JP2021178818A - Method for preparing dihydroquinolinone compound - Google Patents

Abstract

To provide methods for preparing 5-{[(3R, 4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine-4-yl] methoxy}-8-fluoro-3,4-dihydroquinoline-2(1H)-on.SOLUTION: Methods for preparing crystals of 5-{[(3R, 4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine-4-yl] methoxy}-8-fluoro-3,4-dihydroquinoline-2(1H)-on are provided which includes the steps of: (1) recycling 5-{[(3R, 4R)-1-(4-chloro-2,6-difluorophenyl)-3,4-dihydroxypiperidine-4-yl] methoxy}-8-fluoro-3,4-dihydroquinoline-2(1H)-on in a solvent acceptable for preparing pharmaceutical preparations; and (2) cooling and then stirring a solution obtained through the recycling step (1) to obtain the crystal.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a dihydroquinolinone compound.

で示される５−｛［（３Ｒ，４Ｒ）−１−（４−クロロ−２，６−ジフルオロフェニル）−３，４−ジヒドロキシピペリジン−４−イル］メトキシ｝−８−フルオロ−３，４−ジヒドロキノリン−２（１Ｈ）−オン（本明細書において、「化合物Ａ」ともいう。）は、結核菌、多剤耐性結核菌及び／又は非結核性抗酸菌に対して抗菌作用を有する化合物として知られている（特許文献１）。化合物Ａの公知の製法は、精製過程を含め、安定かつ工業的スケールでの製造にはコスト面などの理由で不利である。したがって、化合物Ａの効率的かつ簡便な製造方法が望まれている。 formula:

5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-represented by 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). The known production method of compound A is disadvantageous in terms of cost and the like for stable and industrial scale production including the purification process. Therefore, an efficient and simple method for producing compound A is desired.

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 new and improved method for producing.

As a result of diligent research to solve the above problems, the present inventors have found a novel method applicable to production on an industrial scale as a method for producing compound A, and completed the present invention.

That is, in a certain aspect, it is a method for producing a crystal of compound A.
A method comprising (1) refluxing compound A in a solvent acceptable for pharmaceutical production, and (2) obtaining the crystals by cooling and stirring the solution obtained in the reflux step (1). Is provided.

In another embodiment, two crystal forms of compound A (also referred to herein as "type I crystals" or "type II crystals") are provided.

In yet another embodiment, a pharmaceutical composition comprising a type I crystal or a type II crystal of compound A is provided.

Stable and efficient industry of compound A having antibacterial activity against tubercle bacillus, multidrug-resistant tubercle bacillus and / or nontuberculous mycobacteria and preparations containing the same by the novel and improved production method of the present invention. Production becomes possible.
Since the type I crystal or the type II crystal of compound A is stable during and after the formulation process, it is possible to provide a pharmaceutically useful and safe formulation.

FIG. 1 shows a powder X-ray diffraction pattern of the I-shaped crystal of compound A. FIG. 2 shows a powder X-ray diffraction pattern of the type II crystal of compound A.

Specific embodiments of the present invention 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- A method for producing 2 (1H) -on crystals.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- The crystals are obtained by refluxing dihydroquinoline-2 (1H) -one in a solvent acceptable for pharmaceutical production, and (2) cooling and stirring the solution obtained in the reflux step (1). A method that includes a process.

[Item 2]
Item 2. The method according to Item 1, wherein the solvent acceptable for producing a pharmaceutical product is a solvent containing an aprotic polar solvent and / or an alcohol-based solvent.

[Item 3]
Item 2. The method according to Item 1 or 2, wherein the reflux step (1) comprises a step of adding water to the solution obtained by the reflux and further refluxing.

[Item 4]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing 2 (1H) -on crystals.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- After cooling the step of heating the acetic acid sum of dihydroquinoline-2 (1H) -one in a solvent acceptable for pharmaceutical production, and (2) the solution obtained in the heating step (1), the crystals are formed. A method comprising the step of obtaining.

