JPH0525162A - Quinolone derivative and its production - Google Patents

Abstract

PURPOSE:To provide the subject novel compound useful as an intermediate for synthesizing 5-aminoquinolonecarboxylic acid derivatives useful as antimicroial agents. CONSTITUTION:The objective compound of formula I (R<1> is lower alkyl; R is H or lower alkyl; R<3> is H or amino-protecting group; R<4> is cyclopropyl, fluoroethyl, phenyl or thienyl; R<5> is halogen; Y is H or benzyl; Z is cyano or carbamoyl), for example, 1-cyclopropyl-3-cyano-5-amino-7-(3R,4S)-(3-methoxy-4- methylaminopyrrolidin-1-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline. This compound can be obtained by the following process: a compound of formula II is, as necessary, debenzylated, followed by reaction with a substituted pyrrolidine of formula III, and when benzylamino group exists at 5-site of the product, this group is, if needed, debenzylated to convert into amino group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a quinolone derivative and a method for producing the same, and more particularly to a quinolone derivative which is a synthetic intermediate of a 5-aminoquinolonecarboxylic acid derivative useful as an antibacterial agent and a method for producing the same.

[0002]

As a quinolonecarboxylic acid type antibacterial agent, JP-A-49-14240 and JP-A-57-46 are known.
No. 986, No. 60-228479, No. 60-64979, No. 61-225181, No. 63-198.
Although various compounds described in the specification of Japanese Patent No. 664 and the like are known, these compounds often exhibit central side effects such as convulsions when administered to the human body. As a result of research and development of a quinolonecarboxylic acid type antibacterial agent that exerts a strong antibacterial action without showing such a side effect on the human body, the following 5-described in Japanese Patent Application Laid-Open No. 2-76875 was previously mentioned. Aminoquinolonecarboxylic acid derivatives have been found to be suitable substances for such research purposes:

[Chemical 11] (In the formula, R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, R ³ is hydrogen or amino protecting group, R ⁴ is cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted. Thienyl and R ⁵ represent halogen.)

Since the above 5-aminoquinolonecarboxylic acid derivative (I) contains two asymmetric carbon atoms in the substituent at the 7-position, two stereoisomers, cis and trans, exist. Can exist as an optically active substance or a racemate. The 5-aminoquinolonecarboxylic acid derivative (I) may be present as a free acid, or may be present as a salt such as an acid addition salt or an alkali metal salt. Examples of the acid forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as methanesulfonic acid, lactic acid, oxalic acid and acetic acid. Examples of alkaline metal forming an alkali metal salt include sodium and potassium.

The lower alkyl means C ₁ -C ₃ alkyl, and specific examples thereof include methyl, ethyl, n-propyl and isopropyl. Amino-protecting groups include formyl, acetyl, acyl such as propionyl,
Means carbobenzoxy, trityl and the like. The phenyl which may be substituted means a substituted or unsubstituted phenyl, and examples of the substituent include halogen such as fluorine, chlorine, bromine and iodine.
It may have two or more substituents. The optionally substituted thienyl means a substituted or unsubstituted thienyl,
Examples of the substituent include C ₁ -C ₃ alkyl such as methyl, ethyl, n-propyl and isopropyl, halogen such as fluorine, chlorine and bromine. The optionally substituted benzyl means a benzyl which may have a substituent such as methyl or nitro on the benzene ring. Halogen means fluorine, chlorine, bromine, iodine and the like, with fluorine and chlorine being particularly preferable.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The specification of Japanese Patent Publication No. 75-75 discloses a known method as a method for producing a 5-aminoquinolonecarboxylic acid derivative (I).
-46986 specification and JP-A-61-2252
And a method of reacting a 3,4-di-substituted pyrrolidine with a corresponding 7-fluoro compound produced by the method (Production Method A) and 2,3,4,6-tetrafluoro-
5-halobenzoylacetic acid or its lower alkyl ester is reacted with 3,4-disubstituted pyrrolidine to give 2,3,6-
Trifluoro-4- (3,4-disubstituted pyrrolidine) -5
-A method of obtaining a halobenzoyl acetic acid or a lower alkyl ester thereof and then performing a ring-closing reaction between the 1-position and the 6-position to form a pyridone ring (Production Method B) is disclosed. However, none of these methods is suitable for industrial production of the target substance because of the large number of steps and the low yield of each step, including the method for producing the raw material, and its improvement has been demanded. .

