WO2021230198A1 - 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

Co-crystal of dihydroquinolinone compound

The present invention relates to 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4. -Dihydroquinoline-2 (1H) -On co-crystals or co-crystal solvates thereof, pharmaceutical compositions containing the same, and methods for producing them.

In drug development, not only the medicinal properties of the pharmaceutical compound itself, but also the drug substance form having the physical characteristics (for example, solubility, bioavailability, pharmacokinetics and stability) that can be accepted as a drug even after the formulation process is required. Has been done. As one of such drug substance forms, a co-crystal formed by incorporating an active molecule and a second component (also referred to as "Coformer" in the present specification) into a crystal structure is generally known. Has been done. The formation of a co-crystal is useful for, for example, the formulation of a poorly water-soluble active molecule, but it is necessary to search for a coformer peculiar to the active molecule and find a co-crystal that retains or improves its medicinal usefulness.

formula:

5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- Dihydroquinoline-2 (1H) -one (also referred to herein as "Compound A") is a compound having antibacterial activity against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and / or non-tuberculous mycobacterium. It is known as (Patent Document 1). No pharmaceutically useful co-crystals for compound A have been known so far.

International Publication No. 2016/031255

One of the problems to be solved by the present invention is 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy. } -8-Fluoro-3,4-dihydroquinoline-2 (1H) -one (“Compound A”) is to provide a novel drug substance form, a drug containing the drug substance, and a method for producing the same.

As a result of diligent research to solve the above problems, the present inventors have found a novel co-crystal form of compound A and completed the present invention.

The co-crystal of Compound A or its co-crystal solvate enables more stable and efficient supply of drugs having antibacterial activity against tubercle bacilli, multidrug-resistant tubercle bacilli and / or nontuberculous mycobacteria. Become. A co-crystal of compound A or a co-crystal solvate thereof may also improve the absorption of compound A into the body and improve bioavailability.

FIG. 1 shows a TG / DTA curve of a sample in which compound A (II form crystal) and 2.5 DHBA are physically mixed at a molar ratio of 1: 2.

FIG. 2 shows the TG / DTA curve of compound A (II form crystal).

FIG. 3 shows a TG / DTA curve of 2.5 DHBA.

FIG. 4 shows a TG / DTA curve of a sample in which compound A (II form crystal) and salicylic acid are physically mixed at a molar ratio of 1: 2.

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

FIG. 6 shows the results of simultaneous measurement of DSC / PXRD of a sample in which compound A (II form crystal) and 2.5DHBA are physically mixed at a molar ratio of 1: 2.

FIG. 7 shows the TG / DTA curve of the 2.5DHBA co-crystal THF sum product obtained by the crystallization of the THF / hexane system.

FIG. 8 shows a PXRD pattern after heating a 2,5 DHBA co-crystal THF mixture obtained by THF / hexane-based crystallization to 100 ° C. (2.5 DHBA co-crystal (II type crystal)).

FIG. 9 shows a PXRD pattern after heating a 2,5 DHBA co-crystal THF mixture obtained by THF / hexane-based crystallization to 145 ° C (2.5 DHBA co-crystal (I-shaped crystal)).

FIG. 10 shows the PXRD pattern of compound A (II form crystal).

FIG. 11 shows a PXRD pattern of 2.5 DHBA.

FIG. 12 shows a TG / DTA curve after heating a 2,5 DHBA co-crystal THF mixture obtained by THF / hexane-based crystallization to 100 ° C. (2.5 DHBA co-crystal (II type crystal)).

FIG. 13 shows a TG / DTA curve of a 2.5 DHBA co-crystal (I-shaped crystal) obtained by crystallization of a methanol / aqueous system.

FIG. 14 shows the PXRD pattern of the 2,5 DHBA co-crystal THF sum product obtained by the crystallization of the THF / hexane system.

FIG. 15 shows a TG / DTA curve of a co-crystal 0.5 hydrate of compound A and 2.5 DHBA obtained by methanol / aqueous crystallization.

FIG. 16 shows the PXRD pattern of 2.5 DHBA co-crystal 0.5 hydrate.

FIG. 17 shows an ORTEP diagram of 2.5 DHBA co-crystal 0.5 hydrate obtained under methanol / aqueous crystallization conditions.

FIG. 18 shows an ORTEP diagram of a 2.5 DHBA co-crystal 0.5 hydrate in an asymmetric unit.

FIG. 19 shows an ORTEP diagram of a 2.5 DHBA co-crystal (II form crystal) obtained by drying a 2.5 DHBA co-crystal 0.5 hydrate.

FIG. 20 shows an ORTEP diagram of a 2.5 DHBA co-crystal (II form crystal) in an asymmetric unit.

FIG. 21 shows the PXRD pattern of a sample in which compound A (form II) and salicylic acid are physically mixed at a molar ratio of 1: 1 and heated. From top to bottom, compound A alone, salicylic acid alone, a sample of the physical mixture heated to 100 ° C, a sample heated to 120 ° C, and a sample heated to 150 ° C are shown.

FIG. 22 shows the PXRD pattern of salicylic acid co-crystals in an acetone / aqueous system.

FIG. 23 shows the TG / DTA curves of salicylic acid co-crystals in an acetone / aqueous system.

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

FIG. 25 shows an ORTEP diagram of salicylic acid co-crystals in an asymmetric unit.

FIG. 26 is an superimposed view of the terahertz Raman spectrum for each crystal. Compound A (II type crystal), 2,5 DHBA co-crystal (II type crystal), 2,5 DHBA (I type crystal), salicylic acid co-crystal, The terahertz raman spectra for 2.5DHBA and salicylic acid are shown.

FIG. 27 shows the elution profiles of compound A (II type crystal), 2.5DHBA co-crystal (I type crystal) and salicylic acid co-crystal in 1% hypromellose-dissolved JP1. 〇 indicates a 2.5DHBA co-crystal (I-type crystal), Δ indicates a salicylic acid co-crystal, and × indicates an elution profile of compound A (II-type crystal).

FIG. 28 shows the elution profiles of compound A (II type crystal), 2.5DHBA co-crystal (I type crystal) and salicylic acid co-crystal in 1% hypromellose-dissolved JP2. 〇 indicates a 2.5DHBA co-crystal (I-type crystal), Δ indicates a salicylic acid co-crystal, and × indicates an elution profile of compound A (II-type crystal).

FIG. 29 shows the results of a canine pharmacokinetic test of a 2.5DHBA co-crystal (I-form crystal; 〇) and compound A (II-form crystal; ×).

FIG. 30 shows the results of a canine pharmacokinetic test of a 2,5 DHBA co-crystal (I-form crystal; 〇) and a physical mixture (□) of a 2,5 DHBA co-crystal (I-form crystal) and HPMC (TC-5E).

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

FIG. 32 shows the PXRD pattern before and after the thermal stability test and the thermal humidity stability test of the 2.5DHBA co-crystal (I-shaped crystal). From the top, 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.

FIG. 33 shows the PXRD pattern before and after the thermal stability test and the thermal humidity stability test of the 2.5DHBA co-crystal (II type crystal). From the top, 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.

Some specific embodiments are illustrated below.
[Item 1]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -A co-crystal of on and coformer or a co-crystal solvate thereof.

[Item 2]
Item 2. The co-crystal according to Item 1, or a co-crystal solvate thereof, wherein the coformer is a non-volatile organic acid.

[Item 3]
Item 2. The co-crystal according to Item 2, wherein the non-volatile organic acid is a benzoic acid in which at least one of the o-, m- or p-positions may be substituted with a group selected from the group consisting of hydroxy, amino and carboxyl. Or its co-crystal solvate.

[Item 4]
Item 3. The co-crystal according to Item 3, or a co-crystal solvate thereof, wherein the benzoic acid is gentisic acid or salicylic acid.

[Item 5]
Item 2. The co-crystal according to Item 2, wherein the non-volatile organic acid is a carboxylic acid, or a co-crystal solvate thereof.

[Item 6]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 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. Item 2. The co-crystal according to any one of Items 1 to 5, wherein at least three selected from the group consisting of 2 °, 25.9 ° ± 0.2 ° and 26.9 ° ± 0.2 ° contain diffraction peaks. Or its co-crystal solvent mixture.

[Item 7]
In the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source, the diffraction angles (2θ) are 11.4 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.3 ° ± 0. Item 6. The co-crystal or co-crystal solvent mixture thereof according to Item 6, which contains diffraction peaks at 2 ° and 25.9 ° ± 0.2 °.

[Item 8]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 9.7 ° ± 0.2 °, 11.4 ° ± 0.2 °, 16.0 ° ± 0. Item 6 containing diffraction peaks at 2 °, 18.7 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 ° and 25.9 ° ± 0.2 °. The co-crystal or a co-crystal solvent admixture thereof according to.

[Item 9]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angles (2θ) are 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. Item 6. The co-crystal according to any one of Items 1 to 5, or a co-crystal solvent mixture thereof, which comprises a diffraction peak in at least three selected from the group consisting of 2 ° and 25.8 ° ± 0.2 °.

[Item 10]
In the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source, the diffraction angle (2θ) 14.1 ° ± 0.2 °, 20.0 ° ± 0.2 ° and 24.8 ° ± 0. Item 2. The co-crystal according to Item 9, or a co-crystal solvent admixture thereof, which contains a diffraction peak at 2 °.

[Item 11]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angles (2θ) are 3.9 ° ± 0.2 °, 7.8 ° ± 0.2 °, 11.8 ° ± 0. Item 9 with diffraction peaks at 2 °, 14.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 20.0 ° ± 0.2 ° and 24.8 ° ± 0.2 °. The co-crystal or a co-crystal solvent admixture thereof according to.

[Item 12]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 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. At least selected from the group consisting of 2 °, 24.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.1 ° ± 0.2 ° and 27.3 ° ± 0.2 ° Item 6. The co-crystal according to any one of Items 1 to 5, or a co-crystal solvent admixture thereof, which comprises a diffraction peak in three.

[Item 13]
In the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source, the diffraction angles (2θ) are 11.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.0 ° ± 0. Item 2. The co-crystal according to Item 12, or a co-crystal solvent mixture thereof, which contains diffraction peaks at 2 ° and 26.1 ° ± 0.2 °.

[Item 14]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 9.9 ° ± 0.2 °, 11.4 ° ± 0.2 °, 16.2 ° ± 0. Item 12 with diffraction peaks at 2 °, 18.8 ° ± 0.2 °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 ° and 26.1 ° ± 0.2 °. The co-crystal or a co-crystal solvent admixture thereof according to.

[Item 15]
In the powder X-ray diffraction pattern obtained by using CuKα ray as the X-ray source, the diffraction angles (2θ) are 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. Item 6. The co-crystal according to any one of Items 1 to 5, or a co-crystal solvent mixture thereof, which comprises a diffraction peak in at least three selected from the group consisting of 2 ° and 26.7 ° ± 0.2 °.

[Item 16]
In the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source, the diffraction angles (2θ) are 12.1 ° ± 0.2 °, 15.1 ° ± 0.2 ° and 15.4 ° ± 0. Item 2. The co-crystal according to Item 15, or a co-crystal solvate thereof, which contains a diffraction peak at 2 °.

