Non-pressurized methods for the preparation of conjugrated solid supports for boronic acids

• US 20040039129A1
• Filed: 08/01/2003
• Published: 02/26/2004
• Est. Priority Date: 08/16/2000
• Status: Abandoned Application

• Current Assignee: University of Alberta
• Original Assignee: University of Alberta
• Inventors: Hall, Dennis G.
• Application Number:
  US10/344,778
• Publication Number:
  US 20040039129A1
• Time in Patent Office: Days
• US Class Current: 525/333.3
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C08F 8/30 Introducing nitrogen atoms or nitrogen-containing groups
• CPC Class Codes: C40B 40/00 Libraries per se, e.g. arrays, mixtures

Abstract

The methods of the invention are directed to preparation of dihydroxyalkylaminoalkyl-conjugated solid supports, such as a diethanolamine- or a dipropanolamine-conjugated resin or polystyrene under non-pressurized conditions. The invention also provides novel methods for immobilizing boronic acids. The invention also provides a novel class of solid supports comprising dihydroxyalkyl-aminoalkyl groups

Claims

1. A method for preparing a dihydroxyalklylaminoalkyl or a dihydroxyaminobenzyl-conjugated solid support under non-pressurized conditions comprising the following steps:

(a) providing an alkyl halide, a substituted alkyl halide or a benzyl halide conjugated to a solid support, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20, and X is the halide and is chloride, bromide, iodide or an equivalent thereof;

(b) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(c) providing a halide salt selected from the group consisting of an iodide salt, a bromide salt and equivalents thereof; and

,

(d) mixing the conjugated solid support of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl or a dihydroxyaminobenzyl-conjugated solid support.

2. The method of claim 1, wherein the integer value of x and y of the amine of step (b) is 2.

3. The method of claim 1, wherein the integer value of x and y of the amine of step (b) is 3.

4. The method of claim 1, wherein the integer value of x and y of the amine of step (b) is 4.

5. The method of claim 1, wherein the integer value of x and y of the amine of step (b) is 5.

6. The method of claim 1, wherein the mixing step takes place at about room temperature.

7. The method of claim 1, wherein the alkyl halide of step (a) is methylchloride (ClCH₂—

).

8. The method of claim 1, wherein the benzyl halide of step (a) is benzylchloride (ClCH₂C₆H₄—

).

9. The method of claim 1, wherein the alkyl group of step (a) comprises the formula —

(CH₂)_m—

, wherein m is an integer between 2 to about 5.

10. The method of claim 1, wherein the composition of step (b) is diethanolamine or dipropanolamine or diisopropanolamine.

11. The method of claim 1, wherein the equivalents of amine in the composition of step (b) is in excess of the number of equivalents of alkyl halide, substituted alkyl halide or benzyl halide conjugated to a solid support in step (a).

12. The method of claim 1, wherein the equivalents of amine in the composition of step (b) is substantially equal to the number of equivalents of alkyl halide, substituted alkyl halide or benzyl halide conjugated to a solid support in step (a), and wherein a base is additionally present in the mixture of step (d).

13. The method of claim 12, wherein the base comprises a non-nucleophilic base.

14. The method of claim 13, wherein the base comprises diisopropylethylamine.

15. The method of claim 13, wherein the base comprises a carbonate.

16. The method of claim 1, wherein the composition of step (b) is in a solution comprising NMP, DMF, THF, DMSO, or an equivalent solution thereof.

17. The method of claim 1, wherein the halide salt of step (c) is added to the mixture of step (d) such that the initial amount of halide salt in the mixture is equimolar to or ten times the amount of alkyl halide or substituted alkyl halide or benzyl halide of step (a).

18. The method of claim 17, wherein the halide salt of step (c) is added to the mixture of step (d) such that the initial amount of halide salt in the mixture on a molar basis is two to five times the amount of alkyl halide or substituted alkyl halide or benzyl halide of step (a).

