Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-20
2001-06-26
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06252089
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of producing optically active or racemic 4-hydroxy-2-pyrrolidinone, which is useful as a raw material of drugs, and to a method of purifying optically active 4-hydroxy-2-pyrrolidinone.
BACKGROUND OF THE INVENTION
4-Amino-3-hydroxybutyric acid and its ester derivatives are synthetic intermediate important for the production of 4-hydroxy-2-pyrrolidinone. This compound is derived from 4-azido-3-hydroxybutyric acid or its ester derivatives through reduction or the other methods (Tetrahedron, 46, 4227 (1990), JP-A-Hei-8-119935, etc.).
However, the ring-closing reaction of a 4-amino-3-hydroxybutyric acid derivative to 4-hydroxy-2-pyrrolidinone requires an expensive condensation agent such as hexamethyldisilazane when 4-amino-3-hydroxybutyric acid is used as a starting material (Synthesis, 1978, P.614).
The ring-closing reaction of 4-amino-3-hydroxybutyric acid ester to 4-hydroxy-2-pyrrolidinone can be carried out by heating 4-amino-3-hydroxybutyric acid ester in a solvent such as alcohol. By only such heat treatment, the reaction takes long time since the reaction rate of the ring-closing reaction is low. Also, the isolated yield is reduced because of unreacted 4-amino-3-hydroxybutyric acid ester and the other by-products.
Further, 4-hydroxy-2-pyrrolidinone having a high optical purity cannot be obtained by recrystallization, in the case of 4-hydroxy-2-pyrrolidinone having a low optical purity derived from an optically active starting material having a low optical purity.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above problems so that the reaction for deriving 4-hydroxy-2-pyrrolidinone from an optically active or racemic 4-amino-3-hydroxybutyric acid derivative or a 4-azido-3-hydroxybutyric acid derivative can proceed rapidly and highly selectively to give a high yield. Another object of the present invention is to provide a method of purifying optically active 4-hydroxy-2-pyrrolidinone to give a high purity.
From the fact that a base functions to promote amidation of carboxylic acid ester (Course of New Experimental Chemistry, 14-II, p.1146 (Maruzen)), the present inventors assumed that, if such a base is used as a catalyst in the ring-closing reaction of 4-amino-3-hydroxybutyric acid ester derivative to 4-hydroxy-2-pyrrolidinone, the base functions catalyze intra-molecular amidation of the ester so that the ring-closing reaction can proceed rapidly and highly selectively to give a high yield. As a result of intensive investigation, the present inventors have found that the ring-closing reaction of 4-amino-3-hydroxybutyric acid ester to 4-hydroxy-2-pyrrolidinone can be promoted by adding a catalytic amount of a base to the reaction system, that the reaction can be completed for an extremely short period of time under heating or even without heating as in the conventional method, and that highly pure 4-hydroxy-2-pyrrolidinone can be obtained in a higher yield compared with the conventional method.
The present inventors have also found that, if a base catalyst is contained in the reaction system at the reaction stage just prior to the above conversion reaction, namely the stage that an azido group of 4-azido-3-hydroxybutyric acid ester is converted into an amino group by catalytic hydrogenation or the like, the base catalyst functions to catalyze intramolecular amidation of the ester without inhibiting the reduction reaction, the ring-closing of 4-amino-3-hydroxybutyric acid ester formed by the reduction occurs subsequently without heating or the like treatment to give 4-hydroxy-2-pyrrolidinone in one step.
Since 4-hydroxy-2-pyrrolidinone having a high optical purity could not be obtained by the conventional method when 4-hydroxy-2-pyrrolidinone having a low optical purity derived from an optically active starting material having a low optical purity is recrystallized, the present inventors further intensively studied to solve the problem. The inventors assumed that a poor solvent used for recrystallization in the conventional method can improve the yield in the recrystallization step but thereby lowering solubility of 4-hydroxy-2-pyrrolidinone, which results in additionally crystallizing an unnecessary antipode to reduce the optical purity of resulting 4-hydroxy-2-pyrrolidinone. On the above assumption, the inventors carried out recrystallization without using a poor solvent and have found that highly optically pure 4-hydroxy-2-pyrrolidinone can be obtained by this method.
The present invention relates to a method of producing 4-hydroxy-2-pyrrolidinone represented by the formula (2):
which comprises effecting the ring-closing reaction of 4-amino-3-hydroxybutyric acid ester represented by the formula (1):
wherein R represents a lower alkyl group having 1 to 6 carbon atom(s) or a benzyl group, in the presence of a base catalyst.
The present invention also relates to a method of producing 4-hydroxy-2-pyrrolidinone represented by the formula (2):
which comprises adding a base catalyst to 4-azido-3-hydroxybutyric acid ester represented by the formula (3):
wherein R represents a lower alkyl group having 1 to 6 carbon atom(s) or a benzyl group and effecting catalytic hydrogenation in the presence of a metal catalyst.
The present invention further relates to a method of purifying 4-hydroxy-2-pyrrolidinone which comprises recrystallizing optically active 4-hydroxy-2-pyrrolidinone in the absence of a poor solvent.
REFERENCES:
patent: 4003911 (1977-01-01), Scribner
patent: 5869694 (1999-02-01), Furukawa et al.
patent: 0 787 718 A1 (1997-08-01), None
patent: 2 008 110 (1979-05-01), None
patent: 8-119935 (1996-05-01), None
patent: WO 96/36603 (1996-11-01), None
Larcheveque et al., Tetrahedron, 46:4277-4282 (1990).
Pellegata et al., Synthesis, 614-616 (Aug. 1978).
Kobayaski et al., “Preparation of optically active 2-pyrrolidinones as intermediates for antibacterial carbapenems”, Chemical Abstracts, 125:1151, Aug. 26, 1996.
Daicel Chemical Industries Ltd.
Fish & Richardson P.C.
McKane Joseph K.
Murray Joseph
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