[0006]

The inventors of the present invention have conducted research to meet the above demands, and as a result, the above-mentioned manufacturing method A and manufacturing method B are obtained.
Different from the above, a new production route via a novel compound as an intermediate was established, and the 5-aminoquinolonecarboxylic acid derivative (I) was successfully produced in good yield.

[0007] That is, the present invention provides a production method which enables industrial production of 5-aminoquinolonecarboxylic acid derivative (I), and includes a series of steps summarized in the following figures:

[Chemical 12] (In the formula, R is hydrogen or lower alkyl, X is halogen,
Y represents benzyl which may be substituted. R ¹ ,
R ² , R ³ , R ⁴ and R ⁵ are as defined above. ). Hereinafter, the above method will be described for each step.

The first step is to react the benzoyl halide compound (1) with cyanoacetic acid or its lower alkyl ester, and both are usually reacted in the presence of a base.
If necessary, the treatment may be carried out in a suitable inert solvent at room temperature to under reflux. The base is appropriately selected from sodium hydride, potassium t-butoxide, triethylamine, dimethylaminopyridine and the like. Examples of the inert solvent include tetrahydrofuran, dioxane, methylene chloride, chloroform and the like.

The second step is to decarboxylate the benzoylacetic acid compound (2) produced here, and is carried out by treating in an acidic medium at room temperature to under reflux. As the acidic medium, water, methanol, ethanol, or the like that is acidified with hydrochloric acid is usually used.

In the third step, the cyanoacetophenone compound (3) produced here is reacted with tri (lower) alkyl orthoformate, and then the reaction product and the primary amine (R
⁴ NH ₂ ) and then the reaction product is treated with a base to obtain a 3-cyanoquinolone compound (5). The former reaction is usually carried out by heating in the presence of a dehydrating agent (eg acetic anhydride), if necessary, in an appropriate inert solvent (eg tetrahydrofuran, dioxane) under heating under reflux. The latter reaction is carried out by heating under reflux in a suitable inert solvent (eg tetrahydrofuran, dioxane) as necessary. For the final treatment with a base, a polar aprotic solvent may be used, if necessary, and the mixture may be heated under reflux. Specific examples of the base in this case include tertiary amines (eg, triethylamine, tripropylamine, diisopropylethylamine, dimethylaniline, dimethylaminopyridine) and inorganic bases (eg, sodium hydride,
Potassium t-butoxide, potassium carbonate, sodium hydroxide) and the like, and specific examples of the polar aprotic solvent include dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrile and the like.

In the fourth step, the benzoyl acetic acid compound (2) is subjected to the same reaction and treatment as in the third step to produce a 3-cyanoquinolone compound (5). The reaction and treatment operations are exactly the same as those described for the third step.

In the fifth step, the 3-cyanoquinolone compound (5) is reacted with a substituted or unsubstituted benzylamine to substitute the 5-position fluorine with a substituted or unsubstituted benzylamino group. This reaction is carried out by heating and refluxing the 3-cyanoquinolone compound (5) and a substituted or unsubstituted benzylamine in a suitable inert solvent (eg, chloroform, methylene chloride, dichloroethane). If necessary, the reaction product (III: Y =
Debenzylation of (substituted or unsubstituted benzyl) by a conventional method provides a debenzylated product (III: Y = H). Debenzylation may be carried out, for example, by catalytic reduction. Specifically, palladium carbon is used as a catalyst, and an inert solvent (eg dioxane, tetrahydrofuran, acetic acid) is used.
It may be treated with hydrogen while being heated in medium (for example, around 100 ° C.).