[Item 5]
Item 4. The method according to Item 4, wherein the solvent acceptable for manufacturing a pharmaceutical product is a polar solvent.

[Item 6]
Crystals are 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydro Item 6. The method according to any one of Items 1 to 5, which comprises a quinoline-2 (1H) -one type II crystal.

[Item 7]
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A pharmaceutical composition comprising 2 (1H) -one type II crystals and a pharmaceutically acceptable carrier.

As used herein, the term "crystal" includes any of the crystal forms of compound A, and the crystal form thereof is, for example, an I-type crystal or a II-type crystal. In some embodiments, the crystal is a substantially pure form II crystal, i.e., a form II crystal that is substantially free of any other crystal form. Here, a type II 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 1% by weight, less than 0.5% by weight, 0. It is a type II crystal which may contain any other crystal form of less than 2% by weight, less than 0.1% by weight, or less than 0.08% by weight, for example, type I crystal. In another embodiment, the crystal is a substantially pure I-shaped crystal, i.e., an I-shaped crystal that is substantially free of any other crystal morphology. Here, an I-type 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 1% by weight, less than 0.5% by weight, 0. It is an I-type crystal that may contain any other crystal form of less than 2% by weight, less than 0.1% by weight, or less than 0.08% by weight, for example, type II crystal.

As used herein, the "solvent acceptable for pharmaceutical production" is a polar solvent (that is, an alcohol-based solvent, a protonic polar solvent, an aprotic polar solvent, or a mixed solvent thereof) and does not contain water. Or, in some cases, it may contain water. The solvent acceptable for the production of a pharmaceutical product may be appropriately selected from the above-mentioned solvents in each step.
Examples of the alcohol-based solvent include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and a mixed solvent of two or more thereof at any ratio. Ethanol, n-propanol, or isopropanol is preferable, and ethanol is more preferable.
Examples of the protonic polar solvent include water, alcoholic solvents, acetic acid, and formic acid.
Examples of the aprotic polar solvent include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and ethers (for example, diethyl ether, tetrahydrofuran, etc.). Preferred is dimethyl sulfoxide.
When the solvent acceptable for pharmaceutical production is a mixed solvent containing an aprotonic polar solvent and an alcohol-based solvent, the aprotonic polar solvent and the alcohol-based solvent are preferably in a volume ratio of, for example, 1: 2 to 1: 9. Is 1: 3 to 1: 5, more preferably 1: 3.5 to 1: 4.5, and even more preferably 1: 4.

[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. It may be used in. 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-oxopiperidine-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 with D-epoxone in a solvent was carried out 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- 2 (1H) -one synthesis 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 It can be produced by reacting -4-ol with 8-fluoro-5-hydroxy-3,4-dihydroquinoline-2 (1H) -one in the presence of a base in a solvent.
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 is 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 and a half 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 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 to produce N. -(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 with 5,8-difluoroquinoline-2 (5,8-difluoroquinoline-2 (1H) -on in the presence of aluminum chloride. 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 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-ylacetate can be produced by 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)
Synthesis of 8-fluoro-5-hydroxy-3,4-dihydroquinoline-2 (1H) -one 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)
Synthesis of 8-fluoro-5-hydroxyquinoline-2 (1H) -one 2,5-bis (benzyloxy) -8-fluoroquinoline is reacted in the presence of a palladium catalyst and an acid in a hydrogen atmosphere to 8-. 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]
(Manufacturing method of I-shaped crystal)
The 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., preferably 70 ° C. until the crystals are dissolved, filtered hot, and then slowly cooled to 30. Aged at ° C. or lower, preferably 20 to 30 ° C. for 1 hour or longer to obtain an acetic acid-containing product of Compound A, which is vacuum-dried or blown-dried to produce substantially pure I-type crystals of Compound A. be able to.
Vacuum drying is performed, for example, at 65 to 85 ° C. and 1.0 kPa for 24 to 48 hours.
Blast drying is performed, for example, at 50 ° C. for 18 hours to overnight.
I-form crystals of compound A can also be produced by using, for example, dimethyl sulfoxide instead of acetic acid and / or potassium acetate without forming acetic acid sums.

