WO1993025532A1 - Carboxylic acid derivative and production thereof - Google Patents

Abstract

A compound represented by general formula (I), a compound represented by general formula (II), and a process for producing a compound represented by general formula (Ia) by the ring closure reaction of a compound represented by general formula (IIa) wherein R1 represents hydrogen or alkyl; R2 represents alkyl; R3 represents hydrogen or acyl; R4 represents -NH¿2? or -SCH2R?1¿; and X represents hydrogen or chlorine. The invention process, using these compounds as the intermediates, can provide an alkyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolinecarboxylate in fewer steps than the conventional processes efficiently and economically.

Description

 Specification

 Carbonic acid derivatives and manufacturing technology

 TECHNICAL FIELD The present invention relates to intermediates useful for producing a derivative of thixoquinoline carboxylate useful as an antibacterial agent, and to a method for producing them.

More specifically, the present invention relates, in part, to quinoline carboxylic acid derivatives represented by the general formula [I].

In the formula, R ′ represents chromium or alkyl. R ² represents alkyl; R ³ represents hydrogen or acyl. X represents hydrogen or chlorine.

In addition, the general formula [IIa]

Wherein R ¹ represents hydrogen or alkyl; R ² represents alkyl. The compound represented by the general formula [ _Ia ]

(Wherein R ′ and R ² are the same as those described above), and a method for producing a quinoline carboxylic acid derivative represented by the formula: In addition, the general formula [II]

(Wherein, R ¹ represents hydrogen or alkyl. R ² represents alkyl. R ⁴ represents —NH ₂ or S CH ₂ R ¹ ).

In addition, the general formula [V]

を閉環反応に付すことを特徴とする一般式 [ I _a ]

(Wherein, R ¹ represents hydrogen or alkyl; R ² represents alkyl); and a compound formed by reacting 3,4-difluoronitrolin [IV]

To the ring closure reaction of the general formula [ _Ia ]

(Wherein R ¹ and R ² are the same as described above), and a method for producing a quinoline carboxylic acid derivative represented by the formula:

In addition, the general formula [V] R〗 CH ₂ S, COOR ²

 [V]

R, ^CH 2 ^S COOR ²

(Wherein, R ¹ represents hydrogen or alkyl; R ² represents alkyl) and 3,4-difluorinated nitrine, a general formula [IV] ] Individual o

(Wherein R ¹ and R ² are the same as described above).

 Background technology

 Various thizetoquinoline carboxylic acid derivatives synthesized from the compounds obtained by the production method according to the present invention by the following reaction formula have extremely excellent antibacterial activity, and are resistant to infections and intractable diseases caused by Gram-negative bacteria. It is useful for treating Pseudomonas aeruginosa infections and Gram-positive bacterial infections. Among them, 6-fluoro-1-methyl-7- [4-[(5-methyl-2oxo-1,3-dioxol-4-yl) methyl] -tovidurazur] -4-oxo -4H-[1, 3] thiazet

[3,2-a] quinolin-3 carboxylic acid may have superior properties compared to conventional products in terms of antibacterial activity, antibacterial spectrum, sustainability, safety, etc. It is known (see JP-A-63-107990, JP-A-1-94680, etc.).

 0

(R ² is the same as above. R represents hydrogen, alkyl, fuiryl, etc.) Conventionally, 6,7-difluoroπ which is an important raw material for producing various thizetoquinolinecarboxylic acid derivatives. The process for producing -4-oxo-4H- [1,3] thiazeto [3,2-a] quinolin-3-carboxylate ethyl ester derivative [III] is as shown in the following reaction formula. (See Japanese Patent Publication No. 63-1G799Q).

(P represents a protecting group. R is the same as described above.) This method requires: (1) many equipments due to the long process, (2) it is necessary to protect the mercapto group, and it is necessary to use carcinogenic chloromethyl methyl ether as the protecting group. During the formation, there were drawbacks, such as the need to use an expensive alkylating agent such as a dihalogenoalkane (eg, dibromethane), and the formation of ④ by-products (mainly reverse ring-closures).

