/sodium chloride (4 kg). The organic layer was concentrated under reduced pressure, ethanol (64 L) was poured into the residue, and the mixture was stirred under reflux until the solid was dissolved. It was cooled to around 25°C and aged for 1 hour or more. The precipitated crystals were separated, washed with ethanol (12.6 kg), and air-dried at 60°C for 16 hours to obtain the title compound (7.10 kg) (39% yield) as a white to slightly yellow solid. ¹ HNMR (CDCl ₃ ) δ ppm: 1.76 (1H, dt, J = 13.8 Hz, 4.1 Hz), 2.02-2.17 (1H, m), 2.08 (1H, d, J = 11.1 Hz), 2.70 (1H, d , J = 4.7 Hz), 3.02-3.22 (2H, m), 3.06 (1H, d, J = 4.7 Hz), 3.23-3.36 (1H, m), 3.37-3.48 (1H, m), 3.79-3.91 ( 1H, m), 6.84-6.95 (2H, m).

(Example 16) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- Synthesis of 8-fluoro-3,4-dihydroquinolin-2(1H)-one To the reaction vessel was added (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1 -oxa-6-azaspiro[2.5]oct-4-ol (13.83 kg), 8-fluoro-5-hydroxy 3,4-dihydroquinolin-2(1H)-one (10.00 kg), potassium carbonate (1.39 kg), 2-propanol (69 L), water (14 L), and stirred at reflux for 3 hours. Water (138 L) was poured in, and aging was carried out at 30 to 50°C for 1 hour or more. The precipitated crystals were separated, washed with 2-propanol (42 L), and air-dried at 60°C for 19 hours to obtain the title compound (20.94 kg) (91% yield) as a white to slightly yellow solid. , Type II). ¹ HNMR (DMSO-d ₆ ) δ ppm: 1.62-1.75 (1H, m), 1.83-1.99 (1H, m), 2.40-2.54 (2H, m), 2.80-3.01 (4H, m), 3.15-3.40 (2H, m), 3.62-3.80 (1H, m), 3.68 (1H, d, J = 9.0 Hz), 4.02 (1H, d, J = 9.0 Hz), 4.52 (1H, s), 4.86 (1H, d, J = 6.3 Hz), 6.58 (1H, dd, J = 9.0 Hz, 3.9 Hz), 6.97-7.07 (1H, m), 7.21-7.33 (2H, m), 10.0 (1H, s).

(Example 17) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- Purification of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (1) 5-{[(3R,4R)-1-(4-chloro-2,6- Difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (20.93 kg, type II) , acetic acid (175.65 kg), and stirred at around 70°C until the crystals dissolved. Hot filtration was performed, and water (41.86 kg) heated to around 70° C. was flowed through the filter. Cool slowly, and age at a temperature below 30°C for 1 hour or more. The precipitated crystals were separated, washed with a mixed solution of acetic acid (49.40 kg)/water (15.70 kg), and vacuum-dried at 85°C and 1.0 kPa for 24 hours to obtain the title compound as a white to slightly yellow solid (15.45 kg) (73% yield, Form I). ¹ HNMR: Reference Example 16

(Example 18) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- Purification of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (2) 5-{[(3R,4R)-1-(4-chloro-2,6- Difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (11.10 kg, type II) , potassium acetate (1.91 kg), and acetic acid (100 kg), and stirred at around 70° C. until the crystals were dissolved. Hot filtration was performed, and water (22 kg) heated to around 70° C. was flowed through the filter. Cool slowly, and age at a temperature below 30°C for 1 hour or more. The precipitated crystals were separated, washed with a mixed solution of acetic acid (26 kg)/water (8 kg), and vacuum-dried at 65-70°C and 1.0 kPa for 42 hours to obtain a white to slightly yellow solid. The title compound (8.61 kg) (77% yield, Form I). ¹ HNMR: Reference Example 16

(Example 19) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- Purification of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (3) 5-{[(3R,4R)-1-(4-chloro-2,6- Difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (3.10 kg, type II) , dimethylsulfite (19 L), and slowly flow in water (37 L). After the inflow was completed, aging was performed at room temperature for 1 hour or more. The precipitated crystals were separated, washed with ethanol (25 L), and air-dried at 50°C for 19 hours to obtain the title compound (2.81 kg) (93% yield, type I) as a white to slightly yellow solid. ). ¹ HNMR: Reference Example 16

(Example 20) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}- Purification of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (4) 5-{[(3R,4R)-1-(4-chloro-2,6- Difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (2.00 kg, type II) , acetic acid (16 L), and stirred at around 70°C until the crystals dissolved. Hot filtration was performed, and water (4 L) heated to around 60° C. was poured in. Cool slowly, and age at a temperature below 30°C for 1 hour or more. The precipitated crystals were separated and washed with a mixed solution of acetic acid (45 L)/water (15 L). Water (55 L) was passed through the obtained crystals. The crystals were isolated and air-dried at 50°C overnight to obtain the title compound (1.27 kg) (63% yield, type I) as a white to slightly yellow solid. ¹ HNMR: Reference Example 16

