Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-22
2004-11-30
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06825353
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods for the efficient production of quinolonecarboxylic acid synthetic antibacterial agents which are expected for applications such as excellent medicaments and agricultural chemicals and to intermediate compounds to be used therein.
BACKGROUND ART
Among quinolone synthetic antibacterial agents useful as antibacterial agents, 5-amino-8-methylquinolonecarboxylic acid derivatives are known to have excellent characteristics. As shown below,
synthesis of such quinolone derivatives is carried out by allowing a compound of formula (1) to react with a basic substituent compound (R—H; which means a compound capable of introducing a basic substituent by a substitution reaction). For example, a method of the following formula:
is known, in which a 5-amino-8-methylquinolonecarboxylic acid BF
2
chelate [a compound of the formula (1) wherein R
3
=NH
2
, R
4
=Me and Y=BF
2
] is allowed to react with a basic substituent compound in an appropriate solvent in the presence of an appropriate base.
That is, a method in which (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (or its hydrochloride) is allowed to undergo the reaction at 30° C. for 3 to 4 days in dimethyl sulfoxide in the presence of N,N-diisopropylamine and then purified, and the thus obtained crystals are allowed to undergo the reaction by heating in a mixed solvent of methanol-1,2-dichloroethane in the presence of triethylamine and then purified, thereby obtaining 5-amino-7-[(S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (JP-A-7-309864 and JP-A-8-198819; the term “JP-A” as used herein means an “unexamined published Japanese patent application”) However, this is not an industrially satisfactory method because of the low product yield of approximately from 10 to 30%.
Also known is a method in which 5-amino-8-methylquinolonecarboxylic acid [a compound of the formula (1) wherein R
3
=NH
2
, R
4
=Me and Y=H] and a basic substituent compound are heated in an appropriate solvent in the presence of an appropriate base. That is, a method in which they are stirred and heated at about 100° C. for 87 hours in dimethyl sulfoxide in the presence of triethylamine and then treated, and the thus obtained crystals are purified after carrying out deprotection of amino group in the usual way, thereby obtaining 5-amino-7-[(3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl]-1-cyclo propyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (JP-A-8-259561) (the following formula):
or a method (the following formula):
in which 5-amino-7-[(S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid is obtained (
Chem. Pharm. Bull.,
44, 1376 (1996)).
However, yields of the final products by these methods are still low, namely 38% and 56% respectively, so that, though the yields are slightly improved in comparison with the foregoing method, they are not industrially satisfactory methods.
Thus, the previous methods for the production of 5-amino-8-methylquinolonecarboxylic acid derivatives were not satisfactory as an industrial production method.
Under such a situation, the present inventors have examined the reason of low yield of the previous reaction of a boron chelate compound of Y=—B(R
5
)
2
in the compound of formula (1) of the invention [(5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-O
3
,O
4
)difluoroboron] with a basic substituent compound.
As a result, it was found that the boron chelate compound easily causes de-chelation on heating. Thus, it was confirmed that de-chelation in the boron chelate quinolone compound preferentially proceeds rather than reacting with a basic substituent compound when the reaction temperature is increased for the purpose of accelerating the reaction (e.g., even by a heating at 30 to 40° C.), while substitution reaction of the compound formed by this de-chelation with the basic substituent compound hardly proceeds at this temperature.
In addition, an open system reaction is carried out under a high temperature (110° C.) condition in the case of the substitution reaction of a carboxylic acid type quinolone compound [a compound in which the 3-position carboxyl group is not modified, such as 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid itself] with a pyrrolidine derivative. It was found that, since decomposition reaction of the carboxylic acid quinolone compound itself competitively occurs simultaneously with the substitution reaction by this method, the reaction becomes complex in addition to coloring of the reaction solution. That is, the inventors have considered that yield of the substitution product is reduced due to decomposition of the material compound, and further reduction of the yield occurs because of the difficulty in purifying the final product of interest due to the complex reaction and coloring.
By the way, it is known that the substitution reaction of aromatic halogen compounds with amines sharply progresses when the reaction is carried out in an appropriate solvent under a super-high pressure (cf.
Heterocycles,
27,319 (1988);
Chem. Lett.,
1187 (1987);
Synthesis,
1147 (1990);
Tetrahedron Lett.,
3923 (1990);
Bull. Chem. Soc. Jpn.,
64, 42 (1991)). However, such a substitution reaction under a high pressure is mainly a reaction with a monocyclic halogen compound such as benzene, pyrimidine, pyrazine or thiazole, and only a few examples such as benzoxazole and benzothiazole are known as bicyclic halogen compounds but there are no reports on 4-quinolone compounds.
An object of the invention is to provide a method for the efficient production of quinolone compounds having excellent antibacterial activity, pharmacokinetics and safety, particularly a 7-substituted 5-amino-8-methylquinolonecarboxylic acid derivative.
DISCLOSURE OF THE INVENTION
As a result of intensive studies, the present inventors have found that a 5-amino-8-methylquinolonecarboxylic acid derivative can be efficiently provided through inhibition of the decomposition reaction of the quinolone material compound, by carrying out the substitution reaction of a 5-amino-1-substituted-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid with a basic substituent compound under a high pressure, thereby accomplishing the invention.
The inventors have further found that the substitution reaction with a basic substituent compound quickly proceeds in-the case of a compound in which the 5-position amino group is acylated, and excellent effects are exerted particularly by the reaction under a pressurized condition, thus resulting in the accomplishment of the invention.
Accordingly, the invention relates to a method for producing a compound represented by formula (2):
(wherein R
1
, R
2
, R
3
, R
4
, R, X
1
and Y are as defined in the following) which comprises allowing a compound represented by formula (1):
[wherein R
1
represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxy group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms,
R
2
represents a hydrogen atom or an alkylthio group having from 1 to 6 carbon atoms,
wherein R
2
and R
1
may be combined to form a cyclic structure together with the carbon atom and nitrogen atom, to which they are bonded, and this ring may contain a sulfur atom as a constituting atom and may further have an alkyl group having from 1 to 6 carbon atoms as a substituent,
R
3
represents a hydrogen atom, an amino group, a thiol group, a hal
Akiba Toshifumi
Jouno Toshiaki
Saito Tatsuru
Tani Yuichiro
Daiichi Pharmaceutical Co. Ltd.
Morris Patricia L.
Sughrue & Mion, PLLC
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