WO2003076428A1

WO2003076428A1 - Quinolonecarboxylic acid derivative

Info

Publication number: WO2003076428A1
Application number: PCT/JP2002/002181
Authority: WO
Inventors: Sadahiro Shimizu; Yuichiro Tani; Toshifumi Akiba
Original assignee: Daiichi Pharmaceutical Co., Ltd.
Priority date: 2002-03-08
Filing date: 2002-03-08
Publication date: 2003-09-18
Also published as: JPWO2003076428A1; AU2002236267A1

Abstract

(-)-7-[(7S)-Amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid monohydrochloride 2.5-hydrate, which is represented by the following formula (1); and a process for producing the monohydrochloride monohydrate of this compound. By the process, the compound is stably obtained, which has excellent antibacterial activity and safety and excellent stability to light and humidity and is useful as an antibacterial.

Description

Description Quinolonecarboxylic acid derivative Technical field

The present invention relates to a method for producing an optically active quinolone carboxylic acid derivative having high antibacterial activity and safety and good stability, and an intermediate for producing the same. Technology

Quinolone carboxy derivatives are known as synthetic antibacterial agents. In particular, compounds of the following general formula (I) having a 1,2-cis-12-halogenocyclopropyl group at the 1-position nitrogen atom of the quinoline skeleton are highly potent antibacterial agents. It is known to be useful as a pharmaceutical because of its high activity and high safety (Patent Nos. 271,595 and 297)

(0 1 0) ₀ '

(Wherein, R ¹ represents an amino group, a methylamino group, a hydroxyl group, a thiol group or a hydrogen atom, and R ² is a substituent selected from the following group)

(Wherein, R ³ , R ⁴ , R ⁵ and R ^s each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ^le and R ¹¹ independently represent a hydrogen atom or 1 carbon atom. and meaning taste alkyl group of ~ 6, R ¹² and R ¹³ means the independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms ) Or a 3-hydroxypiperidinyl group which may have an alkyl group having 1 to 6 carbon atoms. A means the CX ³ or nitrogen atom. X ¹ and X ² each independently represent a halogen atom; X ³ represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group or a hydrogen atom I do. Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 6 carbon atoms, a phenyl group, an acetomethyl group, and a bivaloyloxymethyl group. Group, ethoxycarponyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, furidinyl group, 5-substituted 1-2-oxo-11,3-dioxol-4-ylmethyl group, or 3-acetoxy-2- Means an oxobutyl group. However, this excludes the case where the substituent R ² is a 3-aminopyrrolidinyl group and R ¹ and X ³ are hydrogen atoms. )

Fluoroquinolones are evolving into chemotherapeutic drugs that are effective against almost systemic infections. Under such circumstances, there is a need for a compound having higher antibacterial activity and safety, and also having excellent stability to light and humidity. Disclosure of the invention

Under such circumstances, the applicant has filed the above-mentioned Patent No. 27144597 and Patent No. 2991.

Focusing on the Ν, — (1,2-cis-12-fluorocyclopropyl) -substituted pyrrolidonecarboxylic acids described in the specification of No. 7010, and further studied, it was found that the chemical Compound 41 with only structural formula shown, especially

(-)-7-[(7S) -1-7-amino-5-azaspiro [2.4] heptane-5

—Yl] 1-6-fluoro-11-[(1 R, 2 S) -2-fluoro-1 —cyclobutyl pill] 1,4-dihydro-8-methoxy-14-oxo-13-quinolinecarponic acid [Compound (A). Compound (A) is a free compound having the structure of the following formula (A). ], The monohydrochloride monohydrate is significantly more effective than other acid addition salts in terms of not only antibacterial activity and safety but also stability against light and humidity. It was found to be excellent and useful as an antibacterial agent, and a patent application was filed earlier (Japanese Patent Application No. 2000-097690).

As a result of further investigation, the hydrochloride of compound (A) includes 'monohydrochloride' pentahydrate in addition to monohydrochloride · monohydrate, and these two hydrates By properly adjusting the conditions during the crystal production, they found that they could be selectively produced, and completed the present invention.

That is, the present invention provides the following formula (1)

A compound represented by [(-)-17-[(7S) -17-amino-5-azaspiro [2.4] heptane-15-yl] -16-fluoro-1-[(1R, 2S) —2—Fluoro 1-cyclopropyl] —1,4-dihydro-1-methoxy-4-oxo-3-monoquinolinecarboxylic acid · monohydrochloride · 2.5 hydrate. Hereinafter, compound (1). Compound (1) is the monohydrochloride · 2.5 hydrate of compound (Α). ].

