Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-26
2002-01-29
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S556000, C548S557000, C548S569000
Reexamination Certificate
active
06342609
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an intermediate for preparing aromatic amidine derivatives having excellent anticoagulant activity based on inhibition of activated blood coagulation factor X (Japanese Patent Application Laid-Open (kokai) No. 5-208946), and to a process for preparing the intermediate.
BACKGROUND ART
Japanese Patent Application Laid-Open (kokai) No. 5-208946 discloses, as intermediates for preparing an aromatic amidine derivative, a compound represented by formula (3):
wherein R
1
represents a hydrogen atom or an alkyl group; and R
2
represents a hydrogen atom, an alkyl group, a formyl group, an alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino group, an alkanoylaminoalkyl group, an aralkyl group, or an aralkyloxycarbonyl group;
and salts thereof. This publication also discloses a process for preparing the compound and salts.
The process comprises the following steps:
wherein R
1
and R
2
have the same definitions as described above and Et represents an ethyl group. That is, the process comprises reacting a compound represented by formula (1) (hereinafter referred to as nitrile compound (1)) or a salt thereof with ethanol in the presence of an acid; and reacting the thus-formed compound represented by formula (4) or a salt thereof with ammonia, to thereby form a compound represented by formula (3) (hereinafter referred to as amidine compound (3)) or a salt thereof.
However, in the process, when R
2
is a substituent cleaved by an acid (e.g., an alkoxycarbonyl group such as a tert-butoxycarbonyl), a by-product is formed. In addition, epimerization partially proceeds to thereby lower the optical purity of amidine compound (3). In order to suppress epimerization, reaction temperature must be maintained low, which requires a period of one week or more for synthesis of amidine compound (3) from nitrile compound (1) or a salt thereof. Moreover, the process is not suitable for large-scale production, in that a large amount of hydrogen chloride gas and ammonia gas must be used.
DISCLOSURE OF THE INVENTION
In view of the foregoing, the present inventors have conducted earnest studies, and have found an industrially advantageous process for preparing amidine compound (3) or salts thereof, which process permits production of the compound on a large scale at high yield and with a short reaction time without lowering the optical purity of the target compound.
The process according to the present invention is expressed by the following reaction scheme I or II:
Reaction Scheme I
Reaction Scheme II:
wherein R
3
represents a hydrogen atom, an alkyl group, or an alkanoyl group; and R
1
and R
2
have the same definitions as described above.
Accordingly, the present invention is directed to a process for producing amidine compound (3) or a salt thereof—or a compound represented by formula (III) (hereinafter referred to as amidine compound (III)) or a salt thereof—which process comprises reacting nitrile compound (1) or a salt thereof—or a compound represented by formula (I) (hereinafter referred to as nitrile compound (I)) or a salt thereof—with a hydroxylamine compound; and reducing the thus-formed compound represented by formula (2) (hereinafter referred to as amidoxime compound (2)) or a salt thereof, or the thus-formed compound represented by formula (II) (hereinafter referred to as amidoxime compound (II)) or a salt thereof.
The present invention is also directed to amidoxime compound (2) or salts thereof—or amidoxime compound (II) or salts thereof—the compounds and salts being useful intermediates in the process according to the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will next be described in detail. First, substituents of the compounds of the present invention will be described.
R
1
represents a hydrogen atom or an alkyl group. Examples of the alkyl group include linear, branched, or cyclic C1-C6 alkyl groups. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Of these, an alkyl group is preferred, with a methyl group or an ethyl group being more preferred as R
1
.
R
2
represents a hydrogen atom, an alkyl group, a formyl group, an alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino group, an alkanoylaminoalkyl group, an aralkyl group, an aralkyloxycarbonyl group, or an alkanoyl group.
When R
2
is an alkyl group, examples thereof include the same alkyl groups as described in relation to R
1
. Examples of the alkanoyl group include a group formed of a linear, branched, or cyclic C1-C6 alkyl group and a carbonyl group. Specific examples include an acetyl group and a propionyl group.
Examples of the monoalkylcarbamoyl group include a carbamoyl group in which one hydrogen atom is substituted with a linear, branched, or cyclic C1-C6 alkyl group. Specific examples include a monomethylcarbamoyl group, a monoethylcarbamoyl group, and a monoisopropylcarbamoyl group.
Examples of the dialkylcarbamoyl group include a carbamoyl group in which two hydrogen atoms are substituted with linear, branched, or cyclic C1-C6 alkyl groups, which may be identical to or different from each other. Specific examples include a dimethylcarbamoyl group, a diethylcarbamoyl group, and an ethylmethylcarbamoyl group.
The alkanoimidoyl group is a group formed of an alkyl group and a —C(═NH)— group. Examples include a —C(═NH)—C
1-6
alkyl group such as an acetimidoyl group.
Examples of the alkoxycarbonyl group include a group formed of a linear, branched, or cyclic C1-C6 alkoxyl group and a carbonyl group. Specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.
Examples of the carboxyalkyl group include a group formed of a carboxyl group and a linear, branched, or cyclic C1-C6 alkylene group. Specific examples include a carboxymethyl group and a carboxyethyl group.
Examples of the alkylcarbonylalkyl group include a group formed of a linear, branched, or cyclic C1-C6 alkyl group, a carbonyl group, and a linear, branched, or cyclic C1-C6 alkylene group. Specific examples include a methylcarbonylmethyl group, a methylcarbonylethyl group, and a ethylcarbonylmethyl group.
Examples of the aminoalkyl group include a group formed of an amino group and a linear, branched, or cyclic C1-C6 alkylene group. Specific examples include an aminomethyl group, an aminoethyl group, and an aminopropyl group.
Examples of the alkanoylamino group include a group formed of the above-described alkanoyl group and an imino group. Specific examples include a formylamino group, an acetylamino group, and a propionylamino group.
Examples of the alkanoylaminoalkyl group include a group formed of the above-described alkanoylamino group and a linear, branched, or cyclic C1-C6 alkylene group. Specific examples include a formylaminomethyl group, an acetylaminomethyl group, a propionylaminoethyl group.
Examples of the aralkyl group include a group formed of an aryl group such as a phenyl group or a naphthyl group and a linear, branched, or cyclic C1-C6 alkylene group. Specific examples include a benzyl group, a phenethyl group, a triphenylmethyl group, and a naphthylmethyl group.
Examples of the aralkyloxycarbonyl group include a group formed of the above-described aralkyl group and an oxycarbonyl group. Specific examples include a benzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group.
In the present invention, examples of preferred R
2
Makino Toru
Yokoyama Yukio
Daiichi Pharmaceutical Co. Ltd.
Higel Floyd D.
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