Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-08-07
1989-02-07
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546156, C07F 502, C07D21556
Patent
active
048032743
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to new intermediates useful in the preparation of Norfloxacin. More particularly it is concerned with new anhydrides of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and boric acids and a process for the preparation thereof.
BACKGROUND OF THE INVENTION
It is known that ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Journal of Medicinal Chemistry 23, 1358 (1980); Japanese patent specification No. 80 33,453) is an intermediate useful in the preparation of 1-ethyl-6-fluoro-7-substituted-4-oxo-1,4-dihydro-quinoline-3-carboxylic acids having antibacterial effect (Ann. Microbiol, Paris 1981, 132A, 267; Journal of Medicinal Chemistry 1980, 23, 1358; Pathol. Biol. 1982, 30, 394; Cyo Yakuri, 1983, 25, 475; Pathol. Biol. 1983, 31, 501; Antimicrob. Agents Chemother. 1980, 17, 103; 1981, 19, 188; 1981, 20, 265; C. R. Scances Acad. Sci., Ser. 3, 1981, 292, 37).
The latter compounds can be prepared in two steps by reacting ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate with a cyclic amine at a temperature above 100.degree. C. in the presence of a solvent for several hours and subjecting the ethyl-1-ethyl-6-fluoro-7-substituted-4-oxo-1,4-dihydro-quinoline-3-carboxy late thus obtained to hydrolysis; the order of succession of the said two steps can be changed, if desired (Japanese patent specification Nos. 79,138,582 and 80,33,453; Belgian patent specification Nos. 863,429; 870,917; 879,106 and 890,223; DOS No. 2,840,910 and French patent publication No. 2,424,919).
The above processes are accompanied by several drawbacks. The reaction time used is long. Moreover the halogen/amine group replacement reaction is not selective and in addition to the desired chloro/amine reaction in position 7 also a fluoro/amine exchange in position 6 takes place to a considerable extent.
DESCRIPTION OF THE INVENTION
It has been found that the selectivity of the desired halogen/amine replacement reaction in position 7 can be increased significantly by reacting a cyclic amine with an anhydride of the Formula I (wherein R and R.sup.1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms). A further advantage of this process is that the reaction time is significantly shorter.
According to the present invention there is provided a process for the preparation of compounds of the Formula I ##STR4## (wherein R and R.sup.1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of the Formula II ##STR5## (wherein R.sup.2 stands for hydrogen or alkyl comprising 1-4 carbon atoms) with a boron derivative of the Formula III ##STR6## (wherein R.sup.3, R.sup.4 and R.sup.5 stand for an alkyl group comprising 1-4 carbon atoms and optionally substituted by halogen or for an aryl group comprising 6-10 carbon atoms).
The reaction of the quinoline-3-carboxylic acid of the Formula II and the boron derivative of the Formula III can preferably be carried out in an optionally halogenated organic carboxylic acid--which may also contain the corresponding acid anhydride--at a temperature between 0.degree. and 200.degree. C. The compound of the Formula I thus formed precipitates from the reaction mixture either spontaneously or under cooling and can be separated e.g. by filtration.
The reaction may however also be carried out in an other solvent (e.g. sulfoxide, amides, pyridine, aromatic hydrocarbons), if desired.
The boron derivatives of the Formula III can be used in a molar ratio of 1-50 moles related to 1 mole of the quinoline-3-carboxylic acid derivative of the Formula II.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples.
EXAMPLE 1
A mixture of 9.3 g of boric acid and 70 g of propi
REFERENCES:
patent: 4182880 (1980-01-01), Watanabe et al.
Chem. Abstracts, vol. 102, (7), abst. No. 102:62272-y, Feb. 18, 1985.
Chem. Abstracts 103:123491p (1985).
Chem. Abstracts 105:153293j (1986).
Chem. Abstracts Formula Index 1982-1986, p. 13441F and p. 7575F.
Balogh Maria
Hermecz Istvan
Horvath Agnes
Kereszturi Geza
Kovacs Gabor
Chinoin Gyogyszer - es Vegyeszeti Termekek Gyara Rt.
Dubno Herbert
Myers Jonathan
Rotman Alan L.
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