(Method for producing type II crystals 1)
Compound A obtained by the above production method is stirred in a solvent acceptable for pharmaceutical production at room temperature to reflux temperature, cooled, aged, and air-dried to obtain II of substantially pure compound A. Form crystals can be produced.
The solvent acceptable for pharmaceutical production is an alcohol solvent, an aprotonic polar solvent, or a mixed solvent thereof, for example, methanol, ethanol, n-propanol, isopropanol, or dimethyl sulfoxide and ethanol, n-propanol or isopropanol. Examples of the mixed solvent of.
The reflux temperature may be appropriately selected depending on the solvent, and examples thereof include 75 ° C. and higher.
The reflux time is not particularly limited as long as the dissolution of the compound A is confirmed, but examples thereof include 0.5 hours or more, preferably 0.5 to 4 hours, and more preferably 1 to 2 hours.
The cooling conditions are not particularly limited as long as the crystals of compound A are precipitated, but examples thereof include conditions for slowly cooling to −10 ° C. to 30 ° C. over 2 hours, preferably 2 to 6 hours. It is a condition for cooling to 10 ° C. or lower.
The aging conditions are, for example, 30 minutes or more, preferably 1 to 4 hours at the temperature after cooling.
Blast drying is carried out at, for example, 100 ° C. or lower, preferably 60 to 80 ° C. for 17 to 72 hours, preferably 24 to 72 hours.

(Method for producing type II crystals 2)
Compound A obtained by the above production method is stirred in a solvent acceptable for pharmaceutical production at room temperature to reflux temperature, and after confirming the dissolution of compound A, water is added to reflux again, and then the mixture is cooled and aged. Then, by blowing and drying, a substantially pure type II crystal of compound A can be produced.
The water in this production method is water used for manufacturing pharmaceutical products, and examples thereof include purified water, preferably purified water specified in the Japanese Pharmacopoeia. The temperature of water is, for example, 10 ° C to 50 ° C, preferably room temperature, that is, 15 ° C to 25 ° C.
The reperfusion conditions include, for example, the reflux temperature of the solvent, preferably 75 ° C. or higher, and the time during which the dissolution of compound A is confirmed, for example, 0.5 hours or longer, preferably 0.5 to 4 hours, more preferably. 1-2 hours.
Other production conditions are the same as those in the above-mentioned method 1 for producing type II crystals.

(Method for producing type II crystals 3)
Compound A obtained by the above production method is stirred in a solvent acceptable for pharmaceutical production at a temperature of room temperature or higher, and then filtered, washed and dried to produce substantially pure type II crystals of compound A. can do.
The solvent acceptable for the production of a pharmaceutical product in the present production method is an alcohol-based solvent, and examples thereof include methanol, ethanol, n-propanol or isopropanol. Methanol is preferable.
The stirring conditions are, for example, 3 hours or more at the above temperature, preferably 3 to 48 hours at 30 ° C. to 50 ° C., and more preferably 3 to 24 hours at 30 ° C. to 50 ° C.
Drying is preferably carried out at 80 ° C. or higher.

(Method for producing type II crystals 4)
The compound A obtained by the above production method is stirred in the presence of acetic acid in a solvent acceptable for pharmaceutical production at 80 to 90 ° C. until the crystals are dissolved, and after hot filtration, the temperature is 30 ° C. or lower, preferably 10. An acetate product of compound A can be obtained by cooling to a temperature of ° C. or lower, stirring (for example, at the temperature after cooling for 1 hour or more), filtering and washing.
The obtained acetic acid sum of compound A is stirred at 70 to 90 ° C. for 3 hours or longer, preferably 80 ° C. for 3 hours or longer in a solvent acceptable for pharmaceutical production, then cooled and stirred, and then filtered and washed. conduct. By vacuum drying or blast drying this, substantially pure type II crystals of compound A can be produced.
The solvent acceptable for the production of pharmaceuticals in the present production method is a polar solvent, and examples thereof include acetic acid, water, methanol, ethanol, n-propanol, 2-propanol, dimethyl sulfoxide or a mixed solvent thereof. It is preferably acetic acid, water or a mixed solvent thereof.
Vacuum drying is performed, for example, at 70 to 80 ° C. and 2.0 kPa for 2 hours to overnight.
Blast drying is performed at, for example, 80 to 100 ° C. for 2 to 72 hours.