 Disclosure of the invention

 The present inventors have paid attention to the usefulness of thiazetoquinoline carboxylic acid derivatives, and have found that the intermediate 6.7-difluoro-4--4-oxo-4- [1,3] thiazeto [3.2-a] quinoline-3 is an intermediate. —Rubonic acid alkyl ester derivative [III] We have been working on the development of a new and advantageous synthetic method that overcomes the disadvantages of the production method.

 Therefore, an object of the present invention is to provide a production method which is significantly superior to the above-mentioned existing production methods, and an intermediate useful therefor.

 In order to achieve the above object, the present inventors studied various synthetic methods, and as shown in the following reaction formula, as shown in the following reaction formula, 6,7-difluoro-4-oxo-4H-U.3] thiazeto The present inventors have found compounds useful for producing [3.2-a] quinolin-3-carboxylic acid alkyl ester derivatives and advantageous methods for producing them, and have completed the present invention.

(Hereinafter the margin)

 [V] [IV]

(In the formula, R ¹ and R ² are the same as above. R ³³ represents an acyl group.) (1) The gist of the present invention resides in one part in the present compound itself represented by the general formula [1]. is there.

 Another is a method for producing [Ia] by subjecting [IIa] to a ring-closing reaction.

 Another one is the compound of the present invention itself represented by the general formula [II].

In addition, one simple method is to heat 3,4-difluoro-alkylamine and (ylalkylsulfinyl) (ylalkylthio) dialkylalkylene methyl ester [V] without solvent or in a solvent. 2- (3,4-difluoro succinylamino) -2-ylalkylthioethylene-1,1-dicarboxylic acid dialkylester useful for producing [ _Ia ] by _a simple reaction ι V In the method of manufacturing.

—In general formulas [I] to [VI]! ? ¹ and as the alkyl Le represented by R ^2, a linear or branched lower alkyl good or properly having 1 to 6 carbon atoms, for example, methylation, Echiru, [pi - flop D pills, Lee Sopuro pills, Examples thereof include _n -butyl, sec-butyl, tert-butyl, n-pentylene J, isopentylene, _n- hexyl, and isohexyl.

Examples of R ³ represented by R ³ include, for example, C 1 -C 6 carbonyl (eg, formyl, cetyl, propionyl, petyril, isobutylyl J) , Norelyl, isonorelyl, hexisoylyl, isohexanoyl, chloromethyl cetyl, etc.), carbonyls having 7 to 10 carbon atoms (eg benzoyl) , Toluyl, xyl Dil, anisyl, etc.) which can be used as a protecting group for the glacial group.

 The compounds represented by the formulas [I] and [II] according to the present invention are novel compounds not described in any literature.

 The compound [I] according to the present invention can be produced, for example, according to the following reaction formula.

(式中、 R ¹ 、 R ² は、 前記と同じ。 R³³は了シルを表す〉

(Wherein, R ¹ and R ² are the same as described above. R ³³ represents syl>)

 After reacting the compound [VI] with carbon disulfide, the alkylating agent is reacted to produce [IIb]. This is used to produce [I Ia] by amino, and then closed to produce [I a]. The hydroxyl group at position 4 of the quinoline skeleton of [Ia] can be protected with thiol to give [Ib], and [lb] can be reacted with a chlorine agent to produce [Ic]. it can. Each step will be described in more detail.

1st step

The compound [VI] is reacted with carbon disulfide at 0 to 10 in the presence of a base in a solvent, and then reacted with an alkylating agent to produce [IIb]. As the solvent, alcohols such as ethanol and isopropanol, N, N-dimethylformamide, acetate and the like can be used. As the base, potassium carbonate, triethylamine, DBU and the like can be used. Is a completion alkylating agent may Rukoto using methyl iodide, Yo U Kako chill, dimethyl Chill sulfate, the completion alkylating agent corresponding to Jechiru sulfate R ^1. Use 1 to 2 mol of carbon disulfide and 2 to 5 mol of base and alkylating agent per 1 mol of compound [VI]. The reaction time varies depending on [VI] used, the type of solvent and reagent, and the reaction temperature, but is usually 30 minutes to 10 hours.

