Monomer compositions for the synthesis of RNA, methods of synthesis, and methods of deprotection

• US 7,759,471 B2
• Filed: 03/23/2006
• Issued: 07/20/2010
• Est. Priority Date: 10/31/2005
• Status: Active Grant

• Current Assignee: Agilent Technologies, Inc., The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: Agilent Technologies, Inc., The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Sierzchala, Agnieszka, Caruthers, Marvin H., Dellinger, Douglas J., Dellinger, Geraldine, Timar, Zoltan
• Primary Examiner(s): Jiang; Shaojia Anna
• Assistant Examiner(s): Lau; Jonathan S
• Application Number:
  US11/388,112
• Publication Number:
  US 20070100136A1
• Time in Patent Office: 1,580 Days
• Field of Search: 536/22.1, 536/23.1, 536/25.31, 536/25.2
• US Class Current: 536/22.1
• CPC Class Codes: C07H 19/12 Triazine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical

Abstract

Nucleotide monomers, polynucleotides, methods of making each, methods of deprotecting each, and the like are disclosed herein.

Claims

1. A nucleotide monomer comprising:

a compound of structure I having a 2′

-hydroxyl protecting group;

2. The nucleotide monomer of claim 1, wherein 2HPG is Group II.

3. The nucleotide monomer of claim 2, wherein R₆, R₇, and R₈ are each a methyl group.

4. The nucleotide monomer of claim 1, wherein 2HPG is Group VIIb.

5. The nucleotide monomer of claim 1, wherein 2HPG is Group VIII.

6. The nucleotide monomer of claim 1, wherein two or more of R₆, R₇, and R₈ of Group II are cyclically connected to each other.

7. The nucleotide monomer of claim 1, wherein for Groups VIIa and VIIb, R₆ and R₇ are cyclically connected to each other or to the phenyl group.

8. The nucleotide monomer of claim 1, wherein for Group VIII, R₆ and R₇ are cyclically connected to each other or to the phenyl group.

9. The nucleotide monomer of claim 1, wherein B is a base including a base protecting group selected from groups Ic through Xc:

10. A nucleotide monomer comprising:

a structure II having a 2′

-hydroxyl protecting group and a heterobase exocyclic amino protecting group;

11. The nucleotide monomer of claim 10, wherein 2HPG is Group II.

12. The nucleotide monomer of claim 11, wherein R6, R7, R8 are each a methyl group.

13. The nucleotide monomer of claim 10, wherein 2HPG is Group VIIa.

14. The nucleotide monomer of claim 10, wherein 2HPG is Group VIIb.

15. The nucleotide monomer of claim 10, wherein 2HPG is Group VIII.

16. The nucleotide monomer of claim 10, wherein two or more of R₆, R₇, and R₈ of group II are cyclically connected to each other.

17. The nucleotide monomer of claim 10, wherein for group VIIa, R₆ and R₇ are cyclically connected to each other or to the phenyl group.

18. The nucleotide monomer of claim 10, wherein for group VIII, R₆ and R₇ are cyclically connected to each other or to the phenyl group.

19. The nucleotide monomer of claim 10, wherein for group VIIb, R₆ and R₇ are cyclically connected to each other or to the phenyl group.

20. The nucleotide monomer of claim 10, wherein B is a base including a protecting group selected from base protecting groups that are removed under a same set of conditions as the 2HPG.

21. The nucleotide monomer of claim 10, wherein B is a base including a protecting group selected from base protecting groups that are removed under a different set of conditions than the 2HPG.

22. The nucleotide monomer of claim 10, wherein B is a base including a protecting group selected from:

acetyl, chloroacetyl, dicholoracetyl, trichloroacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, nitroacetyl, propionyl, n-butyryl, i-butyryl, n-pentanoyl, i-pentanoyl, t-pentanoyl, phenoxyacetyl, 2-chlorophenoxyacetyl, t-butyl-phenoxyacetyl, methylthioacetyl, phenylthioacetyl, 2-chlorophenylthioacetyl, 3-chlorophenylthioacetyl, 4-chlorophenylthioacetyl, t-butyl-phenylthioacetyl, benzyloxycarbonyl, (9-fluoroenyl)-methoxycarbonyl (Fmoc), 2-nitrophenylsulfenyl, 4-nitrophenylethylcarbonyl, 4-nitrophenylethoxycarbonyl, diphenylcarbamoyl, morpholinocarbamoyl, dialkylformamidines, succinyl, phtaloyl, benzoyl, 4-trifluoromethylbenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2,4-dimethylbenzoyl, 2,6-dimethylbenzoyl, 2,4,6-trimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 2-methylthiobenzoyl, 3-methylthiobenzoyl, 4- methylthiobenzoyl, 2,4-dimethylthiobenzoyl, 2,6-dimethylthiobenzoyl, 2,4,6-trimethylthiobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 2,6-dicholorbenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2,4-difluorobenzoyl, 2,6-difluorobenzoyl, 2,5-difluorobenzoyl, 3,5-difluorobenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 2,4- trifluoromethylbenzoyl, 2,6-trifluoromethylbenzoyl, 2,5-trifluoromethylbenzoyl, 3,5-trifluoromethylbenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, (3-methoxy4-phenoxy)benzoyl, (triphenyl)silylethyleneoxycarbonyl, (diphenylmethyl)silylethyleneoxycarbonyl, (phenyldimethyl)silylethyleneoxycarbonyl, (trimethy)lsilylethyleneoxycarbonyl, (triphenyl)silyl(2,2-dimethyl)ethyleneoxycarbonyl, (diphenylmethyl)silyl[(2,2-dimethyl)ethylene]oxycarbonyl, phenyldimethylsilyl[(2,2-dimethyl)ethylene]oxycarbonyl, trimethylsilyl[(2,2-dimethyl)ethylene]oxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, t-butyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, isopropylthiocarbonyl, butylthiocarbonyl, isobutylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methyloxymethyleneoxycarbonyl, methylthiomethylene-oxycarbonyl, phenyloxymethylene-oxycarbonyl, phenyllthiomethyleneoxycarbonyl, methyloxy(methyl)methyleneoxycarbonyl, methylthio(methyl)methyleneoxycarbonyl, methyloxy(dimethyl)methyleneoxycarbonyl, methylthio(dimethyl)methyleneoxycarbonyl, phenyloxy(methyl)methyleneoxycarbonyl, phenylthio(methyl)methyleneoxycarbonyl, phenyloxy(dimethyl)methyleneoxycarbonyl, and phenylthio(dimethyl)methyleneoxycarbonyl.