The sixth step is the thus obtained 5-
Substituted or unsubstituted benzylaminoquinolone compound (II
I) formula

[Chemical 13] (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) The substituted pyrrolidine represented by the above is reacted to substitute the former fluorine at the 7-position with a substituted pyrrolidino group. In this reaction, 5-substituted or unsubstituted benzylaminoquinolone compound (III) and substituted pyrrolidine are treated with an appropriate inert solvent (eg, water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, dimethylformamide).
It can be carried out by heating and refluxing in the presence of a deoxidizing agent as a condensing agent. Specific examples of the deoxidizing agent include organic bases (eg triethylamine, DBU, pyridine)
And inorganic bases (for example, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide).

In the seventh step, the cyano group present at the 3-position of the 5-substituted or unsubstituted benzylamino-7-substituted pyrrolidinoquinolone compound (IV) thus obtained is hydrolyzed to be converted into a carboxyl group. Thus, the desired 5-substituted or unsubstituted benzylamino-7-substituted pyrrolidinoquinolonecarboxylic acid compound (VI) is obtained. The hydrolysis may be carried out by a conventional method, and depending on the conditions, the 5-substituted or unsubstituted benzylamino-
A 7-substituted pyrrolidinoquinolonecarboxylic acid compound (VI) may be obtained, or a 5-substituted or unsubstituted benzylamino-7-substituted pyrrolidinoquinolonecarboxylic acid amide compound (V) may be formed in the middle. .

For example, when the 3-cyano compound (IV) is heated to around 100 ° C. in the presence of concentrated hydrochloric acid, the corresponding 3-carboxyl compound (VI) is directly produced. At this time, the 3-cyano compound (IV) is produced. Even if there is a substituted or unsubstituted benzyl group at the 5-position amino group, it is possible to remove it at the same time.
Moreover, the 3-cyano compound (VI) was added to 70% in the presence of 50% sulfuric acid.
When heated to about 75 ° C, the corresponding 3-carbamoyl compound (V) is produced, and when heated under reflux in the presence of 20 to 30% sodium hydroxide, the corresponding 3-carboxyl compound (VI) is produced. To do. 3-carbamoyl form (V) and 3
-When a substituted or unsubstituted benzyl group is present in the 5-position amino group of the carboxyl derivative (VI), it is eliminated by applying a conventional debenzylation method as described in the fifth step. It can be done.

Of the various intermediates obtained in the above steps,
5-substituted or unsubstituted benzylamino-7-substituted pyrrolidinoquinolone compound (IV) and 5-substituted or unsubstituted benzylamino-6-substituted pyrrolidinoquinolone carbonamide compound (V), that is, the formula

[Chemical 14] (In the formula, Z represents cyano or carbamoyl. R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ and Y are as defined above. The compound represented by) is a novel substance.

[0017]

EXAMPLES Specific examples of the method of the present invention will be described below with reference to examples. Example 1 (a) To 1.1 g of 60% sodium hydride (oil), 20 ml of anhydrous tetrahydrofuran was added, and 1.9 g of tert-butyl cyanoacetate was diluted with 10 ml of anhydrous tetrahydrofuran under cooling and stirring at -5 to 0 ° C. Is dripped. Then pentafluorobenzoyl chloride (1: R ⁵ = F; X =
When a solution prepared by diluting 3.0 g of Cl) with 10 ml of anhydrous tetrahydrofuran is carefully added dropwise, the internal temperature rises to 20 ° C. After 10 minutes, ice water is added to extract with toluene. The aqueous layer is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography, and 2-cyano-3-oxo-3- (2,3,4,5,6-pentafluorophenyl) -tert-butyl propionate (2:
_{R = t-C 4 H 9} ; obtain R ⁵ = F) 3.7g. mp: 5
6-57 ° C. IR ν _max (Nujol): 3100-3600 (broad), 2240, 1662cm
^-1 . _{NMRδ (CDCl 3): 1.62s (} tC 4 H 9), 14.06 (OH).