Second step

[li] is reacted with ammonia or ammonium salt (eg, ammonium chloride) in a solvent at 50 to 100 t to produce [IIa]. Preferred solvents are alcohols corresponding to R ¹ (eg, ethanol when R ¹ = ethyl). When using ammonia, seal Perform the reaction using a tube, but do not use a sealed tube when using other ammonium salts. It is preferable that the amount of the used salt or the used salt is 1 to 2 mol per 1 mol of [lib]. The reaction time varies depending on [li] and the type of the end monium or the end monium salt, and the reaction temperature, but is usually 5 to 30 hours.

3rd step

 [La] can be produced by subjecting the compound represented by the general formula [IIa] to a ring-closing reaction in a solvent in the presence of a base at 50 to 100 t :, preferably at around 801. Any solvent may be used as long as it is inert to the reaction. For example, N, N-dimethylformamide or the like can be used. As the base, there can be used, for example, hydrogen carbonate bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, DBU and the like. The reaction time varies depending on [IIa:], the kind of the solvent and the base, the reaction temperature and the like, but is usually 12 to 36 hours. The amount of the base to be used is generally 1 mol-3 mol per 1 mol of [IIa]. 4th step

Next, the compound [Ib] is prepared by subjecting the 4-π-hydroxy group at the 4-position of the compound [Ia] to a conventional method. This Ashiru reduction is Ryo silk port Li de (eg, Ryo Sechiruku port Li de and other click D Li de of completion sill mentioned as a specific example of R ³⁾ and Ryo acylation such as acetic anhydride and pyridinium Jin It can be carried out at 0 to 40: using an agent. The reaction time varies depending on [Ia] to be used, the type of the silylating agent and the reaction temperature, but is usually 10 minutes to 12 hours.

Step 5 Further, the compound [Ib] is chlorinated to produce the compound [Ic]. This reaction can be carried out using a chlorinating agent in a solvent inert to the reaction. The reaction usually proceeds at room temperature to 100. Examples of the solvent include black form, dicumethane, trichlorene, halogenated hydrocarbons such as carbon tetrachloride, hexane, dioxane, and tetrahydrofuran. Used. As the chlorinating agent, N-chlorosuccinic acid imide, sulfuryl chloride or molecular chlorine can be used. Usually, the chlorinating agent is used in an amount equivalent to an excess of the compound [Ib] and used in excess. The reaction time varies depending on the compound [Ib] used, the chlorinating agent, the type of solvent and the reaction temperature, but is usually 30 minutes to 3 hours.

 [Ia] according to the present invention can also be produced according to the following reaction formula.

(In the formula, R ¹ and R ² are the same as described above.)

1st step

[IV] is obtained by reacting the compound represented by the general formula [V] with 3,4-difluorinated linoleic acid in a solvent-free or solvent-based solution at around 501 to 100, preferably around 70. Can be manufactured. The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include sonitrile, N-dimethylform amide, and toluene. The reaction time is Although it varies depending on the type of the solvent, the reaction temperature and the like, it is usually 12 to 72 hours, preferably 24 to 48 hours.

 [V] is used in an amount of usually 1 mol to 2 mol per 1 mol of 3,4-difluoroaniline. The raw material compound [V] can be produced by oxidizing bis (alkylthio) methylene α-alkyl dialkyl ester [VII] as described below.

 0

R'CH _? S rise ^{2 RlC} COOR ²

, = C Ri _r u

^RlCH 2 ^S , 圆 2

 [VII] [v]

(In the formula, R ¹ and R ² are the same as described above.) Such an oxidation reaction can be performed by a method known per se. The reaction is performed using an oxidizing agent, for example, perbenzoic acid, ozone, phenyl dichloride, hydrogen peroxide, sodium metaperoxide, sodium hypochlorite, or the like. In particular, m-α-perbenzoic acid is preferred. The oxidizing agent is generally used in an equivalent amount of 1 to the compound [VII]. The reaction is usually carried out in a solvent (eg, a halogenated hydrocarbon such as methylene chloride, octaform, carbon tetrachloride, dioxane, tetrahydrofuran, etc.).