(Example 21) Synthesis of (S)-1-(4-chloro-2,6-difluorophenyl)-4-methylenepiperidin-3-ol To the reaction vessel were added toluene (40 L), 1,2-Dimethoxyethane (40 L), triphenylphosphine (0.62 kg), tetrakis(triphenylphosphine)palladium (0.43 kg), 1,3-bis(hexafluoro-α-hydroxyiso propyl)benzene (3.95 kg), and 2-methyl-2-vinyloxirane (20.51 kg) was slowly flowed in. After the inflow was completed, the mixture was stirred at room temperature for one and a half hours. Add toluene (81 L), paraformaldehyde (5.06 kg), 4-chloro-2,6-difluoroaniline・4-methylbenzenesulfonate (44.25 kg), and stir at room temperature for two and a half hours . Water (101 L) and a 25% aqueous sodium hydroxide solution (34.58 kg) were poured in, and liquid separation was performed. Washed with water (97 L), the organic layer was concentrated under reduced pressure. Toluene (71 L), silica gel 60N (1.02 kg), and activated carbon (0.53 kg) were added to the residue, followed by stirring at room temperature for 30 minutes or more. The precipitate was removed by filtration and washed with toluene (71 L) to obtain [1-(4-chloro-2,6-dichlorophenyl)-1,2,3,6-tetrahydropyridin-4-yl ] Methanol in toluene. Add ZEORUM A-3 (3.45 kg), (D)-(-)-isopropyl tartrate (3.40 kg), titanium tetraisopropoxide (3.75 kg), and make cumene at a temperature not exceeding 0°C Hydrogen peroxide (17.55 kg) and toluene (17 L) were slowly flowed in. After the inflow was completed, the mixture was stirred at a temperature below 0°C for 2 hours. Dimethyl sulfite (10.30 kg) was flowed in and stirred at room temperature for 1 hour. 50% DL-lactic acid (34 L) and water (137 L) were poured, and liquid separation was performed. The organic layer was washed with a mixture of sodium bicarbonate (8.86 kg)/water (137 L). The organic layer was concentrated under reduced pressure, and to the residue were added ethyl acetate (137 L), triethylamine (10.67 kg), 4-dimethylaminopyridine (0.81 kg), and phthalic anhydride (13.66 kg), and stirred at room temperature for 1 hour. A mixed solution of heptane (137 L) and sodium bicarbonate (8.86 kg)/water (102 L) was poured in, and liquid separation was performed. The aqueous layer was washed with a mixture of ethyl acetate (137 L)/heptane (137 L). Toluene (204 L) and a 25% aqueous sodium hydroxide solution (126.52 kg) were poured, and the mixture was stirred at around 70°C for 2 hours. After standing, liquid separation was carried out, and concentrated hydrochloric acid (12.99 kg) and water (137 L) were poured into the organic layer to carry out liquid separation. Washed with a mixed solution of sodium bicarbonate (8.86 kg)/water (137 L), and the organic layer was concentrated under reduced pressure. Toluene (109 L) was poured into the residue to obtain [(1R,6R)-3-(4-chloro-2,6-difluorophenyl)-7-oxa-3-azabicyclo[4.1.0 ]heptane-6-yl]methanol in toluene. Triethylamine (7.33 kg), trimethylamine hydrochloride (0.31 kg), tosyl chloride (12.56 kg) were added and stirred at room temperature for one and a half hours. A mixed solution of sodium bicarbonate (2.27 kg)/water (73 L) was poured in, and liquid separation was performed. The organic layer was concentrated under reduced pressure, acetonitrile (106 L) and sodium iodide (10.87 kg) were added to the residue, and the mixture was stirred at around 70°C for 2 hours. Water (89 L) and ascorbic acid (12.77 kg) were added and stirred at room temperature for 1 hour. Ethyl acetate (145 L) was poured in, and liquid separation was performed. The organic layer was washed with a mixture of sodium sulfite (8.31 kg)/water (89 L) and water (89 L), and concentrated under reduced pressure. Methanol (18 L) was poured into the residue, followed by extraction with heptane (177 L). Silica gel 60N (1.55 kg) was added to the heptane layer, and the mixture was stirred at room temperature for more than 30 minutes. The precipitate was removed by filtration, and washed with a mixture of heptane (18 L)/ethanol (13 L). The filtrate was concentrated under reduced pressure, and ethanol (27 L) and 2-propanol (27 L) were poured into the residue. Under stirring, water (100 L) was gradually flowed in to precipitate crystals. The precipitated crystals were separated, washed with water (27 L), and air-dried at 40°C for 20 hours to obtain the title compound (1.60 kg) (4% yield) as a white to gray solid. ¹ HNMR (CDCl ₃ ) δ ppm: 2.29 (1H, dt, J = 13.8 Hz, 4.9 Hz), 2.54-2.73 (2H, m), 3.01-3.19 (3H, m), 3.29-3.40 (1H, m) , 4.13-4.26 (1H, m), 4.87 (1H, s), 5.00 (1H, s), 6.83-6.95 (2H, m).

(Example 22) Synthesis of (3R,4R)-6-(4-chloro-2,6-difluorophenyl)-1-oxa-6-azaspiro[2.5]oct-4-ol into a reaction vessel Add (S)-1-(4-chloro-2,6-difluorophenyl)-4-methylenepiperidin-3-ol (7.21 kg), ethyl acetate (22 L), water (36 L), and slowly put in m-chloroperbenzoic acid (10.27 kg). After the addition, the mixture was stirred for 3 hours at a temperature not exceeding 10°C. A mixed solution of sodium bicarbonate (3.50 kg) and sodium sulfite (3.50 kg)/water (36 L) was poured in and stirred for more than 30 minutes. The precipitated crystals were separated and washed with water (14 L). Ethanol (10 L) was poured in and stirred under reflux until the crystals dissolved. Cool to around 25°C and mature for 1 hour or more. The precipitated crystals were separated, washed with ethanol (3 L), and air-dried at 60°C for 17 hours to obtain the title compound (1.52 kg) (19% yield) as a white to slightly yellow solid. ¹ HNMR: Reference Example 15

(Example 23) Preparation of acetate compound 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine was added to the reaction vessel -4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (20.93 kg, type II), acetic acid (175.65 kg), and stirred at around 70°C until the crystals dissolve. Hot filtration was performed, and water (41.86 kg) heated to around 70° C. was flowed through the filter. Cool slowly, and age at a temperature below 30°C for 1 hour or more. The precipitated crystals were separated and washed with a mixed solution of acetic acid (49.40 kg)/water (15.70 kg) to obtain an acetic acid compound (18.55 kg) of the title compound. ¹ HNMR (DMSO-d ₆ ) δ ppm: 1.62-1.74 (1H, m), 1.83-1.99 (1H, m), 1.90 (3H, s), 2.40-2.54 (2H, m), 2.80-3.00 (4H , m), 3.14-3.40 (2H, m), 3.62-3.80 (1H, m), 3.68 (1H, d, J = 9.2 Hz), 4.01 (1H, d, J = 9.2 Hz), 4.54 (1H, brs), 4.88 (1H, brs), 6.57 (1H, dd, J = 9.2 Hz, 3.6 Hz), 6.97-7.07 (1H, m), 7.21-7.32 (2H, m), 10.0 (1H, s). 12.0 (1H, brs).