[Item 17]
In the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source, the diffraction angles (2θ) are 12.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.4 ° ± 0. Item 15, including diffraction peaks at 2 °, 17.7 ° ± 0.2 °, 23.6 ° ± 0.2 °, 24.8 ° ± 0.2 ° and 25.4 ° ± 0.2 °. The co-crystal described in 1 or a co-crystal solvent admixture thereof.

[Item 18]
Item 6. The cocrystal solvate according to any one of Items 1 to 17, which is a hydrate, for example, 0.5 hydrate, monohydrate or dihydrate.

[Item 19]
formula:

The compound shown by or a solvate thereof.

[Item 20]
formula:

The compound shown by or a solvate thereof.

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

[Item 22]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A co-crystal of 2 (1H) -one and salicylic acid (that is, 2-hydroxybenzoic acid) or a co-crystal solvate thereof.

[Item 23]
Item 6. The solvate according to any one of Items 19 to 22, which is a hydrate, for example, 0.5 hydrate, monohydrate or dihydrate.

[Item 24]
Item 6. The compound according to any one of Items 1 to 23 or a solvate thereof, which is a substantially pure crystal.

[Item 25]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing a co-crystal of 2 (1H) -one and a coformer or a co-crystal solvate thereof.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- A step of mixing dihydroquinoline-2 (1H) -one and a coformer in a solvent, and (2) a step of collecting the solid precipitated in the step (1) to obtain the cocrystal or a cocrystal solvate thereof. How to include.

[Item 26]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing a co-crystal of 2 (1H) -one and a coformer or a co-crystal solvate thereof.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- A method comprising a step of mixing dihydroquinoline-2 (1H) -one and a coformer in a good solvent and (2) a step of adding a poor solvent to the mixture obtained in the above step (1).

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

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

[Item 29]
An agent for diagnosing, preventing and / or treating tuberculosis, which comprises the compound according to any one of Items 1 to 24 or a co-crystal or a co-crystal solvate thereof.

[Item 30]
Item 6. The compound or cocrystal according to any one of Items 1 to 24 for diagnosing, preventing and / or treating tuberculosis, or a cocrystal solvate thereof.

[Item 31]
Use of the compound or cocrystal according to any one of Items 1 to 24 or a cocrystal solvate thereof in the manufacture of a diagnostic agent, a preventive agent and / or a therapeutic agent for tuberculosis.

[Item 32]
Diagnosis, prevention and / of tuberculosis in a subject comprising administering to a subject in need thereof an effective amount of the compound or co-crystal or co-crystal solvate according to any one of Items 1 to 24. Or how to treat.

As used herein, "cocrystal" is a crystalline substance composed of compound A and an arbitrary second component ("Coformer") present in the same crystal lattice at an arbitrary molar ratio. , Distinguished from solvates. Cocrystals can exist in multiple crystal forms (also referred to herein as "crystal polymorphs"). The compound A forming a co-crystal may be any crystal form or a mixture thereof, or may be amorphous. In the present specification, co-crystals are referred to according to the type of coformer. For example, "2.5DHBA co-crystal" means a co-crystal of compound A and 2,5 DHBA and any crystal polymorph thereof, and "salicylic acid co-crystal" means a co-crystal of compound A and salicylic acid. Means any crystalline polymorph. For example, the 2.5DHBA co-crystals include I-form and II-form crystals.

Examples of the crystal form of the co-crystal include an I-type co-crystal (co-crystal (I-type crystal)) or a II-type co-crystal (co-crystal (II-type crystal)). In some embodiments, the co-crystal is a substantially pure I-shaped co-crystal, i.e., an I-shaped co-crystal that is substantially free of any other crystal form. Here, an I-type co-crystal that does not substantially contain any other crystal morphology is, 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, 0. An I-type co-crystal that may contain any other crystal form, eg, type II co-crystal, in less than 5% by weight. In another embodiment, the co-crystal is a substantially pure form II co-crystal, i.e., a form II co-crystal that is substantially free of any other crystal form. Here, a type II co-crystal that does not substantially contain any other crystal morphology is, 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, 0. It is a type II cocrystal that may contain any other crystal form, eg, type I cocrystal, in less than 5% by weight.

As used herein, a "coformer" is a non-ionized molecule that can form a co-crystal with compound A. Specific examples thereof include organic acids, amino acids, amines and amides, preferably non-volatile organic acids or amino acids. The molar ratio of compound A to the coformer can be any value depending on the coformer, and is, for example, 1: 0.5 to 1: 2.5, 1: 0.8 to 1: 2, preferably 1: 0. It is 9.9 to 1: 1.5, more preferably 1: 1.
In some embodiments, the coformer may elute from the crystal lattice of the co-crystal under predetermined conditions, thereby supersaturating compound A and improving solubility. In this case, the coformer is preferably water soluble. In another embodiment, the coformer is a solid molecule under normal pressure at room temperature (15 ° C to 25 ° C).

In the present specification, the "organic acid" is not particularly limited as long as it is an organic compound showing acidity capable of forming a co-crystal with 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) capable of forming a co-crystal with compound A, but for example, a chain carboxylic acid or an aromatic. Examples thereof include group carboxylic acids and heterocyclic carboxylic acids.

In the present specification, the "nonvolatile organic acid" is not particularly limited as long as it is an organic acid capable of forming a co-crystal with compound A, but is easily volatilized at normal temperature (15 ° C. to 25 ° C.), for example. Examples include organic acids that do not. In some embodiments, the non-volatile organic acid is a water-soluble organic acid. It is preferably a carboxylic acid. More preferably, it is a benzoic acid compound in which at least one of the o-, m- or p-positions may be substituted with a group selected from the group consisting of hydroxy, amino and carboxyl. More preferably, it is 2,5-dihydroxybenzoic acid or salicylic acid.

In the present specification, the "amino acid" is not particularly limited as long as it is an organic compound having both functional groups of an amino group and a carboxyl group, and includes natural amino acids and unnatural amino acids.

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

In the present specification, the "amide" is not particularly limited as long as it is a compound obtained by dehydrating and condensing an oxo acid and ammonia or a primary or secondary amine, and examples thereof include a carboxylic acid amide.

Examples of the coformer include, but are not limited to, the compounds exemplified below.

The co-crystal of compound A may exist as a solvate (also referred to as "co-crystal solvate" in the present specification) formed by the co-crystal and the solvent molecule at an arbitrary molar ratio. Examples of such solvates include hydrates, ethanol solvates and THF solvates. For example, the co-crystal of compound A may have a solvent molecule of 0.5 to 2 molecules as a solvent admixture with respect to one molecule of compound A, for example, 0.5 hydrate, monohydrate, 1. It may be a pentahydrate or a dihydrate.

The following abbreviations may be used herein.
Coformer: Cocrystallformer
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 Analysis PXRD: Powder X-ray Diffraction TG / DTA: Differential Calorie Weight Simultaneous Measurement C _max : Maximum Blood Concentration AUC: Drug Concentration Time Area under the curve JP1: Japanese Pharmacy Dissolution Test Liquid 1 JP2: Japanese Pharmacy Dissolution Test Liquid 2

[Production method]
The method for producing compound A is illustrated below. The compound obtained in each step may be isolated and purified by a known method usually used in the art such as distillation, recrystallization and column chromatography, or may be isolated or purified without being isolated or purified in the next step. You may proceed to. Further, the reagents used in each step may be commercially available, or may be produced according to a method known to those skilled in the art.

(Manufacturing method 1)
Synthesis of 4-chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate 4-Chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate is a chlorinating agent for 2,6-difluoroaniline and alkylthiourea. It can be produced by reacting in a solvent in the presence.
Examples of the chlorinating agent include N-chlorosuccinimide and trichloroisocyanuric acid.
Examples of the alkylthiourea include 1,3-dimethylthiourea.
Examples of the solvent include acetonitrile, ethyl acetate and mixtures thereof.
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-oxopiperidin-1-ium iodide 1-Ethyl-1- (2-methylallyl) -4-oxopiperidin-1-ium iodide is isobutenyl chloride Can be produced by reacting with 1-ethyl-4-piperidin in a solvent in the presence of an iodinating agent.
Examples of the iodinating agent include sodium iodide.
Examples of the solvent include acetone.
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) piperidine-4-one 1- (4-chloro-2,6-difluorophenyl) piperidine-4-one is 4-chloro-2,6-one After treating difluoroaniline and 4-methylbenzenesulfonate with a base to obtain 4-chloro-2,6-difluoroaniline, 1-ethyl-1- (2-methylallyl) in a solvent in the presence of alkylthiourea. It can be produced by reacting with -4-oxopiperidine-1-ium iodide.
Examples of the base include sodium hydroxide.
Examples of the alkylthiourea include 1,3-dimethylthiourea.
Examples of the solvent include water.
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-ium 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] octa-4-ol (1) 1- (4-chloro- 2,6-Difluorophenyl) piperidine-4-one was reacted in a solvent in the presence of a silylating agent and a base, and 4-[(tert-butyldimethylsilyl) oxy] -1- (4-chloro-2) was reacted. , 6-Difluorophenyl) -1,2,3,6-tetrahydropyridine can be produced.
Examples of the silylating agent include tert-butyldimethylsilyl chloride.
Examples of the base include triethylamine.
Examples of the solvent include acetonitrile.
The reaction temperature is, for example, the reflux temperature.
The reaction time is, for example, 1 to 5 hours, preferably 2 hours.
(2) The 4-[(tert-butyldimethylsilyl) oxy] -1- (4-chloro-2,6-difluorophenyl) -1,2,3,6-tetrahydropyridine obtained in (1) was used. In the presence of an additive, asymmetric epoxidation reaction was carried out with D-epoxone in a solvent to (1R, 6R)-[(tert-butyldimethylsilyl) oxy] -3- (4-chloro-2,6-). Difluorophenyl) -7-oxa-3-azabicyclo [4.1.0] heptane can be produced.
Examples of the additive include ethylenediaminetetraacetic acid disodium, potassium carbonate, hydrogen peroxide solution and a mixture thereof.
Examples of the solvent include toluene, propanol, acetonitrile and mixtures thereof.
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 [2] obtained in (2). 4.1.0] Heptane was reacted in a solvent in the presence of an ylide generator and a base to (3R, 4R) -6- (4-chloro-2,6-difluorophenyl) -1-oxa-6. -Azaspiro [2.5] octa-4-ol can be produced.
Examples of the ylide-producing agent include trimethylsulfoxonium iodide.
Examples of the base include potassium hydroxide.
Examples of the solvent include dimethyl sulfoxide.
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-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- Synthesis of 2 (1H) -one (Compound A) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-Fluoro-3,4-dihydroquinoline-2 (1H) -one is (3R, 4R) -6- (4-chloro-2,6-difluorophenyl) -1-oxa-6-azaspiro [2] .5] Octa-4-ol can be produced by reacting with 8-fluoro-5-hydroxy-3,4-dihydroquinoline-2 (1H) -one in a solvent in the presence of a base.
Examples of the base include potassium carbonate.
Examples of the solvent include propanol, water and a mixture thereof.
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] octa-4-ol (another method)
(1) 2-Methyl-2-vinyloxylane was subjected to a vinyl epoxide transfer reaction with 1,3-bis (hexafluoro-α-hydroxyisopropyl) benzene in the presence of a catalyst and an additive, and then 4-chloro-2. , 6-Difluoroaniline, 4-methylbenzenesulfonate and paraformaldehyde to react with [1- (4-chloro-2,6-difluorophenyl) -1,2,3,6-tetrahydropyridine-4-yl] Methanol can be produced.
(1-1) Conditions for Vinyl Epoxide Transition Reaction Examples of the catalyst include a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium.
Examples of the additive include triphenylphosphine.
Examples of the solvent include toluene, 1,2-dimethoxyethane and a mixture thereof.
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 / 4-methylbenzenesulfonate Examples of the solvent include toluene.
The reaction temperature is, for example, room temperature.
The reaction time is, for example, 1 to 4 hours, preferably 2.5 hours.