[Crystal morphology]
(I-shaped crystal)
The type I crystal of compound A has a diffraction angle (2θ) of 4.9 ° ± 0.2 ° and 10.6 ° ± 0.2 ° in a powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source. , 13.9 ° ± 0.2 °, and 21.9 ° ± 0.2 ° can show diffraction peaks. These diffraction peaks are characteristic peaks not found in the powder X-ray diffraction pattern of the type II crystal of compound A. The diffraction angle (2θ) of the I-shaped crystal is 9.9 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 18.2 ° ± 0.2 °. , 23.1 ° ± 0.2 °, 26.2 ° ± 0.2 °, and at least one, three, five, or seven selected from the group consisting of 31.9 ° ± 0.2 °. A diffraction peak may also be shown at the diffraction angle. ± 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.

(Type II crystal)
The type II crystal of compound A has a diffraction angle (2θ) of 10.8 ° ± 0.2 ° and 14.2 ° ± 0.2 ° in a powder X-ray diffraction pattern obtained by using CuKα ray as an X-ray source. Diffraction peaks can be shown at 2, 1.0 ° ± 0.2 °, and 25.3 ° ± 0.2 °. These diffraction peaks are characteristic peaks not found in the powder X-ray diffraction pattern of the I-type crystal of compound A. The diffraction angle (2θ) of the type II crystal is 8.7 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.3 ° ± 0.2 °. , 23.9 ° ± 0.2 °, and at least one, three, five, or six diffraction angles selected from the group consisting of 28.2 ° ± 0.2 ° may also show diffraction peaks. good. ± 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.

[Preparation / Pharmaceutical composition]
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 weights of the entire preparation or nuclear tablets. %, Preferably 1.5 to 35% by weight. Compound A can be administered to mammals including humans. The dose varies depending on the subject, symptoms, dosage form, administration route, etc., but for example, the dose when orally administered to a human adult patient (body weight 65 kg) is usually about 5 mg to 100 mg per dose as compound A. Is the range of.
Examples of the "pharmaceutically acceptable carrier" used for the formulation of compound A include components such as excipients, disintegrants, binders, fluidizers and lubricants commonly used in the art.
Specifically, as the disintegrant, a disintegrant commonly used in the art can be used, for example, low-substituted hydroxypropyl cellulose, starches, carmellose, carmellose calcium, carmellose sodium, crospovidone, cloth. Examples thereof include sodium carmellose and sodium carboxymethyl starch (also referred to as sodium starch glycolate). As the excipient, an excipient commonly used in the art can be used, for example, saccharides (monosaccharides, polysaccharides (lactose, etc.), sugar alcohols, water candy, isomerized saccharides, reduced starch saccharified products, etc.). , Corn starch, crystalline cellulose, phosphates (calcium hydrogen phosphate hydrate, sodium hydrogen phosphate hydrate, etc.) and the like. As the binder, a binder usually used in the art can be used, and starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, etc. can be used. Hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be mentioned. As the fluidizing agent, a fluidizing agent usually used in the art can be used, and examples thereof include light anhydrous silicic acid, hydrous silicon dioxide, magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester. As the lubricant, a lubricant commonly used in the art can be used, and examples thereof include magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid ester, and sodium stearyl fumarate.