(Example 24) Preparation of Type I Crystal 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine was added to the reaction vessel -4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (20.93 kg, type II), acetic acid (175.65 kg), and stirred at around 70°C until the crystals dissolve. Hot filtration was performed, and water (41.86 kg) heated to around 70° C. was flowed through the filter. Cool slowly, and age at a temperature below 30°C for 1 hour or more. The precipitated crystals were separated, washed with a mixed solution of acetic acid (49.40 kg)/water (15.70 kg), and vacuum-dried at 85°C and 1.0 kPa for 24 hours to obtain the title compound as a white to slightly yellow solid (15.45 kg) (73% yield, Form I). ¹ HNMR: Reference Example 16

(Example 25) Preparation of type II crystal 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine was added to the reaction vessel -4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one (200 g, Form I+II), methanol (2 L), and stirred at room temperature for 22 Hour. The precipitated crystals were separated, washed with methanol (600 mL), and air-dried at 80°C for 17 hours to obtain the title compound (181.70 g) (90% yield, type II) as a white to slightly yellow solid. ). ¹ HNMR: Reference Example 16

(Example 26) Preparation and screening of co-crystals: pulverization method ( mechanical pulverization ) Compound A (type II crystal) and the co-crystal former were weighed in a molar ratio of 1:2 to obtain a total amount of about 250 mg, and ethanol 25 was added. μL, mechanically pulverized (model Micro Smash MS-100) at room temperature. During pulverization, 2 zirconia beads with a diameter of 4.5 mm were put in, and two groups were performed at 4000 rpm for 3 minutes. For the sample after pulverization, PXRD measurement (model X'PertPro MPD, PANalytical) was performed.

Screening: Thermal analysis method uses TG/DTA (model TG/DTA7200, Seiko Electronic Nanotechnology Co., Ltd.) at a heating rate of 5°C/min, and the above compound A (type II crystal) prepared by the pulverization method is mixed with the eutectic The physical mixture of the former is heated to a temperature above the melting point of Compound A and the co-crystal former. As another method, 40 mg of compound A (type II crystal) of the eutectic former with a molar ratio of 2 was weighed and pulverized with an agate mortar, and then TG/ DTA assay. As a result, co-crystal formation was confirmed using a physical mixture with 2,5DHBA or salicylic acid. The thermal analysis results of the physical mixture of Compound A and 2,5DHBA are shown in FIG. 1 . According to Fig. 1, an endothermic peak due to the co-melting of Compound A and 2,5DHBA was confirmed at about 134 to 145 °C, an exothermic peak accompanying the formation of co-crystallization was confirmed at about 147 °C, and an exothermic peak was observed at about 150 to 172 °C ( Starting at 154°C), an endothermic peak indicating the melting point of the co-crystal was identified. Figure 2 and Figure 3 show the thermal analysis results of compound A and 2,5DHBA alone, respectively. The results of thermal analysis of the physical mixture of Compound A and salicylic acid are shown in FIG. 4 . According to FIG. 4 , an endothermic peak due to the co-melting of Compound A and salicylic acid was observed at about 131 to 150° C., and an endothermic peak indicating the melting point of the co-crystallization was observed at about 150 to 170° C. (initial 159° C.). Figure 5 shows the results of thermal analysis of salicylic acid alone.

(Example 27) Co-crystallization of Compound A and 2,5DHBA (Sample Analysis) Using an X-ray diffraction-differential scanning calorimetry synchronous measuring device (model TTR2000, DSC/XRD II, Rigaku Corporation), the determination of Compound A (type II crystal ) and a physical mixture of 2,5DHBA in a molar ratio of 1:2. The measurement was carried out under the conditions of a heating rate of 1°C/min and a scan rate of 10°/min. The diffraction pattern shown in FIG. 6 was obtained after the exothermic peak around 143-147°C, so it was confirmed that the mixture was eutectic, and a co-crystal (2,5DHBA co-crystal (I-type crystal)) was formed along with recrystallization.

(Ball mill pulverization method) The pulverization method using a ball mill pulverizer (model RETSCH MIXER MILL MM200, Retsch) was carried out at room temperature. The molar ratio of 2,5DHBA to 500 mg of compound A (type II crystal) was 1:1, and acetone, methanol, or water was used as an additive solvent, or it was performed without adding a solvent. The grinding conditions were set as the grinding time of 99 minutes and the grinding frequency of 30/sec. As a result, 2,5DHBA co-crystals (I-type crystals) and 2,5DHBA co-crystals (II-type crystals) were obtained at a molar ratio of 1:1 without adding a solvent. Under the condition of using water as the additive solvent, a co-crystal of 2,5DHBA (type I crystal) was obtained.

(Crystallization method: THF/hexane system) With respect to 100 mg of compound A (type II crystal), 2,5DHBA was mixed at a molar ratio of 1, 5, 10 or 20, and dissolved in THF (2 mL). To it, 1 mL of hexane was added dropwise and a maximum of 5 mL was added until the solid was precipitated. All operations were carried out at room temperature. Under the condition that the molar ratio of 2,5DHBA is 5, 10 or 20, the co-crystallized THF compound of compound A and 2,5DHBA is obtained as a white to slightly yellow solid. (Crystallization method: methanol/water system) 2,5DHBA was mixed with 10 mg of compound A (type I crystal) at a molar ratio of 100, and dissolved in methanol (2 mL). In it, 1 mL of water was gradually added dropwise until the solid was precipitated, and the 2,5DHBA co-crystal (type I crystal) was obtained in the form of a white to slightly yellow solid. In addition, the operation was carried out at room temperature. (Crystallization method: acetone/water system) 10 mg of compound A (type I crystal) was dissolved in acetone (2 mL) saturated with 2,5DHBA. In it, 1 mL of water was gradually added dropwise until the solid was precipitated. Regarding the obtained precipitate, a mixed crystal of 2,5DHBA co-crystal (I-type crystal) and 2,5DHBA was obtained as a white to slightly yellow solid. In addition, the operation was carried out at room temperature.