(B) 1.36 g of ethyl cyanoacetate, 3 ml of triethylamine and 15 mg of dimethylaminopyridine were dissolved in 20 ml of methylene chloride, and pentafluorobenzoyl chloride (1: R ⁵ = F; X = Cl) was stirred with ice cooling.
Add 2.12 g. After stirring at room temperature for 15 hours, it is extracted with methylene chloride. The extract is washed with water and dried, and then the solvent is distilled off. The residue was subjected to column chromatography on 50 g of silica gel, and as an oily substance from the methylene chloride fraction, 2-
Cyano-3-oxo-3- (2,3,4,5,6-pentafluorophenyl) -ethyl propionate (2: R = C ₂
H ₅ ; R ⁵ = F) 1.8 g are obtained. Oily substance. NMR δ (CDCl ₃ ): 1.44t (J = 7.8Hz) (CH ₃ ), 4.50q
_{(J = 7.8Hz) (CH 2} ).

Example 2 (a) 2-Cyano-3-oxo-3- (2,3,4,5,6)
- pentafluorophenyl) - tert-butyl propionate (2: R = t-C 4 H 9; the R ⁵ = F) 2.7 g was dissolved in a mixture of methanol 10ml and 1N- hydrochloric acid 3 ml, 2 at 60 ° C.
After reacting for a time, the solvent is distilled off. The residue was extracted with methylene chloride, washed with water, dried and evaporated to give a crystalline residue.
1.8 g of 3,4,5,6-pentafluorobenzoylacetonitrile (3: R ⁵ = F) are obtained. mp: 55-56
° C. IRν _max (Nujol): 2260, 1700, 1642 cm ^-1 . _{NMRδ (CDCl 3): 3.99 (} s) (CH 2).

(B) 2-Cyano-3-oxo-3-
1.45 g of ethyl (2,3,4,5,6-pentafluorophenyl) -propionate (2: R = C ₂ H ₅ ; R ⁵ = F) was dissolved in a mixture of 8 ml of methanol and 2 ml of hydrochloric acid, and 70 React at 22 ° C for 22 hours. The reaction mixture was concentrated, water was added,
Extract with methylene chloride. After washing the extract with water and drying, the solvent was distilled off, and the residue was subjected to column chromatography on 30 g of silica gel, and the chloroform fraction was used to give 2,3,4,5,
6-pentafluorobenzoylacetonitrile (3: R
⁵ = F) 220 mg are obtained. mp: 55-56 ° C.

Example 3 To 500 mg of 2,3,4,5,6-pentafluorobenzoylacetonitrile (3: R ⁵ = F) was added acetic anhydride (1.5 ml) and triethyl orthoformate (650 mg) at 40 ° C.
After heating for 1 minute, distill under reduced pressure. 5 ml of anhydrous tetrahydrofuran was added to the residue, 146 mg of cyclopropylamine was further added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Then, 0.35 ml of triethylamine is added and the mixture is refluxed for 2 hours, and then the solvent is distilled off. The residue is extracted with methylene chloride, washed with 1N-hydrochloric acid and then an aqueous solution of sodium chloride, dried over sodium sulfate, and the solvent is distilled off. The residue was subjected to column chromatography on 35 g of silica gel and crystallized from the fraction of 5% ethyl acetate-methylene chloride as 1-cyclopropyl-3-cyano-5,6 ,.
420 mg of 7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline (5: R ⁴ = ▽; R ⁵ = F) are obtained.
mp: 195-196 ° C (hexane).