(2) [1- (4-Chloro-2,6-difluorophenyl) -1,2,3,6-tetrahydropyridine-4-yl] methanol obtained in (1) was used as a peroxide and an additive. After reacting in the presence, in a solvent, and then treated in the presence of a base and additives [(1R, 6R) -3- (4-chloro-2,6-difluorophenyl) -7-oxa-3- Azabicyclo [4.1.0] heptane-6-yl] methanol can be produced.
(2-1) Reaction conditions with peroxide Examples of the peroxide include cumene hydroperoxide.
Additives include, for example, zeolite, (D)-(-)-isopropyl tartrate, titanium tetraisopropoxide and mixtures thereof.
Examples of the solvent include toluene, dimethyl sulfoxide and mixtures thereof.
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) Base Treatment Conditions Examples of the base include triethylamine, 4-dimethylaminopyridine and a mixture thereof.
Examples of the additive include phthalic anhydride.
Examples of the solvent include ethyl acetate.
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] heptane-6- obtained in (2) Il] Methanol was reacted in a solvent in the presence of tosyl lolide and a base, and then desorbed (S) -1- (4-chloro-2,6-difluorophenyl) -4-methylenepiperidin-. 3-All can be manufactured.
(3-1) Tosylation conditions Examples of the base include triethylamine, trimethylamine hydrochloride and a mixture thereof.
Examples of the solvent include toluene.
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) Desorption Conditions As the additive, for example, sodium iodide, ascorbic acid and a mixture thereof may be used.
Examples of the solvent include acetonitrile, water and mixtures thereof.
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) By the epoxidation reaction of (S) -1- (4-chloro-2,6-difluorophenyl) -4-methylenepiperidin-3-ol obtained in (3) with perbenzoic acid (3R, 4R) -6- (4-chloro-2,6-difluorophenyl) -1-oxa-6-azaspiro [2.5] octa-4-ol can be produced.
Examples of the perbenzoic acid include m-chloroperbenzoic acid.
Examples of the solvent include ethyl acetate, water and a mixture thereof.
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-dihydroquinoline-2 (1H) -one (manufacturing method 7-1)
Synthesis of N- (2,5-difluorophenyl) -3-phenylacrylamide 1,4-difluoro-2-nitrobenzene is reacted with cinnamic acid chloride in a solvent under a hydrogen atmosphere and in the presence of a palladium catalyst. -(2,5-Difluorophenyl) -3-phenylacrylamide can be produced.
Examples of the palladium catalyst include 5% palladium carbon.
Examples of the solvent include ethyl acetate.
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-difluoroquinoline-2 (1H) -one N- (2,5-difluorophenyl) -3-phenylacrylamide is reacted in the presence of aluminum chloride to form 5,8-difluoroquinoline-2 (5,8-difluoroquinoline-2 (1H) -one. 1H) -On can be manufactured.
As the additive, for example, sodium chloride, potassium chloride and a mixture thereof may 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 5,8-difluoroquinoline-2 (1H) -one is reacted with thionyl chloride in a solvent to produce 2-chloro-5,8-difluoroquinoline. be able to.
Examples of the solvent include N, N-dimethylformamide.
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 2-Chloro-5,8-difluoroquinoline is reacted with methanol in a solvent in the presence of a base to produce 8-fluoro-2,5-dimethoxyquinoline. be able to.
Examples of the base include tert-butoxypotassium.
Examples of the solvent include N, N-dimethylacetamide.
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)
8-Fluoro-5-Hydroxyquinoline-2 (1H) -On Synthesis 8-Fluoro-2,5-dimethoxyquinoline is reacted in the presence of an acid to form 8-fluoro-5-hydroxyquinoline-2 (1H)-. Can be manufactured on.
Examples of the acid include acetic acid, hydrobromic acid and mixtures thereof.
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-dihydroquinoline-5-ylacetate 8-Fluoro-5-hydroxyquinoline-2 (1H) -one is reacted with acetic anhydride in the presence of an acid to form 8-fluoro-2-oxo-1,2-dihydroquinoline-5-ylacetate. Fluoro-2-oxo-1,2-dihydroquinoline-5-ylacetate can be produced.
Examples of the acid include concentrated sulfuric acid.
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-oxo-1,2,3,4-tetrahydroquinoline-5-yl acetate 8-fluoro-2-oxo-1,2-dihydroquinoline-5-yl acetate under hydrogen atmosphere and palladium 8-Fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-5-yl acetate can be produced by performing a reduction reaction in a solvent in the presence of a catalyst.
Examples of the palladium catalyst include 10% palladium carbon.
Examples of the solvent include acetic acid.
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)
8-Fluoro-5-Hydroxy-3,4-dihydroquinoline-2 (1H) -one synthesis 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-5-yl acetate in the presence of acid , 8-Fluoro-5-hydroxy-3,4-dihydroquinoline-2 (1H) -one can be produced by reacting in a solvent.
Examples of the acid include concentrated hydrochloric acid.
Examples of the solvent include methanol.
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-hydroxyquinoline-2 (1H) -one (another method)
(Manufacturing method 8-1)
Synthesis of 2,5-bis (benzyloxy) -8-fluoroquinoline 2-chloro-5,8-difluoroquinoline is reacted with benzyl alcohol in a solvent in the presence of a base to give 2,5-bis (benzyloxy). ) -8-Fluoroquinoline can be produced.
Examples of the base include tert-butoxypotassium.
Examples of the solvent include N, N-dimethylformamide.
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)
8-Fluoro-5-Hydroxyquinoline-2 (1H) -one synthesis 2,5-bis (benzyloxy) -8-fluoroquinoline is reacted in the presence of a palladium catalyst and an acid in a hydrogen atmosphere to form 8-fluoro-5-hydroxyquinoline-2 (1H) -one. Fluoro-5-hydroxyquinoline-2 (1H) -one can be produced.
Examples of the palladium catalyst include 5% palladium carbon.
Examples of the acid include acetic acid.
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.

[Method for producing crystalline polymorph of compound A]
Compound A obtained by the above production method is stirred in the presence of acetic acid and / or potassium acetate at 60 to 80 ° C. until the crystals are dissolved, filtered hot, then slowly cooled, and cooled at 30 ° C. or lower for 1 hour. The acetic acid sum product of compound A is obtained by aging as described above, and the acetic acid-containing product of compound A is vacuum-dried or blown-dried to produce an I-type crystal of compound A.
Further, the compound A can be produced as a type II crystal of the compound A by stirring the compound A in a solvent at room temperature to a reflux temperature, cooling the mixture, aging the compound A, and air-drying the compound A.

[Method for producing a co-crystal of compound A or a co-crystal solvate thereof]
The co-crystal of compound A or a co-crystal solvate thereof can be obtained by appropriately mixing the compound A and the coformer obtained above in a solvent at room temperature and collecting the precipitated solid.
(Crushing method)
The compound A and the coformer obtained above are mixed at a molar ratio of 1: 0.5 to 1:20 at room temperature, and the compound A is co-crystallized by adding a solvent or pulverizing under non-solvent conditions. Crystals or co-crystal solvates thereof can be obtained.
The molar ratio of compound A and the coformer is preferably 1: 1 or 1: 2, and more preferably 1: 1.
Examples of the solvent include water.
The pulverization is not particularly limited as long as it is a method used in the art, and examples thereof include mechanical pulverization and ball mill pulverization.

(Melting method (thermal analysis method))
A co-crystal of compound A or a co-crystal solvate thereof can be confirmed by simultaneous measurement of the differential calorific value and weight of the physical mixture of compound A and the coformer.

(Cryptography method)
A mixture of compound A and a coformer having a molar ratio of 1: 1 to 1: 200 obtained above is dissolved in a good solvent at room temperature, and then a poor solvent is added dropwise little by little to co-crystallize compound A or a co-crystal thereof. A solvate can be obtained.
The molar ratio of compound A and the coformer is preferably 1: 2 to 1: 150, more preferably 1: 5, 1:10, 1:20, 1:50 or 1: 100.
Good solvents include, for example, THF, acetone, methanol and acetic acid. It is preferably THF, acetone or methanol. The addition amount (volume) is, for example, 0.1 to 10% (w / v), preferably 0.5 to 5% (w / v) with respect to compound A (weight).
Examples of the poor solvent include hexane, water and diethyl ether. Hexane and water are preferred. The addition amount (volume) is, for example, 0.01 to 15% (w / v), preferably 0.01 to 12% (w / v), more preferably 0, with respect to compound A (weight). It is 0.03 to 10% (w / v), more preferably 0.1 to 5% (w / v).
Examples of the combination of the good solvent and the poor solvent include any combination described above. The good solvent / poor solvent combination is preferably a THF / hexane, methanol / water, or acetone / water combination, and more preferably a methanol / water or acetone / water combination.

[Co-crystal]
In some embodiments, the co-crystal of Compound A is a co-crystal of Compound A with 2,5-dihydroxybenzoic acid or salicylic acid (ie, 2-hydroxybenzoic acid). That is, the formula:

Compounds represented by (ie, 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro- 3,4-Dihydroquinoline-2 (1H) -on 2,5-dihydroxybenzoic acid), or formula:

Compounds represented by (ie, 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro- 3,4-Dihydroquinoline-2 (1H) -on 2-hydroxybenzoic acid). Preferably, compound A and 2,5-dihydroxybenzoic acid or salicylic acid may form a co-crystal in a molar ratio of 1: 0.5 to 2.5, for example 1: 1.
As described above, these co-crystals may exist as solvates, for example hydrates, specifically 0.5 hydrates, monohydrates or dihydrates. There may be.

