Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-04-07
1995-08-15
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546249, C07D21522, C07D21518, C07D215227
Patent
active
054420709
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR92/00936, filed Oct. 8, 1992.
FIELD OF THE INVENTION
The present invention relates to fluoro-3quinolinecarboxylic acid derivatives of general formula: ##STR2## in which R is a hydrogen atom or an alkyl radical and Hal is a halogen atom, as well as its salts where they exist.
BACKGROUND OF THE INVENTION
6-Fluoroquinolinecarboxylic acids of structure: ##STR3## in which Hal is a fluorine or chlorine atom, which are useful as intermediates for the preparation of benzo[1,8]naphthyridines having antimicrobial activity, have been described in U.S. Pat. No. 4,970,213.
DESCRIPTION OF THE INVENTION
The preparation of fused pyrimidines, via 2-amino-3-quinolinecarboxamide (or via the corresponding ester or acid) or else, according to another alternative, via alkyl 2-chloro-3-quinolinecarboxylate, has been described in French Patent Application 2,225,166.
Carbostyril derivatives substituted with an azido group or a nitrogen-containing group and with alkyl, alkyloxy, hydroxyl, halogen, etc., radicals have been described in European Application 236,140.
The new quinoline derivatives according to the present invention are also useful for the preparation of antimicrobial benzo[1,8 ]naphthyridine derivatives, but enable improved yields to be obtained and thereby avoid the use of the process involving unstable intermediate products.
In the general formula (I), when R represents an alkyl radical, the latter is unbranched or branched and contains 1 to 4 carbon atoms; moreover, the symbol Hal is advantageously chosen from chlorine and fluorine.
According to the present invention, the new quinoline derivatives of general formula (I) may be prepared by cyclization in an acidic reducing medium of a nitro derivative of general formula: ##STR4## in which Hal is defined as before, R.sub.1 is defined like R with the exception of representing a hydrogen atom and R.sub.2 is defined as COOR.sub.1 or represents a carbamoyl or cyano radical, optionally followed by liberation of the acid function if it is desired to obtain a quinoline derivative for which R is a hydrogen atom.
The treatment in an acid medium is performed in the presence of iron, at a temperature of between 0.degree. and 130.degree. C., by means of any organic or inorganic acid which has no adverse effect on the remainder of the molecule. As an example, the reaction is performed using acetic acid or formic acid; it is also possible to perform it using dilute hydrochloric acid or dilute sulphuric acid in an aqueous-alcoholic medium. It is, of course, understood that the choice of acid is dependent on the product expected. In the case where it is desired to obtain the acid of general formula (I), it is advantageous to work in a stronger acid, under conditions in which hydrolysis of the ester takes place simultaneously; it can also be advantageous to perform the reaction using the product of general formula (II) for which R.sup.2 is cyano. It is, of course, understood that, in cases where the ester has been obtained and where it is desired to obtain the acid of general formula (I) for which R is a hydrogen atom, the hydrolysis of the ester may also be carried out after the cyclization reaction, by any known method for obtaining an acid from an ester without affecting the remainder of the molecule.
Where appropriate, the hydrolysis of the ester is performed in an acid medium, e.g. in the presence of hydrochloric acid, sulphuric acid or methanesulphonic acid. It may also be performed in a basic aqueousalcoholic medium (e.g. sodium hydroxide, potassium hydroxide).
The nitro derivative of general formula (II) may be prepared by the action of a malonic acid derivative of general formula: derivative of general formula: ##STR5## in which Hal is defined as before.
The reaction is generally performed in a basic medium [e.g. in the presence of an alkali metal bicarbonate (sodium bicarbonate), a hydride (sodium hydride) or an alcoholate [lacuna] at a temperature of between 0.degree. and 150.degree. C., in an organic solvent such as an anhydride
REFERENCES:
patent: 4894084 (1990-01-01), Theodoridis
patent: 4909829 (1990-03-01), Theodoridis
patent: 4970213 (1990-11-01), Antoine et al.
patent: 4990515 (1991-02-01), Antoine et al.
patent: 5004745 (1991-04-01), Antoine et al.
patent: 5385913 (1995-01-01), McGuire
Chemical Abstracts 114:62083, 1990.
Daubie Christophe
Legrand Jean-Jacques
Pemberton Clive
Ivy C. Warren
Laboratoire Roger Bellon
M. Mach D. Margaret
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