—Teles, hexanes, etc.) at a temperature of 30 to 60, preferably -5 to room temperature. The reaction time varies depending on [VII] used, the type of solvent and the temperature, but is usually 30 minutes to 3 hours. Second step [Ia] can be produced by subjecting the malonic acid dialkyl ester represented by the general formula [IV] to a ring-closing reaction. Main ring closure The reaction can be performed by a method known per se. For example, a method using heating, a method using an acidic substance, and the like can be used. For example, in the case of heating, the heating is carried out by heating to 100 to 300: preferably 150 to 250 in a solvent or in a solvent. As the solvent, a solvent having a relatively low boiling point, such as xylene, diphenyl ether, liquid paraffin, diethylene glycol dimethyl ether, tetralin, or dichlorobenzene can be used. The reaction time varies depending on the type of the solvent, the reaction temperature and the like, but is usually 30 minutes to 3 hours.

 When an acidic substance is used, the reaction is carried out in an amount of 1 mol to a large excess, preferably 20 to 30 mol, based on 1 mol of [IV], usually at 100 to 100, preferably at D to 60.

As the acidic substance, Okishi chloride Li down, pentachloride Li down, Sanhanikari down, Chioniruku _Ώ Li de, fuming sulfuric acid, concentrated sulfuric acid, Po Li-phosphate, using Po Li Li Nsane ester such be able to.

 The compound of [IV] can be produced by alkylating a metallic alkali salt [VIII] as described below.

[VI II] [IV] Such an alkylation reaction can be carried out by reacting the alkylation agent with [VIII] usually at 0 to 50 in a solvent inert to the reaction. The solvent may be any solvent that is inert to the reaction, for example, methanol, ethanol, isopropanol, etc. And hydrocarbons such as benzene, toluene, and the like, sodium nitrite, N-dimethylformamide, dimethylsulfoxide, dioxane, and the like. As the alkylating agent, those used in ordinary alkylation reactions can be used. For example, alkyl halides corresponding to one CH ₂ R ¹ (eg, pyridine, bromine) ), Sulfates (eg, dimethyl sulfate, getyl sulfate), sulfonates (eg, methanesulfonate, benzenesulfonate, toluenesulfonate) Can be used

 Compound [VIII] can be produced by a known method (eg, JP-A-57-136588).

 The target compounds [I] and [II] thus produced are purified, for example, by concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc. be able to.

 The compound [Ic] of the present invention can be closed as described below to lead to a compound [III] which is an important intermediate for producing a thiocyantoquinoline carboxylic acid derivative having antibacterial activity. (See JP-A-63-107990 and JP-A-1-294680).

^{(Wherein, R 1, R 2, R} 3 3 are the same as above.)

That is, [I c] is dissolved in a solvent in the presence of a base, usually at room temperature to 100. [III] can be produced by liquefaction. At this time, the protecting group is removed at the same time. Any solvent may be used as long as it does not hinder the reaction. For example, hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, N, N A non-protonic solvent such as -dimethylformamide, N, N-dimethylformacetamide, dimethylsulfoxide, sulfolane, or a mixture thereof is used. Examples of the base include an organic acid salt (eg, sodium acetate, succinimidonatodium salt, monopyrrolidone sodium salt), an inorganic base (eg, sodium hydroxide) Lithium, lithium hydroxide) and the like can be used. The base is usually used in an amount of 1 to 10 equivalents to [Ic]. The reaction time varies depending on [Ic], base, type of solvent and reaction temperature, but is 30 minutes to 10 hours.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples relating to the production of the compound of the present invention.

