Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-04-11
2003-04-15
Solola, Taofiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S078000, C562S494000
Reexamination Certificate
active
06548695
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing isocoumarin-3-yl-acetic acid derivatives and to synthetic intermediates to be used in the process.
BACKGROUND ART
It is known that the isocoumarin-3-yl-acetic acid derivatives, for example, a compound represented by a formula:
are effective for preventing and curing an abnormal immunoregulating action or a disease following angiogenesis (International Publication WO97/48693). According to this international publication pamphlet, the above compound is produced from 8-hydroxy-3-methyl-6-methoxy-isocoumarin via several steps. This is an excellent process in terms of that any of the respective steps in this process proceeds at a good yield but can not necessarily provide isocoumarin-3-yl-acetic acid derivatives having various substituents at a good efficacy.
Accordingly, there still exists a need for a process in which an isocoumarin-3-yl-acetic acid derivatives can efficiently be produced and particularly a process for producing the above derivative which can have various substituents in a 2-position of a acetic acid chain capable of exerting a strong effect on a biological activity.
DISCLOSURE OF THE INVENTION
The present inventors have found that a cyclocondensation reaction of some kind of a homophthalic acid derivative with some kind of a malonic acid derivative is allowed to proceed by one pot, whereby a wide variety of isocoumarin-3-yl-acetic acid derivatives can efficiently be produced. Further, we have found as well that in the reaction described above, a corresponding &bgr;-oxocarboxylic acid derivative before the cyclocondensation reaction can efficiently be obtained by selecting the reaction conditions. The present invention is based on such knowledge as described above.
Hence, according to the present invention, provided is the following process, that is, a process for producing isocoumarin-3-yl-acetic acid derivatives which are represented by the following formula (I):
(wherein R represents a hydrogen atom, a non-substituted or substituted alkyl group, a non-substituted or substituted alkenyl group, a non-substituted or substituted alkynyl group, a non-substituted or substituted alkoxyl group, a protected amino group, a hydroxyl group or a protected hydroxyl group; R
a
represents a hydrogen atom or a protecting group for a carboxyl group; R
b
represents a hydrogen atom or a protecting group for a hydroxyl group; and R
c
represents a non-substituted or substituted lower alkyl group), the above process comprising:
reacting a homophthalic acid derivative represented by the following formula (III):
(wherein R
c
represents a non-substituted or substituted alkyl group; R
1
represents a hydrogen atom or a protecting group for a carboxyl group; and R
2
represents a hydrogen atom or protecting group for a hydroxyl group) with a malonic acid derivative represented by the following formula (IV):
(wherein R is synonymous with that defined for formula (I); R
3
represents a protecting group for a carboxyl group; and X represents a —OM group (wherein M is alkaline metal or alkaline earth metal), chlorine or bromine) in an inert organic solvent in the presence of a condensing agent,
wherein a &bgr;-oxocarboxylic acid derivative represented by the following formula (II) in optionally formed during the above reaction:
(wherein R and R
c
are as defined for formula (I), and R
1
R
2
and R
3
are as defined for formulas (III) and (IV)); and the protecting groups for a hydroxyl group and/or a carboxyl group are be subjected to an elimination reaction, if necessary.
On the other hand, both of the (3-oxocarboxylic acid derivative represented by formula (II) described above and a half ester (monoester) of the homophthalic acid derivative in which R
1
in formulas (III) described above represents a protecting group for a carboxyl group are, to knowledge of the present inventors, novel compounds which are not described in conventional technical documents. Hence, according to the present invention, these novel compounds are provided.
BEST MODE FOR CARRYING OUT THE INVENTION
The definitions of the respective groups specifying the compounds represented by the respective formulas related to the present invention shall specifically be explained below.
The “lower alkyl group” means a linear or branched, saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isoamyl and n-hexyl. The preferred alkyl group is the group having four or less carbon atoms. As described later, the examples described above can be applied in the present specification including the case where the lower alkyl group takes a share in a part of some group. Substituents in the case where these alkyl groups are substituted include halogens, a cycloalkyl group having 3 to 7 carbon atoms, a lower alkyl group having at least one carbon atom, an aryl group (for example, phenyl and naphthyl) which may be substituted with halogens and nitro, a lower alkoxy group, a lower alkylthio group and a mono- or di-lower alkyl-substituted amino group. At least one of these substituents can be present. Halogens mean fluorine, chlorine, bromine and iodine, but halogens in the substituents described above are preferably fluorine and chlorine. The lower alkyl groups in the lower alkoxy group, the lower alkylthio group and the lower alkyl-substituted amino group comply with the definition of the “lower alkyl group” described above (hereinafter, this is common through the whole present specification). Specific examples of the substituted alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, cyclopropylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, benzyl, benzhydryl, methoxymethyl, i-propoxymethyl, methylthiomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl and diethylaminomethyl.
The “lower alkenyl group” means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and a carbon—carbon double bond and includes, for example, ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl and n-heptenyl. Substituents in the case where these lower alkenyl groups are substituted can be synonymous with the substituents in the “lower alkyl group” described above. Further, a substitution mode in the substituents applies correspondingly to the case of the lower alkyl group described above.
The “lower alkynyl group” means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and a carbon—carbon triple bond and includes, for example, ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl and n-pentynyl. Substituents in the case where these lower alkynyl groups are substituted can be synonymous with the substituents in the “lower alkyl group” described above. Further, a substitution mode in the substituents applies correspondingly to the case of the lower alkyl group described above.
The “lower alkoxy group” in the definition of the “R” group is common to the lower alkoxy groups given as the examples of the substituents for the lower alkyl group described above and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-botoxy, sec-butoxy, tert-butoxy and n-pentyloxy. Substituents in the case where these lower alkoxy groups are substituted can be synonymous with the substituents in the “lower alkyl group” described above. Specific examples of the substituted lower alkoxy group include fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropylmethoxy, benzyloxy, methoxymethoxy, ethoxymethoxy, ethoxyethoxy, dimethylaminomethoxy and dimethylaminoethoxy.
A protecting group in the “protected amino group”, the “protecting group for a hydroxyl group” and the “protecting group for a carboxyl group” mean groups having a function for blocking or inhibiting a reactivity of the respective corresponding functional groups in order to avoid or reduce undesirable side reactions in the reaction according to the present invention. Further, in the pr
Isshiki Kunio
Konuki Kaname
Kuroda Asako
Nagai Hazuki
Nakashima Takashi
Mercian Corporation
Solola Taofiq
Wenderoth , Lind & Ponack, L.L.P.
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