Further, the present invention is characterized in that the compound having the structure represented by the formula (Α) is treated in a water-containing solvent whose water content is adjusted in the presence of hydrochloric acid, if desired, or recrystallized from the water-containing solvent. (1) 1 7 — [(7S) 1—7—amino—5—azapi mouth [2. 4] Heptane—5—yl] 1—6—Fluoro; 1 [(1 R, 2 S) 1 2 —Fluoro-1-cyclopropyl] — 1,4-dihydro-8-methoxy-4-oxo—3-quinolinecarboxylic acid · monohydrochloride · monohydrate [Hereinafter, Compound (2). Compound (2) is the monohydrochloride monohydrate of compound (II). Or a method for producing compound (1). Further, the present invention provides a method for treating a compound having a structure represented by the formula (A) in a water-containing solvent having a water content of 1 to 5% in the presence of hydrochloric acid, if necessary, or recrystallizing from the water-containing solvent. And a process for producing the compound (2).

Further, the present invention provides that a compound having a structure represented by the formula (A) is treated in a water-containing solvent having a water content of 20 to 40% in the presence of hydrochloric acid, if necessary, or recrystallized from the water-containing solvent. And a process for producing the compound (1) characterized by the following. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a view showing a powder X-ray diffraction spectrum of the compound (1).

FIG. 2 is a view showing an infrared absorption spectrum of the compound (1).

FIG. 3 is a graph showing a change in weight of the compound (1) under the condition of 5 to 95% RH.

FIG. 4 is a view showing a powder X-ray diffraction spectrum of the compound (2).

FIG. 5 is a diagram showing an infrared absorption spectrum of the compound (2). BEST MODE FOR CARRYING OUT THE INVENTION

The compound (1) and the compound (2) of the present invention can be produced, for example, according to the following reaction formula.

(Four)

(3)

1HC1 * 2.5H ₂ 0

(1)

That is, the compound (3) is reacted with the compound (4) to obtain a compound (A), which is then treated in a water-containing solvent having a controlled water content in the presence of hydrochloric acid if desired, or Compound (1) or compound by recrystallization from aqueous solvent

(2) is obtained. Further, the compound (1) and the compound (2) can be selectively converted to each other by treating in a water-containing solvent having a controlled water content. The starting compounds (3) and (4) can both be obtained by the method described in Japanese Patent No. 2714597.

The reaction between compound (3) and compound (4) can be carried out with or without a solvent. The solvent that can be used in the reaction is not particularly limited as long as it is inert to the reaction. Such solvents include, for example, sulfoxides such as dimethyl sulfoxide, nitrogen-containing heterocyclic compounds such as pyridine, nitriles such as acetonitrile, alcohols such as ethanol, halogenated hydrocarbons such as chloroform, dimethylformamide, and the like. Amines such as dimethylacetamide and N-methylpyrrolidone And ethers such as tetrahydrofuran, water, 3-methoxybutanol and the like, and these may be used as a mixture.

The reaction is preferably performed in the presence of an acid acceptor such as an inorganic base or an organic base. Here, the base may be any of an inorganic base and an organic base.Examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and hydrogen hydrogen carbonate. Hydroxides, carbonates, hydrogencarbonates and the like of alkali metals such as potassium. Examples of the organic base include trialkylamines such as triethylamine, tripropylamine, triptylamine, N, N-diisopropylethylamine, dialkylanilines such as getylaniline and dimethylaniline, N-methylmorpholine, Pyridine, N, N-dimethylaminopyridine and the like can be exemplified.

The reaction can be carried out usually at room temperature to 100 ° C., and preferably at room temperature to about 40 ° C. The reaction time may be in the range of 30 minutes to 48 hours, and usually ends in about 30 minutes to 20 hours.

In order to remove the boron chelate of the product after the reaction of the compound (3) with the compound (4), the product is dissolved in aqueous ethanol, triethylamine is added, and the mixture is heated under reflux for several hours. In this case, the hydrous ethanol may be replaced with another protic solvent, for example, hydrous isopropanol, which is a protonic solvent which can be mixed with water, and which can dissolve compound (4) at least when heated. Is preferred. Also, it is not necessary to add triethylamine.