(Analysis of samples obtained by crystallization) Thermal analysis was performed on a sample obtained by mixing 10 moles of 2,5DHBA with Compound A in a THF/hexane system. As a result, an endothermic peak and a weight reduction of 3.8% were confirmed before about 95°C, and thereafter, at about 95°C. An endothermic peak was observed at 142-152°C and melted at about 152-162°C ( FIG. 7 ). Heating to 100°C or 145°C, and then cooling to room temperature, the sample heated to 100°C showed a powder X-ray diffraction pattern of 2,5DHBA co-crystal (type II crystal) (Fig. 8), and the sample heated to 145°C The powder X-ray diffraction pattern of the 2,5DHBA co-crystal (type I) is shown (FIG. 9). From the results of solution NMR, it was confirmed that the weight loss up to around 95°C was THF contained in the crystals. In addition, according to the result of the solution NMR of the crystal after desolvation, the molar ratio of Compound A and 2,5DHBA in the obtained co-crystal was 1:1, and no THF remained. (Powder X-ray Diffraction) The PXRD patterns of the obtained 2,5DHBA co-crystals are shown in FIGS. 8 and 9 . For comparison, the diffraction patterns of compound A (type II crystal) and 2,5DHBA are shown in FIGS. 10 and 11, respectively. According to Fig. 8, the 2,5DHBA co-crystal (type II crystal) exhibits diffraction angles (2θ) around 3.9°, 7.8°, 11.8°, 14.1°, 15.1°, 18.9°, 20.0°, 24.8° and 25.8° peak. According to Fig. 9, the 2,5DHBA co-crystal (type I crystal) has diffraction angles (2θ) of 9.7°, 11.4°, 16.0°, 18.7°, 19.3°, 21.1°, 22.8°, 25.0°, 25.9° and 26.9° A peak appears nearby. (thermal analysis) Fig. 12 shows the TG/DTA curve of the 2,5DHBA co-crystal (type II crystal) obtained by the above-mentioned THF/hexane system crystallization method, and Fig. 13 shows the above-mentioned methanol/water system crystallization The TG/DTA curve of the 2,5DHBA co-crystal (type I crystal) obtained by the method.

(Scale up of crystallization method) In a 500 mL beaker, 5 g of compound A (type II crystal) and 2,5DHBA with a molar ratio of 10 to compound A were dissolved in THF (100 mL) at room temperature. The mixture was stirred with a stirrer, hexane (250 mL) was added to precipitate crystals, and the mixture was stirred for 3 days to obtain a 2,5DHBA co-crystal THF compound ( FIG. 14 ). This was collected by filtration, air-dried at room temperature, and then heated at 110° C. for 20 hours to obtain a 2,5DHBA co-crystal (type I crystal). The obtained 2,5DHBA co-crystal (type I crystal) was pulverized by a jet mill (model AO jet mill, SEISHIN ENTERPRISE company), and the drug particle size with a median diameter of 2.3 μm was obtained by pulverization (particle size measurement model Shimadzu). SALD-3100). It was confirmed that the powder X-ray diffraction pattern did not change after pulverization. (Powder X-ray Diffraction) The PXRD pattern of the co-crystallized THF compound of Compound A and 2,5DHBA is shown in FIG. 14 . According to Fig. 14, 2,5DHBA co-crystallized THF compound at diffraction angles (2θ) 8.4°, 9.2°, 16.0°, 16.3°, 17.6°, 18.9°, 19.5°, 21.7°, 24.7°, 25.4°, 26.5° and a peak around 27.9°.

Co-crystal 0.5 hydrate of compound A and 2,5DHBA (crystallization method: methanol/water system) 10 mg of compound A (type I crystal) was mixed with 2,5DHBA at a molar ratio of 100, and dissolved in methanol (2 mL). )middle. In it, when 5 mL of water was added dropwise, 2,5DHBA co-crystal 0.5 hydrate was obtained in the form of a white to slightly yellow solid. In addition, the operation was carried out at room temperature.

(Analysis of samples obtained by the above-mentioned crystallization method) Thermal analysis was performed on the co-crystal 0.5 hydrate of Compound A and 2,5DHBA obtained by methanol/water system. As a result, a weight loss of 1.0% was confirmed before about 144°C, and thereafter, was observed at about 144 to 152°C. Endothermic peak and melting at about 152-165°C (Figure 15).

(Powder X-ray Diffraction) The PXRD pattern of the obtained 2,5DHBA co-crystal 0.5hydrate is shown in FIG. 16 . According to FIG. 16 , the 2,5DHBA co-crystal 0.5 hydrate showed peaks around diffraction angles (2θ) of 12.1°, 15.1°, 15.4°, 17.7°, 23.4°, 23.6°, 24.8°, 25.4° and 26.7°.