Example 4 Tertiary butyl 2-cyano-3-oxo-3- (2,3,4,5,6-pentafluorophenyl) propionate (2: R
= C ₂ H ₅ ; R ⁵ = F) 24.0 g, acetic anhydride 34.0 g and triethyl orthoformate 30.0 g are added, and the mixture is heated at 150 ° C. for 5 hours and stirred, and then the solvent is distilled off under reduced pressure. Tetrahydrofuran (110 ml) is added to the residue, cyclopropylamine (4.5 g) is added under ice-cooling, the mixture is allowed to stand at 0 to 3 ° C. overnight, triethylamine (11 ml) is added, and the mixture is refluxed for 2 hours. The solvent is distilled off and the residue is extracted with methylene chloride. The extract is washed with 1N-hydrochloric acid, then brine solution, and concentrated. The residue was subjected to column chromatography on 500 g of silica gel,
5% ethyl acetate: 1-cyclopropyl-3-cyano-5,6,7,8-tetrafluoro-from the methylene chloride fraction
1,4-dihydro-4-oxoquinoline (5: R ⁴ = ▽;
R ⁵ = F) 11.1 g are obtained. mp: 198-200
° C.

Example 5 1-Cyclopropyl-3-cyano-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline (5: R ¹ = ▽; R ⁵ = F) 1 0.9 g of benzylamine 1.
It is dissolved in 5 g and 100 ml of methylene chloride, refluxed for 22 hours and then cooled. The precipitate is filtered and the filtrate is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (5
0 g) and crystallized from a fraction of 2% ethyl acetate-methylene chloride as 1-cyclopropyl-3-cyano-5-benzylamino-6,7,8-trifluoro-1,4-dihydro-4-. Oxoquinoline (6: R ⁴ = ▽; R ⁵ = F; Y
= CH ₂ C ₆ H ₅ ) 1.9 g are obtained. mp: 195-19
7 ° C.

Example 6 1-Cyclopropyl-3-cyano-5-benzylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline (III: R ⁴ = ▽; R ⁵ = F; Y = CH ₂ C ₆
3 g of H ₅ ) was dissolved in 80 ml of acetic acid and 80 ml of dioxane,
1.0 g of 0% palladium on carbon is added and catalytically hydrogenated at 100 ° C. After 3 hours, palladium carbon was removed by filtration, methylene chloride was added to the filtrate, and the precipitated crystals were collected by filtration to give 1-cyclopropyl-3-cyano-5-amino-6,7,8-trifluoro-1,4. -Dihydro-4-oxoquinoline (III:
R ⁴ = ∇; R ⁵ = F; Y = H) 900 mg. The mother liquor was concentrated under reduced pressure, and the residue was subjected to column chromatography on 10 g of silica gel to obtain an additional 420 mg from a 5% ethyl acetate-methylene chloride fraction. mp: 240 ° C. IRν _max (Nujol): 3460, 2240, 1660, 1560 cm ^-1 . NMR δ (CDCl ₃ ): 1.02 to 1.13 m (2H), 1.20 to 1.31 m (2
H), 3.79-3.90m (1H), 6.83brs (2H), 7.99s (1H).

Example 7 1-Cyclopropyl-3-cyano-5-amino-6,7,
8-trifluoromethyl-1,4-dihydro-4-oxoquinoline ^{(III: R 4 = ▽;} R 5 = F; Y = H) 600mg and (3R *, 4S *) - 3- methoxy-4-methylamino Pyrrolidine dihydrochloride 650 mg to acetonitrile 15 m
1, DBU (1.4 g) were added and the mixture was heated under reflux for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with acetonitrile and dried to give 1-cyclopropyl-3-cyano-5-amino-7.
-(3R *, 4S *)-(3-methoxy-4-methylaminopyrrolidin-1-yl) -6,8-difluoro-1,
4-dihydro-4-oxo-quinoline _{^{(IV: R 1 = CH 3}} ;
R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = H) 5
90 mg are obtained. mp: 225-228 ° C. IRν _max (Nujol): 2220, 1645, 1575 cm ^-1 . NMR δ (CDCl ₃ ): 0.90 to 1.06 m (2H), 1.06 to 1.22 m (2
H), 3.18 to 3.29m (1H), 3.43s (3H), 3.57 to 3.68m (1H),
3.70-3.68m (1H), 3.70-3.84m (3H), 3.84-3.96m (2
H), 6.51brs (2H), 7.88s (1H).

