JPH089993A - Production of quinolinecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject derivative useful as a raw material for antimicrobial agents, etc., by asymmetrically decomposing a specific 2- thioquinoline-3-carboxylic acid ester with an ester transferase having stereoselective ester transfer actions, then asymmetrically acylating the resultant product and further selectively decomposing and removing either thereof with an enzyme. CONSTITUTION:This method for producing an optically active quinolinecarboxylic acid derivative of formula II [R<2> is H, an alkyl, an alkoxy, amino, a halogen, etc.; R<3> is an alkyl; R<13> is an acyl different from R<12>; B is a protecting group of hydroxyl group; Z is a halogen, a (substituted)cyclic amino group or a (substituted)phenyl; (n) is 1-10] is to carry out the asymmetric alcoholysis of 2-(1-chloroalkyl)thioquinoline-3-carboxylic acids of formula I (R<12> is an acyl) in the presence of an enzyme having stereoselective ester transfer actions, then react an acyl donor having an acyl group different from that of a raw material, asymmetrically acylate an alcohol derivative in the reactional solution, remove the enzyme and subsequently perform the selective alcoholysis of either of the acyl derivatives in a substrate of the reactional solution and separate the resultant derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing an optically active intermediate useful for producing an optically active thiazetoquinolinecarboxylic acid derivative useful as an antibacterial agent.

[0002]

BACKGROUND OF THE INVENTION The present inventors have developed an optically active 2- (1-chloro-2-acyloxyethyl) which is an important intermediate for producing an optically active thiazetoquinolinecarboxylic acid derivative useful as an antibacterial agent. A thio-6-fluoro-7-substituted-4-acyloxyquinoline-3-carboxylic acid ethyl ester derivative was created and filed previously (PCT / JP93 / 01897). This compound was separated by the enzymatic method, but the alcohol body, which is the + body, was unstable and could not be separated.

[0003]

DISCLOSURE OF THE INVENTION The present inventors focused on the usefulness of an optically active thiazetoquinolinecarboxylic acid derivative, and an optically active (+)-2- (1-chloro-2) which is an intermediate thereof. −
Attempts have been made to develop a new and advantageous production method to overcome the drawbacks of the method for producing an acyloxyethyl) thio-6-fluoro-7-substituted-4-acyloxyquinoline-3-carboxylic acid alkyl ester derivative. Therefore, the object of the present invention is to
Optically active compounds useful for the treatment of infectious diseases [IV
b]

[0004]

[Chemical 7]

(In the formula, R ² represents hydrogen, alkyl, alkoxy, amino, nitro or halogen. R ³ represents alkyl. R ¹³ represents acyl. B represents a hydroxyl-protecting group. Z represents halogen, a substituted or unsubstituted cyclic amino group or a phenyl group, and n represents an integer of 1 to 10), which is an important optically active intermediate for the production of the general formula [Ib].

[0006]

[Chemical 8] ^{(Wherein, R 2, R 3, R} 13, B, Z, n are as defined above) is to provide a process for preparing compounds represented by.

[0007]

Means for Solving the Problems In the course of examining various production methods, the present inventors have shown the following general formula [III]

[0008]

[Chemical 9]

(Wherein R ² , R ³ , R ¹³ , B, Z, n
Is synonymous with the above. R ¹² represents acyl), and a mixture of optical isomers represented by the formula (3) is used to remove an enzyme reaction intermediate from the reaction system by using two kinds of enzymes having stereoselectivity and species selectivity of an acyl group. By carrying out a stepwise enzymatic reaction, a large amount of optically active general formula [Ib] can be produced efficiently.

[0010]

[Chemical 10]

The compound represented by: (+)-2- (1-chloro-ω-acyloxyalkyl) thio-6-fluoro-7-
It has been found that a substituted-4-acyloxyquinoline-3-carboxylic acid alkyl ester derivative can be obtained.
More specifically, (1) the following general formula [III]

[0012]

[Chemical 11]

Alcohol having a desired coordination [IIb] by decomposing one of the optical isomers of the substrate in the presence of an enzyme which stereoselectively asymmetrically decomposes the alcohol. The resulting reaction solution is further reacted with an acyl donor different from the acyl group of the raw material to asymmetrically acylate the alcohol, and then the reaction solution is subjected to acylation in the presence of an enzyme having a stereoselective ester transfer action. A general formula [Ib] characterized in that one acyl derivative of a substrate is group-selectively decomposed by alcoholysis and separated.