If the obtained compound (A) is not converted into a hydrochloride under controlled conditions, not only compound (2) but also compound (1) or a mixture thereof is obtained. A mixture of multiple hydrate crystals is unqualified as an API. Therefore, the present inventors have studied a method for selectively producing compound (1) and compound (2) as single hydrate crystals.

First, the present inventors investigated the stability of the crystals of the compounds (1) and (2) in an aqueous solvent. I examined it. The study method is as follows.

Equivalent amounts of the compounds (1) and (2) were mixed, and a water-containing solvent adjusted to various water contents was added thereto. The mixture was stirred at different temperatures, and the ratio of the compounds (1) and (2) contained in the crystals after a certain period of time was analyzed. At the time of treatment, the treatment mixture was in a suspended state, that is, a so-called slurry state. In this treatment, 2-propanol having a water content of 1% to 40% was used as a water-containing solvent. The amount of the solvent used in the treatment was 1.5 to 20 ml based on 1 g of the crystal. The water content of the solvent used is shown as a volume ratio before mixing. For example, 40% aqueous 2-propanol is a mixture of 6 volumes of 2-propanol and 4 volumes of water. The treatment was performed for 1 to 3 days. However, it was also revealed that one to three days are not necessarily required for crystal conversion, and that the conversion may actually be completed within one day. The treatment was performed at 0 ° C to 70 ° C.

As a result of this study, it was found that the type of crystals present changes depending on the treatment temperature and the water content of the solvent used for the treatment. That is, when the water content was 1% to 5%, when the treatment was performed at 0 ° C to 70, only compound (2) was formed (present). When the water content is 7% to 8%, the compound is treated with 20 to 7 Ot:

Only (2) was formed, but from 0 ° C to 10 ° C, it was a mixture of compounds (1) and (2). When the water content is 9%, the treatment at 25 ° C to 70

Only (2) was formed, but from 0 to 20 it was a mixture of compounds (1) and (2). When the water content is 10%, the compound is treated at 30 ° C to 70 ° C.

Only (2) was formed, but at 5 ° C to 25, it became a mixture of compounds (1) and (2). Only compound (1) was produced. If the water content is between 20% and 40%,

After treatment at 0 ° C to 70 ° C, only compound (1) was formed.

From this result, it was clarified that the compound (1) should be treated in a solvent having a water content of 20% to 40% in order to obtain a single compound. Also, the compound

In order to obtain (2) as a single substance, treatment is performed in a solvent having a water content of 1% to 5%. It became clear that we had to do it. These processes are preferably performed under the conditions of 0 to 70.

The term “treat” means that a mixture of crystals and a solvent in a slurry state is stirred at a selected temperature for a certain period of time. In order to obtain a mixture in a slurry state for the treatment, the crystals may be dissolved and then crystallized to form a slurry state, or the solvent and the crystals may be simply mixed.

The raw materials used in this treatment may be any as long as they have the structure represented by the formula (A). For example, an unpurified product (so-called crude crystal) immediately after producing the compound represented by the formula (A), and a free form of the compound having the structure represented by the formula (A) (compound (A)), It may be a hydrate, a hydrochloride, a hydrate of a salt, or a crystal of the formula (1) or the formula (2) itself. These may be in the form of crystals or simply solids. If the acid is weaker than hydrochloric acid, the acid exchange is considered to occur in the solution, so that an acid addition salt other than the hydrochloride may be used. When the starting compound is a hydrochloride, hydrochloric acid need not be added.

The solvent that can be used in the method of the present invention is not particularly limited as long as it is a solvent that dissolves crystals and is miscible with water.Examples include lower alcohols such as methanol, ethanol, and propanols. Can be. Of these, 2-propanol is most preferred.

On the other hand, if the condition in which only the compound (1) or the compound (2) is present in the slurry state is the condition for crystallization, the water content of the compound (A) was adjusted in the presence of hydrochloric acid if desired. By treating in a water-containing solvent or by recrystallization from the water-containing solvent, a single crystal consisting of only the compound (1) or the compound (2) can be selectively produced. Here, the conditions for crystallization refer to the conditions for dissolving the crude crystal in a solvent, followed by a treatment such as activated carbon treatment or concentration, as necessary, to crystallize the crystal. For example, compound (A) is mixed with water-containing 2-propanol adjusted to the above-mentioned water content, hydrochloric acid is added and dissolved by heating, and if necessary, treatment such as activated carbon treatment or concentration is performed to crystallize the crystal. After precipitation, a single crystal consisting of only compound (1) or compound (2) can be selectively produced by filtration. In this case, the hydrochloric acid may be a hydrochloric acid gas or a hydrochloric acid aqueous solution. The amount of hydrochloric acid used may be at least one equivalent to compound (A).