In some embodiments, the co-crystal of compound A has a diffraction angle (2θ) of 9.7 ° ± 0.2 °, 11.4 ° ± 0 in a powder X-ray diffraction diagram obtained using CuKα rays as the X-ray source. .2 °, 16.0 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 22.8 ° ± 0 At least three, four, five, selected from the group consisting of .2 °, 25.0 ° ± 0.2 °, 25.9 ° ± 0.2 ° and 26.9 ° ± 0.2 °. A PXRD pattern containing diffraction peaks at 6, 7, 8 or 9 may be exhibited (2.5 DHBA co-crystal (I-shaped crystal)). For example, co-crystals have diffraction angles (2θ) of 11.4 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.3 ° ± 0.2 ° and 25.9 ° ± 0.2 °. Can show a PXRD pattern containing a diffraction peak (2.5 DHBA co-crystal (I-shaped crystal)). Further, for example, the co-crystal has a diffraction angle (2θ) of 9.7 ° ± 0.2 °, 11.4 ° ± 0.2 °, 16.0 ° ± 0.2 °, and 18.7 ° ± 0.2. PXRD patterns with diffraction peaks at °, 19.3 ° ± 0.2 °, 21.1 ° ± 0.2 ° and 25.9 ° ± 0.2 ° can be shown (2.5DHBA co-crystals (type I). Akira)).
In another embodiment, the co-crystal has a diffraction angle (2θ) of 3.9 ° ± 0.2 °, 7.8 ° ± 0.2 in the powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source. °, 11.8 ° ± 0.2 °, 14.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.0 ° ± 0.2 At least 3, 4, 5, 6, 7, 8 or 9 selected from the group consisting of °, 24.8 ° ± 0.2 ° and 25.8 ° ± 0.2 ° It may show a PXRD pattern containing diffraction peaks (2.5 DHBA co-crystal (II type crystal)). For example, a co-crystal may exhibit a PXRD pattern with diffraction peaks at diffraction angles (2θ) of 14.1 ° ± 0.2 °, 20.0 ° ± 0.2 ° and 24.8 ° ± 0.2 °. (2.5 DHBA co-crystal (II type crystal)). Further, for example, the co-crystal has a diffraction angle (2θ) of 3.9 ° ± 0.2 °, 7.8 ° ± 0.2 °, 11.8 ° ± 0.2 °, 14.1 ° ± 0.2. PXRD patterns with diffraction peaks at °, 15.1 ° ± 0.2 °, 20.0 ° ± 0.2 ° and 24.8 ° ± 0.2 ° can be shown (2.5DHBA co-crystal (type II). Akira)).
In yet another embodiment, the co-crystal has 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 ° ± 0.2 ° and 27.3 ° ± 0. A PXRD pattern containing diffraction peaks at least 3, 4, 5, 6, 7, 8 or 9 selected from the group consisting of 2 ° can be exhibited (salicylic acid co-crystal). For example, co-crystals have diffraction angles (2θ) of 11.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.0 ° ± 0.2 ° and 26.1 ° ± 0.2 °. Can show a PXRD pattern containing diffraction peaks (salicylic acid co-crystal). Further, for example, the co-crystal has a diffraction angle (2θ) of 9.9 ° ± 0.2 °, 11.4 ° ± 0.2 °, 16.2 ° ± 0.2 °, and 18.8 ° ± 0.2. A PXRD pattern containing diffraction peaks at °, 19.0 ° ± 0.2 °, 23.8 ° ± 0.2 ° and 26.1 ° ± 0.2 ° can be shown (salicylic acid co-crystal).
In yet another embodiment, the co-crystal has 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. At least 3, 4, 5, 6, 7, 8 or 9 selected from the group consisting of 2 °, 25.4 ° ± 0.2 ° and 26.7 ° ± 0.2 ° Can show a PXRD pattern containing diffraction peaks (2.5 DHBA co-crystal 0.5 hydrate). For example, a co-crystal may exhibit a PXRD pattern with diffraction peaks at diffraction angles (2θ) of 12.1 ° ± 0.2 °, 15.1 ° ± 0.2 ° and 15.4 ° ± 0.2 °. (2.5 DHBA co-crystal 0.5 hydrate). Further, for example, the co-crystal has a diffraction angle (2θ) of 12.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.7 ° ± 0.2. PXRD patterns with diffraction peaks at °, 23.6 ° ± 0.2 °, 24.8 ° ± 0.2 ° and 25.4 ° ± 0.2 ° can be shown (2.5 DHBA co-crystal 0.5). Hydrate).
± 0.2 ° in the diffraction angle (2θ) is an error that may occur depending on the measuring device, measurement conditions, etc., and the error of the diffraction angle is included in the scope of the present invention as an allowable range.

In some embodiments, the 2,5 DHBA co-crystal (I-shaped crystal) may exhibit a melting point of 155 to 166 ° C. in differential calorimetry by weight. Here, the onset temperature may be 157 ° C and the peak top temperature may be 160 ° C. For example, the 2.5DHBA co-crystal (I-shaped crystal) shows the TG / DTA curve of FIG.
In some embodiments, the 2.5DHBA co-crystal (II form crystal) can exhibit a melting point of 140-150 ° C. in differential calorimetry by weight. Here, the onset temperature may be 145 ° C and the peak top temperature may be 147 ° C. Then, an exothermic peak of 150 ° C. ± 1 ° C. may indicate recrystallization into I-type co-crystals. For example, the 2.5DHBA co-crystal (II form crystal) shows the TG / DTA curve of FIG.
The 2.5DHBA co-crystal (II-type crystal) may be transferred to the I-type co-crystal by arbitrary transition conditions, for example, heating at 100 to 145 ° C.
In some embodiments, the salicylic acid co-crystals can exhibit a melting point of 150-170 ° C. in differential calorimetry. Here, the onset temperature may be 161 ° C and the peak top temperature may be 163 ° C. For example, the salicylic acid co-crystal shows the TG / DTA curve in FIG.

[Preparation / Pharmaceutical composition]
The co-crystal of compound A can be formulated with at least one pharmaceutically acceptable carrier according to a known method commonly used in the art. The content of compound A in the preparation (also referred to as “pharmaceutical composition” in the present specification) varies depending on conditions such as dosage form and dosage, and is, for example, 1 to 50 weight of the entire preparation or nuclear tablets. %, Preferably 1.5 to 35% by weight. The content of co-crystals in the pharmaceutical product is, for example, 1 to 70% by weight, preferably 1.5 to 50% by weight, of the entire pharmaceutical product or the nuclear lock. The co-crystal of Compound A can be administered to humans (including adults and children) and non-human mammals (subjects). The dose (effective amount) varies depending on the administration target, symptom, dosage form, administration route, etc., but for example, the dose when orally administered to a human adult patient (body weight 65 kg) is usually per dose as Compound A. It is in the range of about 1 mg to 100 mg, preferably in the range of about 3 mg to 60 mg. The co-crystal is, for example, in the range of about 1 mg to 150 mg at a time, preferably in the range of about 3 mg to 80 mg.

Examples of the "pharmaceutically acceptable carrier" include components such as water-soluble coating agents, surfactants, excipients, disintegrants, binders, fluidizers, and lubricants commonly used in the art. In some embodiments, the pharmaceutically acceptable carrier may include a water-soluble coating or surfactant to inhibit crystallization of Compound A after it reaches supersaturation and promote elution. Examples of the water-soluble coating agent include water-soluble polymers, specifically, hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, hypromellose phthalate ester, or hypromellose acetate succinic acid ester, and hydroxypropylmethyl cellulose is preferable. be.

Examples of the method for formulating the co-crystal of compound A include a wet granulation method, a dry granulation method and a direct tableting method.

Examples of the dosage form of the pharmaceutical composition containing the co-crystal of Compound A include oral preparations such as tablets (including film-coated tablets), capsules, granules, powders, and troches. Film-coated tablets or capsules are preferred. In some embodiments, the film-coated tablets may be free of non-cellulosic plasticizers (eg polyethylene glycol) to avoid crystal transitions. In another embodiment, the film-coated tablets may contain hydroxypropylmethylcellulose.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
The measurement conditions and the like of the analyzer and the measuring instrument used in the examples are shown below.

(Powder X-ray diffractometer)
Device name: X'Pert PRO MPD
Manufacturer: Spectrox Co., Ltd. Measurement method: Transmission method Radioactive source: CuKα ray (λ = 1.5418Å)
Current: 40mA
Voltage: 45kV
Measurement range: 3 to 39.999 °
Step size: 0.0167113 °
Scan speed: 0.334225 ° / sec

(X-ray diffraction-differential scanning calorimeter simultaneous measurement device)
Simultaneous measurement of X-ray diffraction-differential scanning calorimeter was performed under the conditions described below, and PXRD data and differential scanning calorimetry data were docked and displayed using XRD-DSC software.
Device name: RINT2000, XRD-DSC II
Manufacturer: Rigaku Co., Ltd. Measurement method: Reflection method Radioactive source: CuKα ray (λ = 1.5418Å)
Current: 40mA
Voltage: 40kV
Measurement range: 3-40 °
Scan speed: 10 ° / min
Sampling width: 0.02 °
Heating rate: 1 ° C / min

(Single crystal structure analysis)
Collection of single crystal X-ray diffraction data was performed using XtaLAB Synergy R, DW system, HyPix diffraction datater. The measurement temperature was 100 K, and CuKα ray (λ = 1.5418 Å) was used as the X-ray source. Data acquisition and processing was performed by the CrysAlisPro (Rigaku, V1.171.40.67a, 2019) program.
The structure was determined by the 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 were anisotropically refined, and hydrogen atoms were isotropically refined. All calculations were performed with Crystal Structure refinement software package and SHELXL (Sheldrick, G. M .: Crystal structure refinement with SHELXL. Acta. Cryst. C71 (2015) 3-8.).

(Simultaneous measurement of differential calorific value and weight)
The TG / DTA was measured using a thermal analyzer TG / DTA7200 manufactured by SII Nanotechnology Co., Ltd. A 3 to 10 mg sample was placed in an aluminum pan and heated 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 measurement was carried out using α-alumina as a reference substance for the reference pan or using an empty pan (without reference substance).

(Ultra high performance liquid chromatography measurement)
UHPLC was measured using an Agilent 1290 Infinity LC System from Agilent Technologies, Inc.
(Liquid chromatography-mass spectrometry)
MS / MS was measured using the TSQ Tandem system of Edwards, Inc., and HPLC was measured using the Shimadzu Nexus system of Shimadzu Corporation.

(Measurement of particle size)
The particle size was measured using a laser diffraction type particle size distribution measuring device SALD-3100 manufactured by Shimadzu Corporation. 15 mL of water or a saturated aqueous solution of coformer was placed in a batch cell, and 5 mg of compound A or a co-crystal was suspended in 300 μL of saturated aqueous solution of water or coformer, and the mixture was charged and measured.

(Raman spectroscopy)
LF-Raman measurement (THz-Raman measurement)
Terahertz Raman spectroscope:
The measurement was performed by combining Kaiser's Micro Raman spectrophotometer (Raman WorkStation-785) with Coherent's Low Frequency Raman module (XLF-MICRO Microscope THz-Raman Unit).
Device name: Raman Workstation-785 and XLF-MICRO Microscope THz-Raman Unit
Manufacturer: Kaiser, Coherent Excitation wavelength: 808nm
Measurement range: -200 to 1500 cm ^-1

[Reference example]
(Reference example 1)
Synthesis of 1- (2,6-dichlorobenzyl) -1-methyl-4-oxopiperidine-1-ium bromide Acetone (70L), 2,6-dichlorobenzyl bromide (14.00kg), 1-methyl-4- Piperidine (7.26 kg) was added to the reaction vessel and stirred under reflux for 5 hours. Precipitated crystals were separated, washed with acetone (70 L), and air-dried at 50 ° C. for 20 hours to give the title compound (18.82 kg) as a white to slightly yellow solid (91% yield).
^{1 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) piperidine-4-one Add water (35 mL) and 4-chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate (5 g) to the reaction vessel. A 5 mol / L sodium hydroxide aqueous solution (3.28 mL) was slowly flowed in. After the inflow was completed, the mixture was stirred at room temperature for 1 hour. 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 resulting solid, 2-propanol (15 mL), water (15 mL), 1- (2,6-dichlorobenzyl) -1-methyl-4-oxopiperidine-1-ium bromide (7.57 g), 1, 3-Dimethylthiourea (0.085 g) was added, and the mixture was stirred under reflux for 10 hours. Toluene (15 mL) and sodium chloride (0.375 g) were added, and the liquids were separated. Toluene (15 mL) was added to the aqueous layer for extraction. The organic layers were combined and 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. Precipitated crystals were separated, washed with 2-propanol (5 mL), and air-dried at 35 ° C. for 12 hours or longer to give the title compound (1.27 g) as a white to slightly yellow solid (34% yield). ..
^{1 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).