(Single crystal structure analysis) The single crystal structure analysis of the 2,5DHBA co-crystal 0.5 hydrate obtained under the above methanol/water system crystallization conditions was performed. The obtained crystallographic data and refinement parameters are shown below. [Table 2] Chemical formula (Formula) C ₂₁ H ₂₀ ClF ₃ N ₂ O ₄ · C ₇ H ₆ O ₄ · 1/2H ₂ O Formula weight 628.99 Crystal system triclinic Space group P 1 a (Å) 7.62950(15) b (Å) 7.8200(2) c (Å) 23.3995(5) α (°) 88.5057(19) β (°) 88.7306.(17) γ (°) 82.6001(19) V (Å ³ ) 1383.73(5) Z 2 D _cal (g·cm ^-3 ) 1.482 μ (cm ^-1 ) 19.097 F (000) 637.00 2 θ max(°) 151.8 Reflections collected 15512 Independent reflections, R _int 6746, 0.0464 R ₁ ( I > 2.00 σ ( I )) 0.0520 R (all reflections) 0.0584 w R ₂ (all diffraction points) 0.1469 Flack parameter 0.11(3) ∆ ρ _max , ∆ ρ _min (e Å ^-3 ) 0.56, -0.46 The ORTEP diagram is shown in FIG. 17 . In the asymmetric unit, 2 molecules of compound A and gentisic acid were confirmed, and 1 molecule of water molecule was confirmed, so it was confirmed that 2,5DHBA co-crystal 0.5 hydrate was the molar ratio of compound A, gentisic acid and water molecules. 1:1:0.5 co-crystal (Figure 18).

(Analysis of crystals obtained by drying a hydrate sample) The powder X-ray diffraction pattern upon drying of the 2,5DHBA co-crystal 0.5 hydrate obtained from the methanol/water system in a laboratory setting shows a 2,5DHBA co-crystal (type II).

(Single-crystal structure analysis) The single-crystal structure analysis was performed about the 2,5DHBA co-crystal (II type crystal) obtained by drying the said 2,5DHBA0.5hydrate. The obtained crystallographic data and refinement parameters are shown below. [table 3] chemical formula C ₂₁ H ₂₀ ClF ₃ N ₂ O ₄ ·C ₇ H ₆ O ₄ formula 610.97 crystal system Triclinic space group P 1 a (Å) 9.6924(4) b (Å) 18.5967(7) c (Å) 24.1416(12) α (°) 110.002(4) β (°) 93.613(4) γ (°) 95.315(3) V (Å ³ ) 4050.5(3) Z 6 D _cal (g·cm ^-3 ) 1.503 μ (cm ^-1 ) 19.347 F (000) 1896.00 2 θ max(°) 151.9 Diffraction points collected 55982 Independent Diffraction Point, _{R int} 21430, 0.0930 R ₁ ( I > 2.00 σ ( I )) 0.0772 R (all diffraction points) 0.1110 w R ₂ (all diffraction points) 0.1954 Fleck parameter 0.10(3) ∆ ρ _max , ∆ ρ _min (e Å ^-3 ) 0.42, -0.45 The ORTEP diagram is shown in FIG. 19 . In the asymmetric unit, compound A and gentisic acid were each confirmed to have 6 molecules, so it was confirmed that the 2,5DHBA co-crystal (type II crystal) was a co-crystal of compound A and gentisic acid in a molar ratio of 1:1 (Fig. 20).

(Example 28) Co-crystallization of compound A and salicylic acid (sample analysis) A physical mixture of compound A (type II crystal) and salicylic acid in a molar ratio of 1:1 was prepared, and heated to 100° C., 120° C. or 150° C. °C, then cooled to room temperature, and measured PXRD (FIG. 21). As a result, the diffraction pattern at 100°C was mainly the physical mixture of compound A and salicylic acid. When the sample was heated at 120°C and 150°C, the diffraction pattern of the co-crystal of compound A and salicylic acid was observed. It was judged that a part of Compound A remained, but the main diffraction pattern was the diffraction pattern of the co-crystal with salicylic acid. It was confirmed that this diffraction pattern was also consistent with the PXRD pattern of the co-crystal obtained by the following crystallization.

(Crystallization method: acetone/water system) (1) 10 mg of compound A (type I crystal) was mixed with salicylic acid at a molar ratio of 5, 10 or 50, and dissolved in acetone (2 mL). In it, 1 mL of water was gradually added dropwise until the solid was precipitated. At a molar ratio of salicylic acid of 50, the co-crystal was obtained as a white to slightly yellow solid (Figure 22). In addition, the operation was carried out at room temperature. (2) 1 g of compound A (type II crystal) and salicylic acid having a molar ratio of 50 to compound A were dissolved in acetone (200 mL). Thereto, it was stirred with a stirrer, and water (300 mL) was added to precipitate crystals. The precipitate was collected by filtration, air-dried at room temperature, and then heated at 120° C. for 5 hours to obtain a salicylic acid co-crystal. Using a magnetic mortar, the obtained salicylic acid co-crystals were pulverized to obtain a drug particle size with a median diameter of 25.8 μm (particle size measurement model Shimadzu SALD-3100). (Crystallization method: acetone/hexane system) With respect to 10 mg of compound A (type I crystal), salicylic acid was mixed at a molar ratio of 5, 10 or 50, and dissolved in acetone (2 mL). In it, 1 mL of hexane was gradually added dropwise until the solid was precipitated. Under the condition that the molar ratio of salicylic acid is 50, the co-crystal is obtained in the form of white to slightly yellow solid. In addition, the operation was carried out at room temperature. (Crystallization method: THF/hexane system) With respect to 100 mg of compound A (type I crystal), salicylic acid was mixed at a molar ratio of 5, 10 or 50, and dissolved in THF (2 mL). In it, 1 mL of hexane was gradually added dropwise until the solid was precipitated. Under the condition that the molar ratio of salicylic acid is 50, the co-crystal is obtained in the form of white to slightly yellow solid. In addition, the operation was carried out at room temperature.

(Powder X-ray Diffraction) Figure 22 shows the PXRD pattern of the salicylic acid co-crystal in acetone/water system. According to Figure 22, salicylic acid co-crystallizes at diffraction angles (2θ) of 9.9°, 11.4°, 16.2°, 18.8°, 19.0°, 19.3°, 19.8°, 23.8°, 24.9°, 25.3°, 26.1° and 27.3° A peak appears near °. (thermal analysis) Figure 23 shows the TG/DTA curves of salicylic acid co-crystals in acetone/water systems.

