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WO1993025532A1 - Derive d'acide carboxylique et production de ce derive - Google Patents

Derive d'acide carboxylique et production de ce derive Download PDF

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Publication number
WO1993025532A1
WO1993025532A1 PCT/JP1993/000795 JP9300795W WO9325532A1 WO 1993025532 A1 WO1993025532 A1 WO 1993025532A1 JP 9300795 W JP9300795 W JP 9300795W WO 9325532 A1 WO9325532 A1 WO 9325532A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
general formula
compound
reaction
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1993/000795
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English (en)
Japanese (ja)
Inventor
Jun Segawa
Yoshihiko Makita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Shinyaku Co Ltd
Original Assignee
Nippon Shinyaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Priority to AU43559/93A priority Critical patent/AU4355993A/en
Publication of WO1993025532A1 publication Critical patent/WO1993025532A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • 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.
  • the present invention relates, in part, to quinoline carboxylic acid derivatives represented by the general formula [I].
  • R ′ represents chromium or alkyl.
  • R 2 represents alkyl;
  • R 3 represents hydrogen or acyl.
  • X represents hydrogen or chlorine.
  • R 1 represents hydrogen or alkyl
  • R 2 represents alkyl
  • R 1 represents hydrogen or alkyl.
  • R 2 represents alkyl.
  • R 4 represents —NH 2 or S CH 2 R 1 ).
  • R 1 represents hydrogen or alkyl
  • R 2 represents alkyl
  • 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.
  • [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.).
  • R 2 is the same as above.
  • R represents hydrogen, alkyl, fuiryl, etc.
  • 6,7-difluoro ⁇ 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).
  • 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.
  • 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.
  • R 1 and R 2 are the same as above.
  • R 33 represents an acyl group.
  • the gist of the present invention resides in one part in the present compound itself represented by the general formula [1]. is there.
  • 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 ⁇ V In the method of manufacturing.
  • R 3 represented by R 3 examples 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.
  • 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
  • the compound [I] according to the present invention can be produced, for example, according to the following reaction formula.
  • R 1 and R 2 are the same as described above.
  • R 33 represents syl>
  • 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].
  • a solvent alcohols such as ethanol and isopropanol, N, N-dimethylformamide, acetate and the like can be used.
  • 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.
  • 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.
  • [li] is reacted with ammonia or ammonium salt (eg, ammonium chloride) in a solvent at 50 to 100 t to produce [IIa].
  • 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.
  • [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.
  • 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
  • the compound [Ib] is prepared by subjecting the 4- ⁇ -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 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.
  • the solvent include black form, dicumethane, trichlorene, halogenated hydrocarbons such as carbon tetrachloride, hexane, dioxane, and tetrahydrofuran. Used.
  • the chlorinating agent N-chlorosuccinic acid imide, sulfuryl chloride or molecular chlorine can be used.
  • 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.
  • [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.
  • the raw material compound [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 ⁇ -alkyl dialkyl ester [VII] as described below.
  • 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.
  • m- ⁇ -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.).
  • 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.
  • 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.
  • 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.
  • the compound of [IV] can be produced by alkylating a metallic alkali salt [VIII] as described below.
  • 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.
  • hydrocarbons such as benzene, toluene, and the like, sodium nitrite, N-dimethylformamide, dimethylsulfoxide, dioxane, and the like.
  • the alkylating agent those used in ordinary alkylation reactions can be used.
  • alkyl halides corresponding to one CH 2 R 1 eg, pyridine, bromine
  • Sulfates eg, dimethyl sulfate, getyl sulfate
  • sulfonates eg, methanesulfonate, benzenesulfonate, toluenesulfonate
  • 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).
  • [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.
  • 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.
  • the base examples 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.
  • Elemental analysis value (as a CHFS 0 3 S 2)
  • the solvent was distilled off under reduced pressure to dryness to obtain 217 mg of pale yellow crude crystals.
  • the obtained crystals were recrystallized from ⁇ -hexane to obtain 182 mg of the desired product as white crystals.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Composé représenté par la formule générale (I), composé représenté par la formule générale (II) et procédé d'obtention d'un composé représenté par la formule générale (Ia) par réaction de cyclisation d'un composé représenté par la formule générale (IIa), dans lesquelles R1 représente l'hydrogène ou un alkyle; R2 représente un alkyle; R3 représente l'hydrogène ou un acyle; R4 représente -NH¿2? ou -SCH2R?1¿; et X représente l'hydrogène ou le chlore. Le procédé couvert par l'invention, qui met en ÷uvre ces composés comme intermédiaires, permet d'obtenir un alkyle 6,7-difluoro-1-méthyl-4-oxo-4H-[1,3]thiazéto[3,2-a]quinolinecarboxylate en un moins grand nombre d'étapes que les procédés classiques, de manière efficace et économique.
PCT/JP1993/000795 1992-06-16 1993-06-15 Derive d'acide carboxylique et production de ce derive Ceased WO1993025532A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43559/93A AU4355993A (en) 1992-06-16 1993-06-15 Carboxylic acid derivative and production thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP4/183127 1992-06-16
JP18312792 1992-06-16
JP23288592 1992-08-06
JP4/232885 1992-08-06
JP25733992 1992-08-31
JP4/257339 1992-08-31

Publications (1)

Publication Number Publication Date
WO1993025532A1 true WO1993025532A1 (fr) 1993-12-23

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PCT/JP1993/000795 Ceased WO1993025532A1 (fr) 1992-06-16 1993-06-15 Derive d'acide carboxylique et production de ce derive

Country Status (2)

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AU (1) AU4355993A (fr)
WO (1) WO1993025532A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
JP2020172442A (ja) * 2019-04-08 2020-10-22 国立大学法人千葉大学 キノリン化合物の製造方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57136588A (en) * 1981-02-18 1982-08-23 Nippon Shinyaku Co Ltd Carboxylic acid derivative
JPS58103393A (ja) * 1981-12-12 1983-06-20 Nippon Shinyaku Co Ltd キノリンカルボン酸誘導体
JPS58105965A (ja) * 1981-12-15 1983-06-24 Nippon Shinyaku Co Ltd 置換キノリンカルボン酸誘導体
JPS62175484A (ja) * 1985-12-23 1987-08-01 アボツト　ラボラトリ−ズ イソオキサゾロ−ピリド−フエノキサジン及びイソチアゾロ−ピリド−フエノキサジン誘導体
JPH01160985A (ja) * 1987-12-17 1989-06-23 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物
JPH01193275A (ja) * 1988-01-28 1989-08-03 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57136588A (en) * 1981-02-18 1982-08-23 Nippon Shinyaku Co Ltd Carboxylic acid derivative
JPS58103393A (ja) * 1981-12-12 1983-06-20 Nippon Shinyaku Co Ltd キノリンカルボン酸誘導体
JPS58105965A (ja) * 1981-12-15 1983-06-24 Nippon Shinyaku Co Ltd 置換キノリンカルボン酸誘導体
JPS62175484A (ja) * 1985-12-23 1987-08-01 アボツト　ラボラトリ−ズ イソオキサゾロ−ピリド−フエノキサジン及びイソチアゾロ−ピリド−フエノキサジン誘導体
JPH01160985A (ja) * 1987-12-17 1989-06-23 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物
JPH01193275A (ja) * 1988-01-28 1989-08-03 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
JP2020172442A (ja) * 2019-04-08 2020-10-22 国立大学法人千葉大学 キノリン化合物の製造方法

Also Published As

Publication number Publication date
AU4355993A (en) 1994-01-04

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