Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1987-06-24
1989-10-03
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544363, 546156, C07D40304
Patent
active
048718491
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a new process for the preparation of 7-substituted-6-fluoro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxy lic acid derivatives and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
It is known that 6-fluoro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives of the Formula I ##STR5## (wherein R stands for piperazinyl or 4-methyl-piperazinyl) have outstanding antibacterial effects (Journal of Medicinal Chemistry 1984, 27, 1103; Antimicrobal Agents and Chemotherapy 1984, 25, 377; 1984, 26, 104; 275; 421; 781; 933; 1985, 27, 4 and 499; European Journal of Clinical Microbiology 1984, 3, 344; Clin. Therapy 1984, 7, 73).
The said compounds can be prepared by reacting 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with a cyclic amine in pyridine or methoxyethanol, at the boiling point, under a protecting nitrogen atmosphere for 15-22 hours (European patent specification No. 90, 424; Japanese patent specification No. 84 01,468; Journal of Medicianl Chemistry 25, 377, 1984).
DESCRIPTION OF THE INVENTION
According to the present invention there is provided a process for the preparation of compounds of the Formula I and pharmaceutically acceptable salts thereof (wherein R stands for piperazinyl or 4-methyl-piperazinyl) which comprises reacting a compound of the Formula II ##STR6## (wherein R.sup.1 and R.sup.2 stand for halogen; an aliphatic acyloxy group comprising 2-6 carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms) with a piperazine of the Formula III ##STR7## (wherein R.sup.3 represents hydrogen or methyl) or a salt thereof, hydrolyzing the compound of the Formula IV ##STR8## thus obtained (wherein R, R.sup.1 and R.sup.2 are as stated above) without or after hydrolysis and if desired converting the compound of the Formula I thus obtained into a salt thereof or liberating the compound from its salt.
The process of the present invention enables the preparation of the compounds of the general Formula I in a simple manner, with very high yields and in a short reaction time.
According to a preferred form of realization of the process of the present invention the borate derivatives of the Formula IV are converted into the desired quinoline-3-carboxylic acids of the Formula I without isolation.
The borate derivatives of the Formulae II and IV are new compounds.
The reaction of the borate derivative of the Formula II and the cyclic amine of the general Formula III may be carried out optionally in the presence of an inert organic solvent and an acid binding agent.
The inert organic solvent can be an acid amide (e.g. dimethyl formamide, dimethyl acetamide), a ketone (e.g. 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), or an alcohol (e.g. methanol, ethanol, 1-decanol, butanol, etc.).
As acid binding agent e.g. organic or inorganic bases can be used. From the group of organic bases preferably 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-diazabicyclo(2.2.2)octane) may be mentioned, while as inorganic base e.g. hydroxides or carbonates of alkali or alkaline earth metals may be applied. Thus it is preferred to use potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide or an excess of the amine of the Formula III as acid binding agent.
The reaction of the borone derivative of the Formula II and the amine of the Formula III may be carried out at a temperature of 0.degree.-200.degree. C. during 0.5-10 hours, depending on the solvent used. The reaction time depends on the reaction temperature too. If the reaction temperature is raised, the reaction time can be shortened. The above reaction conditions are but preferable intervals, while other reaction cond
REFERENCES:
patent: 4182880 (1980-01-01), Watanabe et al.
patent: 4528287 (1985-07-01), Itoh et al.
Chem. Abstracts 103:123491p (1985) p. 730.
Chem. Abstracts 105:153293j (1986) p. 715.
Balogh Maria
Hermecz Istvan
Horvath Agnes
Kereszturi Geza
Kovacs Gabor
Chinoin Gyogyszer - es Vegyeszeti Termekek Gyara Rt.
Dubno Herbert
Myers Jonathan
Raymond Richard L.
Turnipseed James H.
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