Separating agent for enantiomeric isomers

Details Separating agent for enantiomeric isomers Separating agent for enantiomeric isomers

2002-06-04

2004-05-18

Therkorn, Ernest G. (Department: 1723)

Liquid purification or separation

With means to add treating material

Chromatography

C210S502100, C210S635000, C210S656000, C502S404000

Reexamination Certificate

active

06736967

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a separating agent for enantiomeric isomers, in particular, a separating agent used for separating enantiomeric isomers in liquid chromatography. More particularly, the present invention relates to a separating agent for enantiomeric isomers that can enantiomerically resolve a broad range of chiral compounds with high separation factors in the analysis of pharmaceuticals, foods, agricultural chemicals, fragrants and the like and a method of evaluating the ability of recognizing asymmetry of such a separating agent.
PRIOR ARTS
Many organic compounds have isomers that have the same physical and chemical properties, such as boiling point, melting point and solubility but show a difference in a physiological activity, i.e., enantiomeric isomers. This difference in physiological activity between the isomers is attributable to the following. In most cases, proteins and carbohydrates that compose a living body of a living organism are composed only of the one of enantiomeric isomers so that they show a difference in the manner of action to the other kinds of enantiomeric isomers, resulting in a difference in the physiological activity. This can be compared to a difference in easiness (difference in physiological activity) of wearing of a glove for left hand (i.e., a living organism as an enantiomerically active substance) between the right hand and the left hand (respective enantiomeric isomers that act).
In particular, in the field of pharmaceutical preparations, in many cases, there are significant differences in medical property and toxicity between the two enantiomeric isomers. Therefore, in the Guideline for the Production of Pharmaceuticals, the Ministry of Health, Labor and Welfare describes a policy for making a sharp distinction between enantiomeric isomers saying “when the drug of interest is a racemic modification, it is desirable to preliminarily study absorption, distribution, metabolism and excretion kinetics of each enantiomeric isomer.”
Since enantiomeric isomers have completely the same physical and chemical properties, such as boiling point, melting point, and solubility as previously stated, they cannot be analyzed by ordinary separation means. For this reason, extensive studies have been made on techniques for separating enantiomeric isomers that analyze a wide variety of enantiomeric isomers conveniently and with high precision. As a result, as an analytical technique that meets these requirements, an enantiomeric resolution method by high performance liquid chromatography (HPLC), in particular an enantiomeric resolution method by using a chiral column for HPLC has been developed. The chiral column referred to herein uses an asymmetry recognition agent itself or a chiral stationary phase composed of an asymmetry recognition agent supported on a suitable carrier.
For example, enantiomerically active poly (triphenylmethyl methacrylate) (cf., JP 57-150432 A), cellulose or amylose derivatives (Y. Okamoto, M. Kawashima and K. Hatada, J. Am. Chem. Soc., 106, 5357, 1984), ovomucoid, which is a protein (JP 63-307829 A) and the like have been developed.
It has been known that among many chiral stationary phases for HPLC, an enantiomeric resolution column having supported cellulose or amylose derivative on silica gel has high asymmetry recognition ability to an extremely wide variety of compounds. Furthermore, in recent years, studies on a liquid chromatographic fractionation method for fractionating enantiomerically active substances on an industrial scale including a chiral stationary phase for HPLC and a simulated moving bed method, which is a continuous liquid chromatographic fractionation method in combination have been developed (Pharm Tech. Japan, 12, 43 (1996)).
For example, enantiomerically active poly (triphenylmethyl methacrylate) (cf., JP 57-150432 A), cellulose or amylose derivatives (Y. Okamoto, M. Kawashima and K. Hatada, J. Am. Chem. Soc., 106, 5357, 1984), ovomucoid, which is a protein (JP 63-307829 A) and the like have been developed.
It has been known that among many chiral stationary phases for HPLC, an enantiomeric resolution column having supported cellulose or amylose derivative on silica gel has high asymmetry recognition ability to an extremely wide variety of compounds. Furthermore, in recent years, studies on a liquid chromatographic fractionation method for fractionating enantiomerically active substances on an industrial scale including a chiral stationary phase for HPLC and a simulated moving bed method, which is a continuous liquid chromatographic fractionation method in combination have been developed (Pharm Tech. Japan, 12, 43 (1996)).
In the case of chiral stationary phase for HPLC used as analysis means, complete separation of two enantiomeric isomer peaks in a short analysis time gives a full satisfaction. However, in order to further increase fractionation productivity, a liquid chromatographic fractionation method as production means has been required to not only completely separate a compound as a target of fractionation but also further separate two enantiomeric isomer peaks of the target compound; that is, a chiral stationary phase having a value of separation factor &agr; as high as possible has been desired.
Under the circumstances, various contrivances have been made to more fully develop the asymmetry recognition ability of the chiral stationary phase including an enantiomerically active polymer compound such as, for example, a polysaccharide derivative as an asymmetry recognition agent to obtain a further increased value of separation factor &agr;. Under the present conditions, however, there are no evaluation methods for high asymmetry recognition ability other than those that use an HPLC measurement in reality. Accordingly, a simpler and easier method of evaluating asymmetry recognition ability has been demanded.
JP-A 2-289601 discloses a separating agent comprising a polysaccharide derivative having —CO—NHR for OH.
SUMMARY OF THE INVENTION
The present invention has been achieved under the above-mentioned circumstances. That is, an object of the present invention is to provide a simpler and easier method of evaluating asymmetry recognition ability. Another object of the present invention is to provide a separating agent for enantiomeric isomers having higher asymmetry recognition ability by using the evaluation method.
As a result of extensive studies for achieving the above-mentioned objects, the inventors of the present invention have now found that those separating agents that cause polymer compounds which have been supported therein to exhibit exothermic peaks before the polymer compounds reach their decomposition temperatures in a differential thermal calorimetric curve obtained in a heat elevation process in differential scanning calorimetry (DSC) have high values of separation factors &agr; of enantiomeric isomers, thereby achieving the present invention.
Therefore, the present invention provides a separating agent for enantiomeric isomers, comprising an enantiomerically active polymer compound supported thereon, wherein the polymer compound has an exothermic peak before a decomposition temperature of the polymer compound supported is reached in a differential calorimetric curve obtained in a process of temperature elevation in differential scanning calorimetry (DSC) on the separating agent.
It then provides a method of evaluating asymmetry recognition ability of a separating agent for enantiomeric isomers, comprising: performing a differential scanning calorimetry (DSC) of the separating agent for enantiomeric isomers having supported thereon an enantiomerically active polymer compound to obtain a differential calorimetric curve in a process of temperature elevation therein; and observing presence or absence of an exothermic peak of the polymer compound in the differential calorimetric curve before a decomposition temperature of the supported polymer compound is reached.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described i

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