Examples of the method for formulating the I-shaped crystal of compound A include a wet granulation method. A fluidized bed granulation method is preferable. When the I-type crystal is directly tableted without granulation during the formulation, it may transfer to the II-type crystal under severe conditions (for example, 50 ° C./75% RH, 9 days). The fluidized bed granulation method can alleviate the aggregation of the drug and suppress the crystal transition by mixing the drug well with the carrier. In some embodiments, the formulation may be packaged with a desiccant commonly used in the art to suppress solvent-mediated transfer by water in order to retain the I-form crystals after formulation.
The method for formulating the type II crystal of compound A includes a direct tableting method in addition to the above-mentioned wet granulation method. Formulations using type II crystals are chemically stable even under harsh conditions without packaging.

Dosage forms of the pharmaceutical composition containing compound A include oral preparations such as tablets (including film-coated tablets), capsules, granules, powders and troches. Film-coated tablets are preferred to avoid coloration under light irradiation. In some embodiments, the film-coated tablets may be free of non-cellulosic plasticizers (eg polyethylene glycol) to avoid crystal transitions.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and 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)
The following (1) or (2) was used.
(1)
D8 Advance (manufactured by Bruker AXS GmbH)
Measurement method: Reflection method Radioactive source: CuKα ray (λ = 1.5418 Å)
Measuring range: 3-40 °
Scan step: 0.02 °
Scan speed: 0.1 sec / step
(2)
XRD-6000 (Shimadzu Corporation)
Measurement method: Reflection method Radioactive source: CuKα ray (λ = 1.5418 Å)
Measuring range: 3-40 °
Scan step: 0.02 °
Scan speed: 5 ° / min

[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 give 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 a reaction vessel In addition, the mixture was stirred at 25-60 ° 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)
Synthesis of 5,8-difluoroquinoline-2 (1H) -one Add sodium chloride (36.0 g), potassium chloride (36.0 g) and aluminum chloride (238.0 g) 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)
Synthesis of 8-fluoro-5-hydroxy-3,4-dihydroquinoline-2 (1H) -one 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 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-piperidin (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. A mixture of 1-propanol (58.9 kg), acetonitrile (74 L), water (99 L) / disodium ethylenediaminetetraacetate (15.0 g) / potassium carbonate (27.0 kg), 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) -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 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) -one (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 65-70 ° 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) -one (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) -one (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 acetic acid sum (1)
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 acetic acid sum (2)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one (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 and washed with a mixed solution of acetic acid (26 kg) / water (8 kg) to obtain a sum of acetic acid (10.15 kg) of the title compound.
^{1 1} HNMR: See Example 23

(Example 25)
Preparation of I-shaped crystals (1)
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). The measurement result by powder X-ray diffraction is shown in FIG.
^{1 1} HNMR: See Example 16.

(Example 26)
Preparation of I-shaped crystals (2)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one (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 65-70 ° 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 27)
Preparation of I-shaped crystals (3)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one (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 28)
Preparation of I-shaped crystals (4)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one (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 29)
Preparation of type II crystals (1)
(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) are added to the reaction vessel, and 3 under reflux. Stirred for 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 1} HNMR: See Example 16.

(Example 30)
Preparation of type II crystals (2)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -on (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 31)
Preparation of type II crystals (3)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A crude product of 2 (1H) -one (20.0 g) was added to methanol (200.0 mL), and the mixture was stirred at 30 ° C. for 180 minutes or more. Then, the crystals in the suspension were collected by filtration and washed with methanol (40.0 mL). After washing, it was dried at 80 ° C. to obtain a white solid (17.90 g, yield 89.50%, chemical purity 99.90%).
The powder X-ray diffraction pattern of the obtained solid was measured, and it was confirmed that it was a type II crystal of compound A. The 2θ value of the characteristic peak is shown below.

(Examples 32 to 34)
When the methanol of Example 31 was replaced with ethanol, n-propanol or 2-propanol and the same treatment was carried out, type II crystals were obtained. The results are shown in the table below.

