WO2003076428A1 - Quinolonecarboxylic acid derivative - Google Patents

Quinolonecarboxylic acid derivative Download PDF

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Publication number
WO2003076428A1
WO2003076428A1 PCT/JP2002/002181 JP0202181W WO03076428A1 WO 2003076428 A1 WO2003076428 A1 WO 2003076428A1 JP 0202181 W JP0202181 W JP 0202181W WO 03076428 A1 WO03076428 A1 WO 03076428A1
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compound
formula
solvent
water
furuoro
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PCT/JP2002/002181
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French (fr)
Japanese (ja)
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Sadahiro Shimizu
Yuichiro Tani
Toshifumi Akiba
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Daiichi Pharmaceutical Co., Ltd.
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Publication of WO2003076428A1 publication Critical patent/WO2003076428A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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

Akira fine manual quinolone carboxylic acid derivatives Technical Field

The present invention has high antibacterial activity and safety, to further process and manufacturing intermediates stability good optically active quinolone carboxylic acid derivative. Back technology

Quinolone carboxylic derivatives are known as synthetic antimicrobial agents, in particular 1 to the nitrogen atom at the 1-position of the quinoline bone price, 2- cis one 2-halogenocyclopropyl potent antibacterial compounds of the following general formula having a cyclopropyl group (I) have activity, and the safety as a pharmaceutical for high have been known to be useful (No. 2 7 1 4 5 9 7 No. and No. 2 9 1 7

0 1 No. 0) 0 '

(In the formula, R 1 is meaning taste Amino group, Mechiruamino group, a hydroxyl group, a thiol group or a hydrogen atom, a substituent R 2 is selected from the following group)

(Wherein, R 3, R 4, R 5 and R s are each independently means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R le and R 11 the number of hydrogen atoms or carbon independently 1 and meaning taste alkyl group of 1-6, or R 12 and R 13 are independently you mean a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), having an alkyl group having 1 to 6 carbon atoms It means also 3-hydroxypivalic port lysinyl group. A means the CX 3 or nitrogen atom. X 1 and X 2 each independently means a halogen atom, X 3 mean a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group of from 1 to 6 carbon, triflumizole Ruo Russia methyl group or a hydrogen atom to. Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, phenylalanine alkyl group of the alkyl chain of 1 to 6 carbon atoms, phenyl group, Asetokishi methyl group, Viva Roy Ruo carboxymethyl group, ethoxy Cal Poni Ruo carboxymethyl group, choline group, dimethylaminoethyl group, 5-indanyl group, full evening lysinyl group, 5-monosubstituted 2-Okiso one 1, 3-Jiokisoru 4 Irumechiru group, or 3- Asetokishi 2- It means Okisobuchiru group. However, the substituents R 2 is 3 § Mino pyrrolidinylmethyl group, except when R 1 and X 3 are hydrogen atoms. )

Furuorokinoron synthetic antibacterial drugs have been developed almost to effective chemotherapeutic agents in infectious diseases of the whole body. Under such circumstances, further high antibacterial activity and safety, and the compound is also excellent in stability against the light and humidity is required. Disclosure of the Invention

Under these circumstances the present applicant, the No. 2 7 1 4 5 9 7 No. and No. 2 9 1

7 0 1 0 Pat according New, - (1, 2-cis one 2- Full O b cyclopropyl) focuses on substituted pyrrolidone carboxylic acids, where has been further investigated, the chemical educts in this specification only only structural formula is shown compound 4 1, especially

(-) - 7 -. [(7 S) one 7-amino-5-Azasupiro [2 4] heptane one 5

- I le] one 6- Furuoro 1 one [(1 R, 2 S) -2- Furuoro 1 - Shikurobu port propyl] one 1, 4 Jihidoro 8-methoxy one 4 one Okiso one 3- Kinorinkarupo phosphate [hereinafter compound (A). Compound (A) is a compound of the educts having a structure mentioned formula (A). For, monohydrochloride monohydrate thereof, as compared to other acid addition salts, in terms of stability to light and humidity as well as antibacterial activity and safety are remarkably excellent, antibiotic useful as an, and patent applications previously (Japanese Patent application No. 2 000-097690).

And was been further investigated, in addition to the monohydrochloride monohydrate is the hydrochloride of the compound (A), 'monohydrochloride' 2. If there pentahydrate, these two hydrate by appropriately adjusting the crystal manufacturing time conditions found to be able to selectively produce each, and completed the present invention.

