Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1994-07-08
1995-10-24
O'Sullivan, Peter
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
210656, 524719, 524724, 544134, 564348, 564349, C07B 5700, B01D 1508
Patent
active
054611750
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE92/00751 filed 30 Oct. 1995.
The present invention relates to a method for separating enantiomers of derivatives of aryloxipropanolamines and a chiral solid-phase chromatography material for use in the method. The invention also relates to the use of the molecular imprinting method for preparing the chiral solid-phase chromatography material.
.beta.-adrenergic blocking compounds (or .beta.-blockers) are important pharmaceutical preparations which are used in the treatment of hypertension, arrhythmia and angina pectoris. There is a great need of using optically pure enantiomers since the stereoisomers express a varying pharmacological activity, and in some cases they can also be used against various symptoms (1). Consequently, intensive research is in progress for preparing optically pure .beta.-blockers, e.g. by using an asymmetric synthesis (2) including biocatalysts (3), a fractional crystallisation (4), as well as indirect (5) or direct (6) chromatographic separation of the enantiomorphs.
According to the present invention, a method is provided for separating enantiomers of derivatives of aryloxipropanolamines by means of a chiral solid-phase chromatograpy material (Chiral Stationary Phase=CSP), which is prepared by the so-called molecular imprinting method (7). The molecular imprinting method used is based on non-covalent complementary interactions between the non-derivatised print molecule and polymerisable monomers.
More precisely, a method is provided for separating enantiomers of derivatives of aryloxipropanolamines, in which the derivatives are contacted with a chiral solid-phase chromatography material containing molecular imprints of an optically pure enantiomer of the derivatives to be separated.
Moreover, a chiral solid-phase chromatography material is provided to be used in the separation of enantiomers of derivatives of aryloxipropanolamines, which material consists of a polymer prepared by polymerisation of a monomer in the presence of a cross-linking agent and of an optically pure enantiomer of the derivatives to be separated, a molecular imprint of the optically pure enantiomer being formed in the polymer by non-covalent interactions between the monomer and the optically pure enantiomer.
According to the invention, there is also provided the use of the molecular imprinting method for preparing a chiral solid-phase chromatography material to be used in the separation of enantiomers of derivatives of aryloxipropanolamines.
Suitable monomers for preparing the chiral solid-phase chromatography material are monomers with functional groups, such as carboxyl-functional monomers. Preferred monomers are methacrylic acid [MAA, H.sub.2 C.dbd.C(CH.sub.3)--COOH] or itaconic acid [ITA, H.sub.2 C.dbd.C(COOH)--(CH.sub.2)--COOH]. These two monomers can, by their functional groups, form non-covalent bonds in organic solvents to the print molecule. Itaconic acid has previously been used in polymer chemistry (8), but it has now surprisingly been found that this acid is highly suited for use as monomer in the preparation of molecular imprints.
The monomers are polymerised in the presence of a cross-linking agent, which results in a three-dimensional network being formed. One cross-linking agent is ethylene glycol dimethacrylate.
Furthermore, the monomers are polymerised in the presence of a so-called print molecule, i.e. in this case an optically pure enantiomer of the derivative to be separated. During the polymerisation, non-covalent complementary interactions arise between the non-derivatised print molecule and the polymerisable monomers. After the polymerisation, the print molecule is removed from the three-dimensional network by extraction with a suitable solvent. As a result, individual sites with complementary points of bonding will probably remain within the polymer.
As aryloxipropanolamine derivatives that can be separated by the method according to the invention, mention can be made of timolol, propranolol, metoprolol and atenolol (formulae, see FIG. 1).
The resolu
REFERENCES:
J. Am. Chem. Soc., vol. 13, 1991, "Direct Enantioseparation of .beta.-Adrenergic Blockers Using a Chiral Stationary Phase Prepared by Molcular Imprinting", Lutz Fischer et al.
Journal of Chromatography, vol. 516, (1990) pp. 313-322, "Enantiomeric Resolution on Molecularly Imprinted Polymers Prepared With Only Non-Covalent and Non-Ionic Interactions", Lars I. Andersson et al.
Journal of Chromatography, vol. 516, (1990), pp. 323-331, "Enantiomeric Resolution of Amino Acid Derivatives on Molecularly Imprinted Polymers as Monitored by Potentiometric Measurements", Lars I. Andresson et al.
Journal of Chromatography, vol. 470, (1989), pp. 391-399, "Recent Advances in the Preparation and Use of Molecularly Imprinted Polymers for Enantiometric Resolution of Amino Acid Derivatives", Daniel J. O'Shannessy et al.
J. Am. Chem. Soc., vol. 110, (1988), pp. 5853-5860, "Highly Enantioselective and Substrate-Selective Polymers Obtained by Molecular Imprinting Utilizing Noncovalent Interactions. NMR and Chromatographic Studies on the Nature of Recognition", Borje Sellergren et al.
Journal of Liquid Chromatography, vol. 13, No. 15, (1990), pp. 2987-3000, "Template Imprinted Polymers for HPLC Separation of Racemates", Gunter Wulff et al.
Journal of Molecular Recognition, vol. 2, No. 1, (1989) pp. 1-5, "Molecular Recognition in Synthetic Polymers", Daniel J. O'Shannessy et al.
Tibtech, Apr. 1989, vol. 7, "Molecular Imprinting: A Technique for Producing Specific Separation Materials", Bjornm Ekberg et al.
Ekberg Bjorn
Fischer Lutz
Mosbach Klaus
Muller Ralf
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