[Example]
(Example 1)
Synthesis of N- (2,5-difluorophenyl) -3-phenylacrylamide 1,4-difluoro-2-nitrobenzene (75.0 g), ethyl acetate (375 mL), 5% palladium carbon (4.0 g) in the reaction vessel In addition, the mixture was stirred at 25 to 60 ° C. for 4 hours under a hydrogen atmosphere. The solid was removed by filtration, water (375 mL) and sodium bicarbonate (59.4 g) were added to the filtrate, and silicate chloride (86.0 g) was slowly flowed in at a temperature not exceeding 0 ° C. After the inflow was completed, the mixture was stirred 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, toluene (375 mL) was added to the residue and recrystallized to give the title compound (100.0 g) as a white solid (81% yield).
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)
5,8-Difluoroquinoline-2 (1H) -one synthesis Sodium chloride (36.0 g), potassium chloride (36.0 g), aluminum chloride (238.0 g) are added to the reaction vessel until the contents are melted. Heated. Under stirring, N- (2,5-difluorophenyl) -3-phenylacrylamide (103 g) was slowly added, and after the addition was completed, the mixture was stirred at 120 ° C. for 1 hour. The reaction solution was gradually poured into ice water (2 L). After the inflow was completed, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration to give 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-difluoroquinoline-2 (1H) -one (69.9 g), N, N-dimethylformamide (350 mL) was added to the reaction vessel to around 0 ° C. Cooled. Thionyl chloride (115.0 g) was slowly flowed in. After the inflow, the mixture was stirred at around 70 ° C. for 1 hour. Acetone / water (2/1) mixture (700 mL) was added to precipitate crystals, and a 25% aqueous sodium hydroxide solution (340 mL) was added for neutralization. The mixture was aged at 40 ° C. for 1 hour, aged at 0 ° C. for 1 hour, the precipitated crystals were collected by filtration and washed with water to give the title compound (63.0 g) as a brown solid (81% yield).
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 t-butoxypotassium (14.1 g), N, N-dimethylacetamide (50 mL) and methanol (1.3 g) were added to the reaction vessel and cooled to 10 ° C. or lower. .. 2-Chloro-5,8-difluoroquinoline (10.0 g) was slowly added at a temperature not exceeding 30 ° C. The mixture was stirred 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 flowed in to precipitate crystals, water (30 mL) was added, and the mixture was stirred at 20-40 ° C. for 1 hour. After further aging at around 0 ° C. for 1 hour, the precipitated crystals were collected by filtration and washed with a mixed solution of water / metall (1/1) to give the title compound (7.7 g) as a brown solid (74%). 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-hydroxyquinoline-2 (1H) -one 8-fluoro-2,5-dimethoxyquinoline (100 g), acetic acid (300 mL), aqueous hydrobromide solution (50%, 1.2 L) In addition to the reaction vessel, the reaction solution was poured into water (3 L) under reflux for 14 hours and aged at 70 to 100 ° C. for 1 hour. Then, the mixture was aged at room temperature for 1 hour, the precipitated crystals were collected by filtration and washed with water to give the title compound (85.7 g) as a beige solid (99% yield).
¹ HNMR (DMSO-d ₆ ) δppm: 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-dihydroquinoline-5-ylacetate 8-fluoro-5-hydroxyquinoline-2 (1H) -one (2.0 g), acetic anhydride (12 mL), concentrated sulfuric acid (0.03 mL) was added to the reaction vessel, and the mixture was stirred at around 120 ° C. for 2 hours. The mixture was cooled to around 0 ° C., and the reaction solution flowed into water (20 mL). After the inflow was completed, it was aged for 1 hour or more. The precipitate was collected by filtration and washed with water to give the title compound (2.13 g) as a white to beige solid (86% yield).
¹ HNMR (DMSO-d ₆ ) δppm: 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-oxo-1,2,3,4-tetrahydroquinoline-5-yl acetate 8-fluoro-2-oxo-1,2-dihydroquinoline-5-yl acetate (128 g), 10% Palladium carbon (12.8 g) and acetic acid (1.0 L) were added to the reaction vessel, and the mixture was 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. It was cooled to around room temperature and aged at around 0 ° C. for 1 hour. The precipitate was collected by filtration and washed with water to give the title compound (104 g) as a white to beige solid (80% yield).
¹ HNMR (DMSO-d ₆ ) δppm: 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)
8-Fluoro-5-Hydroxy-3,4-dihydroquinoline-2 (1H) -one synthesis 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-5-yl acetate (51 g), Methanol (255 mL) and concentrated hydrochloric acid (306 g) were added to the reaction vessel, and the mixture was stirred under reflux for 30 minutes. It was cooled, inflowed with water (1.0 L), and aged at 30-40 ° C. for 1 hour or more. The mixture was cooled to around 0 ° C., the precipitated crystals were collected by filtration and washed with water to give the title compound (40.9 g) as a white to beige solid (98% yield).
¹ HNMR (DMSO-d ₆ ) δppm: 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 tert-butoxypotassium (46.4 g), N, N-dimethylformamide (165 mL) and benzyl alcohol (50.1 g) were added to the reaction vessel, and 30 was added. 2-Chloro-5,8-difluoroquinoline (33.0 g) was slowly added at a temperature not exceeding ° C. The mixture was stirred at around 70 ° C. for 2 hours. The mixture was cooled to around 20 ° C., a mixed solution of water / acetone (1/2) (330 mL) was added for crystallization, water (165 mL) was added, and the mixture was aged at 20-40 ° 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 30 minutes or more. The precipitate was hot filtered and the filtrate was cooled and crystallized to give the title compound (44.2 g) as a light brown solid (74% yield).
¹ HNMR (CDCl ₃ ) δppm: 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-hydroxyquinoline-2 (1H) -one 2,5-bis (benzyloxy) -8-fluoroquinoline (35.6 g), 5% palladium carbon (3.5 g), acetic acid (245 mL) ) Was added to the reaction vessel, and the mixture was 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, heated, cooled and recrystallized. It was aged at 20-40 ° C for 1 hour and at 0 ° C for 1 hour. The precipitate was collected by filtration and washed with water to give the title compound (14.0 g) as a light brown solid (78% yield).
^{1 1} HNMR: See Example 5.

(Example 11)
Synthesis of 4-chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate (1)
Acetonitrile (140 L), N-chlorosuccinimide (22.75 kg) and 1,3-dimethylthiourea (0.32 kg) were added to the reaction vessel, and 2,6-difluoroaniline (20.0 kg) was 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 added and aged for 1 hour or more. Precipitated crystals were separated, washed with ethyl acetate (60 L), and air-dried at 60 ° C. for 19 hours to give the title compound (44.66 kg) as a white to slightly yellow solid (85% yield).
¹ HNMR (DMSO-d ₆ ) δppm: 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 / 4-methylbenzenesulfonate (2)
Acetonitrile (60 L), ethyl acetate (60 L) and 2,6-difluoroaniline (20.0 kg) were added to the reaction vessel, and trichloroisocyanuric acid (12.60 kg) was slowly added. After the completion of charging, the mixture was stirred at room temperature for 1 hour. 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 added and aged for 1 hour or more. 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 give the title compound (44.68 kg) as a white to slightly yellow solid. (85% yield).
^{1 1} HNMR: See Example 11.

(Example 13)
Synthesis of 1-ethyl-1- (2-methylallyl) -4-oxopiperidine-1-ium iodide Acetone (60 L), isobutenyl chloride (18.42 kg) and sodium iodide (28.15 kg) were added to the reaction vessel. In addition, the mixture was stirred at room temperature for 5 hours. Water (200 L) was flowed in and separated to obtain an organic layer (27 L). Acetone (140 L) and 1-ethyl-4-piperidone (20.0 kg) were added to the obtained organic layer, and the mixture was stirred at a temperature not exceeding 50 ° C. for 8 hours. Precipitated crystals were separated, washed with acetone (200 L), and air-dried at 60 ° C. for 11 hours to give the title compound (41.35 kg) as a white to slightly yellow solid (85% yield).
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) piperidine-4-one Water (418L), 4-chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate (59.77kg) is placed in the reaction vessel. In addition, a 25% aqueous sodium hydroxide solution (31.33 kg) was slowly flowed in. After the inflow was completed, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were separated and washed with water (299L) to obtain 4-chloro-2,6-difluoroaniline as a white to gray solid. To the obtained solid 2-propanol (179L), water (179L), 1-ethyl-1- (2-methylallyl) -4-oxopiperidin-1-ium iodide (82.48kg), 1,3-dimethylthiourea (1.02 kg) was added, and the mixture was stirred under reflux for 10 hours. It was cooled to around 0 ° C. and aged for 1 hour or more. Precipitated crystals were separated, washed with a mixed solution of 2-propanol (20 L) / water (20 L), then washed with 2-propanol (20 L), and air-dried at 35 ° C. for 37 hours. Compound (26.30 kg) was obtained as a white to slightly yellow solid (60% yield).
^{1 1} HNMR: See Reference Example 2.

(Example 15)
(3R, 4R) -6- (4-chloro-2,6-difluorophenyl) -1-oxa-6-azaspiro [2.5] Synthesis of octa-4-ol acetonitrile (48L), 1- (4- (4-) Reaction of chloro-2,6-difluorophenyl) piperidine-4-one (16.0 kg), tert-butyldimethylsilyl closide (11.3 kg), sodium iodide (11.2 kg), triethylamine (8.24 kg) It was added to the container and stirred under reflux for 2 hours. A mixed solution of toluene (64 L) and water (64 L) / sodium bicarbonate (3.20 kg) was flowed in and separated. 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, washed with toluene (16.7 kg), and 4-[(tert-butyldimethylsilyl) oxy] -1- (4-chloro-2,6-difluorophenyl) -1,2. , 3,6-Tetrahydropyridine in toluene was obtained. 1-Propanol (58.9 kg), acetonitrile (74 L), water (99 L) / disodium ethylenediaminetetraacetate (15.0 g) / potassium carbonate (27.0 kg) mixed solution, D-epoxone (2.52 kg) In addition, 35% hydrogen peroxide solution (25.3 kg) was slowly flowed in at a temperature not exceeding 10 ° C. After the inflow was completed, the mixture was stirred at 5 to 15 ° C. for 5 hours. A mixed solution of water (131 L) / sodium thiosulfate pentahydrate (65.1 kg) / sodium carbonate (528 g) was slowly flowed in at a temperature not exceeding 20 ° C. and stirred for 30 minutes or more. After standing, the liquid was separated, and the organic layer was washed twice with a mixed solution of water (160 L) / sodium chloride (4 kg), and (1R, 6R)-[(tert-butyldimethylsilyl) oxy] -3-( A toluene / 1-propanol / acetonitrile mixture of 4-chloro-2,6-difluorophenyl) -7-oxa-3-azabicyclo [4.1.0] heptane was obtained. Dimethyl sulfoxide (88.0 kg), trimethylsulfoxonium iodide (15.8 kg) and a 48% aqueous potassium hydroxide solution (8.38 kg) were added, and the mixture was stirred at room temperature for 3 hours. Water (160 L) flowed in and separated. 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. Precipitated crystals were separated, washed with ethanol (12.6 kg), and air-dried at 60 ° C. for 16 hours to give the title compound (7.10 kg) as a white to slightly yellow solid (39% yield).
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-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one synthesis (3R, 4R) -6- (4-chloro-2,6-difluorophenyl) -1-oxa-6-azaspiro [2.5] octa-4-ol (13.83 kg) ), 8-Fluoro-5-hydroxy 3,4-dihydroquinoline-2 (1H) -one (10.00 kg), potassium carbonate (1.39 kg), 2-propanol (69 L), water (14 L) in the reaction vessel. In addition, the mixture was stirred under reflux for 3 hours. Water (138 L) was poured in and aged at 30 to 50 ° C. for 1 hour or more. Precipitated crystals were separated, washed with 2-propanol (42 L), and air-dried at 60 ° C. for 19 hours to give the title compound (20.94 kg) as a white to slightly yellow solid (91% yield, II). shape).
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-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on purification (1)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on (20.93 kg, type II) and acetic acid (175.65 kg) were added to the reaction vessel, and the mixture was stirred at around 70 ° C. until the crystals were dissolved. Water (41.86 kg) that had been filtered at the time of heat and warmed to around 70 ° C. flowed in through the filter. It was cooled slowly and aged at 30 ° C. or lower for 1 hour or more. Precipitated crystals were separated, washed with a mixed solution of acetic acid (49.40 kg) / water (15.70 kg), vacuum dried at 85 ° C. and 1.0 kPa for 24 hours, and the title compound (15.45 kg) was whitened. -Obtained as a slightly yellow solid (73% yield, type I).
^{1 1} HNMR: See Example 16.