Example 8 1-Cyclopropyl-3-cyano-5-amino-7-
(3R *, 4S *)-(3-Methoxy-4-methylaminopyrrolidin-1-yl) -6,8-difluoro-1,4
- dihydro-4-oxo-quinoline _{^{(IV: R 1 = CH 3}} ; R
² = CH ₃ ; R ³ = H; R ⁴ = ∇; R ⁵ = F; Y = H) 10
5 ml of concentrated hydrochloric acid was added to 0 mg, and the mixture was heated in a sealed tube at 100 ° C. for 17 hours for hydrolysis. The reaction mixture was concentrated, ethanol was added to the residue, and the precipitated crystals were collected by filtration, washed with ethanol, and dried to give 1-cyclopropyl-5-amino-7-.
(3R *, 4S *)-(3-Methoxy-4-methylaminopyrrolidin-1-yl) -5-amino-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ( I: R ¹ = CH ₃ ; R ² = CH ₃ ; R ³ = H;
68 mg of the hydrochloride of R ⁴ = ∇; R ⁵ = F) are obtained. mp: 2
72-275 ° C (decomposition).

Example 9 1-Cyclopropyl-3-cyano-5-benzylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline (III: R ⁴ = ▽; R ⁵ = F Y = CH ₂ C ₆
H ₅₎ 200 mg and (3R *, 4S *) - 3- methoxy-4-methylamino-pyridine dihydrochloride (160 mg)
Are mixed in acetonitrile (12 ml) and then DBU
(370 mg) is added and the mixture is refluxed for 2.5 hours. The solvent was evaporated, the residue was subjected to column chromatography on 25 g of silica gel, and crystallized from a 10% methanol-methylene chloride fraction as 1-cyclopropyl-3-cyano-5-benzylamino-7-[(3R * , 4S *)-3-methoxy-
4-Methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxoquinoline (I
V: R ¹ = CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ =
F; Y = CH ₂ C ₆ H ₅ ) 220 mg are obtained. mp: 15
2-155 ° C. IRν _max (CHCl ₃ ): 2230, 1640 cm ^-1 . ¹ H-NMR δ (CDCl ₃ ): 0.86 to 1.20 m (4H), 2.48s (3H),
3.16 ~ 3.26m (1H), 3.41s (3H), 3.50 ~ 3.73m (3H), 3.73
~ 3.92m (3H), 4.56dd (2H, J = 4,6), 7.12 ~ 7.38m (5H),
7.87s (1H), 9.92brs (1H).

Example 10 1-Cyclopropyl-3-cyano-5-benzylamino-7-[(3R *, 4S *)-3-methoxy-4-methylaminopyrrolidin-1-yl] -6,8- Difluoro-1,
4-dihydro-4-oxo-quinoline _{^{(IV: R 1 = CH 3}} ;
R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = CH ₂ C
₆ H ₅ ) (1 g) is added with 50% sulfuric acid (40 ml) and heated at 70 to 75 ° C. for 15 hours. The reaction mixture is ice-cooled, neutralized with aqueous ammonia, and extracted with ethyl acetate. The extract is concentrated and the residue is subjected to silica gel column chromatography to give 5%
From the fraction of methanol-methylene chloride, 1-cyclopropyl-5-benzylamino-7-[(3R *, 4S *)-3-
Methoxy-4-methylaminopyrrolidin-1-yl]-
6,8-difluoro-1,4-dihydro-4-oxo-3
- quinoline carboxamide _{^{(V: R 1 = CH 3}} ; R 2 = C
H ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = CH ₂ C ₆ H ₅ )
830 mg are obtained. mp: 196-198 ° C. IR v _max (CHCl ₃ ): 1665, 1625, 1550, 1440 cm ⁻¹ . ¹ H-NMR δ (CDCl ₃ ): 0.85 to 1.19 m (4H), 2.48s (3H),
3.15 ~ 3.28m (1H), 3.41s (3H), 3.50 ~ 3.72m (3H), 3.78
~ 3.92m (3H), 4.58dd (2H, J = 4, 6), 5.60brs (1H, J =
5), 7.18 ~ 7.40m (5H), 8.62s (1H), 9.53brd (1H, J = 5),
10.03brs (1H).