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

A compound represented by [(-) Single 7- [(7 S) one 7-amino-5-Azasupiro [2.4] heptane one 5- I le] one 6- Furuoro 1- [(1 R, 2 S) -2 Furuo port one 1 over cyclopropyl] -1, 4 Jihidoro one 8-methoxy-one 4 one Okiso one three to quinolinecarboxylic acid monohydrochloride 2.5 hydrate. Hereinafter, the compound (1). Compound (1) is a monohydrochloride 2.5 hydrate of the compound (Alpha). ] Ru Der intended to provide a.

The present invention also features a compound having the structure represented by formula (Alpha), optionally in the presence of hydrochloric acid, or treatment with aqueous solvent with an adjusted water content, or recrystallized from a water solvent that (1) one 7- [(7 S) one 7-Amino - 5 Azasupi opening [2.4] heptane - 5-I le] one 6- Furuoro;! One [(1 R, 2 S) one 2 - Furuoro 1-cyclopropyl] - 1, 4-dihydro-8-methoxy - 4-O Kiso - 3-quinolinecarboxylic acid monohydrochloride monohydrate [hereinafter, compound (2). Compound (2) is a monohydrochloride monohydrate of the compound (Alpha). Or there is provided a process for the preparation of a compound (1). The present invention is a compound having a structure represented by the formula (A), and optionally the presence of hydrochloric acid, or treatment with water content of 1-5% of the aqueous solvent, or recrystallization from hydrous solvent process for the preparation of compounds, wherein (2) the is to provide.

Further the invention, the compound having the structure represented by the formula (A), and optionally in the presence of hydrochloric acid, or treated with moisture content 20-40% of aqueous solvent, or recrystallization from hydrous solvent process for the preparation of compounds, wherein (1) a is to provide. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph illustrating a powder X-ray diffraction spectrum of the compound (1).

Figure 2 is a diagram showing the infrared absorption spectrum of Compound (1).

3, Ru FIG der showing the weight change in. 5 to 95% RH under the conditions of the compound (1).

Figure 4 is a graph illustrating a powder X-ray diffraction spectrum of the compound (2).

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

The compounds of the present invention (1) and the compound (2) may, for example, it to manufacture according to the following reaction scheme.

(Four)

(3)

1HC1 * 2.5H 2 0

(1)

That is, by reacting the compound (4) into the compound (3) to give compound (A), followed by the presence of hydrochloric acid so desired, be accomplished by treatment with aqueous solvent adjusted in moisture content, or compounds by recrystallization from water-containing solvent (1), or the compound

(2) is obtained. The compound (1) and the compound (2) may be converted into one another by treatment with aqueous solvent adjusted in moisture content, it can be selectively obtained. Starting compound, Compound (3) and the compound (4) are all obtained by the process according to the 27145 97 Pat.

The reaction of the compound (3) with the compound (4) can be carried out using a solvent, and without using a solvent. The solvent usable in the reaction is not particularly limited as long as it is inert to the reaction. As such a solvent for example, sulfoxides such as dimethyl sulfoxide, nitrogen-containing heterocyclic compounds such as pyridine, nits Lil such as Asetonitoriru, alcohols such as ethanol, halogenated hydrocarbons such as black hole Holm, dimethylformamide, dimethyl § Seto amide, Ami de such as N- methylpyrrolidone, E one ether such as tetrahydrofuran, water, 3-methoxybutanol or the like can ani gel, or may be used as they are mixtures.

The reaction is carried out in the presence of an acid acceptor such as an inorganic or organic bases preferably used. Inorganic base as the base in here, but may be any of an organic base, for example lithium hydroxide in the inorganic bases include sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen carbonate it can be mentioned hydroxides of Al force Li metal such as potassium, carbonates, bicarbonates and the like. Is an organic base Toriechiruamin, tripropylamine § Min, Toripuchiruamin, N, trialkyl amines such as N- Jie isopropyl E chill § Min, Jechiruanirin, dialkyl § diphosphoric such as dimethylcarbamoyl Ruanirin, N- methylmorpholine, pyridine, N, can be exemplified N- dimethylaminopyridine.

The reaction temperature can usually be carried out in the range from room temperature to 1 0 0 ° C, it is rather preferably a 4 0 ° about C from room temperature. The reaction time may range from 3 0 minutes to 48 hours, usually completed in about 3 0 minutes to 2 0 hours.

Compound (3) with the compound (4) and Meniwa that removing boron chelate of the reaction product after the the product was dissolved in aqueous ethanol, it may be refluxed for several hours pressurized heat added Toryechiruamin. What this case, hydrous ethanol may be replaced by other protic solvents, for example may be a water-containing isopropanol Ichiru, protons solvents that may ^ be mixed with water, capable of dissolving the compound (4) at least heating It is preferred. In addition, it is not always necessary to add a Toryechiruamin.