19. The method of claim 1, wherein the halide salt is a bromide salt.

20. The method of claim 1, wherein the halide salt is an iodide salt.

21. The method of claim 20, wherein the iodide salt comprises sodium iodide.

22. The method of claim 20, wherein the iodide salt comprises a tetraalkylammonium iodide salt.

23. The method of claim 1, wherein the solid support of step (a) comprises a polystyrene or an equivalent composition.

24. The method of claim 23, wherein the polystyrene comprises a poly(styrene-divinylbenzene) (PS-DVB) or an equivalent composition.

25. The method of claim 23, wherein the dihydroxyalkylaminoalkyl-conjugated polystyrene solid support is made by a process comprising the following steps:

(a) swelling the polystyrene with N-methyl-2-pyrrolidone (NMP) before reaction with the secondary amine;

(b) mixing the secondary amine and the halide salt with the swelled polystyrene.

26. The method of claim 1, wherein the solid support of step (a) comprises a plastic or a plastic co-polymer or an equivalent thereof.

27. The method of claim 1, wherein the solid support of step (a) comprises a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or an equivalent thereof, or a mixture thereof.

28. The method of claim 27, wherein the solid support of step (a) comprises a polystyrene-polyethylene glycol copolymer.

29. The method of claim 1, wherein the solid support of step (a) comprises a poly(vinyl alcohol) (PVA) hydrogel.

30. The method of claim 1, wherein the solid support of step (a) comprises a polyacrylamide or an equivalent polymer composition.

31. The method of claim 30, wherein the polyacrylamide comprises a polymethacrylamide, a methyl methacrylate, a glycidyl methacrylate, a dialkylaminoalkyl-(meth)acrylate, or a N,N-dialkylaminoalkyl(meth)acrylate, or an equivalent composition.

32. The method of claim 1, wherein the solid support of step (a) comprises an inorganic composition selected from the group consisting of sand, silica gel, glass, glass fibers, gold, alumina, zirconia, titania, and nickel oxide and combinations thereof and equivalents thereof.

33. The method of claim 32, wherein the diethanolaminoalkyl-conjugated group is covalently bonded to the solid support through a spacer group.

34. The method of claim 33, wherein the solid support comprises silica gel and the spacer group comprises an aryl-silane linker group.

35. The method of claim 1, wherein the mixing of step (d) lasts for about 48 hours.

36. The method of claim 1, wherein the mixing of step (d) lasts from about 12 to about 48 hours.

37. The method of claim 1, further comprising the step of washing the dihydroxyalkylaminoalkyl-conjugated solid support of step (d) at least once with at least one solvent.

38. The method of claim 37 wherein the solvent for washing comprises tetrahydrofuran, methylene chloride, dimethylformamide, dimethylsulfoxide, methanol, ethanol, or an equivalent thereof or a mixture thereof.

39. The method of claim 37, further comprising the step of washing the dihydroxyalkylaminoalkyl-conjugated solid support of step (d) with a tetrahydrofuran solution followed by washing with a methylene chloride solution.

73. The method of claim 1, wherein the mixing step takes place at about room temperature.

40. A method for preparing a diethanolaminomethyl-conjugated solid support under non-pressurized conditions comprising the following steps:

(a) providing a chloromethylated polystyrene solid support;

(b) providing diethanolamine;

(c) providing a halide salt, wherein the halide salt comprises sodium iodide or an equivalent thereof; and

,

(d) mixing the chloromethylated polystyrene solid support of step (a) with the diethanolamine of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming the diethanolaminomethyl-conjugated solid support.

41. The method of claim 40, wherein the mixing step is at about room temperature.

42. A method for preparing a dihydroxyalkylaminoalkyl-conjugated solid support under non-pressurized conditions comprising the following steps:

(a) providing a solid support conjugated with a primary amino group;

(b) providing a composition comprising a halogenated alcohol, wherein the composition has a formula HO(CH₂)_xY and x is an integer between 1 to about 20 and Y is a halide selected from the group consisting of chloride, bromide, and iodide and equivalents thereof;

(c) providing a halide salt selected from the group consisting of an iodide salt or a bromide salt or an equivalent thereof;

(d) providing a base; and

(e) mixing the conjugated solid support of step (a) with the composition of step (b) and the halide salt of step (c) and the base of step (d) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl-conjugated solid support.

