Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1988-06-03
1990-06-19
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D40104
Patent
active
049355120
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a new and simple process for the preparation of quinoline-carboxylic acid derivatives as well as hydrates and therapeutically acceptable salts thereof. In the formulae the meaning of the substituents is as follows: having 1 to 4 carbon atoms, which may be subtituted by a hydroxyl group, a halogen atom or an amino group; or a CH.sub.3 --NH-- group,
The preparation of compounds of the formula (III) ##STR4## was carried out up to the present by reacting a quinoline-carboxylic acid derivative of the formula ##STR5## and formyl-piperazine in dimethyl sulfoxide as solvent (Belgine patent specification No. 870576.) Further a process is known to form the free formyl derivative by formylation with formic acid in a yield of 50% (J. Med. Chem. 23 1358, 1980). This latter process is very corrosive because of the application of formic acid.
The disadvantage of these processes is that they are carried out in several steps and in expensive solvents as pyridine, dimethyl sulfoxide, etc. The yields are very low too.
The present invention relates to a process for the preparation of quinoline-carboxylic acids of the formula (I) the hydrates and salts thereof from compounds of the formula (II) in a way, that the compound of the formula (II) or an acid addition salt thereof is reacted with piperazine in dimethylformamide and--if desired--the compound of the formula (III) thus obtained is subjected to an acidic or alkaline treatment, or is reacted advantageously with hydrazine or preferably with hydrazine-hydrate.
Among the compounds of the formula (I) ##STR6## the 1-ethyl-6-fluoro-7-(4-formyl)-piperazinyl-1,4-dihydro-4-oxo-quinoline-3-ca rboxylic acid possesses a very significant antibacterial effect. It is effective against Pasteurella multocida in an inhibitioning concentration of 0.25 .mu.g/ml, against different Bacillus strains (e.g. Bac. subtilis, Bac. licheniform) in a minimal inhibitioning concentration of 0.5-0.75 g/ml and similarly in a minimal inhibitioning concentration of 0.75 .mu.g/ml against Shigella sonnei and Salmonella cholerae-suis strains, too. According to the present invention the formylation should be carried out advantageously by heating.
Higher temperature (120.degree.-153.degree. C.) results in a shorter reaction time. The yield of the reaction can be increased by assuring an acidic medium, the reaction time can be decreased respectively. The acidic medium can be assured in a way, that the acid addition salt of the compound of the formula (II) is applied, or advantageously the reaction should be carried out in the presence of an acid, advantageously in the presence of hydrochloric or sulphuric acid.
The processing of the reaction mixture, the recovery of the product occurs in a very simple way. The dimethylformamide applied as solvent and a reagent is removed under reduced pressure and it may be used repeatedly. To the residue water is added and the precipitate is recovered by filtration.
Among the compounds of the formula (I), those of the formula (IV) ##STR7## possess valuable antibacterial activities, too (e.g. Antimicrob. Agents Chemother. 1985 581-586). These can be prepared from compounds of the general formula (III) containing the formyl group by acidic or alkaline treatment, or advantageously with hydrazine, preferably with hydrazine-hydrate, optionally in the presence of an acid (e.g. acetic acid).
As acids, first mineral acids, e.g. hydrochloric acid, sulphuric acid, phosphoric acid, etc. are applied in a suitable dilution. As alkali the hydroxides and carbonates of the alkali and alkali earth metals are applied. The removal of the formyl group is carried out in an organic solvent and/or in water. advantageously in an alcohol-water mixture. The most advantageous was a 3:1 mixture of isopropyl alcohol and water. The reaction is carried out at a temperature of 25.degree.-100.degree. C., advantageously at the boiling point higher temperature results in a decreased reaction time.
The product can be obtained advantageously after the neutralization of the acid or alkali exc
REFERENCES:
patent: 4292317 (1981-09-01), Pesson
patent: 4352803 (1982-10-01), Matsumoto et al.
patent: 4599334 (1986-07-01), Petersen et al.
Beres nee Palmai Klara
Frank Judit
Kulcsar Gabor
Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Rt
Dubno Herbert
Myers Jonathan
Raymond Richard L.
Turnipseed James H.
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