The resulting compound (A) unless converted to the hydrochloride salt to control the condition, Compound (2) as well as compound (1) or a mixture thereof is obtained. The crystals of the plurality of hydrate are mixed as the powder pharmaceutical bulk ineligible. The present inventors compound (1) and the compound (2) were respectively examined method for selectively producing a crystal of a single hydrate.

First, the present inventors compound in aqueous solvent (1) were examined about the stability of the crystal (2). Study method is as follows.

Compound (1), (2) an equal amount were mixed, and added water-containing solvent adjusted to various moisture content thereto. And stirring process by changing the temperature of the mixture, the compound that is part of the crystal after a predetermined time (1), and analyzed the ratio of (2). Treatment mixture during the process is a suspension, was a so-called slurry. Aqueous solvent during the process using 2-propanol 40% moisture content from 1%. The amount of the solvent when performing the process was the proportion of 20ml from 1. 5 ml with respect to the crystal lg. Incidentally, the water content of the solvent used are indicated by volume ratio before mixing. For example, 40% aqueous 2-propanol Le is a mixture of 2-propanol 6 volumes of water 4 volumes. Treatment was carried out ¾ from 1 day 3 days. However, three days necessarily from one day to the conversion of the crystal is transformed in less than one day is not actually required became also clear that there also be terminated. Treatment was carried out from 0 ° C at 70 ° C.

The results of this study, that the type of crystals present by the water content of the solvent used in the process temperature and process changes were found. That is, if the water content of 1% to 5%, was subjected to treatment at 70 from 0 ° C, only the compound (2) was formed (present). If the water content is 8% to 7%, 20 7 Ot: Where the process is performed, the compound

(2) only produced, 0 ° 10 ° C In the compounds from C (1), Ivy Do a mixture of (2). If moisture content of 9%, was subjected to treatment at 70 from 25 ° C, the compound

(2) only produced, from 0 to 20, the compound (1), Ivy Do a mixture of (2). If the water content of 10%, was subjected to treatment with 70 ° C from 30 ° C, the compound

(2) only produced, 25 the compound from 5 ° C (1), Ivy Do a mixture of (2). In compound alone (1) was formed. If the water content is 40% to 20%,

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

From this result, to obtain the compound (1) as a single product, it was revealed that processing may be performed in 40% of hydrous rate of solvent 20%. In addition, compound

To obtain a (2) in a single piece, that the processing may be performed in a 5% water content in the solvent from 1% revealed. That these processes are carried out in 7 0 of conditions from 0 both preferred.

Note that the "processing" refers to carrying out the mixture, stirring operation for a predetermined time at selected temperature Ru Ah of slurry consisting of crystals and a solvent. To obtain a mixture in a slurry state for treatment once may be a slurry state by crystallization after dissolving the crystals, may simply of being mixed crystals with a solvent.

The process material used for can be any be of a long as it has a structure represented by formula (A). For example, a formula (A) with a compound what crude immediately after prepared, expressed (so-called crude crystals), free form of a compound having a structure represented by formula (A) (Compound (A)), the hydrate, hydrochloride, hydrate salt, and the formula (1) or formula (2) may be a crystal itself. These may be crystals that of mere solid state. Then, it is considered that the exchange of the acid in solution if weaker acids than hydrochloric occurs, may be an acid addition salt other than hydrochloride. If the starting compound is the hydrochloride salt, it may not be added pressure to the hydrochloride.

The solvent which can be used in the process of the present invention, crystals are dissolved, and is not particularly limited as Re solvent der miscible with water, such as methanol, ethanol, to illustrate the low grade alcohol one le such as propanols can. Among these 2-propanol is most preferred.

On the other hand, if the compound (1) or the compound (2) Nomigason-existing conditions as during crystallization in the slurry state in the presence of hydrochloric acid compound (A) optionally, adjusted moisture content it in therefore compounds recrystallized from the aqueous solvent or treatment with aqueous solvent (1) or compound (2) a single crystal can be selectively prepared consisting only of. Here, the conditions during crystallization is crude crystals were dissolved in a solvent, by performing processing such as activated carbon treatment and concentrated as needed after this, it refers to conditions at the time to crystallize the crystals. For example, Compound (A) was mixed with adjusted moisture 2-propanol to the water content of said, added to and dissolved by heating hydrochloric acid, it was crystallized analyze crystalline performs processing activated carbon treatment and concentrated, if necessary after, selective production of single crystal composed of only the compound (1) or compound (2) by filtration. In this case, hydrochloric acid may be a hydrochloric acid solution in hydrochloric acid gas. The amount of hydrochloric acid may be present one or more equivalents of the compound (A).