[0014]

[Chemical 12]

A method for producing an optically active quinolinecarboxylic acid derivative represented by: (2) Compound [III] is subjected to asymmetric alcoholysis in the presence of an enzyme having a stereoselective transesterification action to prepare a starting material. A method for producing an optically active compound represented by the general formula [Ib], which comprises reacting an acyl donor different from the above-mentioned acyl group with an acyl donor to asymmetrically acylate the alcohol compound in the reaction solution, and (3) The following general formula [III
a] [Ib] [IIa]

[0016]

[Chemical 13]

In the presence of an enzyme having a stereoselective ester transfer activity, a reaction solution containing a compound represented by the formula (1) is subjected to selective alcoholysis of an acyl group in an acyl group for separation and separation. Characterized optically active compound [I
b] relates to a method for producing an optically active quinolinecarboxylic acid derivative. In the formula, R ² represents hydrogen, alkyl, alkoxy, amino, nitro or halogen. R ³ represents alkyl. R ¹² and R ¹³ are different from each other and represent acyl.
B represents a hydroxyl-protecting group. Z represents halogen, a substituted or unsubstituted cyclic amino group, or a phenyl group. n
Represents an integer of 1 to 10. The optically active compound [Ib] obtained by the production method of the present invention is an optically active thiazetoquinolinecarboxylic acid useful for treating infections caused by Gram-negative bacteria, intractable Pseudomonas aeruginosa infections and Gram-positive bacteria infections. Useful as a synthetic intermediate for derivatives (PCT / JP93 / 01897
issue).

The present invention will be described in detail below. In the present invention, examples of the halogen represented by R ² and Z include fluorine, chlorine and bromine. The alkoxy represented by R ² is linear or branched and has 1 to 4 carbon atoms.
Is preferably lower alkoxy, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The alkyl represented by R ² and R ³ is preferably a linear or branched one having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, Examples thereof include isobutyl, sec-butyl, tert-butyl and the like. The acyl represented by R ¹² and R ¹³ includes alkanoyl having 2 to 8 carbon atoms (for example,
Acetyl, n-propionyl, n-butyryl, n-pentanoyl, n-hexanoyl, n-heptanoyl, n-octanoyl) and aroyl having 6 to 10 carbon atoms (eg, benzoyl, 4-methoxybenzoyl) can be mentioned. Among them, R ¹² is preferably alkanoyl having 2 to 4 carbon atoms (for example, acetyl, propionyl, n-butyryl, n-caproyl), and R ¹³ is preferably benzoyl. As the hydroxyl-protecting group represented by B, acyl is preferable, and for example, acetyl, benzoyl or the like can be used.

The cyclic amino group represented by Z includes
It is a 4- to 8-membered ring and may further contain a nitrogen, oxygen or sulfur atom as a constituent atom. Examples of the cyclic amino include azetidino, pyrrolidino, piperidino, azepino, azocino, piperazino, homopiperazino, pyrrino, morpholino, thiomorpholino, 3,7-diazabicyclo 3.3.0 octano (5) -en-3-yl, 4, 7-diazaspiro 2.5 octen-7-yl group and the like can be mentioned. The cyclic amino group may have one or more substituents, and examples of the substituent include alkyl, hydroxyalkyl, aminoalkyl, acyl, amino, hydroxy or (5-methyl-2-oxo-1, 3-dioxole-4-
Ilyl) methyl and the like.

When Z is a substituted phenyl, examples of the phenyl substituent include amino, alkylamino, hydroxy, alkoxy and acyl. As the acyl represented by the substituent of Z, a linear or branched alkanoyl having 1 to 4 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, trifluoroacetyl, and aroyl having 7 to 8 carbon atoms, For example, benzoyl, benzyl carbonyl, etc. can be mentioned. As the alkyl and alkoxy as the substituent of Z, those mentioned above can be mentioned.

As the enzyme having a stereolytic alcoholysis action and a transesterification action in an organic solvent, for example, lipase can be used. As the enzyme used in the present invention, any enzyme can be used as long as it can stereoselectively react one of the optical isomers in the substrate. Specifically, Pseudomonas
Genus, Candida, Alcaligenes
Examples include lipases derived from microorganisms belonging to the genus igenes), the genus Achromobacter, the genus Mucor, and the like. These lipases may be in powder form or may be immobilized on a carrier for immobilization such as Celite or various ion exchange resins. Commercially available products of the enzyme used in the first step and the second step are lipase QL, QLC, QLG, PL and PL.
C, PLG (Meito Sangyo Co., Ltd.), Lipozyme IM, Toyoteam L
IP (manufactured by Toyobo Co., Ltd.) and the like can be mentioned. Commercially available products of the enzyme used in the third step are lipase AL, ALC and ALG.
(Manufactured by Meito Sangyo Co., Ltd.) and Novozyme 435 (manufactured by Novo Nordisk Bioindustry). After the reaction, the enzyme can be reused by filtering. The optically active substance produced by the reaction can be easily separated and purified by extraction, recrystallization, fractional crystallization and column chromatography.