(Single crystal structure analysis) A single crystal structure analysis was performed on the salicylic acid co-crystal obtained under the above-mentioned acetone/water-based crystallization conditions. The obtained crystallographic data and refinement parameters are shown below. [Table 4] chemical formula C ₂₁ H ₂₀ ClF ₃ N ₂ O ₄ ·C ₇ H ₆ O ₃ formula 594.97 crystal system Monoclinic (monoclininc) space group P 2 ₁ a (Å) 16.21513(12) b (Å) 9.34274(8) c (Å) 26.65887(19) α (°) 90.000 β (°) 95.9866(7) γ (°) 90.000 V (Å ³ ) 2496.76(15) Z 6 D _cal (g·cm ^-3 ) 1.476 μ (cm ^-1 ) 19.054 F (000) 1848.00 2 θ max(°) 151.5 Diffraction points collected 30583 independent diffraction point, R _int 13542, 0.0332 R ₁ ( I > 2.00 σ ( I )) 0.0432 R (all diffraction points) 0.0492 w R ₂ (all diffraction points) 0.1264 Fleck parameter 0.026(8) ∆ ρ _max , ∆ ρ _min (e Å ^-3 ) 0.77, -0.45 The ORTEP diagram is shown in FIG. 24 . In the asymmetric unit, 3 molecules of each of compound A and salicylic acid were confirmed, so the salicylic acid co-crystal was confirmed to be a co-crystal of compound A and salicylic acid in a molar ratio of 1:1 ( FIG. 25 ).

(Megahertz Raman Spectroscopy) Raman spectroscopic analysis in the low wavenumber domain was performed on each crystal form. The results are shown in FIG. 26 . According to Figure 26, in the megahertz Raman spectrum, compound A (type II crystal) has characteristic peaks at 15.6, 28.5, 48.0 cm ^-1 , and 2,5DHBA co-crystal (type I crystal) has characteristic peaks at 15.9, 45.3, 70.5 cm ^- 1 ¹ characteristic peak, 2,5DHBA co-crystal (type II) has characteristic peaks at 15.9, 25.8, 52.8 cm ^-1 , salicylic acid co-crystal at 15.6, 25.8, 38.7, 61.5, 96.6 cm ^-1 Characteristic peaks.

[Test example] (dissolution test) The dissolution test was carried out by dissolving 1% hydroxypropyl methylcellulose in test liquids obtained by dissolving 1% hydroxypropyl methylcellulose in JP1 and JP2. Specifically, the test solution was 20 mL, and the 2,5DHBA co-crystal (type I crystal) pulverized by a jet mill as a sample, a salicylic acid co-crystal pulverized by a magnetic mortar, and a control jet mill were pulverized After that, the compound A free form (type II) (median diameter: 2.7 μm) was respectively used as compound A, and about 5 mg of the compound A was dispersed 20 times with lactose, and the dissolution test was carried out at 37°C and 150 rpm. As a stirrer, μDiss Profiler (Pion) was used, and quantification was performed by UHPLC. Both test solutions were rapidly dissolved and showed supersaturation. Regarding their highest concentrations, both JP1 and JP2 were 2,5DHBA co-crystals (I-type crystals) and salicylic acid co-crystals were 12 to 15 times that of the control (Fig. 27). and 28).

(Canine Pharmacokinetic Test 1) The 2,5DHBA co-crystal (type I crystal) after being pulverized by a jet mill and the free form of Compound A (type II crystal) after being pulverized by a jet mill were used as compound A, respectively. 100 mg was administered orally to Gru dogs. The administration is carried out by dispersing the original powder 20 times with lactose monohydrate, and formulating it into capsules. As a result, for the co-crystal/compound A free form (type II crystal), absorption improvement of 6.3 times was confirmed in both C _max and AUC ( FIG. 29 ).

(Canine Pharmacokinetic Test 2) Next, HPMC was encapsulated in a capsule together with the co-crystal, and it was confirmed whether or not an absorption improvement effect was observed. HPMC (TC-5E) (available from Xinyue Chemical Industry Co., Ltd.) was co-crystallized with 2,5DHBA (type I crystal) after 5 times the weight of compound A (500 mg) was pulverized with a magnetic mortar ( Median diameter 19.0 μm) was physically mixed and administered 100 mg orally as Compound A to 6 Miguel dogs. The administration was carried out using lactose monohydrate (500 mg) for 5 times the weight of compound A, and the preparation was carried out into capsules. As a control, instead of a physical mixture of the co-crystal and HPMC, only the above-mentioned co-crystal was used for formulation. As a result, for the physical mixture of 2,5DHBA co-crystal (I-type crystal) and HPMC (TC-5E)/2,5DHBA co-crystal (I-type crystal), a 1.3-fold improvement in absorption was confirmed in _Cmax , and in AUC A 1.4-fold improvement in absorption was confirmed (Figure 30). When the co-crystal is dissolved, the presence of a polymer around the co-crystal suppresses crystallization, and it is considered that the absorption of the co-crystal is improved (the effect of prolonging the supersaturation time).

(Canine Pharmacokinetic Test 3) The co-crystal of salicylic acid pulverized by a jet mill and the free form of Compound A (type II crystal) pulverized by a jet mill were used as Compound A and administered orally to 5 Miguel dogs. Administer 100 mg. The administration is carried out by dispersing the original powder 20 times with lactose monohydrate, and formulating it into capsules. As a result, with respect to the co-crystal/compound A (type II crystal), a 6.6-fold improvement in absorption was observed in _Cmax , and a 5.9-fold improvement in absorption was observed in AUC ( FIG. 31 ).

