WO1993002055A1 - Process for producing quinolonecarboxylic acid derivative - Google Patents

Process for producing quinolonecarboxylic acid derivative Download PDF

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Publication number
WO1993002055A1
WO1993002055A1 PCT/JP1992/000901 JP9200901W WO9302055A1 WO 1993002055 A1 WO1993002055 A1 WO 1993002055A1 JP 9200901 W JP9200901 W JP 9200901W WO 9302055 A1 WO9302055 A1 WO 9302055A1
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WO
WIPO (PCT)
Prior art keywords
group
general formula
substituted
lower alkyl
acid derivative
Prior art date
Application number
PCT/JP1992/000901
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Kiyoshige Ochi
Hirohito Shimizu
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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 Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to EP92915777A priority Critical patent/EP0641782A1/en
Priority to CA002113349A priority patent/CA2113349C/en
Priority to KR1019940700120A priority patent/KR0140158B1/ko
Priority to AU23303/92A priority patent/AU657352B2/en
Publication of WO1993002055A1 publication Critical patent/WO1993002055A1/ja

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link
    • B01J31/0212—Alkoxylates
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel method for producing a quinolonecarboxylic acid derivative represented by the following general formula (4).
  • R represents a lower alkyl group or a cyclic lower alkyl group
  • R 2 represents a hydrogen atom, a halogen atom or a lower alkoxy group
  • X represents —CH 2 —, NB 4 —, 10 —
  • Y represents a hydrogen atom, an amino group or a lower alkylamino group bonded to any carbon atom on a saturated heterocyclic ring, or by a chemical means.
  • the 6-fluoro-7-substituted quinolocarbonylcarboxylic acid derivative represented by the general formula (4) is a compound useful as a drug substance used as an antibacterial agent and as a synthetic intermediate thereof.
  • a method for producing the compound a method in which a quinolone skeleton is formed after a specific substituent is first introduced into a benzene ring at a desired position, or a method in which a specific precursor is added at a desired position. After the introduction of a substituent, a quinolone ring is formed, and then a substituent serving as a precursor is identified. There is a method of converting to a certain substituent.
  • R 2 represents a hydrogen atom, a halogen atom or a lower alkoxy group
  • R 3 represents any function capable of participating in a nucleophilic substitution reaction.
  • X represents CH 2 —, -R 0 —, represents a hydrogen atom or a lower alkyl group
  • Y represents a hydrogen atom or an amino group bonded to any carbon atom on a saturated heterocyclic ring.
  • the lower alkylamino group is a group which can be easily converted to an amino group or a lower alkylamino group by chemical means, and n represents 0 or 1).
  • this reaction is carried out by reacting a compound represented by the general formula (1) Is heated in a solution (JP-A-62-252772, JP-A-64-16746) or a compound represented by the general formula (1) in order to facilitate the nucleophilic substitution reaction at the 7-position. )),
  • the carboxyl group at the 3-position is converted into a hydrofluoroester, and after adding the compound represented by the general formula (2), the mixture is heated in a solution (JP-A-63-316757).
  • a solution JP-A-63-316757
  • the nucleophilicity differs depending on the kind of the amine represented by the general formula (2), so that the reactivity decreases, or the effect of a base added as an acceptor of an acid generated by the reaction is reduced.
  • the yield was low, and the yield was generally low. As a result, the production cost was an obstacle to industrial scale-up.
  • the method of converting the carboxyl group at the 3-position into the ester of borofluoric acid can give the target compound in a relatively high yield.
  • hydrofluoric acid generated by the trifluoroborane used The harmfulness of trifluoroborane itself to humans, the corrosiveness of equipment and equipment, and the waste after reaction treatment were factors that hindered industrial manufacturing.
  • the reaction process also had the disadvantage of complicated operations due to esterification and deesterification.
  • the present inventors have conducted intensive studies on an excellent industrial production method to improve these drawbacks, and as a result, have found that an efficient catalyst for the 7-position nucleophilic substitution reaction of the quinolone skeleton represented by the general formula (1)
  • the present invention has been completed.
  • the present invention provides a compound represented by the general formula (1):
  • ⁇ 2 represents a hydrogen atom, a halogen atom or a lower alkoxy group, and represents an arbitrary functional residue capable of providing a nucleophilic substitution reaction.
  • X is - CH Z -, - ⁇ 4 -, shows an 0-, represents a hydrogen atom or a lower alkyl group
  • Upsilon is hydrogen atom, bonded to a carbon atom arbitrary on saturated heterocyclic Or a lower alkylamino group or a group that can be easily converted to an amino group or a lower alkylamino group by chemical means, and ⁇ represents 0 or 1.
  • R 5 represents a lower alkyl group, an aryl group, or a substituted aryl group, and a substituted aralkyl group
  • the compound represented by the general formula (1) which is a raw material, is derived from metafluorobenzoic acids represented by the general formula (5).