The present invention can be implemented, for example, by the following method.

[0024]

[Chemical 14]

In the formula, R ² , R ³ , R ¹² , R ¹³ , B, Z and n are the same as defined above. The general formula [III] is a mixture of optical isomers of substrates, the general formula [II] is an alcohol compound, the general formula [I] is an alcohol compound acylated with an acyl group different from the starting material, and the subscript a is (-). The body and b represent the (+) body. However, in the general formula [IV], b represents a (−) form. First step In the presence of an enzyme having a stereoselective transesterification action,
One of the optical isomers in the substrate is subjected to alcoholysis. Second step One of the optical isomers in the substrate is selectively reacted with an acyl donor in the presence of an enzyme having a stereoselective transesterification action to perform acylation. Third step, in the presence of an enzyme having a stereoselective ester transfer action,
One of the acyl bodies in the substrate is subjected to alcoholysis.

Each step will be described in detail below. First step In the presence of an enzyme having a stereoselective transesterification action,
One of the optical isomers of the optical isomer mixture represented by the general formula [III] is selectively reacted with alcohol in an organic solvent. The reaction is stopped when all optical isomers in the desired coordination have reacted. As the organic solvent, tetrahydrofuran, acetonitrile, acetone, chloroform, methylene chloride, n-hexane, benzene, toluene, diisopropyl ether, dioxane or the like can be used. As the alcohol, for example, methanol, ethanol,
Linear or branched aliphatic alcohols such as propanol, butanol, heptanol, octanol, benzyl alcohol and aromatic substituted alcohols can be used. The amount of alcohol used is usually 1 to 20 mol, preferably 3 to 5 mol, based on 1 mol of racemate, and the amount of the enzyme used is usually 0.01 to 10 g, preferably 0.05 to 5 g, based on 1 g of racemate. . The reaction is usually carried out at 5-90 ° C, preferably 15-65 ° C with shaking or stirring for 1-100 hours, preferably 2-70 hours. After the reaction, the enzyme can be reused by filtering. The obtained optical isomer is directly used for the next step without separation and purification.

Second step The reaction solution obtained in the first step is reacted with an acyl donor different from the starting material, and the alcohol in the reaction solution represented by the general formula [IIb] is selectively reacted with the acyl donor. . Since the reaction liquid of the first step is used as it is, the same enzyme and organic solvent as those used in the first step are used. After the reaction, the enzyme is filtered off and used in the next reaction. As the acyl donor, for example, benzoic anhydride, vinyl benzoate, or tert-butyl-substituted vinyl benzoate can be used. The amount of acyl donor used is usually substrate 1.
The reaction can be carried out under the same conditions as in the first step, 1 to 20 mol, preferably 3 to 5 mol per mol.

Step 3 In the presence of an enzyme having a stereoselective transesterification action,
Compound [IIIa], which is one of the optical isomers in the reaction solution obtained in the second step, is reacted with an alcohol in an organic solvent in an acyl group-selective manner to cause alcoholysis to separate the alcohol body to obtain an optical isomer. The body [Ib] can be acquired. As the organic solvent, for example, tetrahydrofuran, acetonitrile, acetone, chloroform, methylene chloride, n-hexane, benzene, toluene, diisopropyl ether, dioxane or the like can be used. The same alcohol as in the first step can be used as the alcohol.

The starting compound [III] can be produced by the following reaction formula, which will be described later as a reference example.

[0030]

[Chemical 15]

(Wherein R ² , R ³ , R ¹² , B, Z, n
Is the same as above. (G represents a protecting group for S) As a protecting group for sulfur, alkoxymethyl, substituted benzyl, 2,4-dinitrophenyl, disulfide as a dimer of [III], alkylthiomethyl, substituted carbamoyl, diphenylmethyl, triphenyl Phenylmethyl, picolyl, acetamidomethyl, β, β, β-trifluoro-
It is possible to use α-acylaminoethyl, β, β-diethoxycarbonylethyl, acyl (eg, acetyl, benzoyl), benzoyloxycarbonylethyl, tetrahydropyranyl, benzylthiomethyl, isobutyroxymethyl and the like. Representative examples of such protecting groups include methoxymethyl and methoxybenzyl.

