Process for the synthesis of 2′-O-substituted pyrimidines and oligomeric compounds therefrom
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Yogesh S. Sanghvi, Kelly G. Sprankle, Bruce S. Ross, Rich H. Griffey, Robert H. Springer
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Abstract
Oligonucleotide analogs are disclosed having pyrimidine monomeric sub-units therein that are modified at the 2′ and 5′ positions. Monomeric sub-units having these modifications may be further modified at the 2′ position. Improved processes for the synthesis of 2′-O-substituted pyrimidine nucleosides are also provided. The processes feature alkylation of a 2,2′-anhydropyrimidine nucleoside or a 2S,2′-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.
Claims8
A process for the synthesis of a 2′-O-substituted pyrimidine nucleoside of formula:
- wherein:
- Q is a pyrimidine base or a 2-S pyrimidine base;
- R1 is substituted or unsubstituted C1-C30 alkyl, C1-C30 alkenyl, C1-C30 alkynyl, C6-C14 aryl, or C7-C30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
- and
- R2 and R3 are independently hydrogen or a hydroxyl protecting group;
- comprising the steps of:
- providing a 2-2′-anhydropyrimidine nucleoside;
- selecting an alcohol of the formula R1—OH;
- and
- treating said 2-2′-anhydropyrimidine nucleoside and said alcohol with a di or trivalent hard acid under conditions of time, temperature and pressure effective to yield said 2′-O-substituted pyrimidine nucleoside.
Dependencies are inferred from the claim text.