Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2000-12-15
2002-07-23
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C548S557000
Reexamination Certificate
active
06423843
ABSTRACT:
TECHNICAL FIELD
This invention relates to a production intermediate of antimicrobial compounds and a production method thereof.
BACKGROUND ART
3-Amino-4-fluoromethylpyrrolidinyl group is useful as substituent of quinolone compounds. This substituent exists in four stereoisomer forms originated from the configuration of amino group and fluoromethyl group on the pyrrolidine ring. That is, it exists in two isomers of cis and trans forms, and each of them exists in stereoisomer forms having enantiomorphic relationship, thus existing in four isomer forms. Most useful among these four isomers is (3S,4S)-3-amino-4-fluoromethylpyrrolidinyl group represented by the following formula:
which has one of the enantiomorphic relationship of cis configuration and can provide a quinolone having excellent antimicrobial activity and safety.
In order to introduce this (3S,4S)-3-amino-4-fluoromethylpyrrolidinyl group into a quinolone compound, (3S,4S)-3-amino-4-fluoromethylpyrrolidine (formula (Va)):
or a derivative thereof is required. In order to obtain this (3S,4S)-3-amino-4-fluoromethylpyrrolidine or a derivative thereof, it is convenient to obtain (3S,4S)-3-amino-4-hydroxymethylpyrrolidine (formula (IVa)):
or a derivative thereof and introduce fluorine atom into the compound.
However, though cis-3-amino-4-hydroxymethylpyrrolidine as its racemic compound has been known, a method for the synthesis of (3S,4S)-3-amino-4-hydroxymethylpyrrolidine has not been known. Accordingly, the object of the invention of this application is to provide an efficient method for the production of (3S,4S)-3-amino-4-hydroxymethylpyrrolidine or a derivative thereof which is an excellent substituent supply source for efficiently obtaining excellent quinolone compounds.
DISCLOSURE OF THE INVENTION
As a result of extensive investigation, the present inventors have found that, when a racemic cis-3-amino-4-hydroxymethylpyrrolidine derivative represented by formula (I) is treated with mandelic acid as an optically active compound in acetone (or in the presence of an appropriate ketone compound), a condensed 1,3-oxazine derivative (III) is formed through the progress in an acetone- (or an appropriate ketone compound)-related ring closure reaction between the amino group and hydroxymethyl group, and one of the isomers of this compound forms a salt with the optically active mandelic acid and precipitates as crystals.
That is, it was revealed that separation of enantiomers of the compound of formula (I) is achieved by the precipitation of a salt of the oxazine compound represented by formula (III) with the optically active mandelic acid as crystals. In addition, it was revealed also that, when this salt is converted into its free form by removing mandelic acid and then hydrolyzed, a 3-amino-4-hydroxymethylpyrrolidine derivative comprised of one of the enantiomers is easily regenerated through ring opening of the oxazine ring.
Namely, the present invention was accomplished by finding that one of the enantiomers of the 3-amino-4-hydroxymethylpyrrolidine derivative can be obtained easily in this manner.
Accordingly, the present invention relates to a compound represented by the following formula (IIIa):
or formula (IIIb):
[in the above formulae,
R
1
represents
a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms (which may have one or more substituents selected from the group consisting of a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms),
an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having from 1 to 6 carbon atoms; the aryl group moiety may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms; and the alkyl group moiety may have one or more substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),
an acyl group (which may be either aliphatic or aromatic; in the case of an aliphatic group, it has from 1 to 7 carbon atoms and may have one or more substituents selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms; and in the cases of an aryl group as an aromatic group and an aryl group as a substituent on the fatty chain in the case of an aliphatic group, it may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms),
an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkyl group moiety may have one or more substituents selected from the group consisting of a halogen atom and an alkoxyl groups having from 1 to 6 carbon atoms), or
an aralkyloxycarbonyl group (wherein the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having from 1 to 6 carbon atoms; the aryl group moiety may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms; and the alkyl group moiety may have one or more substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms);
R
2
represents
a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms (which may have one or more substituents selected from the group consisting of a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms),
an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having from 1 to 6 carbon atoms;
the aryl group moiety may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms; and the alkyl group moiety may have one or more substituents selected from the group consisting of an alkyl groups having from 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),
an acyl group (which may be either aliphatic or aromatic; in the case of an aliphatic group, it has from 1 to 7 carbon atoms and may have one or more substituents selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms; and in the cases of an aryl group as an aromatic group and an aryl group as a substituent on the fatty chain in the case of an aliphatic group, it may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms),
an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkyl group moiety may have one or more substituents selected from the group consisting of a halogen atom and an alkoxyl groups having from 1 to 6 carbon atoms), or
an aralkyloxycarbonyl group (wherein the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having from 1 to 6 carbon atoms; the aryl group moiety may have one or more substituents selected from the group consisting of a halogen atom, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms; and the alkyl group moiety may have one or more substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms); and
R
3
and R
4
each independently represents an alkyl group having from 1 to 6 carbon atoms (which may have one or more substituents selected from the group consisting of a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms), or
an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having from 1 to 6 carbon atoms; the aryl group moiety ma
Makino Toru
Ohta Naoki
Shimizu Sadahiro
Balasubramanian Venkataraman
Daiichi Pharmaceutical Co. Ltd.
Raymond Richard L.
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