43. The method of claim 42, wherein the halogenated alcohol comprises 2-chloroethanol.

44. The method of claim 42, wherein the halogenated alcohol comprises 2-bromoethanol.

45. The method of claim 42, wherein the halogenated alcohol comprises 2-iodoethanol.

46. The method of claim 42, wherein the base comprises a non-nucleophilic base.

47. The method of any of claims 42 through 46, wherein the mixing step is at about room temperature.

48. A method for making a solid-supported boronic acid ester comprising the following steps:

(a) providing a conjugated solid support prepared by the following steps;

(i) providing an alkyl halide or a substituted alkyl halide or a benzyl halide conjugated to a solid support, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20, and X is the halide and is chloride, bromide, iodide, or an equivalent thereof;

(ii) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(iii) providing a halide salt, wherein the halide salt is a bromide salt, an iodide salt, or an equivalent thereof; and

,

(iv) mixing the conjugated solid support of step (i) with the composition of step (ii) and the halide salt of step (iii) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl conjugate;

(b) providing a boronic acid solution; and

(c) mixing the dihydroxyalkylaminoalkyl-conjugated solid support of step (a) with the boronic acid solution of step (b), thereby forming a solid-supported boronic acid ester.

50. The method of claim 48 or 49, wherein the integer value of x and y of the amine of step (a)(ii) is 2.

51. The method of claim 48 or 49, wherein the integer value of x and y of the amine of step (a)(ii) is 3.

52. The method of claim 48 or 49, wherein the integer value of x and y of the amine of step (a)(ii) is 4.

53. The method of claim 50 or 51, wherein the integer value of x and y of the amine of step (a)(ii) is 5.

54. The method of claim 50 or 51, wherein the solution of step (b) comprises a non-alcoholic, anhydrous solvent.

49. A method for immobilizing a boronic acid comprising the following steps:

(a) providing a conjugate prepared by the following steps;

(i) providing an alkyl halide or a substituted alkyl halide or a benzyl halide conjugated to an solid support, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20 and the halide is chloride, bromide, iodide, or an equivalent thereof;

(ii) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(iii) providing a halide salt, wherein the halide salt is a bromide salt or an iodide salt, or an equivalent thereof; and

,

(iv) mixing the conjugate of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming the conjugate;

(b) providing a boronic acid solution; and

(c) mixing the dihydroxyalkylaminoalkyl conjugate of step (a) with the boronic acid solution of step (b), thereby immobilizing the boronic acid.

55. A method for preparing a conjugated resin comprising the following steps:

(a) providing an alkyl halide or a substituted alkyl halide or a benzyl halide conjugated to an resin, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20,and the halide is chloride, bromide, iodide, or an equivalent thereof;

(b) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(c) providing a halide salt, wherein the halide salt is a bromide salt or an iodide salt or an equivalent thereof; and

,

(d) mixing the conjugated resin of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl-conjugated resin.

58. The method of claims 55 through 57, wherein the iodide salt comprises sodium iodide.

59. The method of claims 55 through 57, wherein the iodide salt comprises a tetraalkylammonium iodide salt.

60. The method of claims 55 through 57, wherein the mixing step (d) takes place at about room temperature.

56. A method for preparing a conjugated polystyrene bead comprising the following steps:

(a) providing an alkyl halide or a substituted alkyl halide or a benzyl halide conjugated to a polystyrene bead, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20, and the halide is chloride, bromide, iodide, or an equivalent thereof;

(b) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(c) providing a halide salt, wherein the halide salt is a bromide salt or an iodide salt or an equivalent thereof; and

,

(d) mixing the conjugated polystyrene bead of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions for about 24 to about 48 hours, thereby forming the dihydroxyalkylaminoalkyl-conjugated polystyrene beads.

