Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-21
2001-09-04
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S557000
Reexamination Certificate
active
06284902
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a process for manufacturing an optically active (S)-3,4-epoxybutyric acid salt and more particularly, to a method for manufacturing (S)-3,4-epoxybutyric acid salt expressed by the following formula 1, wherein an optically active (S)-3-hydroxybutyrolactone is employed to undergo an economical ring-opening reaction and epoxydation so that its chiral center is maintained in an original form.
Wherein, R
1
represents alkali metal atom, alkaline earth metal atom, alkylamin group or quarternary amine group.
2. Description of the Related Art
An (S)-3,4-epoxybutyric acid salt expressed by the above formula 1 is a pivotal compound as an indispensable intermediate of various chiral drugs because of the synethetic usefulness of epoxy group. In particular, since (S)-3,4-epoxybutyric acid salt expressed by the above formula 1 has a better reactivity under aqueous solution, its availability in various chemical reaction has a broader scope in related fields.
The optically active (S)-3,4-epoxybutyric acid salt has the industrial application as raw material of drugs which may be contained in the cerebral enhancers and senile dementia drugs, antibiotics, antihypertensives and antihyperlipidemia.
The typical manufacturing methods related to (S)-3,4-epoxybutyric acid salt developed hitherto and some compounds with similar reactivity are as follows:
A method of manufacturing (S)-3,4-epoxybutyric acid salt was to introduce epoxy group sterically via asymmetric epoxydation and oxidation in a sequence but the extremely low yield and optical purity of the desired compound (yield: 11~25%, optical purity: 55%) proven to be inadequate for industrial use [J. Org. Chem., 49,3707(1984)].
According to another method [(Helv. Chim. Acta, 70, 142(1987) and European Pat. No. 237,983], it disclosed a method of manufacturing (S)-3,4-epoxybutyric acid salt, wherein a racemic 3,4-epoxybutyric acid ester was prepared and followed by the use of an enzyme based on an optical separation method. This method was proven to have been effective in optical purity but more than 50% yield could not be obtained in consideration of prolonged reaction time, maintenance of reaction conditions in enzyme and optical separation reaction in the light of biological reaction.
In addition, a method of manufacturing (S)-3,4-epoxybutyric acid ester from (S)-3-hydroxybutyrolactone was disclosed (Tetrahedron Letters 28, 1781(1987); Tetrahedron 46, 4277 (1990) and International Patent Publication No. WO93/06826). Its manufacturing process is described in the following scheme 1.
The scheme 1 has recognized some disadvantages in that a) with a high-priced iodotrimethyl silane (SiI(CH
3
)
3
) reagent for iodination and esterification, the reaction should be performed in the presence of anhydrous solvent, b) during epoxydation, a high-priced silver oxide (AgO) reagent should be uneconomically employed, and c) since (S)-3,4-epoxybutyric acid ester, so prepared from the conventional methods has no reactivity in an aqueous solution, its scope of use is extremely restricted. For example, a glycine derivative is insoluble to organic solvents, so it should be modified with benzylaldehye first so as to enhance its solubility to organic solvent during the amination between (S)-3,4-epoxybutyric acid ester and glycine derivative. 4-Hydroxy -2-butenic acid ester is also generated as a byproduct due to elimination reaction associated with the basicity of glycine derivative, when it reacts with (S)-3,4-epoxybutyric acid ester.
By contrast, (S)-3,4-epoxybutyric acid salt, a final product of this invention having a better reactivity in an aqueous solution may be directly aminated with glycine or glycine derivative in an aqueous solution, thus simplifying the complicated manufacturing process.
SUMMERY OF THE INVENTION
As a result of intensive studied performed by the inventor et al. in an effort to develop a process for manufacturing an industrially useful (S)-3,4-epoxybutyric acid salt having an excellent reactivity in an aqueous solution in an effective manner, this invention designed to manufacture the desired compound has been finally completed in such a manner that (S)-3-hydroxybutyrolactone is used as a starting material which may be synthesized from the inexpensive and easily obtainable lactose, followed by a ring-opening reaction using halogen acid-carboxylic acid and epoxydation in the presence of base.
Therefore, an object of this invention is to provide a process for manufacturing a high-purity (S)-3,4-epoxybutyric acid salt with high yield using low-priced reagents without any high-priced reagents or with handling difficulty, as in the conventional method.
Further, the process for manufacturing (S)-3,4-epoxybutyric acid salt according to this invention, which has not been applicable in the related field hitherto, is an economical technology designed to manufacture (S)-3,4-epoxybutyric acid salt in high optical purity via the conversion of an optically active (S)-3-hydroxybutyrolactone, a starting material, to a butyric acid derivative. Thus, this invention is a pioneer in terms of its novelty and application.
DETAILED DESCRIPTION OF THE INVENTION
This invention is characterized by a process for manufacturing (S)-3,4-epoxybutyric acid salt expressed by the following formula 1, wherein the ring-opening reaction of (S)-3-hydroxybutyrolactone expressed by the following formula 2 is performed using halogen acid-carboxylic acid to give a butyric derivative expressed by the following formula 3 and then said derivative is epoxidated in the presence of a base and aqueous solution at the temperature range of −20° C.~100° C.
Where, R
1
is determined depending on the kinds of base used and represents alkali metal atom, alkaline earth metal atom, alkylamine group or quarternary amine group; R
2
represents halogen group which may enable the epoxidation; R
3
represents hydrogen atom or acyl group.
The following scheme 2 is a schematic diagram illustrating the manufacturing process of (S)-3,4-epoxybutyric acid salt according to this invention:
From the above scheme, R
1
, R
2
and R
3
are the same as defined above, respectively.
(S)-3-hydroxybutyrolactone expressed by the formula 2, a starting material of this invention, is synthesized from lactose based on the method as disclosed in European Patent No.513,430.
The ring-opening reaction of (S)-3-hydroxybutyrolactone expressed by the formula 2 is performed in the presence of carboxylic acid containing halogen acid at the constant temperature of 0~150° C. The ring-opening reaction is generally performed in the presence of halogen acid and alcohol solvent. But after the reaction is completed, an epoxide ester compound whose chemical reaction may be available in organic solvent only may be obtained. It is not in the form of epoxide salt which may be reacted in an aqueous solution. The epoxide ester compound is not easily reacted with nucleophilic materials which is insoluble to organic solvents, and 4-hydroxy-2-butenic acid ester as a byproduct is generated due to elimination reaction caused by the basicity of nucleophilic materials.
By contrast, this invention is characterized in that an optically-active (S)-epoxide salt as a final product may be obtained in such a manner to use a mixture of halogen acid and carboxylic acid and to react a base in an aqueous solution. In an aqueous solution, the final product may be easily reacted with nucleophilic materials which is insoluble to organic solvents and without elimination reaction, chiral intermediates for various drugs may be easily synthesized. In addition, the final product of this invention is an useful intermediate which may react with any nucleophilic materials in the presence of organic solvents in that it may acidify an optically active (S)-epoxide salt to form (S)-epoxide acid and then such acid is reacted with an alcohol solvent under a mild acid condition to yield (S)-epoxide ester.
The example of carboxylic acid used from the ring-opening reaction
Bae Jae Young
Byun Il Suk
Cho Yik Haeng
Park Young Mi
Yu Ho Sung
Lowe Hauptman & Gilman & Berner LLP
Samsung Fine Chemicals Co. Ltd.
Trinh Ba K.
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