Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-24
2003-04-29
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06555694
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for production of a pyrrolidinone compound which is useful as, for example, a remedy for central nervous system disorders (e.g. schizophrenia, dementia, manic depressive psychosis, anxiety neurosis, drug poisoning and ischemic encephtalopathy), diseases associated with immunodeficiency and cryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma, etc.; a 3-carboxy-1-substituted-2-pyrrolidinone compound which is a useful intermediate for production of the above pyrrolidinone compound; and a process for production of the 3-carboxy-1-substituted-2-pyrrolidinone compound.
2. Description of the Related Art
Pyrrolidinone compounds having a pyrrolidinone skeleton as the basic structure, which are useful as, for example, a remedy for central nervous system disorders (e.g. schizophrenia, dementia, manic depressive psychosis, anxiety neurosis, drug poisoning and ischemic encephtalopathy), diseases associated with immunodeficiency and cryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma, etc., and processes for production of the compounds are disclosed in EP Publication No. 0668275A1 and Japanese Patent Application Kokai (Laid-Open) No. 40667/1997.
In producing the pyrrolidinone compounds according to the above processes, however, the number of steps is large and a reduction in the number of steps has been desired for the economic reason. There has also been a problem of using a hydrogen-generating substance. There has also been a problem that a corrosive substance must be used.
With respect to the process for production of a 3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as an intermediate for production of the above pyrrolidinone compounds, there are known, for example, a process by Danishefsky et al. described in Org. Synth., 60, 66-71, 1981; and a process of hydrolyzing an ester compound obtained by a process described in Japanese Patent Application Kokai (Laid-Open) No. 40667/1997.
However, the former process uses, as a raw material, 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione which is expensive. Also, the latter process of hydrolyzing an ester compound is not preferred for a safety reason because it may use a moisture sensitive/ignitive reagent in synthesis of the ester compound. None of these processes is satisfactory for industrial application.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for producing the above pyrrolidinone compound useful as a pharmaceutically active ingredient, wherein the number of steps is smaller and neither hydrogen-generating substance nor corrosive substance is used.
Another object of the present invention is to provide a process for producing a 3-carboxy-1-phenyl-2-pyrrolidinone compound useful as an intermediate for production of the above pyrrolidinone compound useful as a pharmaceutically active ingredient, without using any expensive raw material.
Still another object of the present invention is to provide a process for producing the 3-carboxy-1-phenyl-2-pyrrolidinone without using any moisture sensitive/ignitive reagent.
The pyrrolidinone compound obtained by the present process is represented by the following formula (1):
wherein R
1
is an alkyl group of 1 to 12 carbon atoms or a substituent represented by the formula (2):
(wherein R
2
is a hydrogen atom, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a hydroxyl group, a cyano group, an amino group, a nitro group, a carbamoyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carboxyl group; p is an integer of 1 to 5; when p is 2 or more, each R
2
independently has the same definition as given above; and j is an integer of 0 to 2), and Q is a substituent represented by the formula (3a), (3b), (3c) or (3d):
{in the formula (3a), R
3
and R
4
are each independently a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, and R
3
and R
4
may bond to each other to form a morpholine ring; in the formula (3b), m and n are each independently an integer of 1 to 4, X is a hydrogen atom, a hydroxyl group, a cyano group, a carbamoyl group, a halogen atom or an alkyl group of 1 to 4 carbon atoms, and Y is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group; in the formula (3c), W is an alkyl group of 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, or an alkyl group of 1 to 2 carbon atoms substituted with a substituted or unsubstituted phenyl group; and in the formula (3d), m and n are each independently an integer of 1 to 4, Z is a hydrogen atom, an alkyl group of 1 to 18 carbon atoms, a substituted or unsubstituted phenyl group, an alkyl group of 1 to 2 carbon atoms substituted with a substituted or unsubstituted phenyl group, or a substituent represented by the formula (4):
—(CH
2
)
k
—OR
5
(4)
(wherein k is an integer of 2 to 3; and R
5
is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms, an alkenyl group of 2 to 3 carbon atoms or an alkynyl group of 2 to 3 carbon atoms)}.
The compound of the formula (1) is useful as, for example, a remedy for central nervous system disorders (e.g. schizophrenia, dementia, manic depressive psychosis, anxiety neurosis, drug poisoning and ischemic encephtalopathy), diseases associated with immunodeficiency and cryptorrhea, peptic ulcer, diabetes and complications thereof, glaucoma, etc.
The present process for producing the pyrrolidinone compound of the formula (1) includes a step of reacting a compound represented by the formula (5):
(wherein R
1
has the same definition as given above) with an amine derivative represented by the formula (6a), (6b), (6c) or (6d):
{in the formula (6a), R
3
and R
4
have the same definitions as given above; in the formula (6b), X, Y, m and n have the same definitions as given above; in the formula (6c), W has the same definition as given above; and in the formula (6d) Z, m and n have the same definitions as given above) in the, presence of formaldehyde to produce a pyrrolidinone compound of the formula (1).
The 3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as a starting material (an intermediate) for production of the pyrrolidinone compound of the formula (1), is represented by the following formula (12) and is one of the compounds of the formula (5):
(wherein R
21
to R
25
are each independently a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a cyano group, a nitro group, an amino group, a carboxyl group, a thiol group, an alkylthio group of 1 to 4 carbon atoms or a carbamoyl group).
The compound of the formula (12) is useful as an intermediate for production of the pyrrolidinone compound of the formula (1) or as an intermediate for production of an agricultural chemical.
The compound of the formula (12) can be obtained by reacting a compound of the formula (13):
(wherein R
21
to R
25
have the same definitions as given above) with 1,1-cyclopropanedicarboxylic acid.
According to the present invention, there can be provided a process for producing a pyrrolidinone compound of the formula (1), wherein the number of steps is efficiently reduced and neither hydrogen-generating substance nor corrosive substance is used.
According to the present invention, there can also be provided a 3-carboxy-1-phenyl-2-pyrrolidinone compound which is useful as an intermediate for production of the pyrrolidinone compound of the formula (1); and a process for producing the 3-carboxy-1-phenyl-2-pyrrolidinone compound without using any expensive raw material or without using any moisture sensitive/ignitive reagent.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The production processes of the present invention are described in detail belo
Iizuka Hajime
Mita Naruyoshi
Nagase Hiroshi
Burns Doane , Swecker, Mathis LLP
Kifle Bruck
Schering Aktiengesellschaft
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