Method of resolving 2-oxobicyclo [3.1.0]...

Details Method of resolving 2-oxobicyclo [3.1.0]... Method of resolving 2-oxobicyclo [3.1.0]...

2000-04-14

2002-06-18

Leary, Louise N. (Department: 1623)

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

Organic compounds

Carboxylic acids and salts thereof

C435S136000

Reexamination Certificate

active

06407284

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of resolving 2-oxobicyclo [3.1.0]hexane-6-carboxylic ester into an optically active acid or ester derivative thereof.
2. Description of Related Art
Optically 2-oxobicyclo[3.1.0]hexane-6-carboxylic acids and ester compounds thereof are useful intermediate compounds for pharmaceutical preparations etc.
As the method of preparing said optically active 2-oxobicyclo[3.1.0]hexane-6-carboxylic acids, a method of optical resolution and a method of derivatizing them from optically active substances have been known in the art.
As the method of optical resolution, for example a method of optical resolution of racemic (1SR,5RS,6SR)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acids by using an optically active amine such as optically active phenethylamine as an optically resolving agent has been known (JP-A 08-188561, WO 96/04900).
As the method of derivatizing them from optically active substances, a method of derivatizing optically active 2-oxobicyclo[3.1.0]hexane-6-carboxylic acids from optically active dicyclopentane dienone as the starting material has been known (JP-A 08-188561).
However, they have problems in that in industrial production, the method of optical resolution requires a recycling step of recovering the optically resolving agent, thus increasing the number of steps, while the method of derivatizing them from optically active substances makes use of the optically active compound as the starting material, thus raising the cost of the starting material.
SUMMARY OF THE INVENTION
An object of the invention is to provide a method of resolving 2-oxobicyclo[3.1.0]hexane-6-carboxylate into acid and ester derivatives thereof, without using any optically resolving agent, by selectively hydrolyzing an optional optical isomer of 2-oxobicyclo[3.1.0]hexane-6-carboxylates, thereby efficiently producing the desired compound with an enzyme.
The present invention provides:
1. a method of resolving 2-oxobicyclo[3.1.0]hexane-6-carboxylates having the following relative configuration of formula (1):
wherein X
1
, X
2
, R
1
, R
2
and R
3
have the same meanings as defined below, into one enantiomer ester thereof and the other enantiomer acid,
which comprises:
contacting an enzyme having an ability to preferentially hydrolyze one enantiomer ester contained in 2-oxobicyclo[3.1.0]hexane-6-carboxylate of formula (1) as defined above, with 2-oxobicyclo[3.1.0]hexane-6-carboxylate of formula (1) as defined above to obtain one enantiomer as an acid and the other enantiomer as an ester,
wherein R
1
represents
a C
1
to C
10
alkyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, halogen or nitro;
an allyl group;
an arylalkyl group which aryl may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
1
to C
8
alkoxy, halogen or nitro group; or
an aryl group which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
1
to C
8
alkoxy, halogen or nitro;
X
1
and X
2
independently represent a single bond, S, O, SO, SO
2
or NR
4
wherein R
4
represents a hydrogen or a group of formula: (CO)nR
5
wherein n is 0 or 1, and
R
5
represents
a hydrogen atom or a halogen atom;
a C
1
to C
10
allyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a C
2
to C
10
alkenyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a C
2
to C
10
alkynyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro,. thiol or thioalkyl;
an aryl group which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
an arylalkyl group wherein the aryl may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
an aromatic heterocyclic ring which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl; or
a non-aromatic heterocyclic ring which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
R
2
and R
3
independently represent hydrogen, a halogen atom or a nitro group;
a C
1
to C
10
alkyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a C
2
to C
10
alkenyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a C
2
to C
10
alkynyl group which may be substituted with at least one group selected from a C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
an aryl group which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
an arylalkyl group, which aryl may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
an aromatic heterocyclic ring which may be substituted with at least one group selected from a C
1
to C
8
allyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a non-aromatic heterocyclic ring which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl;
a non-aromatic hydrocarbon ring which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl, said non-aromatic hydrocarbon ring being condensed with 1 or 2 aromatic hydrocarbon rings or aromatic heterocyclic rings; or
a non-aromatic heterocyclic ring which may be substituted with at least one group selected from a C
1
to C
8
alkyl, C
2
to C
8
alkenyl, C
2
to C
8
alkynyl, C
1
to C
8
alkoxy, hydroxy, halogen, amino, nitro, thiol or thioalkyl, said non-aromatic heterocyclic ring being condensed with 1 or 2 aromatic hydrocarbon rings or aromatic heterocyclic rings.
Hereinafter, the above-described method is referred to as the present method.


REFERENCES:
patent: 5405763 (1995-04-01), Nishizawa et al.
patent: 5476965 (1995-12-01), Chase et al.
patent: 5661184 (1997-08-01), Helton et al.
patent: 846769 (1998-10-01), None
patent: 846769 (1998-10-01), None
patent: 407213280 (1995-08-01), None
patent: 407213280 (1995-08-01), None
patent: 8188561 (1996-07-01), None
patent: WO9604900 (1996-02-01), None
patent: WO9701526 (1997-01-01), None

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