The above as obtained compound (1) and (2) are proprietary compounds 9 a described in No. 2,917,010 specification, 9 b, 13 b, 18 a, 18 b, 26 bb, 26 aa, 26 ba , 26 ab, 31 a, 31 b, 34b, as compared to 54b, 56 b, 52 bb and 85 bb, have excellent antibacterial activity and are useful as antibacterial agents. Among these, compounds in terms of stability to light and humidity (2) is good preferable than Compound (1).

Compound (2) shows a diffraction angle by X-ray powder diffraction (20) as 6.9, 10.9, 14.4, 23.1, characteristic peaks around 26.9 and 27. 8 (°) while a crystal, the compound (1) shows a characteristic peak around 5. 4 (°) as a diffraction angle by X-ray powder diffraction (20). Further, the compound (2) is, without causing the moisture absorption and desorption in the humidity of RH 5 to 95%, stability to humidity is good. Example

Then examples illustrate the present invention in more detail, the present invention is not intended to be limited thereto. Echiru 3-dimethylamino-2 - (3-methoxy - 2, 4, 5 Torifuruo port base Nzoiru) Akurireto

3-methoxy - 2, 4, 5 Torifuruoro benzoate 206. 1 g (1000m mo 1), N, N- dimethylformamide 2 nil and toluene 2000 nil mixed suspension Nigoeki chloride Chioniru 109. 4 mL of (150 Ommo 1 ) was added dropwise at room temperature. After completion of the dropwise addition, the reaction mixture was stirred for 16 hours in an oil bath at 80 ° C. After cooling, the reaction mixture was concentrated under reduced pressure ■ (toluene was added after concentration, was carried out three more times an operation of concentration.), Thereby preparing an acid chloride.

Echiru 3-dimethylaminopropyl acrylate 171. 8 g (120 Ommo 1) and Toriechiruamin 1 84. OML a (1 32 Ommo 1) was dissolved in anhydrous tetrahydrofuran 1 50 OML prepared, under ice-cooling, previously to the solution It was added dropwise to dissolve the the acid chloride in anhydrous te tetrahydrofuran 50 OML solution. 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, the residue in water 1 50 OML, after stirring was added dichloromethane 1 50 OML, the dichloromethane layer was separated and extracted with aqueous di chloromethane 100 OML. After washing the combined dichloromethane layers with saturated brine 1 50 OML, and dried over anhydrous sodium sulfate. After filtration, the residue was subjected to resulting filtrate was concentrated under reduced pressure to a silica gel chromatography, key San into n-: acetate Echiru = 1: 1 eluate is concentrated and dried under reduced pressure to a pale yellow creamy title compound It was obtained 270. 3 g (81. 6%).

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

Echiru 3- [(1 R, 2 S) - 2- Furuoro -1-cyclopropyl § amino] -2- (3-methoxy one 2, 4, 5 Torifuruo port base Nzoiru) Akurireto Echiru 3-dimethylamino-2- (3-methoxy one 2, 4, base 5 Torifuruo port Nzoiru) was dissolved Akurireto 260. 5 g of (786. 3mmo 1) to Jikurorome Tan 2 200raL, (1 R, 2 S) one 2- Furuoro 1-cyclopropyl propyl Amin of p- toluenesulfonate 223. 6 g (904. 2 mm o 1) was added and the suspension - was cooled to 1 5 ° C. Under stirring, Toryechiruamin 138. 6ml (9

94. Dichloromethane 30 OML solution of 6 mm o 1) was added dropwise over 40 minutes. After Under droplets completion, 1 hour at the same temperature, '1 hour under ice-cooling, followed by stirring at room temperature for 14 hours. After addition of dichloromethane 1 00 OML and water 200 OML to the reaction solution, a sample was collected dichloro Rometan layer, the aqueous layer was extracted with dichloromethane 50 OML. The combined organic layer was washed with saturated brine 1 00 OML, after c filtration and dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure a yellow creamy title compound 227. 5 g (97. 7%) Obtained. Note that this results body, geometrical isomers (mixture of E-form and Z-form) obtained al is as was used in the next reaction without separation 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

Echiru 6, 7-difluoro over 1- [(1 R, 2 S) one 2- Furuoro -1-cyclo propyl] - 1, 4-dihydro-one 8-Methoxy-one 4 one Okiso one 3-quinolin Karupokishireto

Crude previously synthesized Echiru 3- [(1 R, 2 S) one 2- Furuoro 1 Shikuropu port Piruamino] -2- (3-main Bok carboxymethyl one 2, 4, 5-triflate Ruo benzo I le) § acrylate 276. 2 g (764. 5mmo 1) dry N, N-dimethylformamide was dissolved in 2000 mL, carbonate force under ice-cooling helium 3 1 7. 0 g of (2. 2 9 3mmo 1) was added, the suspension was stirred for 72 hours at room temperature. Under ice-cooling and stirring, slowly added dropwise 2 N hydrochloric acid reaction solution, the pH of the suspension was adjusted to about 3. After stirring for 30 min the reaction suspension at room temperature and the resulting precipitate was collected by filtration thereof. Purified water and the crystals excess, to give a small amount of cold ethanol, washed successively excess Jechirue one ether, a white powder of the title compound in vacuo Drying at 70 213. 4g of (81.8%).