Example 1

 -[Bis (ethylthio) methylene] -2,4,5-Trifluoro] Synthesis of 9-oxo-benzenepropionic acid ethyl ester

2,4,5-Trifluoro □-jS-oxobenzenepropionate 3.69 g was dissolved in 30 ml of dry DMF, and under ice-cooled stirring, 6.22 g of anhydrous carbon dioxide rim was added. In addition, 1.-lg of carbon disulfide was added. Five minutes later, 7.02 g of iodo chill was added dropwise with stirring under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was added to ice water 15Dm] and extracted with ethyl acetate. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is concentrated under reduced pressure. And dried to give crystals. Recrystallization from n-hexane gave 4.85 g of the desired product as pale yellow crystals. With melting point 54-56

Elemental analysis value (as a CHFS 0 ₃ S 2)

 Calculated value (%) C: 50.78 H: 4.53

 Measured value (%) C: 50.78 H: 4.40

NR (60MHz, CDC1 ₃ ) δ ppm: 1.04-1.35 (m, 9H, -SCH ₂ CH_3 X 2,

 -COOCH s Cj)

 2.92 (q, 4H, J = 7Hz, -SCH2CH 3 X 2) 4.20 (q, 2H, J = 7Hz, -CODCHaCHa)

6.86-7.18 (m, 1H)

 7.58-8.00 (m, 1H)

Example 2

oc-[(Amino) (ethylthio) methylene]-Synthesis of 2,4,5-trifluoro / 9-ethylbenzeneethylpropionate

-[Bis (ethylthio) methylene] -2,4,5-Trifluoro n-oxo benzenepropionate 3.41 g dissolved in 90 ml anhydrous ethanol, 10% ammonia ethanol 2.30 g of the solution was added, and the tube was sealed in an 80 oil bath for 18 hours. After cooling, ethanol was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the ethyl acetate was reduced in pressure and concentrated to dryness to obtain 3.12 g of an oil. This was subjected to column chromatography (closure: holm: metafur = 100: 1—50: 1) to obtain crude crystals. This was recrystallized from π-hexane to obtain 1.60 g of the desired product as pale yellow crystals. 87-91t

Elemental analysis value (as CH ₁₄ F ₃ N〇 ₃ S)

 Calculated value (%) C: 50.45 H: 4.23 N: 4.20

 Measured value (%) C: 51.21 H: 4.09 N: 4.18

NMR (60MHz, CDC) δ _PP m: 0.88 (t, 3H, J = 7Hz, -CD0CH ₂ CH ₃ )

 2.87 (q, 2H, J = 7Hz, -SCj CHa) 3.96 (q, 2H, J = 7Hz, -COOCf CHs) 6.66-7.42 (m, 2H)

Example 3

 Synthesis of 2-ethylthio-1,6,7-difluoro D-4-hydroxyquinoline-3-ethyl ether ester

 or-[(Ryomino) (ethylthio) methylene〗 —2,4,5-Trifluoro-1-β-oxobenzenepropionate ethyl ester 330 mg is dried and dissolved in 10 ml of dimethylformamide. Under stirring at room temperature, 200 mg of anhydrous hydrogen carbonate was added, and the mixture was heated and stirred at 80 at 24 hours. After cooling, the reaction solution was poured into 50 ml of ice water, and the pH was made weakly acidic with dilute hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and the obtained crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to dryness to obtain 217 mg of pale yellow crude crystals. The obtained crystals are subjected to column chromatography (n-hexane: ethyl acetate = 20: 1-9: 1), and the fraction containing the desired product is concentrated under reduced pressure. The obtained crystals were recrystallized from π-hexane to obtain 182 mg of the desired product as white crystals.

Melting point 124-127t Elemental analysis value (as CH ^ F-N03S)

 Calculated value (%) C: 53.67 H: 4.18 N: 4.47

 Measured value () C: 53.61 H: 4.22 N: 4.41

lz) CDC1 δ pm: 1.26-1.64 (m, 6H, -COOCH ₂ CH ₃ ,

-SCH ₂ CH ₃ )

 3.23 (q, 2H, J = 7Hz, -SCHaCHs)

 4.56 (q, 2H, J = 7Hz, -COOC ^ Cf) 7.27-8.07 (m, 2H)

Example 4

 Synthesis of 4-ethylethoxy-2-ethylthio-6,7-difluoroquinoline-3-ethyl ethyl ester

 Suspension of 17.22 g of 2-ethylthio-6,7-difluoro-4-hydroxyquinoline-3-carbonic acid ethyl ester in 30 ml of glacial acetic acid, add pyridine (8 ml) to the suspension, and stir at room temperature for 2 hours. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, dissolved in ethyl acetate, dried over magnesium sulfate, concentrated in vacuo, and cooled by adding η-hexane. 17.37 g of the compound was obtained as white crystals.

