JPH0952893A - Industrial production of quinolone-carboxylic acid and its synthetic intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously obtain the subject compound useful as an antibacterial agent by reacting a specific 3-aminopyrrolidine with an aldehyde or a ketone to obtain a Schiff's base, temporarily protecting, condens ing with a quinolone skeleton and deprotecting. SOLUTION: The objective quinolone-carboxylic acid derivative expressed by formula V and useful as an antibacterial agent is readily obtained in high purity and a high yield by condensing 3-aminomethyl-3-fluoromethylpyrrolidine of formula I, its R-isomer or its S-isomer with an aldehyde or a ketone of formula II [R<1> and R<2> are each H, an alkyl or a (substituted) aryl], temporarily protecting amino group as a Schiff's base to obtain a compound of formula III, condensing the compound, its R-isomer or its S-isomer with a compound having a quinolone skeleton of formula IV [R<3> is F or a (halogen-substituted) acyloxy; R<4> is a halogen or methoxy; Hal is a halogen] and deprotecting.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrial process for producing a quinolone carboxylic acid derivative useful as an antibacterial agent, and to a synthetic intermediate thereof.

[0002]

2. Description of the Related Art WO 94/14794 discloses a strong antibacterial action against Gram-negative bacteria and Gram-positive bacteria, and in particular, quinolone-resistant MRSA (Methicillin-resistant Staphylococcus aureus), Staphylococcus epidermidis or Enterococcus. (S) -7- (3-Aminomethyl-3-fluoromethylpyrrolidin-1-yl) -1 which has a strong antibacterial action against and the like and also has significantly reduced side effects such as phototoxicity.
-Cyclopropyl-6-fluoro-1,4-dihydro-
8-Methoxy-4-oxo-3-quinolinecarboxylic acid (hereinafter also referred to as compound A) is disclosed.

According to the process described in the specification, compound A
Can be manufactured by the following route. Manufacturing method 1:

[0004]

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Production method 2:

[0006]

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That is, the method for producing compound A described in the specification relates to a method of condensing compound (a) and compound (b) without protecting the primary amine of compound (a) (production method). The compound (d) in which the primary amine of 1) and the compound (a) is protected with a benzyl group is condensed with the compound (b) to give a compound (e), which is then treated with a base to give a compound (f). There is a method (Production Method 2) of catalytically reducing compound (f) to remove the protecting group.

However, these methods have the following problems industrially. In the production method 1, since the compound (a) and the compound (b) are condensed without protecting the primary amine of the compound (a), the compound (c) cannot be obtained with high purity and high yield. In the production method 2, the compound (e) can be obtained in high yield because the compound (d) is reacted with the compound (b) using the compound (d) in which the primary amine of the compound (a) is protected with a benzyl group. However, in the step of obtaining the compound A by catalytic reduction of the compound (f), a large amount of reaction by-products is generated, so that it is necessary to purify the compound in a post-treatment stage, and the compound A cannot be obtained in a high yield. . Also,
When performing catalytic reduction, a special reaction equipment such as an autoclave is required, which is not industrially suitable.

[0009]

In the production of compound A, the above-mentioned conventional production methods have not been satisfactory as industrial methods. Therefore, by a simple method, a large amount of reaction by-products are not generated, post-treatment is easy, no special purification means is required, and no special equipment is required. There has been a demand for an industrially advantageous production method which can be obtained in a yield.

[0010]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies, and as a result, reacted the aminomethyl group on the pyrrolidine ring with an aldehyde or a ketone to form a Schiff base once. After protecting and condensing with the quinolone skeleton, the deprotection reaction is carried out, which is simple, does not produce a large amount of reaction by-products, is easy to perform post-treatment, and does not require any special purification means. High purity,
The present inventors have found an industrially advantageous production method which can be obtained at a high yield and does not require any special equipment, and have completed the present invention.

That is, the present invention is as follows. (1) Compound

[0012]

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The R isomer or the S isomer is represented by the general formula

[0014]

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(Wherein R ¹ and R ² are the same or different and each represent hydrogen, alkyl, aryl or substituted aryl) (hereinafter, compound (I)
General formula (I))

[0016]

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(Wherein R ¹ and R ² are as defined above) (hereinafter referred to as compound (III)
The R isomer or the S isomer and the general formula

[0018]

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(Wherein R ³ represents fluorine, acyloxy or acyloxy substituted by halogen. R ⁴
Represents halogen or methoxy. Hal represents halogen. (Hereinafter, compound (IV)
General formula characterized by condensing

[0020]

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(Wherein each symbol is as defined above) (hereinafter referred to as compound (V)), a method for producing the R isomer or the S isomer thereof. (2) treating compound (V), its R isomer or its S isomer with a base,

[0022]

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Wherein each symbol is as defined above (hereinafter, referred to as compound (VI));
A general formula characterized by treating the product with the R isomer or the S isomer and then treating with an acid.