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). Example 4

6, 7-difluoro over 1- [(1 R, 2 S) one 2- Furuoro 1 Shikuropuro propyl] - 1, 4 Jihidoro 8-methoxy one 4 one Okiso one 3-quinolinecarboxylic acid

Echiru 6, 7-difluoro over 1- [(1 R, 2 S) - 2- Furuoro -1-cyclo propyl] - 1, 4 Jihidoro one 8-methoxy - 4 Okiso 3-quinolin Karupokishireto 1 20. 8 g (354. lmmo 1), glacial acetic acid 2 1 OML, and was heated to reflux for 6 hours concentrated hydrochloric acid 420NiL. The cooled reaction mixture was poured into ice water 1 50 OML under stirring, followed by stirring at room temperature for 30 minutes. The precipitated crystals were collected by filtration, excess purified water, ethanol 30 OML, and washed successively with Jeffrey chill ether 50 OML. Filtered crystals ethanol - purified by recrystallization with acetone system (charcoal treatment Filtration) after 107. The white-like needles of the title compound was dried under reduced pressure at 70 ° C 0 g (9 6. 5% ) was obtained.

'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-Jifuruoro - 1 one [(1 R, 2 S) one 2- Furuoro 1- Shikuropuro propyl] one 1, 4-dihydro-8-methoxy-one 4 one Okiso one 3-quinolinecarboxylic acid - difluorenylamino O Lobo Ron sharp Ichito

6, 7-Jifuruoro - 1- [(1 R, 2 S) -2- Furuoro 1- Shikuropuro propyl] - 1, 4-dihydro-one 8-methoxy - 4- Okiso one 3-quinolinecarboxylic acid 9 0. 30 g in dry GETS chill ether 100 OML suspension Nigoeki of (28 8. 3mmo 1), Jechirue one ether complex, boron trifluoride under ice-cooling

It was added dropwise 65 3mL. After completion of the dropwise addition, the reaction suspension was stirred for 24 hours at room temperature. The precipitated crystals were collected by filtration, washed with excess dry Jefferies chill ether. The formation W crystals were collected by filtration and dried under reduced pressure at room temperature to obtain a white powder of the title compound 96. 47 g (92. 7%).

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 over 1- [(1R, 2 S) one 2- Furuoro 1- Shikuropuro propyl] one 1, 4-dihydro-8-methoxy - 4 one Okiso one 3-quinolinecarboxylic acid over difluorenylamino O Lobo Ron chelate (separately synthesis method)

Echiru 6, 7-difluoro-1 one [(1 R, 2 S) - 2- Furuoro -1-cyclo propyl] - 1, 4 Jihidoro 8- methoxy 4 one Okiso one 3-quinolin force Rupokishire Ichito 260 rag (0. 733mmo 1) and a mixture of 42% tetrafluoropropoxy O b borate 5mL was stirred for 3 hours in an oil bath at 9 0 ° C. The reaction mixture was cooled and the excess of purified water was added, and the precipitated crystals were collected by filtration. A quantity of purified water to obtain washed crystals in the order of Jefferies chill ether, the crystals were collected by filtration and dried under reduced pressure at room temperature a white powder of the title compound 24 lmg of (91.1%). 'H- NMR data of the results thereof were consistent with the data of the results thereof synthesized in otherwise synthesis method described above.

Reference Example 7

(1) one 7- [(7 S)-7-Amino one 5- Azasupiro [2.4] heptane one 5 one I le] one 6- Furuoro 1 one [(1 R, 2 S) - 2- Furuoro 1 - cyclopropyl] one 1, 4-dihydro-8-methoxy - 4 one Okiso 3 Kinorinkaru Bonn acid (compound (A))