With melting point 64-67

Elemental analysis value (as C ₁₆ H _{1 S} F ₂ N〇 ₄ S)

 Calculated value (%) C: 54.08 H: 4.25 N: 3.94

 Measured value (%) C: 54.23 H: 4.29 N: 3.88

Example 5

4-L-Sethoxy-2- (1-chloroethylthio) -6,7-difluoro. Synthesis of Quinolin-3 Ethyl Rubonate Ethyl Ester 4-Toxoxy-2-ethylthio-6,7-difluoroquinoline-3-fluorosulfonic acid ester 1.78 g is suspended in n-hexane 15 ml, and the mixture is heated to reflux and heated to reflux for sulfuryl chloride. A solution of 1.5 g of n-hexane (10 ml) was added dropwise over 2 hours. After the dropwise addition, the solvent was distilled off, followed by drying to obtain 2.2 g of the target compound as a slightly yellow solid. Recrystallization from π-hexane gave crystals with a melting point of 71-73.

Elemental analysis (as a _{C 1 S H 14 C 1 F} 2 N 0 4 S)

 Calculated value (%) C: 49.30 E: 3.62 N: 3.59

 Measured value (%) C: 49.35 H: 3.59 N: 3.58

Example 6

 Synthesis of 4-ethyloxy-2- (1-chloro-D-ethylthio) -6,7-difluoroquinoline-3 ester of rubonic acid (another method for preparing the compound of Example 5)

Suspension of 1.78 g of 4-hydroxy-2-ethylthio-6,7-difluoroquinoline-3-ethyl carboxylate and 1.01 g of ιΜ-chlorosuccinic acid imid in 20 ml of carbon tetrachloride While heating and refluxing, irradiate with a 500W incandescent lamp for 6 hours. After cooling, the insolubles are removed by filtration and the filtrate is concentrated. Add isopropyl ether to the residue and filter off insolubles. The filtrate was dried to obtain 2.09 g of slightly yellow crude crystals. Melting point 72-74t:

Example 7

 Synthesis of 4-ethyl chloroethylthio) -6,7-difluoroquinoline-3 monoethyl ribonate (Another method for preparing the compound of Example 5)

4-Set 2-Ethylthio-6 ,? — To a solution of 3.55 g of difluoroquinoline-3-ethyl carboxylate dissolved in 18 ml of dry tricrine, heat and stir to 901 while stirring 1.89 g of sulfuryl chloride in a dry trickle. A solution dissolved in 2 ml of ren was added dropwise over 1 hour. After stirring at the same temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while heating at 50 to 60 to obtain the desired compound as a yellow oily substance. Used for the next reaction without purification. Example 8

 Synthesis of 6,7-difluor α-4-hydroxy-2-ethylthioquinoline-3-ether ethyl ester of ruponic acid (Another method for preparing the compound of Example 3)

(1) Synthesis of (ethylsilyl) (ethylthio) methyl lenmalonic acid

 A methylene chloride solution (150 ml) of 28.0 g of bisethylthiomethylenmalonic acid dimethyl ester was stirred under ice cooling, and a methylene chloride solution (300 ml) of 21.6 g of m-cycloperbenzoic acid was added dropwise over about 90 minutes. I do. Return to room temperature and stir for 4 hours. The precipitated m-chlorobenzoic acid is filtered off, and the filtrate is extracted by adding aqueous sodium hydrogen carbonate. After the organic layer is dried over magnesium sulfate, the solvent is distilled off. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 5: 1—2: 1) to obtain 27.lg of a yellow oil.

