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

• This invention rel ates to a new process for the preparation of 1-substituted-7-(optionally substituted piperazine )-6-f luoro-8-(optionally fl uoro-substituted)-4-oxo-1 , 4- dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I
• R 1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula - -CH 2 CR 6 R 7 R 8 (wherein R 6 , R 7 and R 8 stand for hydrogen or halogen);
• R 2 stands for piperazlnyl or 4-methyl-piperazinyl;
• R 3 stands for hydrogen or fluorine.
• These compounds can be prepared by reacting 1-substituted phenyl-6-fluoro-7-chloro-4- oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines in the presence of a solvent at a temperature of 100 °C for 20 hours (European patent specification 131839, J . Med. Chem. 1985, 1558., J . Med. Chem. 1987. 504.).
• acetone methyl ethyl ketone
• an ether e.g. dioxane, tetrahydrofuran, diethyl ether
• an ester e.g. ethyl acetate, methyl acetate, ethyl propionate
• a sulfoxide e.g. dimethyl sulfoxide
• an alcohol e.g. methanol, ethanol, 1-decanol, butanol
• an organic or inorganic base may be used. From the group of organic bases trialkyl amines (e.g. triethyl amine, tributyl amine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo/5,4,0/undec-5-ene, 1,5-diazabicyclo/4.3.0/- non-5-ene, 1,4-diazabicyclc/2.2.2/octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be applied.
• acid binding agent advantageously potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of the amine of the general Formula III can be used.
• the boron derivative of the general Formula II and the amine of the general Formula III can be reacted at a temperature between 0 and 200 °C, depending on the solvent used.
• the reaction time may vary between half an hour and 10 hours. The reaction time depends on the reaction temperature, too. If the reaction is carried out at higher temperature, the reaction time can be shortened.
• the above reaction conditions are preferable values and other conditions may be used as well.
• the compounds of the general Formula IV can be hydrolysed to the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic or basic conditions.
• the compound of the general Formula IV pre verted into pharmaceu tically acceptable salts thereof in a known manner.
• acid addition salts can be formed, e.g. salts formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids.
• One may form preferably chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc.
• the compounds of the general Formula I form salts with alkali or alkaline earth metals or other metal ions as well. Accordingly the sodium, potassium, magnesium, silver, copper salts, etc. may be prepared.
• the compounds of the general Formula I and pharmaceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.
• the starting materials of the general Formula II can be prepared by reacting 1-phenyl-6-fluoro-7-chloro-4-oxo-1,4- dihydro-quinoline-3-carboxylic acid (European patent specification 131.839) or 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (GB patent specification 2.057.440) with a boron derivative (e.g. with a compound of the general Formula V
• R is halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms
• fluoroborate in aqueous or in organic medium.
• Example 2 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis- (propionato-0)-boron are reacted with 0.64 g of piperazine in 4 ml of dimethyl sulfoxide. A 6 w /v% of aqueous solution of 6.3 ml of sodium hydroxide are added and the reaction mixture is refluxed for an hour. After filtration the pH value is adjusted to 7 with 96 w /v% acetic acid, 10 ml of water are added and the reaction mixture is cooled overnight. The precipitated crystals are filtered, washed with water and dried.
• Example 3 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis- (propionato-0)-boron are reacted with 0.75 g of 1-methyl-piperazine. Thus 0.79 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo- 7-(1-methyl-piperazino)-quinoline-3-carboxylic acid are obtained. M.p. is 239-240 °C.

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

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Publications (1)

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Cited By (7)

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• 1988
  • 1988-05-20 JP JP63504328A patent/JP2693988B2/ja not_active Expired - Lifetime
  • 1988-05-20 WO PCT/HU1988/000036 patent/WO1988010253A1/en not_active Application Discontinuation
  • 1988-05-20 KR KR1019890700325A patent/KR970005911B1/ko not_active IP Right Cessation
  • 1988-05-20 EP EP88904603A patent/EP0329719A1/en not_active Ceased
  • 1988-06-14 CS CS412388A patent/CS274677B2/cs unknown
  • 1988-06-21 ES ES8801926A patent/ES2006994A6/es not_active Expired
  • 1988-06-23 CA CA000570183A patent/CA1325010C/en not_active Expired - Fee Related
  • 1988-06-23 YU YU121788A patent/YU46570B/sh unknown
  • 1988-06-24 CN CN88103892A patent/CN1025028C/zh not_active Expired - Fee Related
• 1989
  • 1989-02-15 FI FI890723A patent/FI91400C/fi not_active IP Right Cessation
  • 1989-02-23 DK DK084089A patent/DK84089D0/da not_active Application Discontinuation

Non-Patent Citations (2)

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