Example 11 1-Cyclopropyl-5-benzylamino-7-[(3R
*, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxamide (V: R ¹
= CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y
═CH ₂ C ₆ H ₅ ) 850 mg, acetic acid 17 ml and methanol 1
Dissolve in 7 ml, add 40 mg of 10% palladium on carbon,
Catalytic hydrogenation at room temperature. After 5 hours, palladium carbon was removed by filtration, the solvent in the filtrate was concentrated, and the residue was subjected to silica gel column chromatography, and 1-cyclopropyl-5-amino-7-[(3
R *, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxamide (V:
R ¹ = CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ =
F; Y = H) 460 mg are obtained. mp: 221-224
° C. IR ν _max (CHCl ₃ ): 1665, 1625, 1450 cm ⁻¹ . ¹ H-NMRδ (CDCl ₃ ): 0.92 to 1.20 m (4H), 2.50 s (3H),
3.20 ~ 3.30m (1H), 3.43s (3H), 3.58 ~ 3.70m (3H), 3.71
~ 3.98m (5H), 5.60brd (1H, J = 5), 6.55brs (2H), 8.63s
(1H), 9.55brd (1H, J = 5).

Example 12 1-Cyclopropyl-5-amino-7-[(3R *, 4S
*)-3-Methoxy-4-methylaminopyrrolidine-1
-Yl] -6,8-difluoro-1,4-dihydro-4-
Oxo-3-quinolinecarboxamide (V: R ¹ = CH
₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = H)
90 mg is dissolved in 2 ml of 30% NaOH aqueous solution and 4 ml of ethanol and refluxed for 2 hours. The reaction solution was neutralized with 1N-hydrochloric acid, extracted with methylene chloride, dried over sodium sulfate, and the solvent was distilled off to give 1-cyclopropyl-5-amino-7-[(3R
*, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I: R ¹ = CH
₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ∇; R ⁵ = F) 50 mg. mp: 261-262 ° C. IR ν _max (CHCl ₃ ): 1725, 1635, 1615, 1445 cm ⁻¹ . ¹ H-NMR δ (CDCl ₃ ): 0.98 to 1.25 m (4H), 2.50 s (3H),
3.20 ~ 3.30m (1H), 3.44s (3H), 3.58 ~ 3.70m (1H), 3.72
~ 3.98m (5H), 6.41brs (2H), 8.59s (1H).

Example 13 1-Cyclopropyl-3-cyano-5-benzylamino-7-[(3R *, 4S *)-3-methoxy-4-methylaminopyrrolidin-1-yl] -6,8- Difluoro-1,
4-dihydro-4-oxo-quinoline _{^{(IV: R 1 = CH 3}} ;
R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = CH ₂ C
20 ml of concentrated hydrochloric acid is added to 500 mg of ₆ H ₅ ) and the tube is heated and sealed at 100 ° C. for 8 hours. The reaction solution was neutralized with saturated sodium hydrogen carbonate, extracted with methylene chloride, dried over sodium sulfate and evaporated to remove the solvent, 1-cyclopropyl-5-amino-7-[(3R *,
4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxamide (V: R ¹ =
CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y =
H) and 1-cyclopropyl-5-amino-7-[(3R
*, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I: R ¹ = CH
₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = H)
310 mg of a mixture of Further, this mixture was recrystallized from ethanol to give 1-cyclopropyl-5-amino-7-
[(3R *, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I: R ¹
= CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y
= H) 120 mg are obtained.