(Example 18)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on purification (2)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on (11.10 kg, type II), potassium acetate (1.91 kg) and acetic acid (100 kg) were added to the reaction vessel, and the mixture was stirred at around 70 ° C. until the crystals were dissolved. Water (22 kg) that had been filtered at the time of heat and warmed to around 70 ° C. flowed in through the filter. It was cooled slowly and aged at 30 ° C. or lower for 1 hour or more. Precipitated crystals were separated, washed with a mixed solution of acetic acid (26 kg) / water (8 kg), vacuum dried at 65 to 70 ° C. and 1.0 kPa for 42 hours, and the title compound (8.61 kg) was white to fine. Obtained as a yellow solid (77% yield, type I).
^{1 1} HNMR: See Example 16.

(Example 19)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on purification (3)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on (3.10 kg, type II), dimethyl sulfoxide (19 L) was added to the reaction vessel, and water (37 L) was slowly flowed in. After the inflow was completed, it was aged at room temperature for 1 hour or more. Precipitated crystals were separated, washed with ethanol (25 L), and air-dried at 50 ° C. for 19 hours to give the title compound (2.81 kg) as a white to slightly yellow solid (93% yield, type I). ..
^{1 1} HNMR: See Example 16.

(Example 20)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on purification (4)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on (2.00 kg, type II) and acetic acid (16 L) were added to the reaction vessel, and the mixture was stirred at around 70 ° C. until the crystals were dissolved. Water (4 L) that had been filtered at the time of heat and warmed to around 60 ° C. flowed in. It was cooled slowly and aged at 30 ° C. or lower for 1 hour or more. Precipitated crystals were separated and washed with a mixed solution of acetic acid (45 L) / water (15 L). Water (55L) was passed through the obtained crystals. The crystals were separated and air dried overnight at 50 ° C. to give the title compound (1.27 kg) as a white to slightly yellow solid (63% yield, type I).
^{1 1} HNMR: See Example 16.

(Example 21)
(S) Synthesis of -1- (4-chloro-2,6-difluorophenyl) -4-methylenepiperidin-3-ol Toluene (40L), 1,2-dimethoxyethane (40L), triphenylphosphine (0. 62 kg), tetrakis (triphenylphosphine) palladium (0.43 kg), 1,3-bis (hexafluoro-α-hydroxyisopropyl) benzene (3.95 kg) were added to the reaction vessel, and 2-methyl-2-vinyloxylane was added. (20.51 kg) slowly flowed in. After the inflow was completed, the mixture was stirred at room temperature for one and a half hours. Toluene (81 L), paraformaldehyde (5.06 kg), 4-chloro-2,6-difluoroaniline / 4-methylbenzenesulfonate (44.25 kg) were added, and the mixture was stirred at room temperature for 2 and a half hours. Water (101 L) and a 25% aqueous sodium hydroxide solution (34.58 kg) were flowed in and separated. Washing was performed with water (97 L), and 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, and the mixture was stirred at room temperature for 30 minutes or more. The precipitate is removed by filtration, washed with toluene (71L), and [1- (4-chloro-2,6-dichlorophenyl) -1,2,3,6-tetrahydropyridine-4-yl] methanol toluene. A solution was obtained. Add zeolam A-3 (3.45 kg), (D)-(-)-isopropyl tartrate (3.40 kg), titanium tetraisopropoxide (3.75 kg), and cumene hydroperoxide (cumene hydroperoxide) at a temperature not exceeding 0 ° C. 17.55 kg) and toluene (17 L) slowly flowed in. After the inflow was completed, the mixture was stirred at 0 ° C. or lower for 2 hours. Dimethyl sulfoxide (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 flowed in and separated. The organic layer was washed with a mixed solution of sodium bicarbonate (8.86 kg) / water (137 L). The organic layer is concentrated under reduced pressure, ethyl acetate (137 L), triethylamine (10.67 kg), 4-dimethylaminopyridine (0.81 kg) and phthalic anhydride (13.66 kg) are added to the residue, and the mixture is stirred at room temperature for 1 hour. bottom. A mixed solution of heptane (137 L) and sodium bicarbonate (8.86 kg) / water (102 L) was flowed in and separated. The aqueous layer was washed with a mixed solution of ethyl acetate (137L) / heptane (137L). Toluene (204 L) and a 25% aqueous sodium hydroxide solution (126.52 kg) were flowed in, and the mixture was stirred at around 70 ° C. for 2 hours. After standing, the liquid was separated, and concentrated hydrochloric acid (12.99 kg) and water (137 L) were poured into the organic layer to separate the liquid. Washing was performed with a mixed solution of sodium bicarbonate (8.86 kg) / water (137 L), and the organic layer was concentrated under reduced pressure. Toluene (109L) was introduced into the residue, and [(1R, 6R) -3- (4-chloro-2,6-difluorophenyl) -7-oxa-3-azabicyclo [4.1.0] heptane-6- Il] A toluene solution of methanol was obtained. Triethylamine (7.33 kg), trimethylamine hydrochloride (0.31 kg) and tosyl lolide (12.56 kg) were added, and the mixture was stirred at room temperature for 1 and a half hours. A mixed solution of sodium bicarbonate (2.27 kg) / water (73 L) was flowed in and separated. 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 the mixture was stirred at room temperature for 1 hour. Ethyl acetate (145 L) was flowed in and the liquid was separated. The organic layer was washed with a mixed solution 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 and extracted 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 30 minutes or more. The precipitate was removed by filtration and washed with a mixed solution of heptane (18 L) / ethanol (13 L). The filtrate was concentrated under reduced pressure, and ethanol (27 L) and 2-propanol (27 L) flowed into the residue. Water (100 L) slowly flowed under stirring to precipitate crystals. Precipitated crystals were separated, washed with water (27 L), and air-dried at 40 ° C. for 20 hours to give the title compound (1.60 kg) as a white to gray solid (4% yield).
^{1 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] octa-4-ol (S) -1- (4-chloro) Add −2,6-difluorophenyl) -4-methylenepiperidin-3-ol (7.21 kg), ethyl acetate (22 L) and water (36 L) to the reaction vessel, and add m-chloroperbenzoic acid (10.27 kg). Was slowly thrown in. After the completion of charging, the mixture was stirred at a temperature not exceeding 10 ° C. for 3 hours. A mixed solution of sodium bicarbonate (3.50 kg) and sodium sulfite (3.50 kg) / water (36 L) was poured in and stirred for 30 minutes or more. Precipitated crystals were separated and washed with water (14 L). Ethanol (10 L) was flowed in and stirred under reflux until the crystals were dissolved. It was cooled to around 25 ° C. and aged for 1 hour or more. Precipitated crystals were separated, washed with ethanol (3 L), and air-dried at 60 ° C. for 17 hours to give the title compound (1.52 kg) as a white to slightly yellow solid (19% yield).
^{1 1} HNMR: See Example 15.

(Example 23)
Preparation of Japanese acetate 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3, 4-Dihydroquinoline-2 (1H) -one (20.93 kg, type II) and acetic acid (175.65 kg) were added to the reaction vessel, and the mixture was stirred at around 70 ° C. until the crystals were dissolved. Water (41.86 kg) that had been filtered at the time of heat and warmed to around 70 ° C. flowed in through the filter. It was cooled slowly and aged at 30 ° C. or lower for 1 hour or more. Precipitated crystals were separated and washed with a mixed solution of acetic acid (49.40 kg) / water (15.70 kg) to obtain a sum of acetic acid (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 crystals 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3, 4-Dihydroquinoline-2 (1H) -one (20.93 kg, type II) and acetic acid (175.65 kg) were added to the reaction vessel, and the mixture was stirred at around 70 ° C. until the crystals were dissolved. Water (41.86 kg) that had been filtered at the time of heat and warmed to around 70 ° C. flowed in through the filter. It was cooled slowly and aged at 30 ° C. or lower for 1 hour or more. Precipitated crystals were separated, washed with a mixed solution of acetic acid (49.40 kg) / water (15.70 kg), vacuum dried at 85 ° C. and 1.0 kPa for 24 hours, and the title compound (15.45 kg) was whitened. -Obtained as a slightly yellow solid (73% yield, type I).
^{1 1} HNMR: See Example 16.

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

(Example 26)
Preparation of co-crystals
Screening: crushing method (mechanical crushing)
Compound A (form II) and coformer were weighed at a molar ratio of 1: 2 to a total amount of about 250 mg, 25 μL of ethanol was added, and the mixture was mechanically ground at room temperature (model Micro Smash MS-100). At the time of pulverization, two zirconia beads having a diameter of 4.5 mm were put in, and two sets were carried out at 4000 rpm for 3 minutes. PXRD measurement (model X'PertPro MPD, PANalytical) was performed on the sample after grinding.

Screening: Thermal analysis method A physical mixture of compound A (II form crystal) prepared by the above pulverization method and a coformer is heated at a temperature rising rate of 5 ° C./min by TG / DTA (model TG / DTA7200, SI Nanotechnology Co., Ltd.). Was heated to a temperature above the melting point of compound A and the coformer. Alternatively, a coformer having a molar ratio of 2 was weighed against 40 mg of compound A (II form crystal), pulverized in an agate mortar, and then TG / DTA measurement was performed under the same conditions as above. As a result, co-crystal formation was confirmed with a physical mixture of 2.5 DHBA or salicylic acid.
The results of thermal analysis of the physical mixture of compound A and 2.5 DHBA are shown in FIG. According to FIG. 1, an endothermic peak derived from the eutectic of compound A and 2.5 DHBA from about 134 to 145 ° C., an exothermic peak associated with co-crystal formation at about 147 ° C., and about 150 to 172 ° C. (onset 154 ° C.). ), An endothermic peak suggesting the melting point of the cocrystal was observed. 2 and 3 show the results of thermal analysis 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. According to FIG. 4, an endothermic peak derived from the eutectic of compound A and salicylic acid was observed from about 131 to 150 ° C., and an endothermic peak suggesting the melting point of the cocrystal was observed at about 150 to 170 ° C. (onset 159 ° C.). .. FIG. 5 shows the results of thermal analysis of salicylic acid alone.

