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US 5,861,493 AGranted
Process for the synthesis of 2'-O-substituted pyrimidines
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Robert H. Springer, Kelly G. Sprankle, Bruce S. Ross
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Abstract
Improved processes for the synthesis of 2'-O-substituted pyrimidine nucleosides are 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.
Claims12
A process for the synthesis of a 2'-O-substituted pyrimidine nucleoside of formula:
- ##STR5## wherein:
- Q is a pyrimidine base or a 2-S pyrimidine base;
- R.sup.1 is substituted or unsubstituted C.sub.1 -C.sub.30 alkyl, C.sub.1 -C.sub.30 alkenyl, C.sub.1 -C.sub.30 alkynyl, C.sub.6 -C.sub.14 aryl, or C.sub.7 -C.sub.30 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 Lewis acid under conditions of time, temperature and pressure effective to yield said 2'-O-substituted pyrimidine nucleoside.
7 more elements
A process for the synthesis of a 2'-O-substituted cytidine nucleoside of formula:
- ##STR6## wherein:
- X is O or S;
- R.sup.1 is substituted or unsubstituted C.sub.1 -C.sub.30 alkyl, C.sub.1 -C.sub.30 alkenyl, C.sub.1 -C.sub.30 alkynyl, C.sub.6 -C.sub.14 aryl, or C.sub.7 -C.sub.30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether;
- R.sup.2 and R.sup.3 are independently hydrogen or a hydroxyl protecting group;
- R.sup.5 and R.sup.6 are independently H, C.sub.1 -C.sub.30 hydrocarbyl or substituted C.sub.1 -C.sub.30 hydrocarbyl;
- comprising the steps of:
- providing a 2-2'-anhydrouridine nucleoside of formula:
- ##STR7## selecting an alcohol of formula R.sup.1 -OH;
- treating said 2-2'-anhydrouridine nucleoside and said alcohol with a Lewis acid under conditions of time, temperature and pressure effective to form a 2'-O-substituted uridine nucleoside;
- and
- aminating said 2'-O-substituted uridine nucleoside to said 2'-O-substituted cytidine nucleoside.
8 more elements
The process of claim 12 wherein said 2-2'-anhydrouridine nucleoside and said alcohol are treated in a pressure sealed vessel.
Dependencies are inferred from the claim text.