(7 S) - 7- Amino - 5 Azasupiro [2.4] heptane dihydrochloride 6 1. 4 g of (0. 332 mo 1) was dissolved in dimethylsulfoxide 80 OML, nitrogen atmosphere at room temperature under . Toriechiruamin 1 38fflL (0. 994mo]> was stirred for 1 0 hours added the reaction solution 6, 7-difluoro-1 one [(1 R, 2 S) - 2- full Oro -1-cyclopropyl] one 1, 4 -.-dihydro 8- methoxy 4 Okiso one 3-quinolin local Pont acid difluoride O b Poron chelating 1 0 0 g of (0. 27 6mo 1) was added slowly while the powder was stirred for 40 hours at room temperature the reaction mixture It was concentrated in vacuo, and the resulting residue 90% ethanol 100 OML, after cooling the Toryechiruamin 20 mL for 2 hours by heating under reflux added. the reaction solution was collected by filtration to have crystals, ethanol, E one then with ether, the title of and 16 hours drying under reduced pressure at 70 ° C compound 72. 5 g (pale yellow powder; 0.5 Thereof;. 61. The filtrate obtained 4%) and evaporated under reduced pressure, adding water 200 Oral with stirring under ice cooling by addition of 3 N hydroxide sodium © beam aqueous PHI 0. 0 after adjusting, 3 was adjusted to pH 7. 4 by adding N aqueous hydrochloric acid, the crystals were collected by filtration, which has been stirring for 1 6 hours at room temperature. precipitated, washed with water, and dried under reduced pressure at 70 the title compound 1 9. 2 g (pale yellow powder; 0.5 hydrate thereof; 33.6%) was obtained.

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. As H 21 F 2 N 3 0 4 · 0.5¾0:

Theory; 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

(One) - 7 - [(7 S) one 7-amino-5-Azasupiro [2.4] heptane one

5 "Le] one 6- Furuoro 1 one [(1 R, 2 S) - 2- Furuoro 1-cyclopropyl] - 1, 4-dihydro-one 8-Methoxy-one 4 one Okiso 3 Kinorinkaru Bon acid monohydrochloride , 2.5 hydrate (compound (1))

/ Bok 0 one /: ϋ1 £ 8ϊ:

Results were almost identical to 9. a 5% 2. theory as pentahydrate (9. 3%). Test Example 2 (moisture absorption and desorption behavior of compound (1))

Compound moisture absorption and desorption behavior of (1), using a sample of about 10 mg, it was measured by VT I Co. moisture adsorption analyzer (mode 1 SGA-100). Measurement temperature is 25 ° C, in the range of 5 to 95% at 5% or 10% of the width by changing the relative humidity. The change in weight of 3 0 min is within 0.3% 0.1 and equilibrium conditions were measured weight change of the sample under the relative humidity of maximum equilibration time of 180 minutes. As a result, as shown in FIG. 3, Compound (1) does not cause the moisture absorption and desorption in the following 40% RH, it can be seen that the present as 2.5 hydrate at this range.

Test Example 3 (solubility of the compound (1))

Was studied solubility in water of Compound (1) Compound (1) is in respect of water showed high solubility of more than 47. 1 rag / mL.

Example 2

(-) Single 7- [(7 S) - 7- amino-5- Azasupiro [2.4] heptane one 5 f le] - 6- Furuoro 1- [(1 R, 2 S) - 2- Furuoro 1 Shikuro propyl ] -1, 4-dihydro - 8-methoxy-one 4- Okiso one 3- Kinorinkaru Bon acid monohydrochloride monohydrate (compound (2))

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

5-I le] - 6-Furuoro 1 one [(1 R, 2 S) one 2- Furuoro 1- consequent opening propyl] one 1, 4-dihydro-one 8-Methoxy-one 4- Okiso one 3- Kinorinkaru Bonn acid ( after suspension Nigoshi 0.5 hydrate) 21. 365 g of 2-propanol 612. 5 ml, was dissolved in water 77. 6 ml and 5N hydrochloric 9. 87 m 1 was added 60 ° C. After 30 minutes addition of activated carbon 2 g, after yelling wash the activated carbon in the filtration Mashi 2-propanol 100 mi, 2-propanol was added 300m 1. After redissolving the filtrate at 60 ° C, the solvent of about 800ml at an internal temperature of 30 ° C or higher was removed under reduced pressure. After evaporation, 2- flop propanol 100 m 1, and the mixture was stirred for 2 hours at 26t. After cooling to 0 ° C, crystals were filtered, washed twice with 5% aqueous 2-propanol 30 m l, the title compound was dried in vacuo at 50 ° C 20. 876 g (pale yellow crystals; 88.0%) It was obtained.

'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:

Theory; C 52.24; H, 5.26; N, 9.14

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

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

Mp: 199- 208 ° C.

Test Example 5 (Confirmation of the crystalline form of the compound (2))

Compound (2) Powder X-ray diffraction results of the (Ph 1 ips Co. X 'pert powder X-ray diffraction apparatus used) Figure 4, IR spectrum (HOR I BA Co., FT- IR, FT- 7 20 used) It is shown in FIG. 5. The results of the thermal analysis of the compound (2), weight loss 4. 2 wt%, was almost identical to the theoretical value of the monohydrate (3. 9%).

