Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-12-17
2004-11-30
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06825375
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 2-fluoro-2-(3-oxocyclopentyl)acetate derivative and processes for effectively producing 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives using the same.
BACKGROUND ART
The metabotropic glutamate receptors, which are one type of glutamate receptors, are classified pharmacologically into three groups. Of these, group 2 (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (cAMP) (
Trends Pharmacol. Sci
., 14, 13 (1993)), and for this reason, it is suggested that the compounds acting on group 2 metabotropic glutamate receptors have treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
The present inventors have already discovered 6-fluorobicyclo[3.1.0]hexane derivatives to be useful compounds acting on group 2 metabotropic glutamate receptors. In addition, Japanese Unexamined Patent Application, First Publication No. 2000-336071 proposes, as shown in the below reaction schemes, a synthetic method comprising the steps of converting the carboxylic acid moiety of a fluoroacrylic. acid derivative (6) into an active substance, reacting the active substance with diazomethane, followed by reacting in the presence of a metal catalyst to produce a ketone derivative (4′) which is an important intermediate, and subsequently leading to a compound (7).
(in the reaction schemes described above, Y
1
and Y
2
are the same or different, and each represents a hydrogen atom, a C
1-10
alkylthio group, a C
3-8
cycloalkylthio group, a C
3-8
cycloalkyl C
1-5
alkylthio group, a C
1-5
alkoxy group, a C
3-8
cycloalkoxy group, or a C
3-8
cycloalkyl C
1-5
alkoxy group; alternatively, one of them represents a hydrogen atom, and the other represents a hydroxy group, a C
1-5
alkoxy group, a C
3-8
cycloalkyl alkoxy group, or a C
3-8
, cycloalkyl C
1-5
alkoxy group; or, Y
1
and Y
2
together represent an oxygen atom or —X(CH
2
)
n
X— (X represents an oxygen atom or a sulfur atom, and n represents 2 or 3)).
DISCLOSURE OF THE INVENTION
Objects of the present invention are to provide a novel synthetic intermediate useful for efficient syntheses of 6-fluoro-bicyclo[3.1.0]hexane derivatives (7) acting on group 2 metabotropic glutamate receptors, which have treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma, and to provide a process for producing the same.
As a result of a diligent research, the present inventors discovered that a 2-fluoro-2-(3-oxocyclopentyl)acetate derivative easily synthesized from 2-cyclopenten-1-one is useful for efficient syntheses of 6-fluoro-bicyclo[3.1.0]hexane derivatives (7), and consequently, have completed the present invention.
That is, one mode of the present invention relates to a 2-fluoro-2-(3-oxocyclopentyl)acetate derivative represented by the formula (1):
(wherein R
1
is a C
1-10
alkyl group, a C
3-8
cycloalkyl group, a C
3-8
cycloalkyl C
1-6
alkyl group, an aryl group, an aryl C
1-6
alkyl group, a C
1-6
alkoxy C
1-6
alkyl group, a C
1-6
hydroxyalkyl group, a C
1-6
alkylthio C
1-6
alkyl group, a C
1-6
mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group, which may be substituted with more than one or two substituents selected from the group consisting of a halogen atom, a nitro group, an amino group, a hydroxyl group, a thiol group, a formyl group, a carboxyl group, a cyano group, a carbamoyl group, a C
1-6
alkyl group, an aryl group, a heteroaryl group, a (C
1-6
alkoxy)carbonyl group, an acyl group, a C
1-6
alkoxy group, and a C
1-6
alkylthio group; and X
1
is a chlorine atom, a bromine atom, or an iodine atom).
Another mode of the present invention relates to a process for producing the acetate derivative represented by the formula (1), comprising the step of reacting 2-cyclopenten-1-one represented by the formula (2):
with a fluoroketene silyl acetal derivative represented by the formula (3):
(wherein X
1
and R
1
has the same meanings as described above; and R
2
, R
3
, and R
4
are the same or different and each represents a C
1-10
alkyl group, or an aryl group).
In addition, another mode of the present invention relates to a process for producing a 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative represented by the formula (4):
(wherein R
1
has the same meaning as described above) comprising the step of treating the acetate derivative represented by the formula (1) with a base.
Furthermore, another mode of the present invention relates to a process for producing (+), (−), and (±)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives represented by the formula (4′):
(wherein R
1
has the same meaning as described above) comprising the steps of: hydrolyzing the ester moiety of the 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative represented by the formula (4) which is produced as described above to yield a carboxylic acid derivative represented by the formula (5):
as a diasteromer mixture;
resolving the diastereomers of the compound of the formula (5) described above to isolate the compound represented by the formula (5′):
and
esterifying the carboxylic acid moiety of the compound of the formula (5′) described above.
The terms used in the present invention are defined in the following. In the present invention, “C
n-m
” means that the group following the “C
n
-
m
” has a number of carbon atoms n to m.
The C
1-10
alkyl group means a straight-chain or branched-chain alkyl group, examples of which include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 2-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group, a decyl group, and the like.
The C
3-8
cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms, examples of which include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
The C
3-8
cycloalkyl C
1-6
alkyl group means, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like.
The aryl group means a phenyl group, a naphthyl group, or the like, and preferably means a phenyl group. The aryl C
1-6
alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, substituted with at least one aryl group, and preferably substituted with at least one phenyl group. Examples thereof include, for example, a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, a 2-phenylethyl group, and the like.
The C
1-6
alkoxy C
1-6
alkyl group means a group having a combined structure of a C
1-6
alkoxy group and a C
1-6
alkyl group. The C
1-6
alkoxy group means a straight-chain or branched-chain alkoxy group, examples of which include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group, and the like. Therefore, examples of the C
1-6
alkoxy C
1-6
alkyl group include a methoxymethyl group, an
Kumagai Toshihito
Nakazato Atsuro
Sakagami Kazunari
Taguchi Takeo
Killos Paul J.
Taisho Pharmaceutical Co.
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