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|Title:||Process for the synthesis of 2'-O-substituted pyrimidines and oligomeric compounds therefrom|
|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.|
|Inventor(s):||Cook; Phillip Dan (Escondido, CA), Sanghvi; Yogesh S. (Encinitas, CA), Sprankle; Kelly G. (Vista, CA), Ross; Bruce S. (Carlsbad, CA), Griffey; Rich H. (Vista, CA), Springer; Robert H. (Carlsbad, CA)|
|Assignee:||ISIS Pharmaceuticals, Inc. (Carlsbad, CA)|
|Filing Date:||Dec 22, 2000|
|Claims:||1. A process for the synthesis of a 2'-O-substituted pyrimidine nucleoside of formula: ##STR10## |
wherein: Q is a pyrimidine base or a 2-S pyrimidine base; R.sup.1 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 R.sup.2 and R.sup.3 are independently hydrogen or a hydroxyl protecting group; comprising the steps of: providing a 2-2'-anhydropyrimidine nucleoside; selecting an alcohol of the formula R.sup.1 --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.
2. The process of claim 1 wherein said di or tri valent hard acid is a divalent or trivalent cation of a di or tri valent metal, or a complex of said di or tri valent metal.
3. The process of claim 2 wherein said di or trivalent metal is magnesium, calcium, aluminum, zinc, chromium, copper, boron, tin, mercury, iron, manganese, cadmium, gallium or barium.
4. The process of claim 2 in said complex is a hydroxide, alkyl, alkoxide, di halide, trihalide, or an organic acid ligand.
5. The process of claim 2 where said complex is a trifluoride, trichioride, or an acetate.
6. The process of claim 3 wherein said complex is a hydroxide, alkyl, alkoxide, di halide, trihalide, or an organic acid ligand.
7. The process of claim 3 where said complex is a trifluoride, trichioride, or an acetate.
8. The process of claim 3 wherein said complex is a magnesium or calcium alkoxide.
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