Also, from the quantitative water content by the Karl Fischer method, 4. a 1 1%, consistent with the results of thermal analysis.

Example 3

(1) one 7- [(7 S) - 7- Amino one 5- Azasupiro [2.4] heptane one 5- I le] - 6-Furuoro 1 one [(1 R, 2 S) Single 2- Furuoro 1 - cyclopropyl] - 1, 4 Jihidoro 8- methoxy 4- Okiso one 3- Kinorinkaru Bon acid monohydrochloride monohydrate (compound (2))

(1) one 7- [(7 S) - 7- Amino one 5- Azasupiro [2.4] heptane one

5-I le] one 6- Furuoro 1 one [(1 R, 2 S) - 2- Furuoro - 1 Shikuro propyl] - 1, 4-dihydro-one 8-Methoxy-one 4 one Okiso one 3 - Bon acid 1 hydrochloride 2.5 hydrate 1 6. 0 1 g of 2-propanol 3 04M 1, water was added to 1 6 m l, (one) - Ί - C (7 S) _ 7- Amino - 5 Azasupiro

[2.4] heptane one 5- I le] - 6- Furuoro 1- [(1 R, 2 S) - 2- Furuoro _ 1-cyclopropyl] one 1, 4-dihydro-_ 8-methoxy 4 Oki source - inoculated with 3-quinolinecarboxylic acid monohydrochloride monohydrate, the mixture was stirred between at 1.5 at 6 0 ° C, and stirred for 4 5 minutes at 2 5 ° C. The crystals were filtered, washed with 5% aqueous 2-propanol Lumpur 3 0 m 1, 5 0 ° C in a vacuum oven to give the title compound 1 4. 4 g (pale yellow crystal; 9 5.2%) of Obtained. The obtained crystals showed a pattern of characteristic powder X-ray diffraction scan Bae spectrum to the title compound described in Test Example 5.

Example 4

(-) - 7 - [(7 S) one 7-amino-5-Azasupiro [2.4] heptane one 5- I le] one 6- Furuoro 1- [(1 R, 2 S) one 2- Furuoro 1- cyclopropyl] - 1, 4-dihydro-8-methoxy-one 4 one Okiso _ 3 _ Kinorinkaru Bon acid monohydrochloride 2.5 hydrate (compound (1))

(-) - 7 - [(7 S) one 7-Amino one 5- Azasupiro [2.4] heptane one 5- I le] - 6-Furuoro 1 one [(1 R, 2 S) one 2 _ Furuoro 1 - cyclopropyl] one 1, 4 Jihidoro - 8-methoxy-4 one Okiso one 3 _ Kinorinkaru Bon acid monohydrochloride monohydrate 1 3. 6 g 2 _ propanol 245m 1, water 6 2 m 1 plus It was dissolved in 6 0 ° C. Crystals were precipitated was cooled to 2 5 ° C. 5 ° After stirring for 3 0 minutes in C, and crystals were filtered, washed with 5 ° 1 was cooled to C 0% water 2-propanol 1 5 m l, and vacuum dried at 5 0. Was obtained; title compound 1 0. 9 5 g (7 6. 0% yellow crystals) and left half days vessel was adjusted to a relative humidity of 80%. The obtained crystals showed the path evening over emissions of characteristic powder X-ray diffraction scan Bae spectrum to the title compound described in Test Example 1. Industrial Applicability

According to the present invention, which has excellent antibacterial activity and safety, and stability to light and humidity are excellent, compounds useful as antimicrobial agents (2) and compound (1) can be stably obtained.