Compounds (1) and (2) obtained as described above are compounds 9a, 9b, 13b, 18a, 18b, 26bb, 26aa, 26ba described in Japanese Patent No. 2917010. , 26 ab, 31 a, 31 b, 34 b, 54 b, 56 b, 52 bb and 85 bb have excellent antibacterial activity and are useful as antibacterial agents. Of these, compound (2) is preferable to compound (1) in terms of stability against light and humidity.

Compound (2) shows characteristic peaks near 6.9, 10.9, 14.4, 23.1, 26.9 and 27.8 (°) as diffraction angle (20) by powder X-ray diffraction. On the other hand, compound (1) shows a characteristic peak near 5.4 (°) as the diffraction angle (20) by powder X-ray diffraction, while it is crystalline. Compound (2) does not absorb or desorb moisture under the humidity condition of 5 to 95% RH, and has good stability to humidity. Example

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Ethyl 3-dimethylamino-2- (3-methoxy-2,4,5-trifluo benzoyl) acrylate

To a suspension of 206.1 g (1000 mMol) of 3-methoxy-2,4,5-trifluorobenzoic acid (1000 mmol), 2 niL of N, N-dimethylformamide and 2000 niL of toluene was added 109.4 mL of thionyl chloride (150 Ommo 1 ) Was added dropwise at room temperature. After completion of the dropwise addition, the reaction solution was stirred in an oil bath at 80 ° C for 16 hours. After cooling the reaction mixture, the reaction mixture was concentrated under reduced pressure (3). Chloride was prepared.

Ethyl 3-dimethylamino acrylate 171.8 g (120 Ommo 1) and triethylamine 184. OmL (1 32 Ommo 1) were dissolved in anhydrous 50 mL of tetrahydrofuran, and then prepared under ice-cooling in this solution. A solution of the obtained acid chloride in 50 mL of anhydrous tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction suspension was heated to reflux for 5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, 150 OmL of water and 150 OmL of dichloromethane were added to the residue, and the mixture was stirred. The dichloromethane layer was separated, and the aqueous layer was extracted with 100 OmL of dichloromethane. The combined dichloromethane layer was washed with 150 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel chromatography. The n-hexane: ethyl acetate = 1: 1 eluted portion was concentrated and dried under reduced pressure to give the title compound as a yellow-white cream. 270.3 g (81.6%) were obtained.

_{Ή-NMR (400MHz, CDC1 3} ) 6: 1.02 (3H, t, J = 7.08Hz), 2.88 (3H, br), 3.32 (3H, br),

4.00 (2H, q, J = 7.08Hz), 7.09-7.13 (1H, ra), 7.83 (1H, s).

Reference example 2

Ethyl 3-[(1 R, 2 S) -2-fluoro-1-cyclopropylamino] -2- (3-methoxy-1,2,4,5-trifluorobenzoyl) acrylate Ethyl 3-dimethylamino-2- After dissolving 260.5 g (786.3 mmo 1) of (3-methoxy-1,2,4,5-trifluorobenzoyl) acrylate in 200 raL of dichloromethane, (1R, 2S) -12-fluoro-1-cyclo 223.6 g (904.2 mmo 1) of p-toluenesulfonate of propylamine were added, and the suspension was cooled to −15 ° C. With stirring, trytylamine 138.6 ml (9

A solution of 94.6 mm o 1) in 30 OmL of dichloromethane was added dropwise over 40 minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, under ice cooling for 1 hour, and then at room temperature for 14 hours. After 100 OmL of dichloromethane and 200 OmL of water were added to the reaction solution, the dichloromethane layer was separated and the aqueous layer was extracted with 50 OmL of dichloromethane. Combined The organic layer was washed with saturated brine 1 00 OML, to give after _c filtration and dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to a yellow creamy title compound 227. 5 g of (97.7%) . The product was obtained as a geometric isomer (mixture of E-form and Z-form) and used in the next reaction without separation and purification.

