Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1988-11-23
1992-02-25
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544363, 546 13, 546156, C07D40304
Patent
active
050915304
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is national phase of PCT/HU88/00019, filed 8 April 1988 and based upon Hungarian national application 1505/89 filed 8 April 1987 under the International application.
FIELD OF THE INVENTION
This invention relates to a new process for the preparation of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxy lic acid derivatives and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
It is known that the 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxy lic acid derivatives of the Formula (I) ##STR5## wherein R stands for a piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group possess high antibacterial activity (Eur. J. Clin. Microbiol. 1983, 2, page 111; J. Clin. Pharmacol. 1985, 25, page 82; Drugs Exptl. Clin. Res. 1985, 5, page 317).
The quinoline carboxylic acids of the Formula I can be prepared by reacting 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and a cyclic amine in the presence of a solvent at a temperature of 135.degree.-140.degree. C. for 2 hours (German open application 3,033,157; German open application 3,142,854.
DESCRIPTION OF THE INVENTION
According to the present invention there is provided a new process for the preparation of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxy lic acid derivatives of the Formula I, wherein R has the same meaning as stated above, which comprises reacting a compound of the Formula II ##STR6## wherein R.sup.1 and R.sup.2 are the same or different and stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms, with a cyclic amine of the Formula ##STR7## wherein R.sup.3 stands for hydrogen, methyl or ethyl or a salt thereof and subjecting the compound of the Formula IV ##STR8## thus obtained to hydrolysis.
The advantage of the process of the present invention is that it makes the desired compound of the Formula I available in a simple manner with high yields and in a short reaction time.
According to a preferred form of embodiment of the process of the present invention the borate derivative of the Formula IV, wherein R, R.sup.1 and R.sup.2 are as stated above, is converted into the desired quinoline-3-carboxylic acid of the Formula I without isolation.
The borate derivatives of the Formula IV are new compounds.
The borate derivatives of the Formula II and the cyclic amine of the general Formula III can be reacted optionally in the presence of an inert organic solvent and an acid binding agent.
As inert organic solvents preferably acid amides (e.g. dimethyl formamide, dimethyl acetamide), ketones (e.g. acetone, methyl ethyl ketone), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether), esters (e.g. ethyl acetate, methyl acetate, ethyl propionate), sulfoxides (e.g. dimethyl sulfoxide or alcohols e.g. methanol, ethanol, 1-decanol, butanol) may be used.
As acid binding agent 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,O]undec-5-ene, 1,5-diazabicyclo[4,3,O]non-5-ene, 1,4-diazabicyclo-[2,2,2]octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be used. Thus as acid binding agent preferably potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of the amine of the Formula III can be used.
The boron derivative of the Formula II and the cyclic amine of the Formula III can be reacted at a temperature ranging from 0.degree. to 200.degree. C., depending on the solvent used. The reaction time may vary between half an hour and 10 hours depending on the reaction temperature. If the reaction is carried out at an elevated temperature, the reaction time can be shortened. The above reaction conditions are but preferabl
REFERENCES:
patent: 4670444 (1987-06-01), Grohe et al.
patent: 4806645 (1989-02-01), Hermecz et al.
patent: 4871849 (1989-10-01), Hermecz et al.
patent: 4940794 (1990-07-01), Hermecz et al.
Balogh Marie
Hermecz Istvan
Horvath Agnes
Kereszturi Geza
Marmarosi Katalin
Chinoin Gyogyszer- es Vegyeszeti Termekek Gyara RT.
Dubno Herbert
Ivy C. Warren
Myers Jonathan
Turnipseed James H.
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