Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1994-04-08
1996-01-16
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
546 81, 544 55, 544 60, 544 96, 544126, 544238, 544333, C07D40112, C07D47104, C07D41712
Patent
active
054849217
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This application is a 371 of FR 9400937 filed Oct. 8, 1992.
The present invention relates to a new process for preparing benzo[b]naphthyridines of general formula: ##STR5## in which R is a carboxyl, alkyloxycarbonyl, cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl or hydroxyethylcarbamoyl radical or a dialkylaminoethylcarbamoyl or dialkylcarbamoyl radical in which the alkyl portions, with the nitrogen atom to which they are attached, can optionally form a 5- or 6-membered heterocycle optionally containing another hetero atom chosen from oxygen, sulphur and nitrogen and optionally substituted on the nitrogen with an alkyl radical, R' is hydrogen atom or an alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl (containing 3 to 6 carbon atoms), fluorophenyl, difluorophenyl, alkyloxy or alkylamino radical and Hal is a halogen atom, as well as their salts where they exist.
BACKGROUND OF THE INVENTION
The benzo[b]naphthyridines of general formula (I), as well as their preparation and their use for the preparation of antibacterial agents, have been described in U.S. Pat. Nos. 4,970,213 and 4,990,515.
DESCRIPTION OF THE INVENTION
It has been found that the benzo[b]naphthyridine derivatives of general formula (I) may be prepared from a quinoline derivative of general formula: ##STR6## in which Hal is defined as above and R.sub.1 is a hydrogen atom or an alkyl radical, by performing the following operations: carbamoyl, alkylcarbamoyl, benzylcarbamoyl or hydroxyethylcarbamoyl radical or a dialkylaminoethylcarbamoyl or dialkylcarbamoyl radical in which the alkyl portions, with the nitrogen atom to which they are attached, can optionally form a 5- or 6-membered heterocycle optionally containing another hetero atom chosen from oxygen, sulphur and nitrogen and optionally substituted on the nitrogen with an alkyl radical, with a chlorofluoroquinoline of general formula (II) in which R.sub.1 is an alkyl radical, ##STR7## in which R', R" and Hal are defined as before and R.sub.1 is defined as above in 1), formula: ##STR8## in which Hal, R' and R" are defined as before, and then, optionally, conversion of the ester of general formula (I) thereby obtained to an acid for which R is a carboxyl radical and, optionally, conversion of the acid obtained to a salt.
The new process according to the present invention is especially advantageous on account of the fact that it enables improved yields to be obtained and also on account of the fact that it avoids the involvement of unstable intermediate products.
In the general formulae mentioned above or to be mentioned below, it is understood that the alkyl radicals are unbranched or branched and contain 1 to 4 carbon atoms. Moreover, the symbol Hal is advantageously chosen from chlorine or fluorine.
The condensation of the .beta.-amino ester of general formula (III) is performed on the quinoline derivative of general formula (II) in which, where appropriate, the acid function is protected in the ester state. The reaction is performed in a basic medium, in an organic solvent such as an aromatic hydrocarbon (e.g. toluene), an amide (e.g. dimethylformamide, N-methylpyrrolidone), an ether (e.g. tetrahydrofuran), a sulphoxide (e.g. dimethyl sulphoxide), a chlorinated solvent (e.g. dichloromethane, dichloroethane, chlorobenzene) or an alcohol at a temperature of between -10.degree. and 120.degree. C.
As an example, the bases used may be chosen from alkali metal carbonates (sodium or potassium carbonate) alcoholates and an alkali metal hydride (sodium hydride).
It is understood that, in the option where the symbol R' represents a carboxyalkyl radical, the latter is protected prior to the reaction. Removal of the protective radical is preferably performed after the oxidation step 3). Protection and liberation of the acid function are performed according to customary methods which have no adverse effect on the remainder of the molecule; in particular, according to the methods mentioned in the references below.
The cyclization reaction of the product of general formula (IV)
REFERENCES:
Chemical Abstracts, vol. 114(7) Abst. No. 114:62082J, Feb. 18, 1991.
Chemical Abstracts, vol. 114(15) Abst. No. 114:143,393p, Apr. 15, 1991.
Journal of Medicinal Chemistry, vol. 18, No. 10, 1975, pp. 1038-1041 A. A. Santilli "Synthesis and antibacterial evaluation of 1,2,3 4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid esters, carbonitriles, and carboxamides".
Daubie Christophe
Legrand Jean-Jacques
Pemberton Clive
Laboratoire Roger Bellon
Rotman Alan L.
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