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WO1991015477A1 - Procede d'obtention de derives de l'acide 6-fluoro-1,4-dihydro-4-oxo-7-piperazynile-3-quinoleinecarboxylique et derives d'acrylates utilises dans ce procede - Google Patents

Procede d'obtention de derives de l'acide 6-fluoro-1,4-dihydro-4-oxo-7-piperazynile-3-quinoleinecarboxylique et derives d'acrylates utilises dans ce procede Download PDF

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Publication number
WO1991015477A1
WO1991015477A1 PCT/ES1991/000021 ES9100021W WO9115477A1 WO 1991015477 A1 WO1991015477 A1 WO 1991015477A1 ES 9100021 W ES9100021 W ES 9100021W WO 9115477 A1 WO9115477 A1 WO 9115477A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
carbon atoms
linear
process according
Prior art date
Application number
PCT/ES1991/000021
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English (en)
Spanish (es)
Inventor
Enrique Dominguez Buron
Anna Bosch Arcilagos
José MARTINEZ MOYA
Original Assignee
Ercros S.A.
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 Ercros S.A. filed Critical Ercros S.A.
Publication of WO1991015477A1 publication Critical patent/WO1991015477A1/fr

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Classifications

    • 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 invention relates to a new process for obtaining derivatives of 6-fluoro-l, 4-dihydro-4- oxo-7-piperazinyl-3-quinolincarboxylic acid that have antibacterial properties, both against Gram-positive bacteria and against bacteria Gram-negative.
  • the invention also relates to new starting products used in carrying out said process, as well as to its obtaining process.
  • BACKGROUND OF THE INVENTION US Patent 4,292,317 dated 29.9.81 jointly in the name of Laboratorie Roger Bellon and Dainippon Pharmaceutical, describes certain 6-halogen-N-substituted-7-amino-disubstituted-4-oxo-l acids, 4-dihydro-3- quinolincarboxilicos that have antibacterial properties.
  • R can be a linear alkyl group as in the case of US Patent 4,292,317 or cyclic (cyclopropyl) as in the case of DE Patent 3,142,854 and DE Patent 3,248,507, which are made react with piperazine or an N-substituted piperazine to obtain the desired quinolinecarboxylic acids.
  • Patent JP 55/123024 in the name of Kyorin Pharmaceutical Co. Ltd. proposes to use the starting product (V) as an ester, esterifying the carboxylic group with a linear or branched alkyl group of 1 to 5 carbon atoms; formation of undesirable reaction by-products, since piperazine or the N-substituted piperazine derivative can displace F rather than Cl thereby forming undesirable by-products of the formula
  • the present invention provides a process for obtaining quinolinecarboxylic acid derivatives from non-cyclized starting products that incorporate the optionally protected piperazine ring.
  • the differences of the process of the present invention with respect to other known procedures can be summarized in the fact that cyclization occurs to obtain the quinoline ring after carrying out the amination with piperazine or with a piperazine derivative.
  • This mode of operation has the following advantages: increased performance in the 'cyclization step, since on the one hand, the amination is carried out on raw materials less elaborate and therefore cheaper and other side reactions are avoided to produce undesirable by-products such as those mentioned above; - the starting products, to be detailed later, used in carrying out the process of this invention are easily soluble in the usual solvents, which favors not only the purification operations thereof, but also the cyclization reaction; and the products obtained after cyclization, are esters that are easily hydrolyzed in a dilute strong inorganic acid, whereby the corresponding quinolinecarboxylic acid is obtained in, crystallized form and, optionally, in the form of an addition salt and hydrated, which is separated easily by filtration of the reaction medium, with which a final product of good quality and purity is obtained.
  • an object of the present invention is a new procedure for obtaining 6-fluorine-1,4-dihydro-4-oxo-7- piperazinyl-3-quinolincarboxylic acid derivatives.
  • a further object is constituted by a new family of compounds useful as starting products in carrying out the process of the present invention, as well as its obtaining process.
  • the invention relates to a process for obtaining 6-fluoro-l, 4-dihydro-4- oxo-7-piperazinyl-3-quinolincarboxylic acid derivatives of the general formula
  • R can be hydrogen or a linear or branched alkyl or hydroxyalkyl group from 1 to
  • R 2 can be a linear or cyclic alkyl group of 1 to 4 carbon atoms, as well as their acid addition salts for pharmaceutical use and their hydrates.
  • R can be H or a linear or branched alkyl or hydroxyalkyl group of 1 to 4 carbon atoms, or an acyl or alkoxycarbonyl group of 1 to 4 carbon atoms;
  • R_ is a linear or cyclic alkyl group of 1 to 4 carbon atoms
  • R is a linear or branched alkyl group from 1 to
  • a strong base such as sodium hydride can be used as the base and dioxane, dimethylformamide or dimethyl sulfoxide can be used as an anhydrous organic solvent.
  • the cyclized product (VII) obtained after this first stage is treated, after removing the solvent by vacuum distillation, at reflux with an aqueous solution of an inorganic acid, thereby obtaining the corresponding 3-quinolincarboxylic acid of the formula
  • an aqueous solution of HC1 can be conveniently used.
  • the compounds of formula (I) thus obtained are effective antibacterial agents against Gram-positive and Gram-negative bacteria. Numerous publications support this fact, including the patents mentioned in the Background of the invention.
  • the starting compound (VI) used in the above procedure can be prepared according to Reaction Scheme 2.
  • the piperazine (IX) used can be the piperazine base, subsequently protecting if desired, the compound (X) formed, treating it with acetic anhydride or with ethyl chloroformate, whereby forms the corresponding amide or carbamate (XIII and XIV):
  • the residue is dissolved in 300 ce of water and extracted with dichloromethane (2 x 300 ce).
  • the oil that separates is extracted with chloroform (2 x 300 ce).
  • the organic solution is dried with anhydrous sodium sulfate and concentrated to half volume.
  • the solution contains 21.7 g of 2-chloro-5-fluoro-4-piperazinoacetophenone sufficiently pure to carry out the following reaction.