  • R 2 and beta 3 are as defined above, Zeta halogen atom, RS0 2 - group (R is a lower alkyl group, ⁇ rie group or a substituted ⁇ Li Lumpur group) or Shows hydroxyl group or its ester).
  • Z represents a residue capable of forming a N-bond to form a quinolone ring, specifically, fluorine, chlorine, bromine, iodine, methanesulfonyl, benzenesulfonyl, p-toluenes It represents a rufonyl group, a hydroxyl group or its methyl ester, ethyl ester, etc.
  • ⁇ 3 represents any functional residue capable of participating in the nucleophilic substitution reaction.
  • a functional residue include fluorine, chlorine, bromine, iodine, and methyl. Tansulfonyl group, benzenesulfonyl group, ⁇ -toluenesulfonyl group.
  • a compound represented by the general formula (5 ′) may be used.
  • a difluoroquinocarboxylic acid ester (DFQ-ester) represented by the general formula (1 ′) derived from a suitable trifluobenzobenzoic acid chloride may be used as a raw material.
  • R represents an alkyl group, an aryl group, a substituted aryl group, an aralkyl group or a substituted aralkyl group.
  • Y is a hydrogen atom, a It represents a mino group or a lower alkylamino group.
  • Y is a hydrogen atom, an amino group or a lower alkylamino group, or an amino group or a lower alkylamino group by ordinary chemical means. Residues that can be converted to amino groups, i.e., nitro groups, acylamino groups, and carbobenzyloxycarbonylamino groups, etc., e- nitro groups are reduced, acylamino groups are hydrolyzed, and carbobenzyl The hydroxycarbonylamino group can be easily converted to an amino group or a lower alkylamino group by reduction or hydrolysis.
  • Y may be used as a precursor during the nucleophilic substitution reaction at the 7-position according to the present invention, converted into the general formula (4), and then reduced or hydrolyzed into an amino group or a lower alkyl group.
  • the term "lower alkyl group j" means a straight-chain or branched-chain group having 1 to 5 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an n- A tyl group, n-pentyl group and the like.
  • the alkyl borate used in the present invention is represented by the general formula (3).
  • B 5 represents a lower alkyl group, Ariru group, a substituted Ariru group, a ⁇ aralkyl group or a substituted Ararukiru group.
  • E 5 is a methyl group, an ethyl group, an ⁇ -propyl group, an isopropyl group, an ⁇ -butyl group, a phenyl group, a 0-tolyl group, a benzyl group, and a 0-methyl phenyl group And the like.
  • the compound represented by the general formula (3) may be purchased as a commercial product or may be produced from boric acid and alcohols without being separated as the general formula (3) in the reaction system. No particular restrictions.
  • the reaction solvent used in the present invention is not particularly limited, but the reaction is carried out in an anhydrous manner, and the starting materials, amines, and alkyl borate are used. It is preferable to dissolve the telium by heating to raise the reaction temperature to the optimum reaction temperature, and not to reduce the activity as a Lewis acid catalyst, preferably, acetonitrile or propionite. The reaction proceeds smoothly when using lower aliphatic nitriles such as ril, ptyronitrile, and isoptyronitrile.
  • the amount of the alkyl borate to be used is 0.5 to 2 moles, preferably 1 mole, of the compound represented by the formula (1).
  • the reaction temperature can be optimally selected depending on the type of the starting material, the amines and the alkylborate, and the reaction is preferably carried out under heating, preferably in consideration of the added solvent and the boiling point of the alkylborate. I do. Particularly preferably, it is carried out at around 100 ° C. for several hours.
  • reaction mixture is concentrated, then water or an organic solvent is added, and the pH is adjusted to obtain the desired 7-substituted quinolone carboxylic acid derivative represented by the general formula (4) in high yield.
  • the compound which has been conventionally low in yield and has many problems in terms of safety, can be carried out safely and in high yield on an industrial mass scale.
  • the DFQ benzyl ester (E) (1.0 g 0.026 mol) obtained in Reference Example 1 was suspended in acetonitrile (5) and uniformly dissolved by heating to 40 to 5 CTC on an oil bath. Trimethoxyborane (0.54 g, 0.052 mol) was added dropwise thereto, stirred for about 10 minutes, and suspended in acetonitrile (5). (1.19 g> O.OlOmol) was added and the mixture was refluxed for 5 hours on an oil bath. The whole was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. Dried over anhydrous MgSO 4, was separated and purified by silica Kageruka La Mukuroma preparative chromatography (5% MeOH-CHCl 3) , to give purpose was (HI) (0.10 g, 8 % yield).
  • the method of the present invention for producing 6-fluoro-7-substituted-13-quinocarboxylic acids using alkylborates as catalysts solves the drawbacks of the conventional methods and achieves relatively high yields of hazardous substances.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/JP1992/000901 1991-07-16 1992-07-15 Process for producing quinolonecarboxylic acid derivative WO1993002055A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP92915777A EP0641782A1 (en) 1991-07-16 1992-07-15 Process for producing quinolonecarboxylic acid derivative
CA002113349A CA2113349C (en) 1991-07-16 1992-07-15 Method of producing a quinolonecarboxylic acid derivative
KR1019940700120A KR0140158B1 (ko) 1991-07-16 1992-07-15 퀴놀론카르복실산 유도체의 제조방법
AU23303/92A AU657352B2 (en) 1991-07-16 1992-07-15 Process for producing quinolonecarboxylic acid derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP17554791 1991-07-16
JP3/175547 1991-07-16