Elemental analysis (as a C ₂₀ H ₂₀ 〇 _{S S 2 · 1 / 5H 2} 0)

 Calculated value (%) C: 46.19 H: 6.58

 Measured value (%) C: 46.08 H: 6.53

^{_{IR (CHC 1 3) 1720cm- 1}} (C = 0) ·

N (CDC1 ₃ ) δ ppm: 1.3K3H, t, J = 7.2Hz, -CHzCHa)

 1.35 (3H, t, J = 7.2Hz, -CHaCf)

1.44 (3H, t, J = 7.4Hz, -CH ₂ CH ₃ ) 2.88-3.20 (4H, in, -SCH ₂ CH ₃ X 2)

4.26 (2H.q, 3 = 1.2Hz, -OCH ₂ CH ₃ )

4.34 (3H.t, J = 7.4Hz, -QCH ₂ CH ₃ )

 (2) Synthesis of 2- (3,4-difluoronphenylamino) -2- (ethylthio) ethylen-1,1-dicarboxylic acid getyl ester

 Stir 1.29 g of 3,4-difluorene and 3.40 g of (ethylsulfinyl) (ethylthio) methylenic acid getyl acid ester at 70 t for 48 hours. The reaction solution was subjected to column chromatography (silica gel, n-hexane: ethyl acetate = 20: 1) to obtain 2.42 g of a yellow oily substance.

IR (CHC) 3220, 3100, 2980, 2940, 1730, 1665, 1615, 1570,

1510, 1450, 1375 cm- ¹

 (3) Synthesis of 2-ethylethyl-6,7-difluo-4-hydroxyquinoline-3-ether ethyl ribonate

 2- (3,4-Difluorophenylamino) -2- (ethylthio) ethylene-1,1-diethyl carbonate stell 3.65 g of xylene solution (36 ml) is stirred at 170 for 1 hour at 170. After cooling, the reaction solution is evaporated under reduced pressure. To the crystalline residue was added D-isopropyl ether, and the crystals were collected by filtration to give 1.50 g of the desired compound. 127-128 t

Elemental analysis value (as C ₁₄ H ₁₃ F ₂ N〇 ₃ S)

 Calculated value (%) C: 53.67 H: 4.18 N: 4.47

 Measured value (%) C: 53.88 H: 4.10 N: 4.28

Example 9

2-Ethylthio-6,7-difluoro mouth-4-Hydroxyquinoline-3-Hydronic acid :! : Synthesis of tyl ester (Alternative method of compound of Example 3) (1) Under permanent cooling, potassium 2,2-diethoxycarbonyl-1- (3,4-difluorophenyl) methylene-1-thiolate 6.lg To the ethanol suspension (60 ml) was added dropwise 2.43 g of getyl sulfate, and the mixture was stirred at room temperature overnight. Ethanol is distilled off from the reaction mixture under reduced pressure. Add ice to the residue and extract with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off and 2- (3,4-difluorophenylamino) -2-ethylthioethylene-1,1-dicarboxylate getyl ester 5.00g as a pale yellow oil

IR (film, cm " ¹ ) 3220, 3100, 2980, 2940, 1730, 1665, 1615,

 1570, 1510, 1450, 1375

 (2) 2- (3,4-difluorophenylamino) -2-ethylthioethylene-1,1-dicarboxylic acid getyl ester 1.0 g of xylene solution (5 ml) was added at 140-150. Heat to reflux for 3 hours. Add 5tnl of π-hexane and refrigerate. The precipitated crystals were collected by filtration to obtain 806 mg of the desired compound as white crystals. With melting point 127-128

Elemental analysis (as C ₁₄ H ₁₃ F ₂ N_〇 ₃ S)

 Calculated value (%) C: 53.67 H: 4.18 N: 4.4?

 Measured value (%) C: 53.88 H: 4.10 N: 4.28

Reference example 1

 Synthesis of 6,7-difluo-1--1-methyl-4-oxo-4H- [1,3] thiazeto [3,2-a] quinolin-3-ethylcarboxylate

4-Acetoxy-2- (1-chloroethylthio) -6,7-difluoroquinoline-3-Ethyl rubonate 1. Dissolve lg in 10 ml of THF and add sodium acetate 1.23 g was added and the mixture was heated under reflux for 4 hours. Add water and add The extract was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The obtained crude crystals were washed with isopropyl ether and then with methanol to obtain 517.5 mg of the desired compound as white crystals.