Step 1 The hydroxy group at the 4-position of compound [V] is acylated by a conventional method to give compound [VI]. This acylation includes acyl chlorides (eg, acetyl chloride, benzoyl chloride, etc.) and acylating agents (eg, acetic anhydride and pyridine).
Can be used at 0 to 40 ° C. The reaction time varies depending on the type of [V] and the acylating agent used and the reaction temperature, but is usually 10 minutes to 12 hours.

Step 2 The protecting group at the 2-position of compound [VI] is eliminated by a conventional method to give compound [VII]. For example, when G is methoxymethyl, the protecting group can be eliminated by treating it with hydrochloric acid, concentrated sulfuric acid / ethanol, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof under cooling or at room temperature. You can

Step 3 Compound [VII] is acyloxyalkylated to give compound [VIII]. This acyloxyalkylation is carried out by using the compound [VII] and a halide (eg, 1-bromo-
2-acetylisyloxyethane, 1-bromo-3-propionyloxypropane, etc.) in the presence of a deoxidizing agent (eg, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, etc.) in a solvent inert to the reaction, Normally 0-120 ℃
Can be carried out by reacting with. As the solvent, for example, aprotic solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide, dimethylsulfoxide (DMSO) and sulfolane are preferable. The amount of the dihalide and the deoxidizing agent used is equimolar or more, preferably 1.0 to 2.5 mol per 1 mol of [V]. In order to accelerate the reaction, 0.01 to 3.0 molar equivalents of sodium iodide or potassium iodide may be added to carry out the reaction.

Fourth Step Further, compound [VIII] is chlorinated to give compound [II].
I] is manufactured. In this chlorination reaction, [III] is produced by chlorinating with a chlorinating agent in a solvent inert to the reaction. The reaction temperature is usually -30 ° C to 100 ° C. Examples of the solvent include chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, hexane, dioxane, tetrahydrofuran and the like. As the chlorinating agent, N-chlorosuccinimide, sulfuryl chloride, molecular chlorine or the like can be used. Usually, the chlorinating agent is used in an equivalent amount or more to an excess amount based on the compound [VIII]. The reaction time varies depending on the compound [VIII] used, the chlorinating agent, the type of solvent used and the reaction temperature, but is usually 30 minutes to 3 hours.

Compound [I obtained by the production method of the present invention
b] is subjected to ring closure according to a known method as described below to produce an optically active 6-fluoro- which is an important intermediate for producing a thiazetoquinolinecarboxylic acid derivative having antibacterial activity.
7-Substituted-4-oxo-4H-1,3 thiazet 3,2-a quinoline
It can be led to a 3-carboxylic acid alkyl ester derivative [IVb] (eg, WO93 / 25532).

[0037]

[Chemical 16]

(In the formula, R ¹ , R ² , R ³ and Z are the same as the above.) That is, [Ib] is cyclically reacted at room temperature to 100 ° C. in the presence of a base and optionally water. [IVb] can be produced by converting each of the compounds to [IVb]. At this time, the protecting groups are simultaneously removed. The solvent may be one that does not interfere with the reaction, for example, benzene, hydrocarbons such as toluene, tetrahydrofuran, ethers such as dioxane, N, N-dimethylformamide, N, N-dimethylformacetamide, An aprotic solvent such as dimethyl sulfoxide or sulfolane, or a mixture thereof is used. Examples of the base include organic acid salts (eg, sodium acetate, triethylamine, tripropylamine, pyridine, succinimide sodium salt, α-pyrrolidone sodium salt, etc.), inorganic bases (eg, lithium hydroxide, sodium hydrogen carbonate, sodium hydroxide) Etc. can be used. The base is usually used in an amount of 10 to 10 equivalents based on [Ib]. If water is required, it is used in an amount of 5 to 5 equivalents based on [Ib]. The reaction time varies depending on the type of [Ib], the base and the solvent, and the reaction temperature, but is usually 30 minutes to 180 hours.