(Example 27)
Co-crystal of compound A and 2.5 DHBA (sample analysis)
A physical mixture of compound A (II form crystal) and 2.5 DHBA in a molar ratio of 1: 2 was measured with an X-ray diffraction-differential scanning calorimetry simultaneous measuring device (model TTR2000, DSC / XRD II, Rigaku). The measurement conditions were a temperature rise rate of 1 ° C./min and a scan rate of 10 ° C./min. Since the diffraction pattern shown in FIG. 6 was obtained after the exothermic peak near 143 to 147 ° C., it was confirmed that the mixture was co-fused and a co-crystal was formed by recrystallization (2.5 DHBA co-crystal (I). Crystallization)).

(Ball mill crushing method)
The crushing method using a ball mill crusher (model RETSCH MIXER MILL MM200, Retsch) was carried out at room temperature. It was carried out with a molar ratio of 2.5 DHBA to 500 mg of compound A (II form crystal) with acetone, methanol or water as the additive solvent, or without solvent addition. The crushing conditions were a crushing time of 99 minutes and a crushing frequency of 30 / sec. As a result, a 2.5DHBA co-crystal (I-shaped crystal) and a 2.5DHBA co-crystal (II-shaped crystal) were obtained under the condition that the molar ratio was 1: 1 and no solvent was added. Under the condition that water was used as the additive solvent, 2.5DHBA co-crystals (I-shaped crystals) were obtained.

(Cryptography method: THF / hexane system)
Compound A (II form crystal) was mixed with 100 mg of 2,5 DHBA at a molar ratio of 1, 5, 10 or 20, and dissolved in THF (2 mL). A maximum of 5 mL of hexane was added dropwise thereto until 1 mL of each solid was deposited. All operations were performed at room temperature. A co-crystal THF sum of compound A and 2.5 DHBA was obtained as a white to slightly yellow solid under the condition of a molar ratio of 2,5 DHBA of 5, 10 or 20.
(Cryptography method: methanol / water system)
Compound A (I-form crystal) was mixed with 10 mg of 2.5 DHBA at a molar ratio of 100 and dissolved in methanol (2 mL). 1 mL of water was added dropwise thereto until a solid was deposited to obtain 2,5 DHBA co-crystals (I-shaped crystals) as white to slightly yellow solids. The operation was carried out at room temperature.
(Cryptography method: acetone / water system)
Compound A (I-form crystal) was dissolved in 10 mg of acetone (2 mL) saturated with 2.5 DHBA. 1 mL of water was added dropwise thereto until a solid was deposited. The obtained precipitate obtained a mixed crystal of 2.5 DHBA co-crystal (I-shaped crystal) and 2.5 DHBA as a white to slightly yellow solid. The operation was carried out at room temperature.

(Analysis of sample obtained by crystallization method)
When a sample obtained by mixing 10 mol of 2.5 DHBA with compound A in a THF / hexane system was thermally analyzed and measured, a 3.8% weight loss was observed with an endothermic peak by about 95 ° C. An endothermic peak was observed at about 142-152 ° C, and melted at about 152-162 ° C (Fig. 7). When heated to 100 ° C. or 145 ° C. and cooled to room temperature, the sample heated to 100 ° C. showed a powder X-ray diffraction pattern of 2.5DHBA co-crystals (II type crystals) (FIG. 8) and heated to 145 ° C. The sample showed a powder X-ray diffraction pattern of a 2.5DHBA co-crystal (I-shaped crystal) (FIG. 9).
From the results of solution NMR, it was confirmed that the weight loss up to around 95 ° C. was the THF contained in the crystal. In addition, from the results of solution NMR of the crystals after desolvation, it was found that the molar ratio of compound A to 2.5DHBA in the obtained co-crystal was 1: 1 and there was no residue of THF.
(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 (II form crystal) and 2.5 DHBA are shown in FIGS. 10 and 11, respectively.
According to FIG. 8, the 2.5DHBA co-crystal (II type crystal) has a diffraction angle (2θ) of 3.9 °, 7.8 °, 11.8 °, 14.1 °, 15.1 °, 18. Peaks were shown near 9 °, 20.0 °, 24.8 ° and 25.8 °.
According to FIG. 9, the 2.5DHBA co-crystal (I-shaped crystal) has a diffraction angle (2θ) of 9.7 °, 11.4 °, 16.0 °, 18.7 °, 19.3 °, 21. Peaks were shown near 1 °, 22.8 °, 25.0 °, 25.9 ° and 26.9 °.
(Thermal analysis)
The TG / DTA curve of the 2,5 DHBA co-crystal (II form crystal) obtained by the above-mentioned THF / hexane-based crystallization method is shown in FIG. 12, and the 2,5 DHBA co-crystal obtained by the above-mentioned methanol / water-based crystallization method is shown in FIG. The TG / DTA curve of (I-shaped crystal) is shown in FIG.

(Scale up of crystallization method)
At room temperature, 5 g of compound A (II form crystal) and 2.5 DHBA having a molar ratio of 10 to compound A were dissolved in THF (100 mL) in a 500 mL beaker. Hexane (250 mL) was added thereto while stirring with a stirrer to precipitate crystals, and then the mixture was stirred for 3 days to obtain a 2.5DHBA co-crystal THF mixture (FIG. 14). This was collected by filtration, air-dried at room temperature, and then heated at 110 ° C. for 20 hours to obtain a 2.5 DHBA co-crystal (I-shaped crystal). The obtained 2.5DHBA co-crystal (I-shaped crystal) was pulverized by jet mill (model AO jet mill, Seishin Enterprise Co., Ltd.), and the pulverization obtained a drug particle diameter having a median diameter of 2.3 μm (particle size measurement model Shimadzu). SALD-3100). It was confirmed that there was no change in the powder X-ray diffraction pattern even after pulverization.
(Powder X-ray diffraction)
The PXRD pattern of the co-crystal THF sum of compound A and 2.5 DHBA is shown in FIG.
According to FIG. 14, the 2.5DHBA co-crystal THF sum product has a diffraction angle (2θ) of 8.4 °, 9.2 °, 16.0 °, 16.3, 17.6 °, 18.9 °, Peaks were shown near 19.5 °, 21.7 °, 24.7 °, 25.4 °, 26.5 ° and 27.9 °.

Co-crystal 0.5 hydrate of compound A and 2.5 DHBA (crystallization method: methanol / aqueous system)
Compound A (I-form crystal) was mixed with 10 mg of 2.5 DHBA at a molar ratio of 100 and dissolved in methanol (2 mL). When 5 mL of water was added dropwise thereto, 2.5 DHBA co-crystal 0.5 hydrate was obtained as a white to slightly yellow solid. The operation was carried out at room temperature.

(Analysis of the sample obtained by the above crystallization method)
Thermal analysis and measurement of the co-crystal 0.5 hydrate of compound A and 2.5 DHBA obtained in a methanol / aqueous system showed a weight loss of 1.0% by about 144 ° C., and then about. An endothermic peak was observed at 144-152 ° C and melted at about 152-165 ° C (FIG. 15).

(Powder X-ray diffraction)
The PXRD pattern of the obtained 2.5 DHBA co-crystal 0.5 hydrate is shown in FIG. According to FIG. 16, the 2.5DHBA co-crystal 0.5 hydrate has diffraction angles (2θ) of 12.1 °, 15.1 °, 15.4 °, 17.7 °, 23.4 °, 23. Peaks were shown near 6.6 °, 24.8 °, 25.4 ° and 26.7 °.

(Single crystal structure analysis)
Single crystal structure analysis was performed on the 2.5 DHBA co-crystal 0.5 hydrate obtained under the above methanol / water system crystallization conditions.
The obtained crystal data and refinement parameters are shown below.

FIG. 17 shows an ORTEP diagram.
Since two molecules of compound A and two molecules of gentidic acid and one molecule of water were confirmed in the asymmetric unit, the molar ratio of compound A, gentizic acid and water molecule to 2.5 DHBA co-crystal 0.5 hydrate was 1: 1. It was confirmed that it was a 1: 0.5 co-crystal (Fig. 18).

(Analysis of dried crystals of hydrate sample)
The powder X-ray diffraction pattern when the 2.5 DHBA co-crystal 0.5 hydrate obtained in a methanol / water system was dried in a laboratory environment showed a 2.5 DHBA co-crystal (II type crystal). ..

(Single crystal structure analysis)
A single crystal structure analysis was performed on the 2.5DHBA co-crystal (II type crystal) obtained by drying the above 2.5DHBA 0.5 hydrate. The obtained crystal data and refinement parameters are shown below.

FIG. 19 shows an ORTEP diagram.
Since compound A and gentisic acid were confirmed in 6 molecules each in the asymmetric unit, it was confirmed that the 2.5DHBA co-crystal (II form crystal) was a co-crystal with a molar ratio of compound A and gentisic acid of 1: 1. (Fig. 20).

(Example 28)
Co-crystal of compound A and salicylic acid (sample analysis)
A physical mixture of compound A (form II) and salicylic acid having a molar ratio of 1: 1 was prepared, heated to 100 ° C., 120 ° C. or 150 ° C. and cooled to room temperature, and PXRD was measured (FIG. 21). As a result, the diffraction pattern at 100 ° C. was mainly a physical mixture of compound A and salicylic acid, but the diffraction pattern of the co-crystal of compound A and salicylic acid was observed in the 120 ° C. and 150 ° C. heated samples. Although some compound A remains, it was judged that the main diffraction pattern is the diffraction pattern of co-crystal with salicylic acid. It was confirmed that the diffraction pattern was consistent with the PXRD pattern of the co-crystal obtained by the crystallization described later.

(Cryptography method: acetone / water system)
(1) Salicylic acid was mixed with 10 mg of compound A (I-form crystal) at a molar ratio of 5, 10 or 50 and dissolved in acetone (2 mL). 1 mL of water was added dropwise thereto until a solid was deposited. A co-crystal was obtained as a white to slightly yellow solid under the condition of a molar ratio of salicylic acid of 50 (FIG. 22). The operation was carried out at room temperature.
(2) Salicylic acid having a molar ratio of 50 with respect to 1 g of compound A (II form crystal) and compound A was dissolved in acetone (200 mL). Water (300 mL) was added thereto while stirring with a stirrer 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 salicylic acid co-crystals. The obtained salicylic acid co-crystal was crushed in a magnetic mortar to obtain a drug particle size having a median diameter of 25.8 μm (particle size measurement model Shimadzu SALD-3100).
(Cryptography method: acetone / hexane system)
Salicylic acid was mixed with 10 mg of compound A (I-form crystal) at a molar ratio of 5, 10 or 50 and dissolved in acetone (2 mL). Hexane was added dropwise thereto in 1 mL increments until a solid was deposited. A co-crystal was obtained as a white to slightly yellow solid under the condition of a molar ratio of salicylic acid of 50. The operation was carried out at room temperature.
(Cryptography method: THF / hexane system)
Salicylic acid was mixed with 100 mg of compound A (I-form crystal) at a molar ratio of 5, 10 or 50 and dissolved in THF (2 mL). Hexane was added dropwise thereto in 1 mL increments until a solid was deposited. A co-crystal was obtained as a white to slightly yellow solid under the condition of a molar ratio of salicylic acid of 50. The operation was carried out at room temperature.