[0024]

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(Wherein each symbol is as defined above) (hereinafter referred to as compound (VII)), a process for producing the R isomer or the S isomer thereof. (3) treating compound (V), its R isomer or its S isomer with an acid,

[0026]

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(Wherein each symbol is as defined above) (hereinafter referred to as compound (VIII)), its R isomer or its S isomer, and then treated with a base. A compound (VII) characterized by the formula:
A method for producing an isomer or its S isomer. (4) A process for producing compound (III), its R isomer or its S isomer, which comprises condensing compound (I), its R isomer or its S isomer with compound (II).

(5) Method for producing compound (V), its R isomer or its S isomer, which comprises condensing compound (IV) with compound (III), its R isomer or its S isomer . (6) Compound (II) obtained by condensing compound (I), its R isomer or its S isomer with compound (II)
I), its R isomer or its S isomer and a compound (I
V) is condensed to compound (V), its R isomer or its S isomer, and then treated with a base, and the resulting compound (VI), its R isomer or its S isomer is treated with an acid A process for producing compound (VII), its R isomer or its S isomer.

(7) Compound (I), its R isomer or its S isomer is condensed with compound (II) to obtain compound (III), its R isomer or its S isomer and compound (IV) Is condensed into a compound (V), its R isomer or its S isomer, and then treated with an acid. The resulting compound (VI), its R isomer or its S isomer is treated with a base. Characteristic compound (VII), R
A method for producing an isomer or its S isomer.

(8) General formula

[0031]

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(Wherein each symbol is as defined above), its R isomer or its S isomer. (9) General formula

[0033]

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(Wherein each symbol is as defined above), its R isomer, its S isomer or its salt. (10) General formula

[0035]

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(Wherein each symbol is as defined above), its R isomer or its S isomer.

[0037]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the alkyl in R ¹ and R ² is a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
It indicates isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The aryl in R ¹ and R ² represents phenyl, naphthyl and the like, and is preferably phenyl.

The substituted aryl in R ¹ and R ² is 2
-Nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 3-methylphenyl,
-Methylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and the like.

The acyloxy for R ³ represents acetyloxy, propionyloxy, butyryloxy, benzoyloxy, o-toluoyloxy, m-toluoyloxy, p-toluoyloxy, etc., and is preferably acetyloxy. The acyloxy substituted with a halogen in R ³ is the above acyloxy substituted with a halogen, and is, for example, chloroacetyloxy, trifluoroacetyloxy, chlorobenzoyloxy, bromobenzoyloxy, α-bromo-p-toluoyl. Oxy, 3-bromo-4-methylbenzoyloxy and the like.

The halogen in R ⁴ is fluorine, chlorine, bromine or iodine. Note that a preferred substituent for R ⁴ is methoxy. Halogen in Hal represents fluorine, chlorine, bromine or iodine, preferably fluorine. Compound (II) used in the production method of the present invention is
Any material can be used as long as it can easily form a Schiff base by reacting with a primary amine and can be easily removed after the reaction. Specifically, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, (2-, 3- or 4
-) Nitrobenzaldehyde, (2-, 3- or 4
-) Tolualdehyde, (2-, 3- or 4-) hydroxybenzaldehyde, (2-, 3- or 4-) chlorobenzaldehyde, acetone, methyl ethyl ketone,
Acetophenone, (2'-, 3'- or 4 '-) nitroacetophenone, (2'-, 3'- or 4'-) methylacetophenone, (2'-, 3'- or 4'-)
Hydroxyacetophenone, (2'-, 3'- or 4 '-) chloroacetophenone, benzophenone and the like can be mentioned, and benzaldehyde is preferable.

In the present invention, the salt of compound (VI) means a metal salt (a salt of sodium, potassium, calcium, magnesium or the like) such as an alkali metal salt or an alkaline earth metal salt or a heavy metal salt (copper, zinc, iron or the like). , Gold, silver,
Salts of platinum, manganese and the like). Compound (I), Compound (III), Compound (V), Compound (V
In I), compound (VII) and compound (VIII), optical isomers (R isomer, S isomer) based on asymmetric carbon exist, and the present invention relates to these individual isomers and mixtures thereof. Include all.

The reaction of compound (I) with compound (II)
The reaction is performed at 0 to 200 ° C, preferably 20 to 120 ° C, for 1 to 24 hours, preferably 3 to 10 hours in a solvent-free or suitable solvent. Suitable solvents used in this reaction include alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, acetonitrile, benzene, toluene, xylene, chloroform, methylene chloride, dichloroethane, dimethylformamide, dimethylsulfoxide, and the like. It is toluene. In this reaction, generated water can be removed with potassium hydroxide. In order to remove generated water, D
An ean-Stark water separator can also be used.
In this reaction, a catalyst such as benzenesulfonic acid may be used.

The reaction between compound (III) and compound (IV) is carried out, for example, according to the method described in WO 94/14794 or JP-A-4-69388. That is, the compound (II) is compared with the compound (II)
I) is used in a molar amount of 1 to 1.5 times, and without solvent or in a suitable solvent, if necessary, in the presence of a deoxidizing agent, at 0 to 200 ° C, preferably 20 to 100 ° C for 1 to 48 hours, preferably Is 1
Perform the reaction for ~ 24 hours.