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

Abstract

Procédé d'obtention de dérivés de l'acide 6-fluoro-1,4-dihydro-4-oxo-7-piperazinyle-3-quinoléinecarboxylique de formule (I) dans laquelle R1 représente H, un alkyle ou hydroxyalkyle linéaire ou ramifié ayant de 1 à 4 atomes de carbone et R2 est un alkyle linéaire ou cyclique de 1 à 4 atomes de carbone. Le procédé comprend la réaction d'un composé (VI) dans laquelle R3 est un alkyle linéaire ou ramifié ayant de 1 à 5 atomes de carbone et R1 peut être de plus acyle ou alcoxycarbonyle, avec HNa et hydrolyse acide ultérieure de l'ester cyclique obtenu. Certains des composés (VI) de départ sont nouveaux, concrètement 3-(cyclopropylamino)-2-2-chloro-5-fluoro-4-(4-étoxycarbonyle-1-piperazinyle)benzoyle acrylate d'éthyle. Dans les composés (I) pouvant être obtenus selon ce procédé, on trouve la ciprofloxazine, la norfloxazine et l'enrofloxazine qui ont une activité bactérienne les rendant utiles en thérapie.
PCT/ES1991/000021 1990-04-11 1991-04-10 Procede d'obtention de derives de l'acide 6-fluoro-1,4-dihydro-4-oxo-7-piperazynile-3-quinoleinecarboxylique et derives d'acrylates utilises dans ce procede WO1991015477A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9001050 1990-04-11
ES9001050A ES2019551A6 (es) 1990-04-11 1990-04-11 Procedimiento para la obtencion de derivados del acido 6-fluor-1, 4-dihidro-4-oxo-7-piperacinil-3-quinlincarboxilico.

Publications (1)

Publication Number Publication Date
WO1991015477A1 true WO1991015477A1 (fr) 1991-10-17

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Application Number Title Priority Date Filing Date
PCT/ES1991/000021 WO1991015477A1 (fr) 1990-04-11 1991-04-10 Procede d'obtention de derives de l'acide 6-fluoro-1,4-dihydro-4-oxo-7-piperazynile-3-quinoleinecarboxylique et derives d'acrylates utilises dans ce procede

Country Status (4)

Country Link
ES (1) ES2019551A6 (fr)
MA (1) MA22120A1 (fr)
PT (1) PT97320B (fr)
WO (1) WO1991015477A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574924A (zh) * 2019-01-16 2019-04-05 浙江国邦药业有限公司 一种恩诺沙星残液回收利用方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0131839A1 (fr) * 1983-07-18 1985-01-23 Abbott Laboratories Composés quinoléiniques antibactériens
EP0242789A2 (fr) * 1986-04-25 1987-10-28 Dainippon Pharmaceutical Co., Ltd. Dérivés de quinoléine et procédés pour leur préparation
EP0247464A1 (fr) * 1986-05-19 1987-12-02 Fujisawa Pharmaceutical Co., Ltd. Composés de quinolone et procédé pour leur préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0131839A1 (fr) * 1983-07-18 1985-01-23 Abbott Laboratories Composés quinoléiniques antibactériens
EP0242789A2 (fr) * 1986-04-25 1987-10-28 Dainippon Pharmaceutical Co., Ltd. Dérivés de quinoléine et procédés pour leur préparation
EP0247464A1 (fr) * 1986-05-19 1987-12-02 Fujisawa Pharmaceutical Co., Ltd. Composés de quinolone et procédé pour leur préparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574924A (zh) * 2019-01-16 2019-04-05 浙江国邦药业有限公司 一种恩诺沙星残液回收利用方法

Also Published As

Publication number Publication date
MA22120A1 (fr) 1991-12-31
PT97320A (pt) 1992-01-31
ES2019551A6 (es) 1991-06-16
PT97320B (pt) 1998-08-31

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