Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-04-25
2002-05-21
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S252500, C435S170000, C435S833000
Reexamination Certificate
active
06391597
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for producing optically active 1(4-t-butylphenyl)-5-oxo-3-pyrrolidine carboxylic acid (hereinafter, referred to as TBPA) and/or an enantiomeric ester thereof.
2. Description of the Related Art
The TBPA is useful as an intermediate for producing an optically active compound expressed by general formula (1):
where R represents a hydrogen atom or a lower alkyl group, and * represents an asymmetric carbon atom. The compound expressed by general formula (1) inhibits fatty acid synthesis and cholesterol synthesis, and is useful as an agent for treating hyperlipemia. Hereinafter, the compound expressed by general formula (1) is referred to as Compound (1).
Conventionally, a large number of compounds having pharmacological activities have been used in the form of a mixture of optical isomers. However, in many cases, only one of the optical isomers has desirable activities. Further, it is known that the other isomer, which is unnecessary, may be toxic. Therefore, there is a great demand for a stereochemically pure compound for the purpose of providing effective and safe medicines.
Regarding Compound (1), Japanese Laid-Open Patent Publication No 3-275666 discloses the use of Compound (1) as an agent for treating hyperlipemia because it is effective in inhibition of fatty acid synthesis and cholesterol synthesis. Following this disclosure, it is desired to provide a practical and industrial method for producing an optically active intermediate for producing Compound (1).
The aforementioned Japanese Laid-Open Patent Publication No. 3-275666 describes the racemic and optically active compounds expressed by general formula (1). However, although this publication provides a general description of a method for producing either one of the optically active compounds, it does not specifically disclose any method that can be used practically as an industrial method.
On the other hand, Japanese Laid-Open Patent Publication No. 6-192221 discloses a method for producing an optically active TBPA which is an intermediate of Compound (1). According to this method, an optically active TBPA and an enantiomeric ester thereof are produced by treating an ester of (±) TBPA with a hydrolytic enzyme derived from
Aspergillus oryzae
or
Trichoderma harzianum
. This publication also discloses a method for obtaining Compound (1), using TBPA produced by the above method as a raw material.
In the enzymatic production of such an organic compound as described above, it is preferable that a starting material should be dissolved in an organic solvent of various types at a high concentration and reacted at relatively high temperature in order to ensure a high reaction efficiency. Since an enzyme derived from
Aspergillus oryzae
or
Trichoderma harzianum
is unstable with respect to organic solvents and heat, its activity deteriorates significantly during the reaction. For this reason, a large amount of enzyme is required for the reaction and the other conditions for the reaction are also restricted. Therefore, a method using such an enzyme is not preferable as an industrial method.
SUMMARY OF THE INVENTION
Therefore, with the foregoing in mind, it is an object of the present invention to provide a method for efficiently producing TBPA having a high optical purity by utilizing an enzyme having high substrate specificity and optical selectivity.
The present invention provides a method for producing an optically active TBPA and/or an enantiomeric ester thereof, which includes reacting an ester of (±) TBPA with a thermally stable and solvent-resistant esterase derived from
Bacillus brevis
042-24.
In a preferable embodiment of the present invention, the ester of (±) TBPA is an ester selected from the group consisting of alkyl esters having 1 to 10 carbon atoms and alkoxyalkyl esters having 2 to 10 carbon atoms.
In a preferable embodiment of the present invention, the ester of (±) TBPA is an alkoxyalkyl ester having 2 to 10 carbon atoms.
The method of the present invention allows efficient production of an optically active TBPA having high optical purity and/or an enantiomeric ester thereof. Thus, the present invention provides an optically active intermediate for producing Compound (1), which is useful as an agent for treating hyperlipemia.
These and other advantages of the present invention will become apparent to those skilled in the art upon reading and understanding the following detailed description.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Hereinafter, the present invention will be described more specifically.
The present invention is directed to a method for producing an optically active TBPA and/or an enantiomeric ester thereof by treating an ester of TBPA as a substrate with a hydrolytic enzyme derived from a microorganism. The reaction formula of the present invention is as follows.
The ester of TBPA, which is the starting material of the present invention, can be selected in view of the substrate specificity of an enzyme used, the solubility in the reaction solvent, the ease of the separation after reaction, the availability of the alcohol as a raw material or the like.
Examples of the ester of TBPA include alkyl ester, alkoxyalkyl ester, alkenyl ester, haloalkyl ester, aryl ester and aryl alkyl ester. That is, in the above formula, an alkyl group, an alkoxyalkyl group, an alkenyl group, a haloalkyl group, an aryl group and an aryl alkyl group are preferably used as R
1
.
As the alkyl group, an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched decyl group can be used. As the alkoxyalkyl group, the one having 2 to 10 carbon atoms, for example, methoxymethyl, methoxyethyl, ethoxyethyl or butoxyethyl group can be used. As the alkenyl group, for example, vinyl, allyl, isopropenyl or butenyl group can be used. As the haloalkyl group, for example, chlorethyl, chlorpropyl, bromoethyl, bromopropyl group can be used. As the aryl group and the arylalkyl group, for example, phenyl, benzyl, or phenethyl group where an alkyl, alkoxy, halogen, nitro, or acyl group may be introduced to the phenyl group can be used. Preferably, an alkyl group having 1 to 10 carbon atoms or an alkoxyalkyl group having 2 to 10 carbon atoms are used. Most preferable TBPA esters are alkoxyalkyl esters such as methoxyethyl ester.
The racemic isomer of TBPA (hereinafter referred to as racemic TBPA) and its ester can be synthesized easily by the method described in Japanese Laid-Open Patent Publication No. 3-275666. TBPA can be synthesized by reacting 4-t-butylaniline with itaconic acid under heating and melting. Then, the TBPA thus obtained is subjected to esterification to give an ester of TBPA easily. For example, the TBPA and alcohol are reacted in the presence of an acid catalyst such as a mineral acid or a Lewis acid so that an ester of the TBPA can be obtained. Alternatively, the racemic TBPA can be obtained by recemizing an optically active TBPA or its enantiomeric ester that is obtained as a result of the following enzyme reaction. The unnecessary optical isomer can be reused. Racemization can be effected, for example, by heating the optically active TBPA or its enantiomeric ester in water or a suitable organic solvent in the presence of a base.
As the enzyme derived from a microorganism used in the present invention, any one can be used, as long as it can hydrolyze an ester of the racemic TBPA in an optically selective manner so as to produce an optically active TBPA. An enzyme having high resistance to an organic solvent and high heat-stability can be preferably used. Examples of a preferable microorganism that produces the enzyme include the
Bacillus brevis
042-24.
An ester-hydrolyzing enzyme (hereinafter referred to as esterase) can be obtained by culturing a microorganism which can produce esterase or a transformant to which an expression vector including a gene encoding an esterase is introduced
Kamiyama Shunji
Moriwaki Masafumi
Ohtsuka Koutaro
Afremova Vera
Marx Irene
Nagase & Company, Ltd.
Renner , Otto, Boisselle & Sklar, LLP
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