Suitable solvents used in this reaction include water,
Alcohols such as methanol, ethanol, propanol and isopropyl alcohol, acetonitrile, pyridine, dimethylformamide, dimethyl sulfoxide,
Hexamethylphosphoric triamide, 1-methyl-2
-Pyrrolidone and the like, preferably acetonitrile.

The deoxidizing agent that can be used as required includes
Triethylamine, diisopropylethylamine, 1,
Organic bases such as 8-diazabicyclo [5.4.0] undec-7-ene or potassium carbonate, sodium carbonate,
Inorganic bases such as potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, and sodium hydroxide can be mentioned, and triethylamine is preferable.

Compound (V) is obtained by reacting compound (I) with compound (II) and then obtaining compound (III)
Can be obtained by subsequent reaction with compound (IV) without isolation. Compound (IV) used in this reaction can be produced according to WO94 / 14794 or JP-A-59-67290.

The reaction from the compound (V) to the compound (VI) and the reaction from the compound (VIII) to the compound (VII) are carried out in accordance with WO 94/14794.
1 to 150 ° C. in a suitable solvent in the presence of a base.
It is performed for 24 hours, preferably for 1 to 12 hours. As a base to be used, an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene or sodium hydride, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, water Examples thereof include inorganic bases such as sodium oxide and potassium hydroxide, and preferred is triethylamine.

Suitable solvents used in this reaction include water,
Examples thereof include alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, and mixtures thereof. Compound (VI) to compound (VII)
The reaction from compound (V) to compound (VIII) is carried out in a suitable solvent in the presence of an acid at room temperature to 100
C. for 1 to 24 hours, preferably 1 to 12 hours.

Suitable solvents used in this reaction include water,
Examples thereof include alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, acetonitrile, acetone, dioxane, dimethylformamide, dimethylsulfoxide, and mixtures thereof, and are preferably water and acetone. Examples of the acid used in this reaction include acetic acid, hydrochloric acid, sulfuric acid, potassium hydrogen sulfate, sulfamic acid, trifluoroacetic acid, methanesulfonic acid and the like, with hydrochloric acid being preferred.

Compound (I) used in the production method of the present invention can be produced according to the method described in International Publication WO94 / 14794. For example, compound (I) can be produced by the following route.

[0051]

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In the above reaction step, Ra represents a lower alkyl, acyl, amino protecting group, Rb, Rc represents a lower alkyl, phenylalkyl, Rd, Re represents a lower alkyl, amino protecting group, and Rf represents methanesulfonyl. , Trifluoromethanesulfonyl and paratoluenesulfonyl. Here, acyl refers to alkanoyl having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, or aroyl such as benzoyl, toluoyl, and naphthoyl.

The amino protecting group is a protecting group usually used in organic synthesis, such as benzyl, substituted benzyl (2-, 3- or 4-chlorobenzyl, 2-, 3-
Or 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-nitrobenzyl,
3,4-dimethoxybenzyl), α-methylbenzyl,
(S) -α-methylbenzyl, (R) -α-methylbenzyl, diphenylmethyl, bis (4-methoxyphenyl) methyl, triphenylmethyl, phenacyl, acetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxy Carbonyl, tertiary butoxycarbonyl and the like.

Compound (1), which is a starting material in this production method, is
For example, it can be produced according to the method described in JP-A-3-209382. Step a Step a is carried out in an alcohol such as methanol, ethanol and isopropyl alcohol, water or a mixed solvent thereof in the presence of an inorganic base such as lithium hydroxide, sodium hydroxide and potassium hydroxide or an acid such as hydrochloric acid and sulfuric acid.
By hydrolyzing compound (1), compound (2)
This is the step of obtaining

The compound (1) can be prepared using a microorganism-derived lipase, a microorganism-derived lipoprotein lipase, an animal tissue-derived esterase (such as an acetone extract from pig liver) and a plant tissue-derived esterase.
It can be asymmetrically hydrolyzed. The pH at which the hydrolysis is carried out by the enzyme is appropriately selected depending on the enzyme to be used, but is usually in the range of pH 4 to 9. The reaction temperature is appropriately selected depending on the enzyme to be used, but is usually from 10 to 10.
It is performed in the range of 50 ° C. Examples of the solvent used include a potassium phosphate buffer. The reaction can also be carried out by adding a solvent such as dimethyl sulfoxide to the solvent.

Step b In step b, compound (2) is prepared by using an acid chloride such as an acid chloride in a solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dimethylformamide, dimethyl sulfoxide, dichloroethane, chloroform or methylene chloride using thionyl chloride or the like. After leading to
In a solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dimethylformamide, dimethyl sulfoxide, toluene, xylene, benzene, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium methoxide,
This is a step of obtaining a compound (3) by reacting an amine of RdReNH in the presence of a base such as sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydride, triethylamine, diisopropylethylamine, and pyridine.

Step c Step c is a step of obtaining compound (4) by subjecting compound (3) to the same operation as in step a. Step d In step d, compound (4) is prepared by adding tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, toluene, xylene, benzene, dimethylformamide,
In solvents such as dimethylacetamide, dimethylsulfoxide, hexane, methylene chloride, chloroform and dichloroethane, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, chlorocarbonate (methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), Reaction with dimethylformamide-oxalyl chloride or the like leads to its reactive derivative, and then tetrahydrofuran, diethyl ether, diisopropyl ether, toluene, xylene, benzene, diethylene glycol dimethyl ether, acetonitrile, dimethylformamide, dimethylacetamide, water or a mixture thereof. Sodium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum in a solvent such as a mixture of With a step of obtaining compound (5) by subjecting to a reduction reaction.