[0039]

EXAMPLES The present invention will be described in more detail with reference to Reference Examples and Examples for the production of the compounds of the present invention. Using an HPLC column for optical isomer separation, the optical isomers produced by the reaction and the unchanged isomers were quantified under the following conditions, and the optical purity and conversion rate (%) of each were calculated. HPLC conditions Column: Daicel Chiralcel AD φ 4.6 × 250 mm Mobile phase solvent: Hexane: 2-propanol = 20: 1 Flow rate: 1 ml / min Detector: Hitachi UV detector L-4200, wavelength 254 nm

Reference Example 1 Synthesis of 2- (2-acetoxy-1-chloroethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (1) 4-benzoyloxy-6,7 Synthesis of -difluoro-2-methoxymethylthioquinoline-3-carboxylic acid ethyl ester 6,7-difluoro-4-hydroxy-2-methoxymethylthioquinoline-3-carboxylic acid ethyl ester 100 g pyridine
Dissolve in 500 ml and stir with ice-cooled benzoyl chloride 4
6.95 g was added dropwise, and the mixture was reacted at the same temperature for 2 hours. Ice water in the reaction solution
1.5 L (liter) was added and stirred for a while. The precipitated crystals were collected by filtration, washed with water, dissolved in chloroform,
The extract was washed with water, a dilute aqueous hydrochloric acid solution and saturated saline, and concentrated. 132 g of the target product was obtained as a pale yellow solid. Melting point 98-99 ° C

(2) 4-benzoyloxy-6,7-difluoro
Synthesis of 2-mercaptoquinoline-3-carboxylic acid ethyl ester 4-benzoyloxy-6,7-difluoro-2-methoxymethylthioquinoline-3-carboxylic acid ethyl ester 132 g, 35
A suspension of 38% of concentrated hydrochloric acid and 1280 ml of ethanol was reacted at room temperature for 22 hours. The precipitated crystals were collected by filtration, washed with ether and then dried to obtain 102.6 g of the desired product as a yellow solid. Melting point 162 ℃

(3) Synthesis of 2- (2-acetoxyethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester 4-benzoyloxy-6,7-difluoro-2-mercapto Quinoline-3-carboxylic acid ethyl ester (194.69 g) and sodium hydrogen carbonate (42.005 g) were suspended in DMF (1.5 l), and 1-acetoxy-2-bromoethane (83.505 g) was added over 45 minutes with stirring at room temperature, and the mixture was reacted for 30 minutes. After distilling off the solvent from the reaction solution,
Water was added and extracted with chloroform. Wash the extract with water,
It was dried over magnesium sulfate and then concentrated. The residue was washed with n-hexane and recrystallized from isopropyl alcohol.
120.6 g of the desired crystal was obtained. Melting point 97 ℃

(4) 2- (2-acetoxy-1-chloroethyl)
Thio-4-benzoyloxy-6,7-difluoroquinoline-3
-Synthesis of Carboxylic Acid Ethyl Ester A mixture of 30.0 g of the compound obtained in (3) and 300 ml of methylene chloride was added dropwise over 30 minutes while stirring under cooling with ice. After the dropping, the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off and the precipitated crystals were washed with n-hexane and recrystallized from isopropyl ether to obtain 19.0 g of the desired crystals. Melting point 106-107 ℃

Example 1 (+)-2- (2-benzoyloxy-1-chloroethyl) thio-4
-Benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (1) Racemic 2- (2-acetoxy-1) obtained in Reference Example 1 (4)
-Chloroethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester 2 g was dissolved in tetrahydrofuran 19.2 ml to give ethyl alcohol 0.8
Add 1 ml of lipase QL from Meito Sangyo Co., Ltd.
The mixture was added and stirred at 30 ° C. for 9 hours to carry out asymmetric alcoholysis reaction, and a part of the reaction solution was taken to produce by reaction.
(+)-2- (2-Hydroxy-1-chloroethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (hereinafter referred to as (+)-alcohol) and unchanged (-)-2- (2-acetoxy-1-chloroethyl) thio
-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (hereinafter referred to as (-)-acetoxy form) was quantified by an HPLC column for optical isomer separation,
The optical purity and conversion rate (%) of each were calculated. Optical purity: (+)-alcohol 82.5% ee (-)-acetoxy 97.8% ee Conversion: 54.2%

(2) Next, 4 g of benzoic anhydride was added to this reaction solution, and the mixture was stirred at 30 ° C. for 22 hours to carry out an asymmetric acylation reaction, and a part of the reaction solution was taken and produced by the reaction ( +)-2- (2
-Benzoyloxy-1-chloroethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (hereinafter referred to as (+)-benzoyloxy form)
And the unreacted (-)-acetoxy form as H for optical isomer separation.
It quantified with the PLC column, and calculated each optical purity and conversion rate (%). Optical purity: (+)-benzoyloxy form 99.0% ee (-)-acetoxy form 86.0% ee Conversion rate: 88.7%