Melting point 207-208

'HNMR δ ppm (D S0-D ₆ ): 1.27 (t, 3H, J = 7Hz, CH ₂ CHa)

2.07 (d, 3H, J = 7Hz, CH ₂ CH3)

 4.15 (q, 2H, J = 7Hz, CHsCHa)

6.08 (q. 1H, J = 7Hz, CHaCH ₃ )

 7.60 (dd, 1H, J = 6Hz, 11Hz, 8H)

 7.88 (dd, 1H, J = 9Hz, 11Hz, 5H)

IR (KBr) cm " ¹ : 3450, 3000, 1720, 1610, 1500

Reference example 2

 6, Synthesis of フ ル -difluoro □ -1 -methyl-4-oxo-4H-U, 3] ethyl [3,2-a] quinolin-3-carboxylate (alternative method)

 4-Ethoxy-2- (1-chloroethylthio) -6,7-difluoroquinoline-3-carboxylic acid ethyl ester obtained in Example 6 was dissolved in 36 ml of THF, and ice-free lithium hydroxide was added to the solution. 0.335 g was added, and the mixture was stirred at 70 at 4.5 hours. After the reaction solution was cooled with water, the precipitated crystals were collected by filtration and washed with 7 ml of tetrahydrofuran. The obtained crystals were washed by stirring in 15 ml of water at room temperature for 15 minutes, washed, filtered, further washed with 15 ml of water, and dried under reduced pressure at room temperature for 12 hours to obtain the desired compound. 2.50 g of crystals were obtained.

 The invention's effect

(1) When [I] is produced using the compound [II] of the present invention, complicated preparations such as attaching and detaching of a protecting group are not required. When [I] is used, In the method for producing a zetoquinoline carboxylic acid derivative, the carbon of CHXR ′ substituted with the 2-position sulfur atom of compound [I] when forming the thiazeto ring produced by the production method of the present invention is a thiazeto ring. The expensive 1, 1-dihalo-alkane is not required because it is used for construction.

 In the production method of the present invention using the compound of the present invention as an intermediate, the 6,7-difluoro-1-methyl-4oxo-4H- [1,3] thizyze is efficiently and economically used. 3,2-a] It is possible to produce quinoline carboxylic acid alkyl esters.

(2) If 2- (3,4-difluorophenylamino) -2-alkylthioalkylene-1,1-dicarboxylic acid dialkylester is used, the process can be performed more efficiently in a shorter process than before, and Overcoming the conventional shortcomings, 6,7-difluoro ¹ D -4-oxo-4H— [1,3] thiazeto [3,2-a] quinolin-3—force Alkyl rubonate derivative Can be manufactured.

Claims

The scope of the claims 1. A quinoline carboxylic acid derivative represented by the general formula [I]

In the formula, R ¹ represents hydrogen or alkyl. R ² represents thiol, R ³ represents hydrogen or thiol. X represents hydrogen or chlorine. 2. General formula [IIa]

(Wherein, R ¹ represents hydrogen or alkyl; R ² represents alkyl). A compound represented by the general formula [Ia], wherein the compound is subjected to a closure reaction.

(Wherein R ¹ and R ² are the same as described above). 3. General formula [II]

(Wherein, R ¹ represents hydrogen or alkyl. R ² represents alkyl. R ⁴ represents -NH ₂ or S CH ₂ R ¹ ) 4. General formula [V]

(Wherein, R ¹ represents hydrogen or alkyl; R ² represents alkyl); and a compound formed by reacting 3,4-diflurylaniline with [IV]

To the ring closure reaction, wherein the general formula " _Ia "

(Wherein, R ¹ and R ² are the same as described above).  General formula [V] [V]

(Wherein, R ¹ represents hydrogen or alkyl); R ² represents alkyl, and 3,4-difluoroethylene is reacted with a general formula [IV]

(Wherein R ¹ R ² is the same as described above).