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Electrochromatographic device for use in enantioselective separation, and enantioselective separation medium for use therein

Imported: 24 Feb '17 | Published: 09 Sep '03

Jean M. J. Fréchet, Frantisek Svec, Michael Lämmerhofer

USPTO - Utility Patents

Abstract

An electrochromatographic device is provided for conducting enantioselective separation of enantiomers. The device is comprised of a conduit containing a monolithic enantioselective separation medium, and may be, for example, a capillary tube or a microchannel in a substrate. The enantioselective separation medium is prepared by copolymerization of (a1) an ionizable chiral monomer or (a2) a chiral monomer and an ionizable comonomer, along with (b) a crosslinking comonomer and (c) a polymerization initiator, in (d) a porogenic solvent. Following ionization, the enantioselective separation medium serves as a charge carrier as well as a chiral separation medium, and further acts as an electroosmotic pump to facilitate the flow of a fluid. The invention also provides methods for preparing the enantioselective separation medium and electrochromatographic devices fabricated therewith.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a representation of the chemical structure of the chiral monolithic polymer prepared by copolymerization of O-[2-(methacryloyloxy)ethylcarbamoyl]-10,11-dihydroquinidine (1), as described in Example 2.

FIGS. 2A and 2B illustrate in graph form the effect of thermal (FIG. 2A) and UV initiation (FIG.

2B), type of comonomer, and percentage of 1-dodecanol in the polymerization mixture on the mode pore diameter of quinidine-functionalized chiral monoliths, as evaluated in Example 9 (in the figures, □ represents glycidyl methacrylate, and ▪ represents 2-hydroxyethyl methacrylate).

FIGS. 3A and 3B illustrate the differential pore size distribution profiles of poly (1-co-hydroxyethyl methacrylate-co-ethylene dimethacrylate) monoliths prepared using thermal (FIG. 3A) and UV initiated (FIG. 3B) polymerization, as evaluated in Example 9.

FIGS. 4A and 4B illustrate the effect of the percentage of chiral monomer 1 on pore size of the monoliths prepared using UV initiated (FIG. 4A) and thermally initiated (FIG. 4B) polymerization, as described in Example 9.

FIG. 5 illustrates the effect of pH of the mobile phase on electroosmotic mobility in quinidine-functionalized chiral monoliths, as evaluated in Example 10.

FIGS. 6A,

6B and

6C illustrate the enantioseparation of N-3,5-dinitrobenzyloxycarbonyl (DNZ)-leucine on standard columns with 25 cm (FIG.

6A), 15 cm (FIG.

6B), and 8.5 cm (FIG. 6C) long monolith, carried out as described in Example 11.

FIGS. 7A,

7B and

7C illustrate CEC separations of N-2,4-dinitrophenyl (DNP)-valine (FIG.

7A), N-benzoyl (Bz)-leucine (FIG.

7B), and Fenoprop (FIG. 7C) enantiomers on a 150 mm long quinidine-functionalized chiral monolith, as described in Example 12.

Claims

1. A device for use in conducting chiral electrochromatography, comprising an electrochromatographic conduit within which is an enantioselective separation medium comprised of a monolithic, ionizable copolymer that acts as a continuous separation medium and contains pendant chiral selector groups, wherein the pendant chiral selector groups each contain a stereogenic center.

2. The device of claim 1, wherein the monolithic, ionizable copolymer is a porous organic polymer.

3. The device of claim 1, comprising a capillary tube containing the enantioselective separation medium.

4. The device of claim 1, comprising an electrochromatographic column containing the enantioselective separation medium.

5. The device of claim 1, comprising a microfluidic separation device.

6. The device of claim 5, wherein the conduit is a microchannel containing the enantioselective separation medium.

7. The device of claim 6, wherein the microchannel is tubular.

8. The device of claim 6, wherein the microchannel is planar.

9. The device of claim 5, comprising two or more conduits.

10. The device of claim 9, wherein each conduit is a microchannel containing the enantioselective separation medium.

11. The device of claim 1, wherein the monolith is fabricated by in situ polymerization within the conduit.

12. The device of claim 11, wherein the in situ polymerization is carried out by copolymerization of a mixture comprised of an ionizable chiral monomer, a crosslinking comonomer, a polymerization initiator, and a porogenic solvent.

13. The device of claim 12, wherein the mixture further comprises a functional monovinyl comonomer.

14. The device of claim 13, wherein the functional monovinyl comonomer contains a hydrophilic group or a precursor to a hydrophilic group.

15. The device of claim 11, wherein the in situ polymerization is carried out by copolymerization of a mixture comprised of a chiral monomer, an ionizable comonomer, a crosslinking comonomer, a polymerization initiator, and a porogenic solvent.

16. The device of claim 15, wherein the mixture further comprises a functional monovinyl comonomer.

17. The device of claim 16, wherein the functional monovinyl comonomer contains a hydrophilic group or a precursor to a hydrophilic group.

18. A method for making an electrochromatographic device useful in conducting enantioselective separations, comprising:

19. A method for making an electrochromatographic device useful in conducting enantioselective separations, comprising:

20. A method for making a microelectrochromatographic device useful in conducting enantioselective separations, comprising:

21. A method for making a microelectrochromatographic device useful in conducting enantioselective separations, comprising:

22. The method of any one of claim 18,

19,

20 or

21, wherein the polymerization mixture further includes a functional monovinyl comonomer.

