Intermediates and process for producing fluorine-containing...

Details Intermediates and process for producing fluorine-containing... Intermediates and process for producing fluorine-containing...

2001-06-07

2002-05-21

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S114000, C560S118000, C560S125000, C560S128000, C562S400000, C562S498000, C562S500000, C562S501000, C562S510000, C564S123000

Reexamination Certificate

active

06392086

ABSTRACT:

FIELD OF TECHNOLOGY
The present invention relates to 3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivatives and a process for producing the same, and a process for producing a fluorine-containing amino acid derivative (2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid).
BACKGROUND ART
In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are roughly classified into two types: the “ionotropic type”, in which the receptor has an ion channel type structure, and the “metabotropic type”, in which the receptor is coupled to G-proteins. Ionotropic receptors are classified pharmacologically into three types: N-methyl-D-aspartic acid (NMDA), &agr;-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; Neuropharmacol., 34, 1-26, 1995).
The metabotropic 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 prevention effects on psychiatric disorders such as, for example, schizophrenia, anxiety and its associated diseases, depression, bipolar disorder and epilepsy; and 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.
In addition, in PCT/JP99/00324 which is the International Patent Application by the present applicant, 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid as a compound acting on group 2 metabotropic glutamate receptors is disclosed. Furthermore, in the specification of the same, a preparation method thereof as described below, which comprises steps of subjecting an (1S, 5R, 6S)- or (1SR, 5RS, 6SR)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative (8) to fluorination, and then, hydantoination, followed by hydrolysis, is proposed.
Heretofore, no synthesis methods of 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, other than that of the synthesis schemes described above, have been reported.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a process for further efficiently producing a fluorine-containing amino acid derivative (2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid) acting on group 2 metabotropic glutamate receptors, which has treatment effects and prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy, and 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, as well as novel intermediates which are useful for said production process, and a process for producing the intermediates.
After conducting diligent research with regard to a process for producing a fluorine-containing amino acid derivative [(1S, 2S, 3S, 5R, 6S)- or (1SR, 2SR, 3SR, 5RS, 6SR)-2-amino-3-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid], the present inventors discovered a process for efficiently producing the same, which to employ an (1S, 5R, 6S)- or (1SR, 5RS, 6SR)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative as a starting material, via an (1S, 5R, 6S)- or (1SR, 5RS, 6SR)-3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative which is a novel intermediate, consequently completed the present invention.
That is, the present invention corresponds to a 3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative represented by Formula (1):
[in the formula, R represents OR
1
or NR
1
R
2
, wherein R
1
and R
2
are identical or different, and each represents a hydrogen atom, a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a (C
3
-C
6
cycloalkyl) (C
1
-C
6
alkyl) group, an aryl group, an aryl (C
1
-C
6
alkyl) group, a (C
1
-C
6
alkoxy) (C
1
-C
6
alkyl) group, a C
1
-C
6
hydroxyalkyl group, a (C
1
-C
6
alkylthio) (C
1
-C
6
alkyl) group, or a C
1
-C
6
mercaptoalkyl group], and a process for producing the derivative of Formula (1), characterized in that the process comprises the steps of:
oxidizing an (1S, 5R, 6S)- or (1SR, 5RS, 6SR)-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative represented by Formula (2):
 [in the formula, R is the same as described above] by means of a peroxide, to produce an (1S, 3R, 4R, 5R, 6S)- or (1SR, 3RS, 4RS, 5RS, 6SR)-epoxy derivative represented by Formula (3):
 [in the formula, R is the same as described above]; and reacting said epoxy derivative with a fluorination agent, and a process for producing (1S, 2S, 3S, 5R, 6S)- or (1SR, 2SR, 3SR, 5RS, 6SR)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid represented by Formula (7):
 a pharmaceutically acceptable salt thereof, or a hydrate thereof, characterized in that the process comprises the steps of:
hydrogenating the derivative represented by Formula (1), to produce an (1S, 3S, 5R, 6S)- or (1SR, 3SR, 5RS, 6SR)-3-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative represented by Formula (4):
 [in the formula, R is the same as described above];
subjecting the same to hydantoination or aminocyanidation, to produce an (1S, 2S, 3S, 5R, 6S)- or (1SR, 2SR, 3SR, 5RS, 6SR)-hydantoin derivative represented by Formula (5):
 [in the formula, R is the same as described above], or an (1S, 2S, 3S, 5R, 6S)- or (1SR, 2SR, 3SR, 5RS, 6SR)-aminocyanide derivative represented by Formula (6):
 [in the formula, R is the same as described above]; and
subjecting them to a hydrolysis.
The terms used in the present invention are defined in the following. In the present invention, “C
n
-C
m
” means that the group following the “C
n
-C
m
” has from n to m carbon atoms.
The C
1
-C
6
alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, 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 hexyl group, an isohexyl group, and the like.
The C
3
-C
6
cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, including, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, or the like.
The (C
3
-C
6
cycloalkyl) (C
1
-C
6
alkyl) group means a group having a form mixed with a C
3
-C
6
cycloalkyl group and a C
1
-C
6
alkyl group, examples of which include 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 is preferably a phenyl group. The aryl (C
1
-C
6
alkyl) means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, substituted with at least one aryl group, and preferably a 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
-C
6
alkoxy) (C
1
-C
6
alkyl) group means a group having a form mixed with a C
1-6
alkoxy group and a C
1-6
alkyl group. The C
1
-C
6
alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, including, fo

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