Regioselective synthesis of 2'-O-modified nucleosides
AssigneeIsis Pharmaceuticals, Inc.
InventorsAndrew M. Kawasaki, Allister S. Fraser, Muthiah Manoharan, P. Dan Cook, Thazha P. Prakash
Life of this patent
Estimating the term…
Abstract
Methods for the regioselective alkylation at the 2′-hydroxy position over the 3′-hydroxy position of nucleosides and nucleoside analogs, forming 2′-O-ester modified compounds, are disclosed. Reduction and derivatization of the 2′-O-ester provides 2′-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.
Claims35
A method for the selective alkylation of the 2′ position of a 2′,3′-dihydroxy sugar moiety of a nucleoside comprising the steps of:
- (a) dissolving said nucleoside in at least one solvent to form a solution;
- (b) cooling said solution to a temperature of from about 5° C. to about minus 50° C.;
- (c) treating said cooled solution with a base to give a mixture;
- (d) warming said mixture to a temperature of from about minus 30° C. to about 35° C.;
- (e) cooling said mixture of step (d) to a temperature of from about 5° C. to about minus 50° C.;
- and
- (f) reacting said cooled mixture of step (e) with a reactive ester to effect said alkylation.
A method for the preparation of a compound of formula:
- 11
- wherein:
- Q is H or a hydroxyl protecting group;
- Bx is a heterocyclic base moiety;
- and
- Z is C1 to C12 alkyl;
- comprising the steps of:
- (a) selecting a nucleoside of formula:
- 12
- (b) dissolving said nucleoside in at least one solvent to form a solution;
- (c) cooling said solution to a temperature of from about 5° C. to about minus 50° C.;
- (d) treating said cooled solution with a base to give a mixture;
- (e) warming said mixture to a temperature of from about minus 30° C. to 35° C.;
- (f) cooling said mixture of step (e) to a temperature of from about 5° C. to about minus 50° C.;
- and
- (g) reacting said cooled mixture of step (f) with an ester of the formula:
- 13
- wherein:
- Z is as defined above;
- and
- J is a leaving group;
- to give said compound.
Dependencies are inferred from the claim text.