57. A method for preparing a dihydroxyalkylaminoalkyl-conjugated scavenger resin comprising the following steps:

(a) providing an alkyl halide or a substituted alkyl halide or a benzyl halide conjugated to a resin, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20, and the halide is chloride, bromide, iodide, or an equivalent thereof;

(b) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(c) providing a halide salt, wherein the halide salt is a bromide salt or an iodide salt or an equivalent thereof; and

,

(d) mixing the conjugated resin of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl-conjugated scavenger resin.

61. A solid support derivatized with a dihydroxyalkylaminoalkyl group wherein the dihydroxyalkylaminoalkyl comprises a tertiary amine having two hydroxyalkyl substituents having a formula HO(CH₂)_xN (CH₂)_yOH, wherein x and y are integers between 1 to about 20.

62. The solid support of claim 64, wherein the dihydroxyalkylaminoalkyl is a dihydroxyalkylaminomethyl group, a dihydroxyalkylaminoethyl, a dihydroxyalkylaminopropyl, or a dihydroxyalkylaminobutyl group.

63. The solid support of claim 61, wherein the solid support comprises one of the following:

i. a polystyrene or an equivalent composition;

ii. a plastic or a plastic co-polymer or an equivalent thereof;

iii. a silica or a silica gel or an equivalent thereof;

iv. cellulose or cellulose acetate or an equivalent thereof;

v. a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or an equivalent thereof, or a co-polymeric mixture thereof;

vi. a poly(vinyl alcohol) (PVA) hydrogel, or an equivalent composition;

vii. a polyacrylamide or an equivalent polymer composition.

64. The solid support of claim 63, wherein the polyacrylamide comprises a polymethacrylamide, a methyl methacrylate, a glycidyl methacrylate, a dialkylaminoalkyl-(meth)acrylate, or an N,N-dialkylaminoalkyl(meth)acrylate, or an equivalent composition.

65. The solid support of claim 63, wherein the polystyrene is a poly(styrene-divinylbenzene) (PS-DVB) or an equivalent composition.

66. The solid support of claim 61, further comprising a boronic acid attached as a boronic ester-dioxyalkylaminoalkyl-conjugated support.

67. The solid support of claim 66, wherein the boronic acid is an aryl boronic acid, a vinylboronic acid or an alkylboronic acid.

68. The use of an iodide or bromide salt for the formation under non-pressurized conditions of a dihydroxyalkylaminoalkyl-conjugated solid support from an alkyl halide, a substituted alkyl halide or a benzyl halide conjugated to a solid support and a secondary amine comprising two hydroxyalkyl substituents, wherein the secondary amine has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20.

69. The use of claim 68, wherein the alkyl halide, substituted alkyl halide or benzyl halide conjugated to a solid support is converted in situ to the iodide or the bromide, which is subsequently displaced by the secondary amine to yield the dihydroxyalkylaminoalkyl-conjugated solid support.

70. The use of claim 69, wherein the formation is at room temperature.

71. The use of claim 70, wherein the halide salt comprises sodium iodide.

72. A method for preparing a conjugated support under non-pressurized conditions comprising the following steps:

(a) providing an alkyl halide, a substituted alkyl halide or a benzyl halide conjugated to a solid support, wherein the alkyl halide has a formula —

(CH₂)_m—

X and m is an integer between 1 to about 20, and the halide is chloride, bromide, iodide or an equivalent thereof;

(b) providing a composition comprising a secondary amine comprising two hydroxyalkyl substituents, wherein the composition has a formula HO(CH₂)_xHN(CH₂)_yOH and x and y are integers between 1 to about 20;

(c) providing a halide salt selected from the group consisting of an iodide salt, a bromide salt and equivalents thereof; and

,

(d) mixing the conjugated solid support of step (a) with the composition of step (b) and the halide salt of step (c) under non-pressurized conditions, thereby forming a dihydroxyalkylaminoalkyl or a dihydroxyaminobenzyl-conjugated solid support.