Step e In the step e, compound (5) was prepared by adding tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, toluene, xylene, benzene, dimethylformamide,
Paratoluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride in a solvent such as dimethylacetamide, dimethylsulfoxide, hexane, methylene chloride, chloroform and dichloroethane, if necessary, in the presence of a base (pyridine, triethylamine, etc.) In this step, the compound (6) is obtained by reacting a substance or the like.

Step f In Step f, compound (6) is prepared by converting alcohols such as methanol, ethanol and isopropyl alcohol, tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, toluene, acetone, acetonitrile, dimethylformamide, dimethylacetamide and dimethyl In a solvent such as sulfoxide, hexane, methylene chloride, chloroform, dichloroethane, ethylene glycol monomethyl ether, water or a mixed solvent thereof, a fluorinating agent (sodium fluoride, potassium fluoride, magnesium fluoride, calcium fluoride, tetrabutyl) Ammonium fluoride, etc.) to obtain the compound (7).

Step g In the step g, compound (7) is prepared by treating a compound such as lithium aluminum hydride and bis (2-methoxyethoxy) in a solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, toluene, xylene, benzene or diethylene glycol dimethyl ether. A) a step of obtaining a compound (8) by subjecting it to a reduction reaction with sodium aluminum, diborane, sodium borohydride-iodine, sodium borohydride-sulfuric acid and the like;

Step h In the step h, the compound (8) is prepared in an alcohol such as methanol, ethanol, propanol or isopropyl alcohol or a solvent such as acetic acid in the presence of a catalyst such as palladium carbon, palladium hydroxide carbon or palladium black. If necessary, perform a hydrogenolysis reaction under heating and pressure, or in a solvent such as methanol, ethanol, propanol, isopropyl alcohol or acetic acid, or a catalyst such as palladium carbon, palladium hydroxide carbon, palladium black. This is a step in which a compound (I) is obtained by adding water-containing hydrazine, ammonium formate, or the like in the presence and heating and refluxing to deprotect the compound (I).

When the ester of the compound (1) or the compound (3) is asymmetrically hydrolyzed, the obtained optically active compound (2) or the compound (4) is reacted according to each of the above steps. By doing so, an optically active compound (I) can be produced. As described later, the compound (VII) is particularly preferably a compound in which R ⁴ is methoxy, Hal is fluorine, and the compound is an optically active S isomer. Compound (VI
In producing the S isomer of I), the compound (I) is preferably an S isomer, the compound (III) is preferably an R isomer, the compound (V) is preferably an R isomer, and the compound (V)
I) is preferably an R isomer, and compound (VIII) is preferably an S isomer.

The target product obtained in each reaction can be isolated and purified by appropriately combining ordinary means such as centrifugation, concentration, separation, washing, drying, recrystallization, and distillation. Compound (VI) produced by the production method of the present invention
I), especially R ⁴ is methoxy, Hal is fluorine, and (S) -7- (3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-which is an optically active S isomer
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid has an excellent antibacterial activity, and has a strong antibacterial activity against Gram-negative bacteria and Gram-positive bacteria. In particular, it has a strong antibacterial activity against quinolone-resistant MRSA (methicillin-resistant Staphylococcus aureus), Staphylococcus epidermidis, enterococci, and the like, and is useful as an antibacterial agent with significantly reduced side effects such as phototoxicity. .

Further, compound (V), compound (VI) and compound (VII) produced by the production method of the present invention
I) is useful as an intermediate for synthesizing compound (VII), which is useful as an antibacterial agent.

[0065]

The present invention will be described in more detail with reference to the following Preparation Examples and Examples, which should not be construed as limiting the invention. Bn in the structural formula represents benzyl. Preparation Example 1:

[0066]

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Dimethyl sulfoxide 11 ml, 0.5 M
1-to 210 ml of potassium phosphate buffer (pH 8.0)
13.9 g of dimethyl benzyl-5-oxopyrrolidine-3,3-dicarboxylate and 1.38 g of pig liver acetone powder were added, followed by stirring at 30 ° C. for 7 hours. The reaction solution was filtered through celite, acidified with hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give (R)-(+)-1-benzyl-5-oxopyrrolidine-3,3-dicarboxylic acid monomethyl ester 9.
0 g was obtained. Melting point: 137 to 139 ° C (decomposition) [α] _D = + 7.24 ° (C = 1, methanol) NMR (DMSO-d ₆ ) δ: 7.20 to 7.38 (5H), 4.38 (S, 2H), 3.63
-3.68 (5H), 2.88 (S, 2H) Preparation Example 2:

[0068]