(Example 35)
Preparation of type II crystals (4)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A crude product of 2 (1H) -one (5.0 g) was added to dimethyl sulfoxide (10.0 mL) and ethanol (40.0 mL), and the temperature was raised to the reflux temperature to dissolve the mixture. After confirming the dissolution, the mixture was cooled to 10 ° C. or lower and stirred for 60 minutes or longer. After stirring, the precipitated crystals were collected by filtration and washed with ethanol (10.0 mL). After washing, it was dried at 80 ° C. to obtain a white solid (3.05 g, yield 61.00%, chemical purity 99.94%).
The powder X-ray diffraction pattern of the obtained solid was measured, and it was confirmed that it was a type II crystal of compound A. The 2θ value of the characteristic peak is shown below.

(Examples 36 to 37)
When the ethanol of Example 35 was replaced with n-propanol or 2-propanol and the same treatment was carried out, type II crystals were obtained. The results are shown in the table below.

(Example 38)
Preparation of type II crystals (5)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A crude product of 2 (1H) -one (5.0 g) was added to dimethyl sulfoxide (10.0 mL) and ethanol (40.0 mL), and the temperature was raised to the reflux temperature to dissolve the mixture. After confirming the dissolution, purified water (5.0 mL) was added, and the temperature was raised until reflux was performed again. After confirming reflux, the mixture was cooled to 10 ° C. or lower and stirred for 60 minutes or longer. After stirring, the precipitated crystals were collected by filtration and washed with ethanol (10.0 mL). After washing, it was dried at 80 ° C. to obtain a white solid (4.41 g, yield 88.20%, chemical purity 99.94%).
The powder X-ray diffraction pattern of the obtained solid was measured, and it was confirmed that it was a type II crystal of compound A. The results are shown in FIG. 2, and the 2θ values of the characteristic peaks are shown below.

(Example 39)
When the ethanol of Example 38 was replaced with 2-propanol and the same treatment was carried out, type II crystals were obtained. The results are shown in the table below.

(Example 40)
Preparation of type II crystals (6)
5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- 2 (1H) -one crude (30.0 g), acetic acid (240 mL) and water (60 mL) were added to the reaction vessel and stirred at around 80 ° C. until the crystals were dissolved. It was filtered at hot temperature, cooled to 10 ° C. or lower, and aged for 1 hour. Precipitated crystals were separated and washed with a mixed solution of acetic acid (67.5 mL) / water (22.5 mL) to obtain a sum of acetic acid. The obtained acetic acid sum (12 mL) and water (108 mL) were added to the reaction vessel, and the mixture was stirred at 70 ° C. for 3 hours. The mixture was cooled to 40 ° C. or lower, the precipitated crystals were separated, washed with water (120 mL), and air-dried at 80 ° C. for 2 hours to obtain a white to slightly yellow solid (24.96 g, yield 83.20). %, Chemical purity 99.76%, Optical purity 99.85% ee, Residual solvent (acetic acid) 374 ppm).
The powder X-ray diffraction pattern of the obtained solid was measured, and it was confirmed that it was a type II crystal of compound A. The results are shown in FIG. 2, and the 2θ values of the characteristic peaks are shown below.

(Examples 41 to 45)
The acetic acid / water used as the solvent for stirring the acetic acid sum of Example 40 at 70 ° C. was replaced with the following solvent, and the same treatment was carried out to obtain type II crystals. The results are shown in the table below.

(Prescription of I-shaped crystal)
The type I crystals of compound A were mechanically crushed using a jet mill (model: PJM-100SP, manufactured by Nippon Pneumatic Industries; air pressure: 0.4 MPa; feed speed: 20 rpm) to obtain drug fine particles. The crushed I-shaped crystals, lactose hydrate, corn starch and silicon dioxide were put into the above fluidized bed granulator (model: FD-MP-01, manufactured by Paulec) and mixed. Separately, a fluidized bed was granulated and dried with a binding solution prepared by dissolving hydroxypropyl cellulose (HPC) in water to obtain granulated products. The obtained granules were put into a sieve or a crushing type granulator (model: P-3S, manufactured by Dalton) to obtain granules. The obtained granules and low-substituted hydroxypropyl cellulose (L-HPC) were placed in a container rotary mixer (manufactured by Ishihi Seisakusho Co., Ltd.) and mixed. The mixing composition and magnesium stearate were placed in a rotary container mixer and mixed. This final mixture was tableted using a rotary tableting machine (model: 0512SS, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets (uncoated tablets). The tablets were made to contain about 5-100 mg of compound A.
An example of the formulation of the I-shaped crystal is shown below.