23. The method of claim 22, wherein the functional monovinyl comonomer contains a hydrophilic group or a precursor to a hydrophilic group.

24. The method of claim 18,

19,

20 or

21, further comprising ionizing the ionizable groups by passing an ionizing composition through the monolithic enantioselective separation medium.

25. The method of claim 24, wherein the ionizing composition is a buffer solution.

26. The method of claim 24, wherein the ionizing composition is a chemical reagent capable of ionizing the ionizable groups.

27. A chiral copolymer suitable for electrochromatographic resolution of racemic compounds, prepared by copolymerization of a mixture comprising (a) an ionizable chiral monomer, (b) a crosslinking comonomer, (c) a polymerization initiator, and (d) a porogenic solvent.

28. The chiral copolymer of claim 27, wherein the ionizable chiral monomer is an addition polymerizable monomer containing a pendant chiral selector moiety.

29. The chiral copolymer of claim 28, wherein the ionizable chiral monomer is a vinyl monomer.

30. The chiral copolymer of claim 29, wherein the ionizable chiral monomer is an acrylate or methacrylate having a pendant chiral selector moiety selected from the group consisting of cinchona alkaloids, 4-substituted dihydropyrimidines, 1,4-disubstituted dihydropyrimidines, 1,2-disubstituted cycloalkanes, amino acids, derivatives thereof, and combinations of any of the foregoing.

31. The chiral copolymer of claim 30, wherein the pendant chiral selector moiety is a cinchona alkaloid.

32. A chiral copolymer suitable for electrochromatographic resolution of racemic compounds, prepared by copolymerization of a mixture comprising (a) a chiral monomer, (b) an ionizable comonomer, (c) a crosslinking comonomer, (d) a polymerization initiator, and (e) a porogenic solvent.

33. The chiral copolymer of claim 32, wherein the chiral monomer is an addition polymerizable monomer having a pendant chiral selector moiety.

34. The chiral copolymer of claim 33, wherein the chiral monomer is a vinyl monomer.

35. The chiral copolymer of claim 34, wherein the chiral monomer is an acrylate or methacrylate having a pendant chiral selector moiety selected from the group consisting of cinchona alkaloids, 4-substituted dihydropyrimidines, 1,4-disubstituted dihydropyrimidines, 1,2-disubstituted cycloalkanes, amino acids, derivatives thereof, and combinations of any of the foregoing.

36. The chiral copolymer of claim 34, wherein the pendant chiral selector moiety is selected from the group consisting of carbohydrates, amino acids, alcohols, amines, thiols, peptides, derivatives thereof, and combinations of any of the foregoing.

37. The chiral copolymer of claim 36, wherein the ionizable comonomer is selected from the group consisting of acrylic or methacrylic acid, itaconic acid, maleic anhydride, acrylic and methacrylic amides of amino acids, 2-vinylpyridine, 4-vinylpyridine, 2-(dialkylamino)ethyl acrylate and methacrylate, 2-(morpholino)ethyl acrylate and methacrylate, glycidyl acrylate and methacrylate, and combinations thereof.

38. The chiral copolymer of claim 32, wherein the ionizable comonomer is a vinyl monomer.

39. The chiral copolymer of claim 38, wherein the ionizable monomer includes an amino group or a carboxylic acid group.

40. The chiral copolymer of claim 27 or 32, wherein the crosslinking comonomer is a polyvinyl monomer.

41. The chiral copolymer of claim 40, wherein the polyvinyl comonomer is a lower alkylene or lower alkanol diacrylate, dimethacrylate, triacrylate or trimethacrylate.

42. The chiral copolymer of claim 41, wherein the polyvinyl comonomer is ethylene diacrylate, ethylene dimethacrylate, trimethylolpropane triacrylate, or trimethylolpropane trimethacrylate.

43. The chiral copolymer of claim 27 or 32, wherein the mixture further comprises a functional monovinyl comonomer.

44. The chiral copolymer of claim 43, wherein the functional monovinyl comonomer contains a hydrophilic group or a precursor to a hydrophilic group.

45. The chiral copolymer of claim 44, wherein the functional monovinyl comonomer is selected from the group consisting of 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, glycidyl methacrylate, glycidyl acrylate, and combinations thereof.

46. A method for preparing a chiral copolymer useful as an enantioselective separation material, wherein the method comprises admixing an ionizable chiral monomer with a crosslinking comonomer and a polymerization initiator in a porogenic solvent, to form a polymerization mixture, and applying heat or radiation to the polymerization mixture to initiate polymerization.

47. A method for preparing a chiral copolymer useful as an enantioselective separation material, wherein the method comprises admixing a chiral monomer with an ionizable comonomer, a crosslinking comonomer and a polymerization initiator in a porogenic solvent, to form a polymerization mixture, and applying heat or radiation to the polymerization mixture to initiate polymerization.

48. The method of claim 46 or 47, wherein the polymerization mixture further includes a functional monovinyl comonomer.

49. The method of claim 48, wherein the functional monovinyl comonomer contains a hydrophilic group or a precursor to a hydrophilic group.