Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-07
1997-04-29
Bleutoe, John C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514312, 544 36, 544 60, 544 96, 544126, 544238, 544361, 546 81, 546101, 546110, 546156, 546157, 546170, 546249, 546258, H01N 4342, C07D21520, C07D41300
Patent
active
056249330
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the preparation of a 6-fluoro-2-haloquinoline of general formula: ##STR1## in which R is a hydrogen atom or an alkyl radical, and Hal and Hal' are identical or different halogen atoms.
U.S. Pat. No. 4,970,213 has described 6-fluoro-2-chloroquinolinecarboxylic acids of structure: ##STR2## in which Hal is a fluorine or chlorine atom, which are useful as intermediates for the preparation of 1,8-benzonaphthyridines having an antimicrobial activity.
The process according to the present invention is also useful for the preparation of antimicrobial 1,8-benzonaphthyridine derivatives, and it furthermore makes it possible to work under mild conditions and to obtain improved yields and avoids proceeding via unstable intermediate products.
In the general formula (I) when R represents an alkyl radical, the latter is straight or branched and contains 1 to 4 carbon atoms; the symbol Hal is advantageously chosen from chlorine or fluorine and the symbol Hal' is chosen from chlorine or bromine.
According to the present invention, the quinoline derivative of general formula (I) may be prepared by the action of a halogenating agent on the 1-hydroxyquinolone of general formula: ##STR3## in which Hal is defined as above and R.sub.1 is defined as R with the exception of representing a hydrogen atom, optionally followed by freeing the acidic function if it is desired to obtain a quinoline derivative of general formula (I) for which R is a hydrogen atom.
The reaction is carried out in an organic solvent such as, for example, a halogenated solvent (particularly a chlorinated solvent such as dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chlorobenzene or dichlorobenzene especially) or in an aromatic solvent (for example toluene, nitrobenzene, diphenyl ether, etc.) at a temperature between 20.degree. C. and the reflux temperature of the reaction mixture.
When it is desired to obtain 2-chloroquinoline, the halogenating agent may be chosen from phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulphuryl chloride, sulphur dichloride, stannous chloride, cuprous chloride, titanium trichloride, ferrous chloride, chromium(II) chloride, triphenylphosphine hydrochloride, dichlorotriphenylphosphorane or chlorine. When it is desired to obtain 2-bromoquinoline, the halogenating agent may be chosen from phosphorus tribromide, triphenylphosphine hydrobromide or dibromotriphenylphosphorane.
In the 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, hydrolysis of the ester may be carried out by any known method for obtaining an acid from an ester without affecting the remainder of the molecule. The hydrolysis is in particular carried out in acidic medium, for example in the presence of hydrochloric acid, sulphuric acid or methanesulphonic acid. It may also be carried out in basic aqueous-alcoholic medium (for example sodium hydroxide or potassium hydroxide).
The 1-hydroxyquinolone of general formula (II) may be obtained by cyclization of a nitro derivative of general formula: ##STR4## in which Hal and R.sub.1 are defined as above, and R.sub.2 is defined as R.sub.1 or represents a carbamoyl or cyano radical, by catalytic hydrogenation in acidic medium.
The catalytic hydrogenation is carried out in the presence of palladium on charcoal or platinum, at a temperature between 0.degree. and 130.degree. C., in the presence of an organic or inorganic acid which does not alter the remainder of the molecule. By way of example, the process is performed in acetic acid or in formic acid, and it is also possible to perform the process using dilute hydrochloric acid or dilute sulphuric acid in an aqueous-alcoholic medium. The reaction is carried out until the hydrogen consumption decreases sharply. The process is preferably carried out at atmospheric pressure.
The nitro derivative of general formula (III) may be prepared by the action of a malonic acid derivative of general formula: derivative of general formula: ##
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Garcia Herve
Jacquot Roland
Leon Patrick
Bleutoe John C.
Gulakowski Randy
Rhone-Poulenc Rorer S.A.
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