(Powder X-ray diffraction)
The PXRD pattern of salicylic acid co-crystals in an acetone / water system is shown in FIG.
According to FIG. 22, the salicylic acid co-crystal has a diffraction angle (2θ) of 9.9 °, 11.4 °, 16.2 °, 18.8 °, 19.0 °, 19.3 °, and 19.8 °. , 23.8 °, 24.9 °, 25.3 °, 26.1 ° and 27.3 °.
(Thermal analysis)
The TG / DTA curve of the salicylic acid co-crystal in the acetone / water system is shown in FIG.

(Single crystal structure analysis)
A single crystal structure analysis was performed on the salicylic acid co-crystals obtained under the above-mentioned acetone / water-based crystallization conditions. The obtained crystal data and refinement parameters are shown below.

FIG. 24 shows an ORTEP diagram.
Since compound A and salicylic acid were confirmed in 3 molecules each in the asymmetric unit, it was confirmed that the salicylic acid co-crystal was a co-crystal having a molar ratio of compound A and salicylic acid of 1: 1 (FIG. 25).

(Terahertz Raman spectroscopy)
Raman spectroscopy was performed in the low wavenumber region for each crystal form. The results are shown in FIG. According to FIG. 26, in the terahertz Raman spectrum, compound A (II form crystal) is 15.6 ^{, 28.5, 48.0 cm -1} , 2,5DHBA co-crystal (I form crystal) is 15.9, 45.3 ^{, 70.5 cm -1} , 2,5 DHBA co-crystals (II form crystals) are 15.9, 25.8, 52.8 cm ^-1 , and salicylic acid co-crystals are 15.6, 25.8, 38. It had a characteristic peak at .7, 61.5, 96.6 cm ^-1.

[Test example]
(Elution test)
The elution test was carried out with a test solution in which 1% hydroxypropylmethylcellulose was dissolved in JP1 and JP2. Specifically, 20 mL of the test solution, the sample is a 2.5 DHBA co-crystal (I-shaped crystal) after crushing with a jet mill and a salicylic acid co-crystal after crushing with a magnetic mortar, and as a control, a compound A-free form (II-type) after crushing with a jet mill. ) (Median diameter 2.7 μm) as compound A, about 5 mg was dispersed 20 times with lactose, and an elution test was carried out at 37 ° C. and 150 rpm. The stirrer was quantified by UHPLC using μDissProfiler (Pion). Both test solutions showed supersaturation after rapid elution, and the maximum concentration of both JP1 and JP2 was 12 to 15 times that of the control for 2.5DHBA co-crystals (I-shaped crystals) and salicylic acid co-crystals (FIGS. 27 and 28). ).

(Dog pharmacokinetic test 1)
Four Beagle dogs were orally administered 100 mg of the 2.5 DHBA co-crystal (I-form crystal) after jet mill pulverization and the compound A-free compound (II-form crystal) after jet mill pulverization as compound A, respectively. The drug substance was administered 20 times with lactose monohydrate and formulated into capsules. As a result, in the co-crystal / compound A-free form (II form crystal), _{both C max} and AUC were found to have a 6.3-fold improvement in absorption (Fig. 29).

(Dog pharmacokinetic test 2)
Next, HPMC was encapsulated in the capsule together with the co-crystal, and it was confirmed whether the absorption improving effect was observed.
HPMC (TC-5E) (available from Shin-Etsu Chemical Co., Ltd.) in 2.5 DHBA co-crystals (I-shaped crystals) (median diameter 19.0 μm) after crushing in a magnetic mortar is 5 times as heavy as compound A ( 500 mg) was physically mixed, and 100 mg of compound A was orally administered to 6 beagle dogs. The administration was carried out by dissolving 5 times the weight of compound A with lactose monohydrate (500 mg) and formulating it into capsules. As a control, the product was formulated using only the co-crystal instead of the physical mixture of co-crystal and HPMC. As a result, the physical mixture of 2.5DHBA co-crystal (I-shaped crystal) and HPMC (TC-5E) / 2,5DHBA co-crystal (I-shaped crystal) had a C _max of 1.3 times and an AUC of 1.4 times. Absorption improvement was observed (Fig. 30). When the co-crystals were dissolved, the presence of a polymer around them suppressed crystallization, which is considered to have improved the absorption of the co-crystals (effect of extending the supersaturation time).

(Dog pharmacokinetic test 3)
100 mg of salicylic acid co-crystals after jet mill pulverization and compound A-free compound (II form crystal) after jet mill pulverization were orally administered to 5 beagle dogs. The drug substance was administered 20 times with lactose monohydrate and formulated into capsules. As a result, in the case of co-crystal / compound A (II form crystal), _{absorption improvement of C max} 6.6 times and AUC 5.9 times was observed (FIG. 31).

(Optical stability test)
The solid state photostability of the 2.5DHBA co-crystals (I-form and II-form) and salicylic acid co-crystals was evaluated. Samples used were 2.5DHBA co-crystals (I-form and II-form) and salicylic acid co-crystals, and compound A-free (II-form) as a control. The storage conditions were 2 weeks under light irradiation (white fluorescent lamp and near-ultraviolet fluorescent lamp). The appearance was observed two weeks later. As a result of the photostability test, the surface discoloration (white to slightly yellowish white) of the free form of compound A (II form crystal) was observed under light irradiation, but the 2.5DHBA co-crystal (I form crystal and II type crystal) was observed. No particular changes were observed between the morphic crystals) and the salicylic acid co-crystals.

(Thermal stability test)
The thermal stability of the 2.5DHBA co-crystals (I-form and II-form) and salicylic acid co-crystals in the solid state was evaluated. Samples used were 2.5DHBA co-crystals (I-form and II-form) and salicylic acid co-crystals, and compound A-free (II-form) as a control. The storage conditions were 70 ° C. (Close system) for 2 weeks. After 2 weeks, in addition to appearance observation, purity (UHPLC) and crystallinity (PXRD, TG / DTA) were evaluated. As a result of the thermal stability test, no particular change was observed in any of the items before and after the test.

(Heat and humidity stability test)
The thermal-humidity stability of the 2.5DHBA co-crystal (I-shaped crystal) in the solid state was evaluated. The storage conditions were 40 ° C./75% RH (Open system, Close system) and 60 ° C. (Close system) for 4 weeks. After 4 weeks, in addition to appearance observation, purity (UHPLC) and crystallinity (PXRD, TG / DTA) were evaluated. As a result of the thermal-humidity stability test, no particular change was observed in any of the items before and after the test.

The PXRD patterns before and after the thermal stability test and the thermal humidity stability test of the 2.5DHBA co-crystals (I-form and II-form crystals) are shown in FIGS. 32 and 33, respectively. No change was observed in the crystal form of any of the cocrystals under heat and heat and humidity.

The co-crystal of Compound A or its co-crystal solvate enables more stable and efficient supply of drugs having antibacterial activity against tubercle bacilli, multidrug-resistant tubercle bacilli and / or nontuberculous mycobacteria. Become. The co-crystal of compound A or a co-crystal solvate thereof exhibits improved pharmacokinetic properties such as excellent oral absorbability and is useful as a raw material for pharmaceutical products.

Claims (16)

1. 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -A co-crystal of on and coformer or a co-crystal solvate thereof.
2. The co-crystal according to claim 1 or a co-crystal solvate thereof, wherein the coformer is a non-volatile organic acid.
3. The co-form according to claim 2, wherein the non-volatile organic acid is a benzoic acid in which at least one of the o-, m- or p-positions may be substituted with a group selected from the group consisting of hydroxy, amino and carboxyl. Crystals or their co-crystal solvates.
4. The co-crystal according to claim 3, wherein the benzoic acid is gentisic acid or salicylic acid, or a co-crystal solvate thereof.
5. In the powder X-ray diffraction diagram obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 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. The co-operation according to any one of claims 1 to 4, wherein at least three selected from the group consisting of 2 °, 25.9 ° ± 0.2 ° and 26.9 ° ± 0.2 ° contain diffraction peaks. Crystals or their co-crystal solvents.
6. In the powder X-ray diffraction diagram obtained by using CuKα ray as an X-ray source, the diffraction angles (2θ) are 3.9 ° ± 0.2 °, 7.8 ° ± 0.2 °, and 11.8 ° ± 0. 2 °, 14.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 24.8 ° ± 0. The co-crystal according to any one of claims 1 to 4, or a co-crystal solvent mixture thereof, which comprises a diffraction peak in at least three selected from the group consisting of 2 ° and 25.8 ° ± 0.2 °.
7. In the powder X-ray diffraction diagram obtained by using CuKα ray as the X-ray source, the diffraction angle (2θ) is 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. At least selected from the group consisting of 2 °, 24.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 26.1 ° ± 0.2 ° and 27.3 ° ± 0.2 ° The co-crystal according to any one of claims 1 to 4, or a co-crystal solvent mixture thereof, which comprises a diffraction peak in three.
8. In the powder X-ray diffraction diagram obtained by using CuKα ray as the X-ray source, the diffraction angles (2θ) are 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. The co-crystal according to any one of claims 1 to 4, or a co-crystal solvent mixture thereof, which comprises a diffraction peak in at least three selected from the group consisting of 2 ° and 26.7 ° ± 0.2 °.
9. 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing a co-crystal of 2 (1H) -one and a coformer or a co-crystal solvate thereof.
   (1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- A step of mixing dihydroquinoline-2 (1H) -one and a coformer in a solvent, and (2) a step of collecting the solid precipitated in the step (1) to obtain the cocrystal or a cocrystal solvate thereof. How to include.
10. 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing a co-crystal of 2 (1H) -one and a coformer or a co-crystal solvate thereof.
    (1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- A method comprising a step of mixing dihydroquinoline-2 (1H) -one and a coformer in a good solvent and (2) a step of adding a poor solvent to the mixture obtained in the above step (1).
11. The method according to claim 10, wherein the good solvent is tetrahydrofuran, acetone or methanol, and the poor solvent is hexane or water.
12. A pharmaceutical composition containing the co-crystal according to any one of claims 1 to 8 or a co-crystal solvate thereof and a pharmaceutically acceptable carrier.
13. An agent for diagnosing, preventing and / or treating tuberculosis, which comprises the co-crystal according to any one of claims 1 to 8 or a co-crystal solvate thereof.
14. The co-crystal according to any one of claims 1 to 8 for diagnosing, preventing and / or treating tuberculosis, or a co-crystal solvate thereof.
15. Use of the co-crystal according to any one of claims 1 to 8 or a co-crystal solvate thereof in the manufacture of a diagnostic agent, a preventive agent and / or a therapeutic agent for tuberculosis.
16. Diagnosis, prevention and / or diagnosis of tuberculosis in a subject comprising administering to a subject in need thereof an effective amount of the co-crystal or co-crystal solvate according to any one of claims 1 to 8. How to treat.

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