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5.6 g of (R)-(+)-1-benzyl-5-oxopyrrolidine-3,3-dicarboxylic acid monomethyl ester was dissolved in 60 ml of 1,2-dichloroethane, and 4.4 ml of thionyl chloride was added. Thereafter, the mixture was refluxed for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The obtained oil was dissolved in 10 ml of toluene, and dibenzylamine 4.8 was added.
g, 3.4 ml of triethylamine and 100 parts of toluene
The resulting mixture was added dropwise to the resulting solution under ice-cooling and then stirred at room temperature for 3 hours. After the reaction, the reaction solution was water, sodium hydrogen carbonate,
The extract was washed successively with 10% aqueous hydrochloric acid and water, and dried. After the solvent was distilled off, recrystallization from isopropyl alcohol gave (R)-(+)-1-benzyl-3-.
7.8 g of (N, N-dibenzylcarbamoyl) -5-oxopyrrolidine-3-carboxylic acid methyl ester was obtained. Melting point: 132-134 ° C. [α] _D = + 10.5 ° (C = 1, ethyl acetate) NMR (DMSO-d ₆ ) δ: 7.06-7.48 (15H), 4.23-4.56 (6H),
3.93 (d, 1H), 3.70 (d, 1H), 3.52 (S, 3H), 3.17 (d, 1H), 2.
90 (d, 1H) Preparation Example 3:

[0070]

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(R)-(+)-1-benzyl-3-
(N, N-dibenzylcarbamoyl) -5-oxopyrrolidine-3-carboxylic acid methyl ester (30 g) was treated with sodium hydroxide (11 g), water (100 ml) and methanol (30).
0 ml of the solution was added and stirred at 40 ° C. for 4 hours.
After methanol was distilled off after the reaction, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and the solvent was distilled off. By performing recrystallization from toluene, (R)-(+)-1-benzyl-3- (N, N-
Dibenzylcarbamoyl) -5-oxopyrrolidine-3
-27.8 g of carboxylic acid were obtained. Melting point: 136-138
° C (decomposition) [α] _D = + 4.2 ° (C = 1, methanol) NMR (CDCl ₃ ) δ: 6.96-7.36 (15H), 4.15-4.66 (6H), 3.99
(d, 1H), 3.70 (d, 1H), 3.33 (d, 1H), 3.05 (d, 1H) Preparation Example 4:

[0072]

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(R)-(+)-1-benzyl-3-
To a solution consisting of 13.7 g of (N, N-dibenzylcarbamoyl) -5-oxopyrrolidine-3-carboxylic acid, 41 ml of 1,2-dichloroethane and 5.2 ml of triethylamine, 2.7 ml of thionyl chloride was added dropwise under ice cooling. ,
After stirring at room temperature for 15 minutes, the mixture was stirred under reflux for 30 minutes. After the reaction, the reaction solution was concentrated under reduced pressure. The obtained oil is dissolved in 20 ml of tetrahydrofuran, and tetrahydrofuran 60 is dissolved.
ml, water 20 ml and sodium borohydride 2.9
g, and the mixture was added dropwise under ice-cooling, followed by stirring at room temperature for 30 minutes. After extracting the reaction solution with toluene, the toluene layer was washed with water and dried. After evaporating the solvent, recrystallization from ethyl acetate-hexane gave (S)-(+)-
1-benzyl-3- (N, N-dibenzylcarbamoyl) -3-hydroxymethyl-5-oxopyrrolidine 1
1.3 g were obtained. Melting point: 116-118 ° C. [α] _D = + 26.8 ° (C = 1, methanol) NMR (CDCl ₃ ) δ: 7.02-7.29 (15H), 4.27-4.48 (6H), 3.7
5 (d, 1H), 3.64 (d, 1H), 3.57 (d, 1H), 3.40 (d, 1H), 2.80 (d, 1
H), 2.60 (d, 1H) Preparation Example 5:

[0074]

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(S)-(+) 1-benzyl-3- (N,
3. N-dibenzylcarbamoyl) -3-hydroxymethyl-5-oxopyrrolidine 10 g, triethylamine
2 ml was dissolved in 50 ml of chloroform, 3.4 g of mesyl chloride was added dropwise under ice cooling, and the mixture was further stirred for 30 minutes under ice cooling. The reaction solution was washed with water, diluted hydrochloric acid and water in that order, and dried. By concentrating the solvent, (S)-(+)-1-
Benzyl-3- (N, N-dibenzylcarbamoyl)-
3-mesyloxymethyl-5-oxopyrrolidine 10.
8 g were obtained as white crystals. Melting point: 167-170 ° C. [α] _D = + 6.0 ° (C = 1, chloroform) NMR (CDCl ₃ ) δ: 7.08-7.30 (5H), 4.47 (d, 1H), 4.35 (d,
1H), 4.25-4.31 (6H), 3.81 (d, 1H), 3.37 (d, 1H), 2.95 (d, 1
H), 2.79 (s, 3H), 2.61 (d, 1H) Preparation Example 6:

[0076]

