Synthesis of oligonucleotides
AssigneeIsis Pharmaceuticals, Inc.
InventorsVasulinga Ravikumar, Douglas L. Cole
Life of this patent
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Abstract
Synthetic processes are provided for the solution phase synthesis of oligonucleotides, especially phosphorothioate oligonucleotides, and intermediate compounds useful in the processes. Intermediates having structure ##STR1## are prepared in accord with preferred embodiments.
Claims16
A method for the solution phase preparation of an oligonucleotide comprising reacting, in solution, a first synthon having the structure ##STR20## with a second synthon having the structure ##STR21## to form a moiety having the structure ##STR22## where each Q is independently O or S;
- each B.sub.x is independently a nucleosidic base;
- each X is independently, H, OH, F, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl or N-alkenyl;
- each Y is independently a 5' hydroxyl protecting group;
- W is a 3' hydroxyl protecting group;
- each Z is independently O or S;
- each T is independently --O--(CH.sub.2).sub.x SiR.sub.3 R.sub.4 R.sub.5 ;
- R.sub.3, R.sub.4 and R.sub.5 are each independently alkyl or aryl;
- U is a phosphite activating group;
- n is an integer from 0 to 50;
- and
- x is 1 to about 7.
A method for preparing an oligomer comprising reacting together, in solution,
- a first synthon comprising at least two nucleoside units and having a 5' location protected with a 5' hydroxylic blocking group and a 3' location substituted with a function having the formula
- U--P--T
- wherein U is a phosphite activating group and T is --O--(CH.sub.2).sub.x SiR.sub.3 R.sub.4 R.sub.5 wherein R.sub.3, R.sub.4 and R.sub.5 are each independently alkyl or aryl, and x is 1 to about 7,
- with a second synthon comprising a nucleoside unit having a 3' location protected with a 3' hydroxylic blocking group and a 5' location capable of reacting with the U--P--T function.
A compound having one of the formulas ##STR23## where each Q is independently O or S;
- each B.sub.x is independently a nucleosidic base;
- each X is independently, H, OH, F, O-alkyl, S-alkyl, N-alkyl O-alkenyl, S-alkenyl or N-alkenyl;
- each Z is independently O or S;
- Y is H or a hydroxyl protecting group;
- U is a phosphite activating group;
- each T is independently --O--(CH.sub.2).sub.x SiR.sub.3 R.sub.4 R.sub.5 ;
- R.sub.3, R.sub.4 and R.sub.5 are each independently alkyl or aryl;
- n is an integer from 0 to 200;
- and
- x is 1 to about 7.
Dependencies are inferred from the claim text.