(light stability test) The photostability of the solid state of 2,5DHBA co-crystals (type I crystal and type II crystal) and salicylic acid co-crystals was evaluated. The samples used 2,5DHBA co-crystals (I-type crystals and II-type crystals) and salicylic acid co-crystals, and Compound A free form (II-type crystals) as a control. The storage conditions were set under light irradiation (white fluorescent lamp and near-ultraviolet fluorescent lamp) for 2 weeks. After 2 weeks, the appearance observation was carried out. As a result of the photostability test, the free form of compound A (type II crystal) was confirmed to have discoloration on the surface (white to slightly yellowish white) under light irradiation. crystal) and salicylic acid co-crystal, no particular change was observed.

(thermal stability test) The thermal stability of the solid state of 2,5DHBA co-crystals (type I crystal and type II crystal) and salicylic acid co-crystals was evaluated. The samples used 2,5DHBA co-crystals (I-type crystals and II-type crystals) and salicylic acid co-crystals, and Compound A free form (II-type crystals) as a control. The storage conditions were set at 70°C (Close system) for 2 weeks. After 2 weeks, in addition to the appearance observation, the evaluation of the purity (UHPLC) and the crystallinity (PXRD, TG/DTA) was performed. As a result of the thermal stability test, no particular change was observed in any item before and after the test.

(Thermal Humidity Stability Test) The thermal humidity stability of the solid state of the 2,5DHBA co-crystal (type I crystal) was evaluated. The storage conditions were set at 40°C/75%RH (open system, closed system) and 60°C (closed system) for 4 weeks. After 4 weeks, in addition to the appearance observation, the evaluation of purity (UHPLC) and crystallinity (PXRD, TG/DTA) was performed. As a result of the thermal-humidity stability test, no particular change was observed in any item before and after the test.

32 and 33 show the PXRD patterns before and after the thermal stability test and the thermal humidity stability test of the 2,5DHBA co-crystal (type I crystal and type II crystal), respectively. In any of the co-crystals, no change in crystal form was observed under heat and heat and humidity. [Industrial Availability]

The co-crystal of Compound A or its co-crystal solvate can more stably and efficiently supply medicines having antibacterial effects against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and/or nontuberculous mycobacteria. The co-crystal of Compound A or its co-crystal solvate exhibits improved pharmacokinetic properties such as excellent oral absorbability, and thus can be used as a raw material for pharmaceuticals.

Figure 1 shows the TG/DTA (TG/DTA ( thermogravimetric/differential thermal analysis, thermogravimetric/differential thermal analysis) curves.

Figure 2 shows the TG/DTA curve of compound A (type II crystal).

Figure 3 shows the TG/DTA curve of 2,5DHBA.

Figure 4 shows the TG/DTA curve of a sample obtained by physically mixing Compound A (type II crystal) and salicylic acid at a molar ratio of 1:2.

Figure 5 shows the TG/DTA curve of salicylic acid.

Figure 6 shows the DSC/PXRD (differential scanning calorimetry/powder X-ray diffraction, differential scanning calorimetry/powder X-ray diffraction) of the sample obtained by physically mixing compound A (type II crystal) and 2,5DHBA at a molar ratio of 1:2 ray diffraction) synchronous measurement results.

FIG. 7 shows the TG/DTA curve of the 2,5DHBA co-crystal THF compound obtained by crystallization of THF (tetrahydrofuran, tetrahydrofuran)/hexane system.

Fig. 8 shows the PXRD pattern (2,5DHBA co-crystal (type II crystal)) after heating the 2,5DHBA co-crystal THF compound obtained by crystallization of THF/hexane system to 100°C.

FIG. 9 shows the PXRD pattern (2,5DHBA co-crystal (I-type crystal)) after heating the 2,5DHBA co-crystal THF compound obtained by crystallization of the THF/hexane system to 145°C.

Figure 10 shows the PXRD pattern of compound A (type II crystal).

Figure 11 shows the PXRD pattern of 2,5DHBA.

Fig. 12 shows the TG/DTA curve of the 2,5DHBA co-crystal THF compound obtained by crystallization of THF/hexane system at 100°C (2,5DHBA co-crystal (type II crystal)).

Figure 13 shows the TG/DTA curve of the 2,5DHBA co-crystal (type I crystal) obtained by crystallization from methanol/water system.

Figure 14 shows the PXRD pattern of the 2,5DHBA co-crystallized THF compound obtained by crystallization from the THF/hexane system.

Figure 15 shows the TG/DTA curve of the co-crystal 0.5 hydrate of Compound A and 2,5DHBA obtained by crystallization from methanol/water system.

Figure 16 shows the PXRD pattern of the 2,5DHBA co-crystal 0.5hydrate.

Figure 17 shows the ORTEP plot (oak ridge thermal ellipsoid plot) of the 2,5DHBA co-crystal 0.5 hydrate obtained under methanol/water crystallization conditions.

Figure 18 shows the ORTEP diagram of the 2,5DHBA co-crystallized 0.5 hydrate in the asymmetric unit.

Figure 19 shows the ORTEP diagram of the 2,5DHBA co-crystal (type II crystal) obtained by drying the 2,5DHBA co-crystal 0.5 hydrate.

Figure 20 shows the ORTEP diagram of the 2,5DHBA co-crystal (type II) in the asymmetric unit.

Figure 21 shows the PXRD pattern of a sample obtained by physically mixing Compound A (type II crystal) and salicylic acid at a molar ratio of 1:1 and heating. The single component of compound A, the single component of salicylic acid, the sample obtained by heating the physical mixture to 100°C, the sample obtained by heating to 120°C, and the sample obtained by heating to 150°C are shown in order from the top.

Figure 22 shows the PXRD pattern of a salicylic acid co-crystal in an acetone/water system.

Figure 23 shows the TG/DTA curve of the salicylic acid co-crystal in acetone/water system.

Figure 24 shows an ORTEP diagram of salicylic acid co-crystals in an acetone/water system.

Figure 25 shows an ORTEP diagram of salicylic acid co-crystals in asymmetric units.