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(S)-(+)-1-benzyl-3-
10.1 g of (N, N-dibenzylcarbamoyl) -3-mesyloxymethyl-5-oxopyrrolidine, 1.4 g of potassium fluoride and 50 ml of ethylene glycol monomethyl ether were mixed and refluxed for 2 hours. Water 20
0 ml was added and extracted with toluene. The toluene layer was washed with water and dried. By concentrating the solvent, (S)-
7.4 g of (+)-1-benzyl-3- (N, N-dibenzylcarbamoyl) -3-fluoromethyl-5-oxopyrrolidine was obtained as white crystals. Melting point: 154-15
6 ° C. [α] _D = + 22.8 ° (C = 1, chloroform) NMR (CDCl ₃ ) δ: 7.07-7.32 (15H), 4.29-4.62 (8H), 3.8
Preparation Example 7: 4 (d, 1H), 3.30 (d, 1H), 2.95 (d, 1H), 2.65 (d, 1H)

[0078]

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(S)-(+)-1-benzyl-3-
In a suspension of 7.3 g of (N, N-dibenzylcarbamoyl) -3-fluoromethyl-5-oxopyrrolidine, 3.9 g of sodium borohydride and 150 ml of tetrahydrofuran, 2.8 ml of concentrated sulfuric acid and 30 parts of tetrahydrofuran were added.
ml of the mixed solution was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
The mixture was stirred under reflux for 3 hours. After cooling the reaction solution, a mixed solvent of 2.5 ml of water and 2.5 ml of tetrahydrofuran was added dropwise, and then 20 ml of 3N hydrochloric acid was added, and the mixture was stirred and refluxed for 3 hours. After cooling, the mixture was made alkaline with an aqueous sodium hydroxide solution, extracted with toluene, dried, and concentrated. The residue was dissolved in 30 ml of acetone, and 2.8 ml of concentrated hydrochloric acid was added to give (R)-(+)-1-benzyl-3- (N, N
-Dibenzylaminomethyl) -3-fluoromethylpyrrolidine hydrochloride (7.5 g) was obtained as white crystals. Melting point:
208-210 ° C. [α] _D + 15.0 ° (C = 1, dimethylformamide) NMR of the free base (CDCl ₃ ) δ: 7.15-7.31 (15H), 4.43 (q,
1H), 4.25 (q, 1H) 3.60 (4H), 3.46 (d, 1H), 3.39 (d, 1H), 2.65
(S, 2H), 2.06-2.55 (4H), 1.38-1.59 (m, 2H) Preparation Example 8:

[0080]

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(R)-(+)-1-benzyl-3-
13.4 g of (N, N-dibenzylaminomethyl) -3-fluoromethylpyrrolidine was added to isopropyl alcohol 1
Dissolved in 30 ml and 10% palladium carbon 2.8 at room temperature
g and hydrazine monohydrate (5.0 g) were added, and the mixture was refluxed for 3 hours. After the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure. The residue was purified by distillation to obtain 3.8 g of (S)-(+)-3-aminomethyl-3-fluoromethylpyrrolidine as an oil. Boiling point: 103-105 ° C / 15m
mHg NMR (CDCl ₃ ) δ: 4.44 (dd, 1H), 4.26 (dd, 1H), 2.96 (t, 2
H), 2.69-2.85 (4H), 1.56 (t, 2H), 1.38 (3H)

[0082]

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(S)-(+)-3-Aminomethyl-3-
A mixture of 6.0 g of fluoromethylpyrrolidine, 5.1 g of benzaldehyde and 60 ml of toluene was mixed with Dean-S
A star water separator was attached, and the mixture was heated under reflux for 5 hours to remove water. After the reaction, by distilling off the solvent under reduced pressure,
(R)-(+)-3-benzylideneaminomethyl-3-
10.0 g of fluoromethylpyrrolidine (100% yield)
Was obtained as a colorless oil.

NMR (CDCl ₃ ) δ: 8.32 (s, 1H), 7.12-7.75
(5H), 4.48 (dd, 1H), 4.31 (dd, 1H), 3.66 (s, 2H), 2.73-3.03
(4H), 1.97 (1H), 1.54-1.82 (m, 2H) Example 2:

[0085]

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(R)-(+)-3-benzylideneaminomethyl-3-fluoromethylpyrrolidine 10.5 g, 1
-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid / difluoroborane complex 14.2 g, triethylamine 5.7 ml, and acetonitrile 100 ml were mixed at room temperature. Stirred for 16 hours. After concentrating the reaction solution under reduced pressure, recrystallization from methanol gave (R)-(+)
-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-
6-fluoro-1,4-dihydro-8-methoxy-4-
21.3 g (yield 95.0%) of oxo-3-quinolinecarboxylic acid / difluoroborane complex was obtained as yellow crystals. Melting point: 149 to 151 ° C. [α] _D = + 72.6 ° (C = 1, chloroform) NMR (CDCl ₃ ) δ: 8.91 (s, 1H), 8.37 (s, 1H), 7.80 (d, 1H),
7.40-7.77 (5H), 4.63 (dd, 1H), 4.45 (dd, 1H), 4.29-4.37 (m,
1H), 3.78-3.94 (6H), 3.66 (s, 3H), 2.03-2.19 (m, 2H), 1.18-
1.37 (m, 4H) Example 3:

[0087]