(3) Next, this reaction solution was filtered to remove the enzyme, 0.8 ml of ethyl alcohol was added to the filtrate, and 2 g of lipase Novozyme 435 manufactured by Novo Nordisk was added at 30 ° C.
After stirring for 8.5 hours, the asymmetric alcoholysis reaction was carried out, and (-)-2- (2-hydroxy-1-chloroethyl) thio-4-benzoyloxy-6,7-difluoroquinoline-3- Carboxylic acid ethyl ester (hereinafter referred to as (-)-alcohol form) and unreacted (+)-benzoyloxy form were quantified by an HPLC column for optical isomer separation,
The optical purity and conversion rate (%) of each were calculated. Optical purity: (+)-benzoyloxy derivative 98.7% ee conversion: 47.3% Next, this reaction solution was filtered through No. 2 (same as above) filter paper to remove the enzyme, and separated and purified by the following method.

(4) The reaction solution was concentrated under reduced pressure and purified by column chromatography (Wakogel C-200 / registered trademark, n-hexane: ethyl acetate = 10: 1) to give (+)-benzoyloxy compound 0.824 g. Got The hydroxy form was decomposed in the column, and 0.16 g of 4-benzoyloxy-6,7-difluoro-2-mercaptoquinoline-3-carboxylic acid ethyl ester was recovered. HP for separating optical isomers of (+)-benzoyloxy form
It quantified by LC column and calculated the optical purity conversion rate (%). Optical purity: (+)-benzoyloxy form 98.4% ee (+)-benzoyloxy form: melting point 76 ° C Specific rotation α _D ＋ 69.84 ° (CHCl ₃ , c = 1.071) Elemental analysis value (C ₂₈ H ₂₀ ClF ₂ NO ₆ S) Calculated value (%) C: 58.80 H: 3.52 N: 2.45 Measured value (%) C: 59.01 H: 3.71 N: 2.27

Reference Example 2 6,7-Difluoro-1-benzoyloxymethyl-4-oxo
-4H-1,3 Thiazeto 3,2-a quinoline-3-carboxylic acid ethyl ester (production of acyl derivative) 0.82 g of (+)-benzoyloxy derivative obtained in (4) above, 0.435 g of triethylamine, 0.052 g of water And tetrahydrofuran 10
The ml mixture was refluxed at 80 ° C. for 4 hours. The reaction solution was cooled and the precipitated crystals were collected by filtration, washed with water and dried to obtain 0.40 g of the desired product. Melting point 193 ° C Specific rotation α _D −46.70 ° (CHCl ₃ , c = 1.062 Elemental analysis value (as C ₂₁ H ₁₅ F ₂ NO ₅ S) Calculated value (%) C: 58.47 H: 3.50 N: 3.25 Measured value ( %) C: 57.95 H: 3.58 N: 3.16

Claims (3)

[Claims] 1. The following general formula [III]: In the presence of an enzyme having a stereoselective ester transfer activity of the compound represented by, the reaction solution obtained by asymmetric alcoholysis is reacted with an acyl donor different from the starting acyl group to give an alcohol compound in the reaction solution. After asymmetric acylation and removal of the enzyme, in the presence of an enzyme having a stereoselective transesterification action, one acyl derivative of the substrate in this reaction solution is selectively subjected to alcoholysis with an acyl group and separated, General formula [Ib] wherein the other acyl derivative is obtained A method for producing an optically active quinolinecarboxylic acid derivative represented by: In the formula, R ² represents hydrogen, alkyl, alkoxy, amino, nitro or halogen. R ³ represents alkyl. R ¹² and R ¹³ represent different acyls. B represents a hydroxyl-protecting group. Z represents halogen, a substituted or unsubstituted cyclic amino group, or a phenyl group. n is 1 to 1
Represents an integer of 0. 2. The following general formula [III]: In the presence of an enzyme having a stereoselective ester transfer activity of the compound represented by, the reaction solution obtained by asymmetric alcoholysis is reacted with an acyl donor different from the starting acyl group to give an alcohol compound in the reaction solution. A process for producing an optically active general formula [Ib], which comprises asymmetric acylation. [Chemical 4] 3. The following general formula [IIIa] [Ib] [II
a] In the presence of an enzyme having a stereoselective ester transfer activity, a reaction solution containing a compound represented by the formula (1) is characterized in that one acyl derivative of the substrate is selectively alcoholysed and separated. A method for producing the general formula [Ib]. [Chemical 6]