Catalyst – solid sorbent – or support therefor: product or process – Solid sorbent – Organic
Reexamination Certificate
2001-06-22
2004-04-13
Silverman, Stanley S. (Department: 1754)
Catalyst, solid sorbent, or support therefor: product or process
Solid sorbent
Organic
Reexamination Certificate
active
06720285
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the development of novel materials that can be used in a process such as high performance liquid chromatography (HPLC), liquid chromatography (LC), thin layer chromatography (TLC), capillary electro chromatography (CEC) and counter-current chromatography. The materials are composed of support materials and saccharide moieties, especially glucose moieties preferably in the form of cyclodextrins, mutually cross-linked and chemically bonded via urea linkages. The invention further relates to processes for the production of these materials and their use in separating compounds and especially resolving enantiomeric mixtures.
BACKGROUND OF THE INVENTION
Generic applicability of cyclodextrins in chromatographic separation and purification processes is described at length in reviews by W. L. Hinze,
Separation and purification methods,
1981, 10(2), 159-237. Y. Kawaguchi, et al.,
Anal. Chem.,
1983, 55, 1852; D. W. Armstrong, et al.,
Anal. Chem.,
1985, 57, 234 and S. Li, et al.,
Chem. Rev.,
1992, 92, 1457. Chromatographic separation on chiral stationary phases (CSP) is also the most convenient analytical method for the determination of enantiomeric purity (see for example S. G. Allenmark,
Chromatographic Enantioseparations: Methods and Applications,
2
nd
ed., Prentice Hall, N.J., 1991). In recent years, tremendous research efforts were made in bonding cyclodextrins to solid matrices, such as silica gel, via amino or amido linkages. However, these bonds are inherently unstable to hydrolysis, thus placing severe limitations on use of these materials in aqueous media. Alternative approaches for immobilizing cyclodextrin using hydrolytically more stable ether linkages (U.S. Pat. No. 4,539,399) or carbamic acid moieties (U.S. Pat. No. 5,104,547) were also investigated. However, in all these approaches, regioselective derivatisation of cyclodextrin cannot be readily effected due to the presence of multiple hydroxy moieties in the cyclodextrin starting materials. Thus, reaction may take place on the 2, 3 or 6-position of glucose moieties of cyclodextrin, which is hard to resolve.
It has been reported that derivatised cyclodextrin stationary phases for liquid chromatography show definite enantioselectivity for a variety of compounds while pristine cyclodextrin bonded stationary phases display low enantioselectivity. Enantioselectivity of the materials was generally improved by increasing the degree of derivatisation of the —OH groups on cyclodextrin with carbamate groups, and by increasing the surface concentration of cyclodextrin immobilized on the support materials (D. W. Armstrong et al.,
Anal. Chem.,
1990, 62, 1610; T. Hargitai et al.,
J. Chromatogr.,
1993, 628, 11; T. Hargitai, et al.,
J. Liq. Chromatogr.,
1993, 16(4), 843). In order to maximize the extent of cyclodextrin derivatisation, large molar excesses of derivatising reagents under vigorous conditions were often used. However, the derivatisation processes invariably involved the prior immobilisation of underivatised cyclodextrin on the support material followed by derivatisation procedures involving solid-liquid phases. This usually results in partial derivatisation of the hydroxyl groups of the cyclodextrin and also in large, sterically encumbered cyclodextrins having a low extent of derivatisation. These methods did not give good reproducibility or uniformity of product, with the consequence that separation of enantiomers may vary from batch to batch of the obtained CD-based CSP.
Ng, et al., U.S. Pat. No. 6,017,458 describe a procedure of immobilizing perfunctionalized cyclodextrin onto the surface of a support. The patent says that the cyclodextrin is immobilized via a urethane linkage, but it is believed that this is not correct and the linkage is a urea linkage. The procedure provides an efficient method with well-defined chemical structure and very good reproducibility. However, in these examples, and in the other instances listed above, the cyclodextrins were immobilized onto the support as small molecules, which potentially limit their stability in mobile phases with high aqueous content. Although the patent mentions monoazido and diazido cyclodextrins, only monoazido cyclodextrins are used in the examples of the patent and each immobilized cyclodextrin will have only one urea linkage linking it to the support material.
Polysiloxane with cyclodextrin anchored to its side chain has been prepared and coated onto the surface of silica gel. This material exhibits interesting properties in reverse phase HPLC. (V. Schurig, et al.,
J. Chromatogr. A,
1996, 755, 299; V. Schurig, et al., Ger Offen DE 43 24 636 A1 (1994), V. Schurig, et al.,
Angew. Chem. Int. Ed. Engl.,
1994, 33, 2222). However, there is no report of the cyclodextrin polymer immobilized onto a support and applied in chiral separation.
SUMMARY OF THE INVENTION
In one aspect the invention provides a conjugate comprising a support material linked to oligomers or polymers of a saccharide which linking is via urea linkages between the saccharide moieties and the support material, and wherein the oligomers or polymers of the saccharide are also cross-linked via urea linkages.
In another aspect the invention provides a process for preparing a conjugate of the invention, which process comprises: (a) reacting an oligomer or polymer of a saccharide bearing a plurality of azide groups with an amine, preferably a primary amine, a phosphine and CO
2
, the amine being on the surface of a support material; or (b) reacting an oligomer or polymer of a saccharide bearing a plurality of azide groups with an amine, preferably a primary amine, a phosphine and CO
2
, wherein the amine is an alkenylamine, subsequently hydrosilylating the alkenyl moiety of the product with a hydrosilylating agent that bears one or more readily hydrolysable groups on the silicon atom and thereafter reacting with a support member; or (c) reacting an oligomer or polymer of a saccharide bearing a plurality of azide groups with an amine, preferably a primary amine, a phosphine and CO
2
, wherein the amine is present in a molecule that bears a silicon atom bearing at least one readily hydrolysable group, and thereafter reacting with a support member; or (d) reacting an oligomer or polymer of a saccharide bearing a plurality of amine groups, preferably primary amine groups, with an azide group, a phosphine and CO
2
, the azide group being on the surface of a support material; or (e) reacting an oligomer or polymer of a saccharide bearing a plurality of amine groups, preferably primary amine groups, with an azide, a phosphine and CO
2
, wherein the azide is an alkenylazide, subsequently hydrosilylating the alkenyl moiety of the product with a hydrosilylating agent that bears one or more readily hydrolysable groups on the silicon atom and thereafter reacting with a support member; or (f) reacting an oligomer or polymer of a saccharide bearing a plurality of amine groups, preferably primary amine groups, with an azide, a phosphine and CO
2
, wherein the azide is present in a molecule that bears a silicon atom bearing at least one readily hydrolysable group, and thereafter reacting with a support member.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention makes use of a Staudinger reaction, in which an azide group, an amine group, CO
2
and a phosphine react to form a urea. Azide groups can be present on the oligomer or polymer of a saccharide, and amine groups can be present on the support material, or on a molecule that will subsequently be linked to the support material, so that the saccharide is linked via urea to the support material. Alternatively, amine groups can be present on the oligomer or polymer of the saccharide, and the azide groups can be present on the support material, or on a molecule that will subsequently be linked to the support material, so that again the saccharide is linked via urea to the support material. It is preferred that the azide groups are on the saccharide and the amine groups are on the support materia
Chen Lei
Ching Chi Bun
Ng Siu Choon
Zhang Lifeng
Johnson Edward M.
Klarquist & Sparkman, LLP
National University of Singapore
Silverman Stanley S.
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