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(S)-(+)-3-Aminomethyl-3-
A mixture of 6.0 g of fluoromethylpyrrolidine, 5.1 g of benzaldehyde and 100 ml of acetonitrile was mixed at 60 ° C.
For 1 hour, and then 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid / difluoroborane complex 1
5.6 g and 6.3 ml of triethylamine were added, and the mixture was stirred at room temperature for 23 hours. After concentrating the reaction solution under reduced pressure, recrystallization from methanol gave (R)-(+)-7.
-(3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-
Fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid / difluoroborane complex 2
2.3 g (91.3% yield) were obtained as yellow crystals. Melting point: 149 to 151 ° C. [α] _D = + 72.6 ° (C = 1, chloroform) NMR (CDCl ₃ ) δ: 8.91 (s, 1H), 8.37 (s, 1H), 7.80 (d, 1H),
7.40-7.77 (5H), 4.63 (dd, 1H), 4.45 (dd, 1H), 4.29-4.37 (m,
1H), 3.78-3.94 (6H), 3.66 (s, 3H), 2.03-2.19 (m, 2H), 1.18-
1.37 (m, 4H) Example 4:

[0089]

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(R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy- A mixture of 20.0 g of 4-oxo-3-quinolinecarboxylic acid / difluoroborane complex, 30.0 ml of triethylamine and 110 ml of methanol was heated and refluxed for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and then recrystallized from ethanol,
(R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-
Methoxy-4-oxo-3-quinolinecarboxylic acid
2 g (yield 94.0%) was obtained as white crystals. Melting point:
150-152 ° C. [α] _D = + 52.9 ° (C = 1, dimethylformamide) NMR (CDCl ₃ ) δ: 8.77 (s, 1H), 8.37 (s, 1H), 7.80 (d, 1H),
7.38-7.76 (5H), 4.60 (dd, 1H), 4.43 (dd, 1H), 3.96-4.05 (m,
1H) 3.69-3.82 (6H), 3.60 (s, 3H), 1.95-2.14 (m, 2H), 0.98-
1.24 (m, 4H) Example 5:

[0091]

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6.3 g of (R)-(+)-3-benzylideneaminomethyl-3-fluoromethylpyrrolidine, (1
-Cyclopropyl-6,7-difluoro-1,4 dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid / diacetoxyborane complex 10 g, triethylamine 7.0 ml and acetonitrile 60 ml
Stirred at 0 ° C. for 15 hours. After the reaction, the solvent was distilled off under reduced pressure to give (R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1. , 4-Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid / diacetoxyborane complex was obtained.

NMR (CDCl ₃ ) δ: 9.04 (s, 1H), 8.37 (s, 1
H), 7.85 (d, 1H), 7.42-7.76 (5H), 4.61 (dd, 1H), 4.43 (dd, 1
H), 4.14-4.22 (m, 1H), 3.76-3.88 (6H), 3.58 (s, 3H), 2.04
(s, 6H), 2.00-2.15 (m, 2H), 1.11-1.35 (m, 4H) Triethylamine 20ml and ethanol 10
The mixture was mixed with 0 ml and heated under reflux for 25 hours. After the reaction, the reaction solution is concentrated under reduced pressure, and then recrystallized from ethanol to give (R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-yl. 9.5 g (yield: 81.3%) of cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid was obtained as white crystals. Melting point: 150-152 ° C. [α] _D = + 52.9 ° (C = 1, dimethylformamide) NMR (CDCl ₃ ) δ: 8.77 (s, 1H), 8.37 (s, 1H), 7.80 (d, 1H) ,
7.38-7.76 (5H) 4.60 (dd, 1H), 4.43 (dd, 1H), 3.96-4.05 (m,
1H) 3.69-3.82 (m, 6H), 3.60 (s, 3H), 1.95-2.14 (m, 2H), 0.98
-1.24 (m, 4H) Example 6:

[0094]

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(R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy- 5.0 g of 4-oxo-3-quinolinecarboxylic acid and 100 ml of acetone were mixed,
0.9 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 6 hours. After the reaction, the solvent was distilled off, and the resulting crystals were collected by filtration to give (S)-(+)-7- (3-aminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclocyclohexane. Propyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride 3.9
g (88.5% yield) as pale yellow crystals. Melting point:
213-217 ° C Example 7:

[0096]

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(R)-(+)-7- (3-benzylideneaminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy- 5.0 g of 4-oxo-3-quinolinecarboxylic acid, 15 ml of 2N hydrochloric acid and 100 ml of water
And stirred at 40 ° C. for 2 hours. After the reaction, the reaction solution was washed with chloroform, and the aqueous layer was adjusted to pH 7.2 with an aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration to give (S)-(+)-7- (3-aminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-.
Cyclopropyl-6-fluoro-1,4-dihydro-8
-Methoxy-4-oxo-3-quinolinecarboxylic acid3.
8 g (yield 92.3%) was obtained as pale yellow crystals. Melting point: 195 ° -197 ° C. [α] _D = + 65.3 ° (C = 1, 0.1N aqueous hydrochloric acid) NMR (DMSO-d ₆ ) δ: 8.66 (s, 1H), 7.65 (d, 1H), 4.59 (dd, 1
H), 4.42 (dd, 1H), 4.14-4.15 (m, 1H), 3.17-3.73 (7H), 2.70
(s, 2H), 1.72-1.93 (m, 2H), 1.00-1.11 (m, 4H) The following compounds are produced in the same manner as in the above Examples.

