Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-23
2001-04-17
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06218548
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel process for the synthesis of material compounds to be used in the production of a quinolone derivative which is expected as an excellent antibacterial agent (JP-A-2-231475; the term “JP-A” as used herein means an “unexamined published Japanese patent application”) and to an intermediate compound useful for the production.
BACKGROUND ART
The aforementioned compound represented by formula (VI):
(wherein n is an integer of 2 to 5)
has been produced via a multi-step production process using ethyl acetoacetate as the starting material (JP-A-2-231475). In addition, an optically active form of this compound is obtained by preparing a diastereomer compound having an optically active protecting group, isolating it using a preparative high performance liquid chromatography and then removing the protecting group (JP-A-3-95176). However, such a method requires complex handling, hence leaving room for the improvement as an industrial production process.
It is accordingly an object of the present invention to provide a process for the inexpensive, short-step and industrially advantageous production of nitrogen-containing heterocyclic compounds having a spiro-cyclic structure, particularly an optically active azaspiro[2.4]heptane derivative.
DISCLOSURE OF INVENTION
Taking the aforementioned circumstances into consideration, the inventors of the present invention have conducted intensive studies and found that a compound of formula (I)
can be obtained from a known compound of formula (IV)
easily with a high yield, and that the compound of formula (I) obtained therefrom can be converted easily into a compound of the following formula (II).
The present invention has been accomplished on the basis of such findings.
The present inventors have also found a method by which the intended compound of formula (VI):
can be obtained easily from a compound of formula (III-1):
which is obtained by reducing the compound of formula (II).
Also, the present inventors have found that, when the compound (IV) is allowed to react with hydrogen cyanide in the presence of an optically single amine or a salt thereof, one of the thus formed two diastereomers is obtained on a preferential basis.
The present inventors have found also that one of the two diastereomers obtained above is easily epimerized when treated in a protic solvent, so that a mixture of two diastereomers can be obtained.
Accordingly, the present invention relates to a compound represented by formula (I):
wherein
n is an integer of 2 to 5;
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms; and
R
2
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, with the proviso that a compound, in which n is 2, R
1
is hydrogen atom and R
2
is an ethyl group, is excluded, and a salt thereof.
The present invention also relates to a compound represented by formula (II):
wherein
n is an integer of 2 to 5; and
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, and a salt thereof.
The present invention also relates to a compound represented by formula (III):
wherein
n is an integer of 2 to 5; and
R
11
represents a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, with the proviso that R
a
, R
b
and R
c
are different from one another, and a salt thereof.
The present invention also relates to a process for the production of a compound represented by formula (I):
wherein
n is an integer of 2 to 5;
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, with the proviso that R
a
, R
b
and R
c
are not hydrogen atoms at the same time; and
R
2
represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
which comprises allowing a compound represented by formula (IV):
wherein
n is an integer of 2 to 5 and R
2
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, to react with hydrogen cyanide in the presence of a compound represented by the following formula (V) or a salt thereof:
NH
2
R
1
(V)
wherein
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, with the proviso that R
a
, R
b
and R
c
are not hydrogen atoms at the same time.
The present invention also relates to a process for the production of a compound represented by formula (II):
wherein
n is an integer of 2 to 5; and
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms,
which comprises reducing the cyano group of a compound represented by formula (I):
wherein
n is an integer of 2 to 5;
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least: one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms; and
R
2
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and subsequently effecting cyclization of the resulting amino compound.
The present invention also relates to a process for the production of a compound represented by formula (III-1):
wherein
n is an integer of 2 to 5; and
R
1
represents a hydrogen atom or a substituent group represented by formula:
wherein
R
a
, R
b
and R
c
each represents a phenyl, phenylmethyl or naphthyl group (which may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a halogen atom and a nitro group), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms,
which comprises reducing the just described compound of formula (II).
The present invention
Akiba Toshifumi
Ebata Tutomu
Hirai Keiichi
Ohta Naoki
Saito Tatsuru
Daiichi Paharmaceutical Co., Ltd.
Higel Floyd D.
Sackey Ebenezer
Sughrue Mion Zinn Macpeak & Seas, PLLC
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