Example 14 1-Cyclopropyl-3-cyano-5-benzylamino-7-[(3R *, 4S *)-3-methoxy-4-methylaminopyrrolidin-1-yl] -6,8- Difluoro-1,
4-dihydro-4-oxo-quinoline _{^{(IV: R 1 = CH 3}} ;
R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y = CH ₂ C
₆ H ₅ ) 150 mg, 50% sulfuric acid 6 ml was added, and 90 ° C
Heat for 3.5 hours. The reaction solution is ice-cooled, neutralized with aqueous ammonia, and extracted with ethyl acetate and methylene chloride. The extract was concentrated, the residue was subjected to silica gel column chromatography, and 1-cyclopropyl-5-benzylamino-7-[(3R
*, 4S *)-3-Methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxamide (V: R ¹
= CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵ = F; Y
= CH ₂ C ₆ H ₅ ) 70 mg and 10% methanol-methylene chloride fraction to give 1-cyclopropyl-5-amino-7.
-[(3R *, 4S *)-3-methoxy-4-methylaminopyrrolidin-1-yl] -6,8-difluoro-1,4-
Dihydro-4-oxo-3-quinolinecarboxamide (V: R ¹ = CH ₃ ; R ² = CH ₃ ; R ³ = H; R ⁴ = ▽; R ⁵
= F; Y = H) 30 mg are obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 215: 00) (C07D 409/14 207: 00 215: 00 333: 00)

Claims (5)

[Claims] 1. The formula: (In the formula, R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, R ³ is hydrogen or amino protecting group, R ⁴ is cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted. Thienyl, R ⁵ is halogen, Y is hydrogen or optionally substituted benzyl, Z
Represents cyano or carbamoyl. ) The quinolone derivative represented by. 2. The formula: (In the formula, R ⁴ represents cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted thienyl, R ⁵ represents halogen, Y represents hydrogen or optionally substituted benzyl.) The compound shown is debenzylated with or without debenzylation. (Wherein R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, R ³ is hydrogen or an amino-protecting group), and then substituted or not at the 5-position of the reaction product. When a substituted benzylamino group is present, it may be debenzylated if necessary to convert it to an amino group. (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y have the same meanings as described above.) A method for producing a quinolone derivative, characterized in that the compound is obtained. 3. The starting compound, compound (III), has the formula: (Wherein R ⁵ represents halogen and X represents halogen), and the compound represented by the formula: is reacted with cyanoacetic acid or its lower alkyl ester. (In the formula, R represents hydrogen or lower alkyl. R ⁵ has the same meaning as described above.) A compound (tri (lower) alkyl ortho-formate and a primary alkyl (ortho-formate)) with or without decarboxylation is obtained. After sequentially reacting with an amine, it was treated with a base to give a compound of the formula (In the formula, R ⁴ represents cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted thienyl, and R ⁵ has the same meaning as above.). Alternatively, by reacting with an unsubstituted benzylamine, the compound of the formula: (In the formula, Y represents a substituted or unsubstituted benzyl. R ⁴
And R ⁵ are as defined above. The method according to claim 2, which is obtained by debenzylating the compound represented by the formula (1) and, if necessary, debenzylating the compound. 4. A compound (I obtained by the method according to claim 2)
V) is hydrolyzed, and if a substituted or unsubstituted benzylamino group is present at the 5-position of the reaction product, it is optionally debenzylated to convert it into an amino group. ] (In the formula, R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, R ³ is hydrogen or amino protecting group, R ⁴ is cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted. Thienyl, R ⁵ is halogen, Y is hydrogen or benzyl which may be substituted.) A process for producing a quinolone derivative, which comprises: 5. The compound (I obtained by the method according to claim 2)
V) or the compound (V) obtained by the production method of claim 4 is hydrolyzed, and if a substituted or unsubstituted benzylamino group is present at the 5-position of the reaction product, this is optionally converted to this. By debenzylation and conversion to an amino group, the formula: (In the formula, R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, R ³ is hydrogen or amino protecting group, R ⁴ is cyclopropyl, fluoroethyl, optionally substituted phenyl or optionally substituted. Thienyl, R ⁵ is halogen, Y is hydrogen or benzyl which may be substituted.) A process for producing a quinolone derivative, which comprises: