JP2000247970A - Production of 5-amino-8-methyl-7-pyprolidinylquinoline-3- carboxylic acid derivative and intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in high yield and purity on a practical production scale the subject compound having excellent antibacterial activity by reacting a specific amino group-protected aminopyrrolidine derivative with a specific quinolinecarboxylic acid derivative after protecting its amino group and thereafter deprotection. SOLUTION: This compound of formula V is obtained by the following process: the 5-position amino group of a compound of formula I is protected and the compound is converted to a compound of formula III [R1 is an acyl, (substituted) alkoxycarbonyl or the like] (e.g. 5-acetylamino-1-cyclopropyl-6,7- difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid), and thereafter, the compound of formula II is reacted with a compound shown by formula III [R2 is an acyl, (substituted) aralkyloxycarbonyl or the like; R3 and R4 are each H, methyl or the like] with its 3-position amino group protected e.g. (S)-7-tert-butoxycarnbonylamino-5-azaspiro [2.4]heptane} to obtain a compound of formula IV, and thereafter, the compound of formula IV is deprotected.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel process for producing 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative having an excellent antibacterial activity and an intermediate for the production thereof. .

[0002]

2. Description of the Related Art With respect to the 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative according to the present invention, Chemical & Pharmaceutical Bulletin is used.
n), 44, 1376-1386, 1996, Japanese Patent No. 2673937 and JP-A-8-259561.
No. 4,985,077 describes its excellent antibacterial activity and its production method. As a specific production method, 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-
8-methyl-4-oxoquinoline-3-carboxylic acid;
A method in which a 3-aminopyrrolidine derivative having a protected amino group at the 3-position is condensed and then deprotected to produce (hereinafter referred to as A
Method) or 5-amino-1-cyclopropyl-6,7-
After converting difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid to the corresponding boron chelate derivative with boron trifluoride diethyl ether complex (BF ₃ .OEt ₂ ), the 3-position amino A method is disclosed in which a 3-aminopyrrolidine derivative having a protected group is condensed and then dechelated and deprotected to produce (hereinafter referred to as Method B).

[0003]

However, since the condensation reaction of the method A requires a high reaction temperature of 100 ° C. or more,
Undesirable side reactions occur, and complicated separation and purification operations are required to obtain a high-purity target product, and the total yield is not so high. Further, in the method B, although the condensation reaction proceeds at a reaction temperature near room temperature, the decomposition of the boron chelate derivative gradually occurs even at that temperature, so that the total yield is not so high. Under such circumstances, there is still room for improvement in a method for producing a 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative having an excellent antibacterial activity on an actual production scale, and there is still room for improvement. It is hard to say that it has been established.

[0004]

Means for Solving the Problems To solve these problems, the present inventors have developed a high-purity 5
-Amino-8-methyl-7-pyrrolidinylquinoline-3
As a result of intensive studies on a production method for obtaining a carboxylic acid derivative at a high yield on an actual production scale, 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-
5-methyl-4-oxoquinoline-3-carboxylic acid 5
After introducing a protecting group into the amino group at the 3-position, a 3-aminopyrrolidine derivative having the amino group at the 3-position protected is condensed and then deprotected to give the desired 5-amino-
The present inventors have found that an 8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative can be obtained with high yield and high purity on an actual production scale, and have completed the present invention.

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

Embedded image Protecting the 5-position amino group of the compound represented by the following formula (II)

Embedded image (In the formula, R ¹ represents an acyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted aralkyloxycarbonyl group.)
-After conversion to a carboxylic acid derivative, the following general formula (III)

Embedded image (Wherein, R ² represents an acyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted aralkyloxycarbonyl group, and R ³ and R ⁴ each independently represent a hydrogen atom, methyl Or a 3-aminopyrrolidine derivative in which the 3-position amino group represented by an ethylene chain (which forms a spirocyclic structure together with a pyrrolidine ring) is represented by R ³ and R ⁴ together. And the following general formula (IV)

Embedded image (Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), and lead to a 7-pyrrolidinylquinoline-3-carboxylic acid derivative, followed by deprotection. The following general formula (V)

Embedded image (Wherein, R ³ and R ⁴ have the same meanings as described above.) The present invention relates to a novel method for producing a 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the formula: .

[0006] In a preferred embodiment of the present invention, in the production method from the general formulas (I) to (V), in the compounds represented by the general formulas (II), (III) and (IV), R ¹ is acetyl. A process is provided wherein the group and R ² are tert-butoxycarbonyl groups.

In another aspect of the present invention, a compound represented by the above general formula (IV) and a compound represented by the following general formula (VI)

Embedded image (Wherein, R ¹ , R ³ and R ⁴ have the same meanings as described above), and a novel 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the formula: The provided compounds represented by the general formulas (IV) and (VI) are useful as intermediates for producing the compound represented by the general formula (V), and have a protecting group in the production process of the present invention. It is a novel compound isolated as a 7-pyrrolidinylquinoline-3-carboxylic acid derivative.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The novel process for producing the compound represented by the above general formula (V) of the present invention will be described in detail below. In the production method exemplified below, the steps of deprotection in steps 3 and 4 are described in two steps,
It goes without saying that deprotection can be carried out in one step depending on the combination of the protecting groups R ¹ and R ² in the compound (IV).

Embedded image (In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.)

In the production method of the present invention, the compound represented by the general formula (I)
In the compounds represented by I), (III), (IV) and (VI),
As the protective group for the amino group represented by R ¹ and R ² , an amide-type protective group represented by an acyl group and a urethane-type protective group represented by an alkoxycarbonyl group and an aralkyloxycarbonyl group can be used. Examples of the acyl group represented by R ¹ and R ² include a formyl group, an acetyl group, a propionyl group, a butyryl group, a pivaloyl group,
Examples of the alkoxycarbonyl group which may have a substituent include a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a methoxyacetyl group, a benzoyl group, and a phenylacetyl group. Examples of the aralkyloxycarbonyl group which may have a substituent include a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a tert-butoxycarbonyl group, and a 1-adamantyloxycarbonyl group. , Benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-
And a nitrobenzyloxycarbonyl group. For the introduction and deprotection of these protecting groups, a reaction known per se can be used, for example, Protective Groups in Organic Synthesis (Protective Gross).
ups in Organic Synthesis), 2nd edition, TWGreene, P.
GMWuts, John Wiley & Sons, Inc., New York, 1
It can be introduced and deprotected as described in Chapter 7, 991.

The combination of these protecting groups in the production method of the present invention can be independently selected arbitrarily. Even if different types of protecting groups are introduced into R ¹ and R ² , the same combination is obtained. May be introduced. When the same protecting group is introduced, the deprotection reaction shown in Step 3 and Step 4 of the above production route can be shortened to one step, but the purification effect of each production intermediate is reduced. Considering this, a combination in which protecting groups having different deprotection reaction conditions are introduced into R ¹ and R ² is preferable. In order to further facilitate the condensation reaction in Step 2, a particularly preferred protecting group is a combination of R ¹ as an amide-type protecting group and R ² as a urethane-type protecting group.

In the following, R ¹ which is a preferred combination of protecting groups is
Is an amide-type protecting group, and the production method of the present invention will be described in detail for each step by way of example where R ² is a urethane-type protecting group, but the present invention is not limited to these.

(Step 1) In the production method of the present invention, a quinoline-3-carboxylic acid derivative having an amide-type protecting group introduced at the 5-position amino group represented by the general formula (II) is converted to a compound represented by the formula (I) The compound can be produced by reacting the compound shown with an amide-type protecting group-introducing reagent in a solvent in the presence or absence of a base. As the amide-type protecting group-introducing reagent used in this step, a corresponding acyl halide, carboxylic acid anhydride, activated carboxylic acid ester, carboxylic acid / carboxylic anhydride, carboxylic acid / dehydrating condensing agent and the like are used. For example, when an acetyl group is introduced as a protecting group, acetyl chloride, acetic anhydride, p-nitrophenyl acetate,
Acetic acid / acetic anhydride, acetic acid / N, N-dicyclohexylcarbodiimide and the like. The amount of the amide-type protecting group-introducing reagent to be used is generally 1- to 10-fold, preferably 1- to 5-fold the molar amount of the compound represented by the formula (I).
The solvent used in this step may be any solvent as long as it does not inhibit the reaction. For example, aprotic polar solvents such as acetonitrile, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene, Aromatic hydrocarbon solvents such as xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; organic base solvents such as pyridine, picoline and lutidine; organic acid solvents such as acetic acid; or these solvents And the amount of these solvents used is not particularly limited. As the base used in this step, for example, triethylamine,
N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine,
Sodium carbonate, potassium carbonate, sodium bicarbonate,
Potassium hydrogen carbonate, sodium acetate and the like can be mentioned. The amount of the base used is based on the compound represented by the formula (I).
Usually, it is 1 to 50 times mol, preferably 1 to 10 times mol. When an organic base solvent is used as the solvent, the base to be used can be used instead. The reaction temperature depends on the amide-type protecting group-introducing reagent used, but is usually 0 to 150 ° C. The reaction time is not particularly limited, and the end point of the reaction can be confirmed by TLC or HPLC.

(Step 2) The novel 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (IV) of the present invention is represented by the general formula (II) obtained in the step 1. In a solvent, in the presence or absence of a base, a quinoline-3-carboxylic acid derivative represented by the formula (III):
It can be produced by reacting a 3-aminopyrrolidine derivative having a urethane-type protecting group introduced into the amino group. The amount of the 3-aminopyrrolidine derivative represented by the general formula (III) used in this step is determined by the amount of the general formula (I
It is usually 1 to 5 moles, preferably 1 to 3 moles, based on the quinoline-3-carboxylic acid derivative represented by I). The solvent used in this step may be any solvent as long as it does not inhibit the reaction. For example, aprotic polar solvents such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, tetramethylene sulfoxide, tetramethylene sulfone, dimethyl sulfoxide, etc. Benzene, toluene, xylene and other aromatic hydrocarbon solvents, dichloromethane, chloroform, 1,2-dichloroethane and other halogenated hydrocarbon solvents, pyridine,
Examples thereof include organic base solvents such as picoline and lutidine, and mixed solvents of these solvents. Particularly preferred solvents include acetonitrile, N, N-dimethylformamide, tetramethylene sulfone, and dimethyl sulfoxide. The amount of these solvents to be used is generally 1 to 50 times (V / W), preferably 3 to 10 times (V / W) the quinoline-3-carboxylic acid derivative represented by the general formula (II).
W). As the base used in this step, for example, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-
Undecene, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and the like can be mentioned.
For a quinoline-3-carboxylic acid derivative represented by
It is usually 1 to 50 times mol, preferably 1 to 10 times mol. When an organic base solvent is used as the solvent, the base to be used can be used instead. The reaction temperature is usually 40 to 90 ° C, preferably 60 to 80 ° C. The reaction time is not particularly limited, and the end point of the reaction can be confirmed by TLC or HPLC.

(Step 3) The novel 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (VI) of the present invention is represented by the general formula (IV) obtained in the step 2. It can be produced by deprotecting a urethane-type protecting group of a 7-pyrrolidinylquinoline-3-carboxylic acid derivative. This deprotection reaction is a reaction known per se,
For example, when a tert-butoxycarbonyl group is used as the urethane-type protecting group, the reaction can be usually performed in an appropriate solvent using an acid or a Lewis acid. In the case of deprotection using an acid, examples of the acid used include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. In an organic solvent such as methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, 1,4-dioxane, ethyl acetate,
Alternatively, they are used in a mixed solvent containing water. The amount of the acid to be used is generally 100-fold, preferably 1- to 10-fold the molar amount of the catalyst based on the 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (IV). still,
The amount of the solvent used is not particularly limited. The reaction temperature varies depending on the acid and solvent used, but is usually from 0 to 150 ° C. The reaction time is not particularly limited, and the end point of the reaction can be confirmed by TLC or HPLC.

In the case of deprotection using a Lewis acid, examples of the Lewis acid used include aluminum chloride, ytterbium trifluoromethanesulfonate, iodotrimethylsilane, trimethylsilyltrifluoromethanesulfonate and the like. Lewis acid is benzene,
It is used in a solvent such as toluene, xylene, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane or a mixed solvent thereof. The amount of the Lewis acid used is usually based on the amount of the 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (IV).
The amount is 100 times, preferably 1 to 10 times, the molar amount of the catalyst. The amount of the solvent used is not particularly limited. The reaction temperature varies depending on the Lewis acid and solvent used, but is usually
-50 to 100 ° C. The reaction time is not particularly limited, and the end point of the reaction can be confirmed by TLC or HPLC.

(Step 4) In the production method of the present invention, 5-amino-8-methyl-7 represented by the general formula (V) is used.
The -pyrrolidinylquinoline-3-carboxylic acid derivative hydrolyzes (deprotects) the amide-type protecting group of the 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the above general formula (VI) obtained in Step 3. (Protection). This hydrolysis reaction is a reaction known per se, and is usually performed using an alkali. Examples of the alkali used include, for example, sodium hydroxide, potassium hydroxide,
Examples thereof include sodium carbonate and potassium carbonate. The alkali is used in an aqueous solution, an organic solvent such as methanol, ethanol, n-propanol, or isopropanol, or a mixed solvent containing these. The amount of the alkali to be used is usually 1 to 1 with respect to the 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (VI).
The molar amount is 00 times, preferably 1 to 10 times. The amount of the solvent used is not particularly limited. The reaction temperature varies depending on the base and the solvent used, but is usually 0 to 200 ° C. The reaction time is not particularly limited, and the end point of the reaction can be confirmed by TLC or HPLC.

The 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formula (V) obtained in the step 4 is recrystallized by an ordinary method.
Alternatively, conversion into an acid addition salt or an alkali addition salt and / or re-releasing enables purification to a high-purity product. Acid addition salts used for purification include hydrochloride, sulfate, acetate, methanesulfonate, p-toluenesulfonate and the like, and alkali addition salts include sodium, potassium and calcium salts. Salt, triethylamine salt, ethanolamine salt, diethanolamine salt,
Triethanolamine salts and the like. Further, the 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative obtained by this purification operation can be converted to a pharmacologically acceptable salt, if necessary.

In the production method of the present invention, the compound represented by the general formula (II)
Compounds represented by I), (IV), (V) and (VI) are 1
It has one or two asymmetric carbons and may have several stereoisomers, and the present invention also includes a production method using these isomers and a mixture thereof. That is, in step 2, by using an optical isomer of the 3-aminopyrrolidine derivative represented by the general formula (III) or a mixture thereof, the compound represented by the general formula (V) through the steps 3 and 4 is obtained. An optical isomer of -amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative or a mixture thereof can be synthesized.

The 7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the general formulas (IV) and (VI) produced by the production method of the present invention is a novel compound,
The compound is useful as an intermediate for producing a 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative useful as an antibacterial agent represented by the general formula (V). These compounds (IV) and (VI) are optionally salts,
Preferably, the compound can be converted into a pharmacologically acceptable salt, and the base or acid can be liberated from the resulting salt to convert into a compound in a free form.

The salts of the 7-pyrrolidinylquinoline-3-carboxylic acid derivatives represented by the general formulas (IV) and (VI) of the present invention, preferably the pharmaceutically acceptable salts, include:
Acid addition salts or alkali addition salts are mentioned. Examples of the acid addition salt include mineral salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate, and acetates.
Maleate, fumarate, oxalate, citrate,
Organic acid salts such as malate, mandelate, tartrate, lactate, methanesulfonate, p-toluenesulfonate, 10-camphorsulfonate and the like, and examples of the alkali addition salt include And inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts or salts of organic bases such as ethanolamine salts, triethanolamine salts and N, N-dialkylethanolamine salts.

The compounds of the present invention represented by the general formulas (IV) and (VI) have one or two asymmetric carbons and may exist in stereoisomers. These isomers and mixtures thereof are also included. Also, the compounds (IV), (VI) and salts thereof of the present invention existing in any crystal form, and any hydrates and solvates of the compounds (IV), (VI) and salts thereof of the present invention And mixtures thereof are also included in the scope of the present invention.

The compounds represented by the above general formulas (IV) and (VI) of the present invention include, for example, the following compounds and stereoisomers thereof, but the present invention is not limited to these examples. Not something. (1) 5-acetylamino-7- (7-tert-butoxycarbonylamino-5-azaspiro [2.4] hept-5
-Yl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (2) 5-acetylamino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl -6-fluoro-1,4-dihydro-8-methyl-
4-oxoquinoline-3-carboxylic acid (3) 5-acetylamino-7- (3-tert-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1
-Cyclopropyl-6-fluoro-1,4-dihydro-
8-methyl-4-oxoquinoline-3-carboxylic acid (4) 5-acetylamino-7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4- Dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

The compound represented by the formula (I) as a starting material in the production method of the present invention is described in Japanese Patent No. 267.
It is a known compound disclosed in No. 3937. or,
A 3-aminopyrrolidine derivative having a protected amino group at the 3-position represented by the general formula (III) used in the production method of the present invention,
For example, compounds in which the protecting group is a tert-butoxycarbonyl group are described in Japanese Patent Nos. 2,673,937 and 2,714.
No. 597.

[0024]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 Method for producing 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (step 1) Amino-1-cyclopropyl-6,7-difluoro-1,4
-Dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 20.0 g (68 mmol), acetic anhydride 12.8 ml
(136 mmol) and 60 ml of acetic acid at 80.degree.
The mixture was heated and stirred for hours. After cooling the reaction mixture to room temperature,
The mixture was poured into 400 ml of water while stirring at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried with warm air at 60 ° C. for 23 hours.
22.0 g (yield: 96%) of pale yellow crystal of 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was obtained. Obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.94-1.04 (2H, m),
1.16-1.26 (2H, m), 2.15 (3H, s), 2.77 (3H, d, J = 3.5Hz), 4.33
-4.42 (1H, m), 8.81 (1H, s), 10.37 (1H, s)

Example 2 (S) -5-Acetylamino-7- (7-tert-butoxycarbonylamino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methyl-4-oxoquinoline-
Production method of 3-carboxylic acid (Step 2) 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8- obtained in Example 1
Methyl-4-oxoquinoline-3-carboxylic acid 21.2.
g (63 mmol), (S) -7-tert-butoxycarbonylamino-5-azaspiro [2.4] heptane 20.1
g (95 mmol), triethylamine 8.8 ml (63 mmol)
A mixture of l) and 85 ml of dimethyl sulfoxide was heated and stirred at 70 ° C. for 96 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was poured into 430 ml of water while stirring at room temperature. After adjusting the pH to 5 to 6 by adding 10% hydrochloric acid, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water, dried under reduced pressure at 50 ° C. for 21 hours, and then dried at 60 ° C. for 24 hours with warm air to obtain pale yellow crystals of (S) -5-acetylamino-7- ( 7-tert-butoxycarbonylamino-5
32.8 g of a crude product of -azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was obtained. Obtained. The obtained crude product is washed with hot methyl isobutyl ketone, and has a melting point of 217 to 219 ° C. (decomposition).
Was obtained as pale yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.50-0.60 (1H, m),
0.61-0.70 (2H, m), 0.73-0.89 (3H, m), 1.10-1.22 (2H, m), 1.
39 (9H, s), 2.10 (3H, s), 2.52 (3H, s), 3.25-3.35 (1H, m), 3.4
5-3.54 (1H, m), 3.71-3.80 (1H, m), 3.83-3.97 (2H, m), 4.22-
4.32 (1H, m), 7.05 (1H, brs), 8.74 (1H, s), 10.05 (1H, s)

Example 3 (S) -5-Acetylamino-7- (7-amino-5
Method for producing azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid hydrochloride (Step 3) ) The (S) -5-acetylamino-7- obtained in Example 2
(7-tert-butoxycarbonylamino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-
32.5 g of crude product of oxoquinoline-3-carboxylic acid
(About 62 mmol), 12.7 ml of 36% concentrated hydrochloric acid (148 mmol)
A mixture of l) and 488 ml of isopropanol was heated at reflux for 1 hour. The reaction mixture was cooled to 5 ° C and
Stirred for hours. The precipitated crystals were collected by filtration, washed with cold isopropanol, and dried with warm air at 60 ° C. for 19 hours to give
(S)-as pale yellow crystals at 45-250 ° C (decomposition)
5-acetylamino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-
Oxoquinoline-3-carboxylic acid hydrochloride 22.3 g
(Yield in two steps of Examples 2 and 3: 77%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.70-0.95 (5H, m),
1.08-1.25 (3H, m), 2.11 (3H, s), 2.59 (3H, s), 3.10-3.17 (1
H, m), 3.42-3.52 (1H, m), 3.67-3.75 (1H, m), 3.95-4.02 (1H, m
m), 4.10-4.18 (1H, m), 4.26-4.34 (1H, m), 8.36 (3H, brs), 8.
76 (1H, s), 10.10 (1H, s)

Example 4 (S) -5-Amino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro -8-methyl-4-
Method for producing oxoquinoline-3-carboxylic acid (Step 4) (S) -5-acetylamino-7- obtained in Example 3
(7-amino-5-azaspiro [2.4] hept-5-
Yl) -1-cyclopropyl-6-fluoro-1,4-
A mixture of 21.5 g (46 mmol) of dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid hydrochloride and 108 ml of a 20% aqueous potassium hydroxide solution was heated under reflux for 1 hour. After cooling the reaction mixture to room temperature,
The pH was adjusted to 8.4 (using a pH meter) by adding 0% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried in warm air at 60 ° C. for 43 hours to obtain yellow crystals of (S) -5-amino-7- (7-amino-5-azaspiro [2.4]. Hept-5-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methyl-4-oxoquinoline-
17.8 g of a crude product of 3-carboxylic acid (hydrate) was obtained.

Example 5 (S) -5-Amino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro -8-methyl-4-
Purification of oxoquinoline-3-carboxylic acid (S) -5 obtained in Example 4 in a mixture of 2.6 ml (45 mmol) of acetic acid and 96 ml of methanol under stirring at 50 ° C.
-Amino-7- (7-amino-5-azaspiro [2.
4] Hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (hydrate), crude product 17.5
g (about 45 mmol) was added in small portions. Add 10 reaction mixtures
After heating under reflux for 1 minute, the mixture was gradually cooled to 15 ° C and further stirred at 15 ° C for 2 hours. The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C for 5 hours to give yellow crystals of (S) -5-amino-
7- (7-amino-5-azaspiro [2.4] hept-
5-yl) -1-cyclopropyl-6-fluoro-1,
4-dihydro-8-methyl-4-oxoquinoline-3-
17.5 g of a carboxylic acid / acetic acid salt was obtained. Obtained (S)
-5-amino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-
85 ml of water was added to 17.0 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid acetate, and the mixture was stirred at room temperature for 30 minutes to dissolve, followed by filtration to remove insolubles. After that, the filtrate was adjusted to pH 12 by adding a 20% aqueous potassium hydroxide solution. 10% under stirring at room temperature
Hydrochloric acid was added to adjust the pH to 8.4 (using a pH meter). The precipitated crystals are collected by filtration, washed with water, and then
After drying in warm air for hours, yellow crystals of (S) -5-amino-7
-(7-Amino-5-azaspiro [2.4] hept-5
-Yl) -1-cyclopropyl-6-fluoro-1,4
15.1 g of 2-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (hydrate) (yield in two steps of Examples 4 and 5: 84%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.38-0.47 (1H, m),
0.54-0.64 (2H, m), 0.70-0.88 (3H, m), 1.05-1.17 (2H, m), 2.
35 (3H, s), 3.11-3.20 (1H, m), 3.24-3.33 (1H, m), 3.39-3.46
(1H, m), 3.57-3.64 (1H, m), 3.75-3.84 (1H, m), 4.08-4.18 (1
H, m), 7.05 (2H, brs), 8.60 (1H, s) HPLC purity: 99% Measurement conditions Column: TSKgel ODS-80Ts Column temperature: 30 ° C. Measurement wavelength: 220 nm Mobile phase: pH 7.0 phosphate buffer: CH ₃ CN (7: 3) Flow rate: 1.0 ml / min Injection volume: 20 μl (500 μg / ml)

Example 6 (S) -5-Amino-7- (7-amino-5-azaspiro [2.4] hept-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro -8-methyl-4-
Method for producing oxoquinoline-3-carboxylic acid / methanesulfonate (S) -5-amino-7- (7-amino-5-azaspiro [2.4] hept-5-yl obtained in Example 5 )-
A mixture of 14.5 g (36 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (hydrate) and 73 ml of 90% ethanol was stirred at room temperature. Below, 2.4 ml (38 mmol) of methanesulfonic acid were added. The reaction mixture was added at room temperature for 3 hours.
After stirring for 5 hours, the mixture was cooled to 5 ° C. and stirred for 1.5 hours.
The precipitated crystals were collected by filtration, washed with ethanol, and dried in warm air at 60 ° C. for 10 hours to give yellow crystals of (S) -5-amino-7- (7-amino-5-azaspiro [2.4]. Hept-5-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methyl-4-oxoquinoline-
16.9 g of 3-carboxylic acid / methanesulfonate (HPLC purity: 9 under the same measurement conditions as those used in Example 5)
9% or more). Physical property data of this product is
937 was consistent with that disclosed.

[0031]

According to the production method of the present invention, 5-amino-8 represented by the general formula (V) having an excellent antibacterial action is provided.
-Methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative can be produced with high yield and high purity on an actual production scale, and the above-mentioned general formula (V) is useful as an intermediate for producing these antibacterial agents. Compounds represented by IV) and (VI) are provided.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C063 AA01 BB02 CC14 DD03 EE01 4C086 AA03 AA04 BC29 GA07 GA12 NA20 ZB35

Claims (4)

[Claims] (1) The following formula: By protecting the 5-position amino group of the compound represented by the formula, the following general formula: (In the formula, R ¹ represents an acyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted aralkyloxycarbonyl group.)
-After conversion to a carboxylic acid derivative, the following general formula: (Wherein R ² represents an acyl group, an alkoxycarbonyl group which may have a substituent or an aralkyloxycarbonyl group which may have a substituent, and R ³ and R ⁴ each independently represent a hydrogen atom, methyl Or a 3-aminopyrrolidine derivative in which the 3-position amino group represented by an ethylene chain (which forms a spirocyclic structure together with a pyrrolidine ring) is represented by R ³ and R ⁴ together. And the following general formula: (Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), and lead to a 7-pyrrolidinylquinoline-3-carboxylic acid derivative, followed by deprotection. The following general formula characterized by the following: (Wherein, R ³ and R ⁴ have the same meanings as described above.) A method for producing a 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative represented by the formula: 2. The method according to claim 1, wherein R ¹ is an acetyl group and R ² is a tert-butoxycarbonyl group. 3. The following general formula: (Wherein, R ¹ and R ² each independently represent an acyl group, an alkoxycarbonyl group which may have a substituent or an aralkyloxycarbonyl group which may have a substituent, and R ³ and R ⁴ each represent independently a hydrogen atom, or a methyl group, or R ³ and 7 pyrrolidinylcarbonyl quinoline R ⁴ is represented by ethylene chain together represent a (pyrrolidine to form a spiro cyclic structure together with the ring)). - 3-carboxylic acid derivatives or salts thereof. 4. A compound represented by the following general formula: (Wherein, R ¹ represents an acyl group, an alkoxycarbonyl group which may have a substituent or an aralkyloxycarbonyl group which may have a substituent, and R ³ and R ⁴ each independently represent a hydrogen atom, methyl or a group, or R ³ and R ⁴ 7 pyrrolidinylmethyl-3-carboxylic acid derivative represented by.) representing the ethylene chain together (with pyrrolidine ring to form a spiro cyclic structure) or salt.