(8) 7- (3-Aminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-
4-oxo-3-quinolinecarboxylic acid

[0099]

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Mp 192-194 ° C. (9) (R)-(-)-7- (3-aminomethyl-3-
Fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

[0101]

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[Α] _D = −39.4 ° (1.50% methanol-chloroform).

[0103]

According to the production method of the present invention, (S) -7- (3-aminomethyl-3-fluoromethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-1 is useful as an antibacterial agent. , A compound represented by 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (VI
The present invention provides a production method which is capable of producing I) with high purity and high yield by a simple method and which is excellent in industrial production. That is, by protecting the primary amine of the compound (I) with a Schiff base and reacting with the compound (IV), the compound (V) can be easily produced with high purity, high yield and high yield. Further, the compound (V) obtained can easily convert its Schiff base to the corresponding primary amine by treating with an acid, and the post-reaction of the reaction is easy. ) Can be produced very simply, with high purity and high yield.

Further, compound (V), compound (VI) and compound (VIII) are useful as intermediates for synthesizing compound (VII), which is useful as an antibacterial agent.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Mineo Tsuruta 955, Kozai, Oaza, Yoshitomi-cho, Tsukigami-gun, Fukuoka Inside the development laboratory of Yoshitomi Pharmaceutical Co., Ltd.

Claims (10)

[Claims] 1. Compound 1 , Its R isomer or its S isomer, and a compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl or substituted aryl.)
Is obtained by condensing a compound represented by the following formula: (Wherein R ¹ and R ² have the same meanings as described above), its R isomer or its S isomer, and a compound represented by the general formula: Wherein R ³ represents fluorine, acyloxy or acyloxy substituted by halogen; R ⁴ represents halogen or methoxy; Hal represents halogen. Formula (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 2. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl or substituted aryl.
³ represents fluorine, acyloxy or acyloxy substituted by halogen. R ⁴ represents halogen or methoxy. Hal represents halogen. ), Its R isomer or its S isomer is treated with a base to give a compound of the general formula (Wherein each symbol has the same meaning as described above), a compound represented by the formula: R isomer or S isomer thereof, and then treated with an acid. (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 3. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl or substituted aryl.
³ represents fluorine, acyloxy or acyloxy substituted by halogen. R ⁴ represents halogen or methoxy. Hal represents halogen. ), Its R isomer or its S isomer is treated with an acid to give a compound of the general formula (Wherein each symbol is as defined above), an R isomer or an S isomer thereof, and then treated with a base. (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 4. A compound of the formula , Its R isomer or its S isomer, and a compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl, or substituted aryl.)
Wherein the compound represented by the general formula is condensed. (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 5. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl, or substituted aryl.)
And an R isomer or an S isomer thereof, and a compound represented by the general formula: Wherein R ³ represents fluorine, acyloxy or acyloxy substituted by halogen; R ⁴ represents halogen or methoxy; Hal represents halogen. Formula 17 (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 6. Compound: embedded image , Its R isomer or its S isomer and the general formula: (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl, or substituted aryl.)
Is obtained by condensing a compound represented by the following formula: (Wherein R ¹ and R ² are as defined above), its R isomer or its S isomer, and a compound represented by the general formula: (Wherein R ³ represents fluorine, acyloxy or acyloxy substituted by halogen; R ⁴ represents halogen or methoxy; Hal represents halogen), and condensed to give a compound represented by the general formula: ] (Wherein each symbol is as defined above), an R isomer or an S isomer thereof, and then treated with a base to obtain a compound represented by the following general formula: (Wherein each symbol has the same meaning as described above), and a compound represented by the general formula: wherein the R isomer or the S isomer thereof is treated with an acid. (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 7. Compound: embedded image , Its R isomer or its S isomer and the general formula: (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl, or substituted aryl.)
Is obtained by condensing a compound represented by the following formula: (Wherein R ¹ and R ² have the same meanings as described above), its R isomer or its S isomer, and a compound represented by the general formula: (Wherein, R ³ represents fluorine, acyloxy, or acyloxy substituted by halogen; R ⁴ represents halogen or methoxy; Hal represents halogen), and condensed to give a compound represented by the general formula: ] (Wherein each symbol is as defined above), an R isomer or an S isomer thereof, and then treated with an acid to obtain a compound represented by the following general formula: (Wherein each symbol is as defined above), and the R isomer or the S isomer thereof is treated with a base. (Wherein each symbol is as defined above), a process for producing the R isomer or the S isomer thereof. 8. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl or substituted aryl.
³ represents fluorine, acyloxy or acyloxy substituted by halogen. R ⁴ represents halogen or methoxy. Hal represents halogen. Or a R isomer or an S isomer thereof. 9. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl or substituted aryl.
⁴ represents halogen or methoxy. Hal represents halogen. ), Its R isomer or its S isomer, or a salt thereof. 10. A compound of the general formula (In the formula, R ¹ and R ² are the same or different and each represents hydrogen, alkyl, aryl, or substituted aryl.)
Or an R isomer or an S isomer thereof.