Claims

The scope of the claims
The following equation (1)
Compound represented by.
2. diffraction angle by powder X-ray diffraction (2 theta) as 5. 4 (°) characteristic peak compound according to claim 1, wherein a crystal showing the click around.
3. the following formula (A)
(A)
Following formula a compound having the structure represented by, characterized in that optionally the presence of hydrochloric acid, or treatment with aqueous solvent with an adjusted water content, or recrystallized from the aqueous solvent in (2)
COOH
1HC1- 1H 2 0 COOH
• 1HC1.2.5H 2 0
(1)
H, the manufacturing method of the compound represented by N.
4. the following formula (A)
(A)
A compound having a structure represented by the, and wherein the recrystallized optionally in the presence of hydrochloric acid, or treatment with water content 1-5% aqueous solvent, or a water-containing solvent, the following equation (2 )
(2)
Method for producing a compound represented by.
5. the following formula (A)
(A)
A compound having a structure represented by the, characterized in that optionally the presence of hydrochloric acid, or treatment with water content 2 0-4 0% hydrous solvent, or recrystallization from hydrous solvent, the following equation (1)
Method for producing a compound represented by.
6. Compounds having a structure represented by formula (A) is free of a compound represented by the formula (A), its hydrochloride, or any of claims 3 Power et al. 5 is a hydrate thereof the method according (1).
7. Compounds having a structure represented by formula (A) is free of a compound represented by the formula (A), the manufacturing method of their hydrates, or claim 4 wherein the compound of formula (1) .
8. Compounds having a structure represented by formula (A) is free of a compound represented by the formula (A), the manufacturing method of their hydrates, or claim 5, wherein the compound of formula (2) .
9. Any one Kouki mounting method of the hydrous solvent claim 3 is a water-containing 2-propanol Ichiru 8.
PCT/JP2002/002181 2002-03-08 2002-03-08 Quinolonecarboxylic acid derivative WO2003076428A1 (en)

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Cited By (4)

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EP1757598A1 (en) * 2004-05-13 2007-02-28 Daiichi Pharmaceutical Co., Ltd. Substituted pyrrolidine derivative
US8003666B2 (en) * 2006-03-27 2011-08-23 Daiichi Sankyo Company, Limited Hydrate for medical purposes
WO2012018105A1 (en) * 2010-08-06 2012-02-09 第一三共株式会社 Crystal of anti-bacterial compound
WO2013069297A1 (en) * 2011-11-10 2013-05-16 杏林製薬株式会社 7-{(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal

Citations (2)

* Cited by examiner, † Cited by third party
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WO2001058876A1 (en) * 2000-02-09 2001-08-16 Daiichi Pharmaceutical Co., Ltd. Anti-acid-fast bacterial agents containing pyridonecarboxylic acids as the active ingredient
WO2001072738A1 (en) * 2000-03-31 2001-10-04 Daiichi Pharmaceutical Co., Ltd. Quinolonecarboxylic acid derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058876A1 (en) * 2000-02-09 2001-08-16 Daiichi Pharmaceutical Co., Ltd. Anti-acid-fast bacterial agents containing pyridonecarboxylic acids as the active ingredient
WO2001072738A1 (en) * 2000-03-31 2001-10-04 Daiichi Pharmaceutical Co., Ltd. Quinolonecarboxylic acid derivative

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US8455482B2 (en) 2004-05-13 2013-06-04 Daiichi Sankyo Company, Limited Substituted pyrrolidine derivative
EP1757598A4 (en) * 2004-05-13 2010-07-21 Daiichi Seiyaku Co Substituted pyrrolidine derivative
US7977327B2 (en) 2004-05-13 2011-07-12 Daiichi Sankyo Company, Limited Substituted pyrrolidine derivative
EP1757598A1 (en) * 2004-05-13 2007-02-28 Daiichi Pharmaceutical Co., Ltd. Substituted pyrrolidine derivative
US8003666B2 (en) * 2006-03-27 2011-08-23 Daiichi Sankyo Company, Limited Hydrate for medical purposes
WO2012018105A1 (en) * 2010-08-06 2012-02-09 第一三共株式会社 Crystal of anti-bacterial compound
US8674107B2 (en) 2010-08-06 2014-03-18 Daiichi Sankyo Company, Limited Crystal of anti-bacterial compound
US20140288310A1 (en) * 2011-11-10 2014-09-25 Kyorin Pharmaceutical Co., Ltd 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
WO2013069297A1 (en) * 2011-11-10 2013-05-16 杏林製薬株式会社 7-{(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
JPWO2013069297A1 (en) * 2011-11-10 2015-04-02 杏林製薬株式会社 7-{(3S, 4S) -3-[(cyclopropylamino) methyl] -4-fluoropyrrolidin-1-yl} -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo Of 1,4-dihydroquinoline-3-carboxylic acid
US9090587B2 (en) * 2011-11-10 2015-07-28 Kyorin Pharmaceutical Co., Ltd. 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluorodethyl)-acid crystal
CN104945375A (en) * 2011-11-10 2015-09-30 杏林制药株式会社 7-{(3S, 4S)-3-[cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
US20150284361A1 (en) * 2011-11-10 2015-10-08 Kyorin Pharmaceutical Co., Ltd. 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
JP2016027045A (en) * 2011-11-10 2016-02-18 杏林製薬株式会社 Crystals of 7-{(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
US9328089B2 (en) 2011-11-10 2016-05-03 Kyorin Pharmaceutical Co., Ltd. 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-YL}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
JP2017160243A (en) * 2011-11-10 2017-09-14 杏林製薬株式会社 Crystals of 7-{(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

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