'H-NMR (400MHz, CDC1 3) δ: 0.97, 1.09 (total 3H, each t, J = 7.08Hz),

1.21-1.37 (2H, m), 2.90-2.99 (1H, m), 4.01 (3H, s),

4.03, 4.06 (total 2H, each q, J = 7.08Hz), 4.73 (1H, dm, J = 63.72Hz),

6.86-6.92,6.98-7.04 (total lH.each i),

8.16, 8.23 (total 1H, each d, J = 13.67Hz)

Reference example 3

Ethyl 6,7-difluoro-1-[(1R, 2S) -12-fluoro-1-cyclopropyl] — 1,4-dihydro-18-methoxy-14-oxo-1-3-quinoline carboxylate

Previously synthesized crude ethyl 3-[(1R, 2S) -12-fluoro-1-cyclopropyl pyramino] -2- (3-methoxy-1,2,4,5-trifluorobenzoyl) acrylate Dissolve 276.2 g (764.5 mmo 1) in dry N, N-dimethylformamide (2000 mL), add 37.0 g (2.293 mmo 1) of potassium carbonate under ice-cooling, This suspension was stirred at room temperature for 72 hours. Under ice-cooling and stirring, 2N hydrochloric acid was gradually added dropwise to the reaction solution to adjust the pH of the suspension to about 3. After stirring the reaction suspension at room temperature for 30 minutes, the resulting precipitate was collected by filtration. The crystals were washed with an excess of purified water, a small amount of cold ethanol, and an excess of ethyl ether in that order, and dried under reduced pressure at 70 to obtain 213.4 g (81.8%) of the title compound as a white powder.

_{Ή-NMR (400MHz, CDC1 3} ) δ: 1.41 (3Η, t, J = 7.08Hz), 1.56-1.68 (2H, m),

3.83-3.88 (1H, m), 10 (3H, d, J = 2.20Hz), 4.39 (2H, q, J = 7.08Hz),

4.85 (1H, dm, J = 62.99Hz), 8.05 (1H, dd, J = 8.55, 10.01Hz),

8.57 (lH, d, J = 1.22Hz). Reference example 4

6,7-difluoro-1-[(1R, 2S) -1-fluoro-1-cyclopropyl] — 1,4-dihydro-8-methoxy-14-oxo-13-quinolinecarboxylic acid

Ethyl 6,7-difluoro-1-[(1R, 2S) —2-fluoro-1-cyclopropyl] —1,4-dihydro-18-methoxy-4-oxo-3-quinoline carboxylate 1 20.8 g A mixture of (354. lmmo 1), 21 OmL of glacial acetic acid, and 420 niL of concentrated hydrochloric acid was heated to reflux for 6 hours. The cooled reaction solution was poured into ice water (150 OmL) with stirring, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed in the order of an excess amount of purified water, 30 OmL of ethanol, and 50 OmL of getyl ether. The crystals collected by filtration were purified by recrystallization in an ethanol-acetone system (treated with activated carbon, filtered), and dried at 70 ° C under reduced pressure to give 107.0 g (96.5%) of the title compound as white needles. ).

'H-NMR (400MHz, CDC1 3) δ: 1.64-1.75 (2H, m), 3.97-4.00 (lH, m),

4.17 (3H, d, J = 2.20Hz), 4.91 (1H, dm, J = 63.23Hz), 8.05 (1H, dd, J = 8.55, 10.01Hz), 8.84 (1H, s), "14.31 (lH, s).

Reference example 5

6,7-difluoro-1-1-[(1R, 2S) -12-fluoro-1-cyclopropyl] 1-1,4-dihydro-8-methoxy-14-oxo-1-3-quinolinecarboxylic acid-difluoroborone One

6,7-difluoro- 1-[(1R, 2S) -2-Fluoro-1-cyclopropyl]-1,4-dihydro-18-methoxy-4-oxo-13-quinolinecarboxylic acid 90.30 g (288.3 mmo 1) dry getyl ether 100 OmL suspension in ice-cooled boron trifluoride geethylether complex

65 3 mL was added dropwise. After completion of the dropwise addition, the reaction suspension was stirred at room temperature for 24 hours. The precipitated crystals were collected by filtration and washed with an excess amount of dry getyl ether. Knot filtered The W crystals were dried under reduced pressure at room temperature to obtain 96.47 g (92.7%) of the title compound as a white powder.

_{Ή-NR (400MHz, CDC1 3} ) δ: 1.77-1.98 (2Η, m), 4.30 (3Η, d, J = 2.93Hz),

4.38-4.44 (1H, m), 5.03 (1H, dm, J = 62.50Hz), 8.17 (1H, dd, J = 8.06, 8.79Hz), 9.14 (1H, s).

Reference example 6

6,7-difluoro-1-[(1R, 2S) -12-fluoro-1-cyclopropyl] -1,4-dihydro-8-methoxy-4-oxo-13-quinolinecarboxylic acid difluoroboron chelate (separately Synthesis method)

Ethyl 6,7-difluoro-11-[(1R, 2S) -2-fluoro-1-cyclopropyl] — 1,4-dihydro-8-methoxy-4-oxo-13-quinoline propyloxylate 260 rag (0. A mixture of 733 mmo 1) and 5 mL of 42% tetrafluoroboric acid was stirred in an oil bath at 90 ° C for 3 hours. After cooling the reaction solution, excess purified water was added, and the precipitated crystals were collected by filtration. The crystals were washed with excess purified water and getyl ether in this order, and the crystals collected by filtration were dried under reduced pressure at room temperature to obtain 24 lmg (91.1%) of the title compound as a white powder. The 'H-NMR data of this product matched the data of the product synthesized by the separate synthesis method described above.

Reference Example 7

(1) 1 7 — [(7 S) —7—Amino 1—5—azaspiro [2. 4] Heptane-1—51-yl] —1-6-fluoro—1-1 — ((1 R, 2 S) —2-—fluoro-1 —Cyclopropyl] 1, 4-dihydro-8-methoxy—4-oxo-3-quinoline carboxylic acid (Compound (A))

(7 S) — 7-Amino-5-azaspiro [2.4] Heptane dihydrochloride 61.4 g (0.332 mo 1) is dissolved in dimethyl sulfoxide (80 OmL) at room temperature under a nitrogen atmosphere. Triethylamine 1 38fflL (0.994mo)> was added and stirred for 10 hours The reaction mixture was added with 6,7-difluoro-11-[(1R, 2S) -2-2-fur Oro 1-cyclopropyl] 1,1,4-dihydro-8-methoxy-4-oxo-1-3-quinolinecarponic acid difluoropolone chelate 100 g (0.276mo1) as a powder is slowly added as it is to the room temperature. And stirred for 40 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was added with 90% ethanol (100 OmL) and triethylamine (20 mL), and heated under reflux for 2.5 hours. After allowing the reaction mixture to cool, the precipitated crystals were collected by filtration, washed with ethanol and ether in that order, and dried at 70 ° C for 16 hours under reduced pressure to give 72.5 g of the title compound (light yellow powder; .Pentahydrate; 61.4%). The filtrate was evaporated under reduced pressure, 200 OraL of water was added, and the mixture was adjusted to PHI 0.0 with 3N aqueous sodium hydroxide while stirring under ice-cooling. After adjusting to 7.4, the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure at 70 to give the title compound (19.2 g, pale yellow powder; 0.5 hydrate; 33.6%).

Ή-NM (400MHz, 0.IN NaOD) δ 0.53-0.59 (2Η, m), 0.62-0.66 (1H, m),

0.78-0.82 (1H, m), l.38-1.60 (2H, m), 3.07 (1H, s), 3.39 (1H, dd, J = 10.3, 26.0Hz),

3.52 (3H, s), 3.72 (1H, d, J = 10.0Hz), 3.89-4.00 (2H, m),

4.93 (1H, dm, J = 64.2Hz), 7.62 (1H, d, J = 14.2Hz), 8.43 (1H, s).

Elemental analysis; C _2. H ₂₁ F ₂ N ₃ 0 ₄ · 0.5¾0:

Theoretical, C, 57.97; Η, 5.35; Ν, ΙΟ.14

Found: C, 57.97; H, 5.31; N, 10.11.

Specific _{^{rotation: [] D 22 - 25.5 °}} (c = 0.832, 0. IN NaOH).

Melting point: 207-209.

Example 1

(I)-7-[(7 S) I 7-Amino-5-azaspiro [2.4] Heptane I

5 [R] 1-6-fluoro-11-[(1 R, 2 S)-2-fluoro-1-cyclopropyl] — 1,4-dihydro-18-methoxy-4-oxoxo-3-quinolinecarbonic acid monohydrochloride , 2.5 pentahydrate (compound (1))

/ Uri 0 //: ϋ1 £ 8ϊ:

As a result, it was 9.5%, which almost coincided with the theoretical value of pentahydrate (9.3%). Test Example 2 (Moisture absorption / desorption behavior of compound (1))

The moisture absorption and desorption behavior of compound (1) was measured using a water adsorption analyzer (mode 1 SGA-100, manufactured by VTI) using about 10 mg of the sample. The measurement temperature was 25 ° C, and the relative humidity was changed in the range of 5 to 95% by 5% or 10%. The equilibrium condition was that the weight change within 30 minutes was within 0.03%, and the maximum equilibrium time was 180 minutes, and the weight change of the sample under each relative humidity was measured. As a result, as shown in FIG. 3, it can be seen that compound (1) does not absorb and desorb at 40% RH or less, and exists as a pentahydrate in this range.

Test Example 3 (Solubility of Compound (1))

When the solubility of compound (1) in water was examined, compound (1) showed a high solubility of 47.1 rag / mL or more in water.

Example 2

(—) 1 7— [(7 S) — 7-Amino-5-azaspiro [2.4] heptane 1 5 fl] — 6-Fluoro 1-[(1 R, 2 S) — 2-Fluoro-1-cyclopropyl ] —1,4-Dihydro-8-methoxy-14-oxo-13-quinolinecarboxylic acid · monohydrochloride · monohydrate (Compound (2))

(1) 1 7-[(7 S) -7-amino-5-azaspiro [2.4] heptane

5-yl] -6-fluoro-11-[(1R, 2S) -12-fluoro-1-cyclopropyl] 1,4-dihydro-1-methoxy-4-oxo-13-quinoline carboxylic acid ( 0.5 pentahydrate) 21. 365 g was suspended in 612.5 ml of 2-propanol, and then 77.6 ml of water and 9.87 ml of 5N hydrochloric acid were added and dissolved at 60 ° C. After adding 2 g of activated carbon and treating for 30 minutes, the activated carbon was filtered off, washed with 100 mi of 2-propanol, and then 300 ml of 2-propanol was added. After re-dissolving the filtrate at 60 ° C, about 800 ml of the solvent was distilled off under reduced pressure at an internal temperature of 30 ° C or more. After distillation, 100 ml of 2-propanol was added, and the mixture was stirred at 26 t for 2 hours. After cooling to 0 ° C, the crystals The mixture was filtered, washed twice with 30 ml of 2-propanol containing 5% water, and dried under reduced pressure at 50 ° C to obtain 20.876 g of the title compound (pale yellow crystals; 88.0%).

'H-NMR (400MHz, 0.1N NaOD) δ: 0.57-0.70 (3H, in), 0.81-0.85 (lH, m),

1.40-1.64 (2H, m), 3.13 (IH, t, J = 4.39Hz), 3.46 (IH, dd, J = 10.5, 24.6Hz),

3.60 (3H, s), 3.84 (IH, dd, J = 7.81, 10.3Hz), 3.99-4.06 (2H, m),

5.01 (IH, dm, J = 64.5Hz), 7.66 (IH, d, J = 14.1Hz), 8.2 (1H, d, J = 1.95Hz)

Elemental analysis; as _{_{_{_{C 20 H 21 F 2 N 3}}}} 0 4 · 1.0HC1 · 1 0:

Theoretical; C 52.24; H, 5.26; N, 9.14.

Found: C, 52.1.5; H, 5.25; N, 9.07

Specific rotation: [Hi] — 166.5 ° (c = 0.990, H ₂ 0).

Melting point: 199-208 ° C.

Test Example 5 (Confirmation of crystal form of compound (2))

Fig. 4 shows the powder X-ray diffraction results of compound (2) (using X'pert powder X-ray diffractometer manufactured by Ph 1 ips), and the IR spectrum (using FT-IR, FT-720 manufactured by Horiba) Is shown in FIG. The thermal analysis of compound (2) showed that the weight loss was 4.2% by weight, which almost coincided with the theoretical value as a monohydrate (3.9%).

The water content was determined by Karl Fischer's method to be 4.11%, which was consistent with the result of thermal analysis.