(I-shaped crystal film-coated lock)
The I-form crystal of compound A is formulated according to the following method.
Prepare the film coating liquid in advance as follows. OPADRY (trademark registration) or OPADRY amb II (trademark registration), which is a film coating component, is dissolved in water and dispersed to prepare a film coating liquid by a conventional method. OPADRY consists of hypromellose (HPMC), talc, titanium oxide and dye components, and may further contain polyethylene glycol (PEG) as appropriate. OPADRY amb II contains polyvinyl alcohol (PVA) and further contains a plasticizer. An uncoated tablet containing I-shaped crystals of compound A is placed in a coating device (model: DRC-200, manufactured by Paulec), coated with this film coating solution, and dried to obtain a film-coated tablet.

(Prescription of type II crystal)
Form II crystals of compound A were mechanically crushed by jet mill pulverization to obtain drug fine particles. The crushed type II crystals, lactose hydrate, corn starch and silicon dioxide were put into a fluidized bed granulator and mixed. A binding solution prepared by dissolving hydroxypropyl cellulose (HPC) in water was added thereto, and the fluidized bed was granulated and dried to obtain granulated products. The obtained granules were put into a sieve or a crushing type granulator to obtain granules. The obtained granules and low-substituted hydroxypropyl cellulose (L-HPC) were placed in a rotary container mixer and mixed. Then, magnesium stearate was added and mixed. This final mixture was tableted using a rotary tableting machine to obtain tablets (uncoated tablets). The tablets contained about 10 to 30 mg of the active ingredient. OPADRY (trademark registration), which is a film coating component, was dissolved and dispersed in water to prepare a film coating liquid by a conventional method. OPADRY consists of hypromellose (HPMC), talc, titanium oxide and pigment components. In addition, they may contain polyethylene glycol (PEG). An uncoated tablet containing type II crystals was placed in a coating device, coated with this film coating solution, and dried to obtain a film-coated tablet.
An example of the formulation of the II type crystal is shown below.

The production method of the present invention is useful for stable and efficient industrial production of compound A having an antibacterial activity against tubercle bacillus, multidrug-resistant tubercle bacillus and / or nontuberculous mycobacteria and a preparation containing the same. be.

Claims (5)

5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing 2 (1H) -on crystals.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- The crystals are obtained by refluxing dihydroquinoline-2 (1H) -one in a solvent acceptable for pharmaceutical production, and (2) cooling and stirring the solution obtained in the reflux step (1). A method that includes a process. The method according to claim 1, wherein the solvent acceptable for the production of a pharmaceutical product is a solvent containing an aprotic polar solvent and / or an alcohol-based solvent. The method according to claim 1 or 2, wherein the reflux step (1) comprises a step of adding water to the solution obtained by the reflux and further refluxing. 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4-dihydroquinoline- A method for producing 2 (1H) -on crystals.
(1) 5-{[(3R, 4R) -1- (4-chloro-2,6-difluorophenyl) -3,4-dihydroxypiperidine-4-yl] methoxy} -8-fluoro-3,4- After cooling the step of heating the acetic acid sum of dihydroquinoline-2 (1H) -one in a solvent acceptable for pharmaceutical production, and (2) the solution obtained in the heating step (1), the crystals are formed. A method comprising the step of obtaining. The method according to claim 4, wherein the solvent acceptable for the production of a pharmaceutical product is a polar solvent.

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