Publications (1)

Publication Number Publication Date
WO1993002055A1 true WO1993002055A1 (en) 1993-02-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/000901 WO1993002055A1 (en) 1991-07-16 1992-07-15 Process for producing quinolonecarboxylic acid derivative

Country Status (7)

Country Link
EP (1) EP0641782A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JP3165742B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
KR (1) KR0140158B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AU (1) AU657352B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CA (1) CA2113349C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW202443B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1993002055A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069157A (en) * 1997-11-25 2000-05-30 Pfizer Inc. Parasiticidal compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI362386B (en) 2007-03-30 2012-04-21 Daiichi Sankyo Co Ltd A production method for the qunolon-carboxylic acid derivative

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122470A (ja) * 1982-12-27 1984-07-14 Dai Ichi Seiyaku Co Ltd キノリン−３−カルボン酸誘導体の製造法
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735949A (en) * 1986-02-18 1988-04-05 Warner-Lambert Company Disubstituted-7-pyrrolidinonaphthyridine antibacterial agents
EP0329719A1 (en) * 1987-06-24 1989-08-30 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Process for the preparation of quinoline carboxylic acid derivatives
FI95130C (fi) * 1988-07-20 1995-12-27 Sankyo Co Menetelmä lääkeaineena käyttökelpoisten 4-oksokinoliini-3-karboksyylihapon johdannaisten valmistamiseksi
DE69231422T2 (de) * 1991-05-28 2001-03-29 Daiichi Pharmaceutical Co., Ltd. Pyridoncarbonsäurederivate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122470A (ja) * 1982-12-27 1984-07-14 Dai Ichi Seiyaku Co Ltd キノリン−３−カルボン酸誘導体の製造法
JPS62252772A (ja) * 1986-01-21 1987-11-04 Kyorin Pharmaceut Co Ltd 選択毒性に優れた８−アルコキシキノロンカルボン酸およびその塩並びにその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0641782A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156782A (en) * 1996-11-30 2000-12-05 Pfizer Inc Parasiticidal compounds
US6069157A (en) * 1997-11-25 2000-05-30 Pfizer Inc. Parasiticidal compounds

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Publication number Publication date
TW202443B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1993-03-21
CA2113349A1 (en) 1993-02-04
CA2113349C (en) 2003-08-05
EP0641782A4 (en) 1994-10-17
AU2330392A (en) 1993-02-23
JP3165742B2 (ja) 2001-05-14
EP0641782A1 (en) 1995-03-08
JPH05294938A (ja) 1993-11-09
AU657352B2 (en) 1995-03-09
KR0140158B1 (ko) 1998-06-01

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