Example 3

(1) 1 7— [(7 S) — 7—amino-1 5—azaspiro [2.4] heptane-5-yl] — 6-fluoro-1-1 [(1 R, 2 S) 1-2-fluoro-1 —Cyclopropyl] — 1,4-dihydro-8-methoxy-4-oxo-13-quinolinecarboxylic acid · monohydrochloride · monohydrate (Compound (2))

(1) 1 7— [(7 S) —7—amino-1 5—azaspiro [2.4] heptane

5-yl] 1-6-fluoro-11-[(1R, 2S) -2-fluoro-1-cyclopropyl] — 1,4-dihydro-1-methoxy-4- 4-oxo-3- Bonic acid · monohydrochloride · pentahydrate 16.0 1 g of 2-propanol (304 ml) and water (16 ml) was added. (1) — Ί — C (7 S) _ 7 — Amino-5-azaspiro

[2.4] Heptane-5-yl] — 6-Fluoro-1— [(1 R, 2 S) — 2-Fluoro — 1-cyclopropyl] 1-1,4-Dihydro —8-methoxy-4-oxo— 3-Quinolinecarboxylic acid · monohydrochloride · monohydrate was inoculated, stirred at 60 ° C. for 1.5 hours, and then stirred at 25 ° C. for 45 minutes. The crystals were filtered, washed with 30 ml of 5% aqueous 2-propanol, dried at 50 ° C under reduced pressure, and 14.4 g of the title compound (light yellow crystals; 95.2%) was obtained. Obtained. The obtained crystal showed a powder X-ray diffraction spectrum pattern characteristic of the title compound described in Test Example 5.

Example 4

(―)-7-[(7 S) 1 7-amino-5-azaspiro [2.4] heptane 1-5-yl] 1-6-fluoro 1- [(1 R, 2 S) 1-2-fluoro 1- Cyclopropyl] — 1,4-dihydro-8-methoxy- 14-oxo _ 3 _ quinolinecarboxylic acid · monohydrochloride · pentahydrate (Compound (1))

(-)-7-[(7 S) 1 7-amino-1 5-azaspiro [2.4] heptane 5-yl] — 6-fluoro-1 1 [(1 R, 2 S) 1 2 _fluoro-1 —Cyclopropyl] -1,4-dihydro—8-methoxy-4-oxo-3-3-quinolinecarbonic acid · monohydrochloride · monohydrate 1 To 3.6 g, add 245 ml of 2-propanol and 62 ml of water Dissolved at 60 ° C. When cooled to 25 ° C, crystals precipitated. After stirring at 5 ° C for 30 minutes, the crystals were filtered, washed with 15 ml of 10% aqueous 2-propanol cooled to 5 ° C, and dried at 50 under reduced pressure. The container was allowed to stand for half a day in a vessel adjusted to a relative humidity of 80% to obtain 10.95 g of the title compound (yellow crystals; 76.0%). The obtained crystals exhibited a powder X-ray diffraction spectrum pattern characteristic of the title compound described in Test Example 1. Industrial applicability

According to the present invention, compounds (2) and (1), which have excellent antibacterial activity and safety, and also have excellent stability against light and humidity, are useful as antibacterial agents.

Claims

The scope of the claims

The following equation (1)

A compound represented by the formula:

2. The compound according to claim 1, wherein the compound is a crystal showing a characteristic peak at around 5.4 (°) as a diffraction angle (2 °) by powder X-ray diffraction.

3. Next equation (A)

(A)

Wherein the compound having the structure represented by the formula is treated in a water-containing solvent whose water content is adjusted in the presence of hydrochloric acid, if necessary, or is recrystallized from the water-containing solvent.

COOH

1HC1- 1H ₂ 0 COOH

• 1HC 1.2.5H ₂ 0

(1)

A method for producing a compound represented by H, N.

4. Next equation (A)

(A)

Wherein the compound having the structure represented by the formula is treated in a water-containing solvent having a water content of 1 to 5% in the presence of hydrochloric acid, if desired, or recrystallized from the water-containing solvent. )

(2)

A method for producing a compound represented by the formula:

5. The following equation (A)

(A)

Wherein the compound having the structure represented by the formula is treated in a water-containing solvent having a water content of 20 to 40% in the presence of hydrochloric acid if necessary, or recrystallized from the water-containing solvent. (1)

A method for producing a compound represented by the formula:

6. The compound having the structure represented by the formula (A) is a free form of the compound represented by the formula (A), a hydrochloride thereof, or a hydrate thereof. The manufacturing method according to item 1.

7. The method according to claim 4, wherein the compound having the structure represented by the formula (A) is a free form of the compound represented by the formula (A), a hydrate thereof, or a compound represented by the formula (1). .

8. The method according to claim 5, wherein the compound having the structure represented by the formula (A) is a free form of the compound represented by the formula (A), a hydrate thereof, or a compound represented by the formula (2). .

9. The method according to any one of claims 3 to 8, wherein the aqueous solvent is aqueous 2-propanol.