Fig. 26 is an overlay of the megahertz Raman spectra of each crystal, showing that compound A (type II crystal), 2,5DHBA co-crystal (type II crystal), 2,5DHBA (type I crystal), and salicylic acid co-crystal , 2,5DHBA and salicylic acid Megaheraman spectra.

Figure 27 shows the dissolution curves of compound A (type II crystal), 2,5DHBA co-crystal (type I crystal) and salicylic acid co-crystal in JP1 dissolved in 1% hypromellose. ○ represents the dissolution curve of 2,5DHBA co-crystal (type I crystal), △ represents the dissolution curve of salicylic acid co-crystal, and × represents the dissolution curve of compound A (type II crystal).

Figure 28 shows the dissolution curves of Compound A (type II crystal), 2,5DHBA co-crystal (type I crystal) and salicylic acid co-crystal in JP2 dissolved in 1% hypromellose. ○ represents the dissolution curve of 2,5DHBA co-crystal (type I crystal), △ represents the dissolution curve of salicylic acid co-crystal, and × represents the dissolution curve of compound A (type II crystal).

Figure 29 shows the results of the canine pharmacokinetic test of 2,5DHBA co-crystal (I-type crystal; 0) and Compound A (II-type crystal; ×).

Figure 30 shows the results of the canine pharmacokinetic test of the physical mixture (□) of 2,5DHBA co-crystal (I-type crystal; O), 2,5DHBA co-crystal (I-type crystal) and HPMC (TC-5E).

Fig. 31 shows the results of the canine pharmacokinetic test of salicylic acid co-crystal (Δ) and compound A (type II crystal; ×).

FIG. 32 shows the PXRD patterns of the 2,5DHBA co-crystal (type I crystal) before and after the thermal stability test and the thermal humidity stability test. The PXRD patterns before the start of the test, after the thermal stability test (70°C, 2 weeks), and after the thermal humidity stability test (70°C/75%RH, 2 weeks) are shown from the upper side.

FIG. 33 shows the PXRD patterns of the 2,5DHBA co-crystal (type II crystal) before and after the thermal stability test and the thermal humidity stability test. The PXRD patterns before the start of the test, after the thermal stability test (70°C, 2 weeks), and after the thermal humidity stability test (70°C/75%RH, 2 weeks) are shown from the upper side.

Claims (16)

A co-crystal or a co-crystal solvate thereof, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine Co-crystals of pyridin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and co-crystal formers. The co-crystal or its co-crystal solvate of claim 1, wherein the co-crystal former is a nonvolatile organic acid. As claimed in claim 2, the co-crystal or its co-crystal solvate, wherein the non-volatile organic acid is at least one of the ortho, meta or para positions can be selected from the group consisting of hydroxyl, amine and carboxyl groups substituted benzoic acid. The co-crystal or its co-crystal solvate of claim 3, wherein the benzoic acid is gentisic acid or salicylic acid. The co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 4, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, at the angle selected from the diffraction angle (2θ) 9.7°±0.2°, 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 22.8°±0.2°, 25.0°±0.2°, 25.9° At least 3 of the group consisting of ±0.2° and 26.9°±0.2° contain diffraction peaks. The co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 4, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, at the angle selected from the diffraction angle (2θ) 3.9°±0.2°, 7.8°±0.2°, 11.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 20.0°±0.2°, 24.8°±0.2° and 25.8° At least 3 of the group consisting of ±0.2° contain diffraction peaks. The co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 4, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, at the angle selected from the diffraction angle (2θ) 9.9°±0.2°, 11.4°±0.2°, 16.2°±0.2°, 18.8°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 19.8°±0.2°, 23.8°±0.2°, 24.9° At least three of the group consisting of ±0.2°, 25.3°±0.2°, 26.1°±0.2° and 27.3°±0.2° contain diffraction peaks. The co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 4, wherein in a powder X-ray diffraction pattern obtained by using CuKα rays as the X-ray source, at the angle selected from the diffraction angle (2θ) 12.1°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 17.7°±0.2°, 23.4°±0.2°, 23.6°±0.2°, 24.8°±0.2°, 25.4°±0.2° and 26.7° At least 3 of the group consisting of ±0.2° contain diffraction peaks. A method for producing a co-crystal or a co-crystal solvate, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4- A co-crystallization of dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and a co-crystal former, the manufacturing method comprising the following steps: (1) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8 - Fluoro-3,4-dihydroquinolin-2(1H)-one and the co-crystal former are mixed in a solvent; and (2) The solid precipitated in the above-mentioned step (1) is collected by filtration to obtain the above-mentioned co-crystal or a co-crystal solvate thereof. A method for producing a co-crystal or a co-crystal solvate, wherein the co-crystal is 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4- A co-crystallization of dihydroxypiperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one and a co-crystal former, the manufacturing method comprising the following steps: (1) 5-{[(3R,4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidin-4-yl]methoxy}-8 - Fluoro-3,4-dihydroquinolin-2(1H)-one and co-crystal former are mixed in a good solvent; and (2) A poor solvent is added to the mixture obtained in the above step (1). The method of claim 10, wherein the good solvent is tetrahydrofuran, acetone or methanol, and the poor solvent is hexane or water. A pharmaceutical composition comprising the co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier. An agent for diagnosing, preventing and/or treating tuberculosis, comprising the co-crystal according to any one of claims 1 to 8 or a co-crystal solvate thereof. The co-crystal of any one of claims 1 to 8 or a co-crystal solvate thereof, which is used for the diagnosis, prevention and/or treatment of tuberculosis. A use of the co-crystal or a co-crystal solvate thereof according to any one of claims 1 to 8, for the manufacture of a diagnostic, preventive and/or therapeutic drug for tuberculosis. A method for preventing and/or treating tuberculosis in a subject, characterized in that: the subject needs an effective dose of the co-crystal or co-crystal solvate of any one of claims 1 to 8, and the method is administered to the subject An effective dose of a co-crystal or a co-crystal solvate thereof as claimed in any one of claims 1 to 8 is administered.

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