Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-26
2002-01-08
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S405000, C514S312000
Reexamination Certificate
active
06337399
ABSTRACT:
TECHNICAL FIELD
This invention relates to processes for producing a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1] and its intermediate as well as a salt of 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1], its hydrate and a composition comprising the same as an active ingredient:
wherein R
1
represents a hydrogen atom or a carboxyl-protecting group; R
2
represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R
3
represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R
4
represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane ring with the carbon atom to which R
4
bonds; R
5
represents a hydrogen atom, an amino-protecting group or a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R
6
represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or C—R
7
in which R
7
represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group.
BACKGROUND ART
As the process for producing a compound of the general formula [1], there has been known the process described in WO97/29102. That is to say, said publication describes that a compound of the general formula [1] can be produced by subjecting a 5-halogenoisoindoline derivative represented by the following general formula [4] or its salt:
wherein R
3
, R
4
and R
5
have the same meanings as mentioned above and X
1
represents a halogen atom, to lithiation or Grignard reaction and thereafter to reaction with a trialkyl borate to form an isoindoline-5-boronic acid derivative represented by the following general formula [2c] or its salt:
wherein R
3
, R
4
and R
5
have the same meanings as mentioned above and R
11
represents a hydrogen atom or an alkyl group; and subsequently reacting the isoindoline-5-boronic acid derivative or its salt with a 7-halogenoquinolonecarboxylic acid represented by the following general formula [3b]:
wherein R
1
, R
2
, R
6
and A have the same meanings as mentioned above and X
3
represents a halogen atom, in the presence of a palladium complex such as bis(triphenylphosphine)-palladium(II) chloride, tetrakis(triphenylphosphine)-palladium(0) or the like.
Among the compounds of the general formula [1], (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid represented by the formula:
(referred to hereinafter as T-3811) is a compound excellent in activity against Gram-positive and Gram-negative bacteria and the development of a process for industrially producing the same has been desired.
Moreover, T-3811 is low in solubility in the vicinity of neutral, so that the enhancement of solubility at a physiologically acceptable pH has been desired.
DISCLOSURE OF THE INVENTION
In order to develop a process for industrially producing a 7-isoindoline-quinolonecarboxylic acid derivative of the general formula [1] including T-3811, the present inventors have diligently made research to find consequently that a coupling reaction between an isoindoline-5-boronic acid derivative represented by the following general formula [2]:
wherein R
3
, R
4
and R
5
have the same meanings as mentioned above and R
8
and R
9
represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, and a 7-leaving group-substituted quinolone-carboxylic acid represented by the following general formula [3]:
wherein R
1
, R
2
, R
6
and A have the same meanings as mentioned above and X
2
represents a leaving group, can be easily carried out in the presence of metallic palladium.
Furthermore, it has been found that an isoindoline-5-boronic acid derivative represented by the following general formula [2a]:
wherein R
3
, R
4
and R
5
have the same meanings as mentioned above and Z represents an alkylene group can easily be obtained not by the conventional borodation through lithiation or Grignard reaction but by the reaction of a 5-halogenoisoindoline derivative represented by the following general formula [4]:
wherein R
3
, R
4
, R
5
and X
1
have the same meanings as mentioned above, with a dialkoxyborane or an alkoxydiborane in the presence of a palladium catalyst, and further found that the compound of the general formula [2a] can be applied, without being isolated, to the so-called one-pot reaction by which the compound of the general formula [3] is reacted to produce a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1].
Also, the present inventors have found that a 1-alkylisoindoline-5-boronic acid derivative represented by the following general formula [2b]:
wherein R
4a
represents an alkyl group and R
5
, R
8
and R
9
have the same meanings as mentioned above is an excellent intermediate for producing a 7-isoindoline-quinolone-carboxylic acid derivative represented by the following general formula [1a]:
wherein R
4a
, R
1
, R
2
, R
5
, R
6
and A have the same meanings as mentioned above among the compounds of the general formula [1].
Moreover, it has been found that a 1-alkyl-5-halogenoisoindoline derivative represented by the following general formula [4a]:
wherein R
4a
, R
5
and X
1
have the same meanings as mentioned above, can be produced by using a 4-halogenobenzylamine derivative as the starting material.
Furthermore, it has been found that as the process for producing a 7-bromo-quinolonecarboxylic acid derivative represented by the following general formula [3a] which is a useful intermediate for producing T-3811:
wherein R
1b
represents a carboxyl-protecting group; R
7a
represents a substituted or unsubstituted alkyl group; and R
2a
represents a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group, a process in which a 2,4-dibromo-3-hydroxybenzoic acid ester is used as the starting material and which is through various intermediates as mentioned hereinafter is an excellent industrial production process.
As mentioned above, the present inventors have diligently made research on 7-isoindoline-quinolone-carboxylic acid derivatives represented by the general formula [1] including T-3811 and intermediates for producing the same and have accomplished this invention.
In addition, the present inventors have examined various salts of T-3811 which have never been known, and have consequently found that among them, methanesulfonate of T-3811 is much higher in solubility at a physiologically acceptable pH than the other salts of T-3811 and further that T-3811 methanesulfonate hydrate has no polymorphism and is good in stability against humidity, and hence, it has a very high usefulness as a composition, particularly as a starting material for preparation, whereby this invention has been accomplished.
In the present specification, unless otherwise specified, the term “halogen atom” means fluorine atom, chlorine atom, bromine atom or iodine atom; the term “alkyl group” means a straight or branched chain C
1-10
alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-bu
Hamamoto Shoichi
Hayashi Kazuya
Kiyoto Taro
Kotsubo Hironori
Matsukura Hiroko
Seaman D. Margaret
Toyama Chemical Co., Ltd.
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