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US 2003/0114662 A1Published application
Method of synthesizing phosphorothioate oligonucleotides
AssigneeIsis Pharmaceuticals, Inc.
InventorsDouglas L. Cole, Vasulinga Ravikumar
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Abstract
This invention presents novel methods for synthesizing phosphorothioate oligonucleotides, using support-bound phosphoramidites. Novel intermediates useful in the methods are also provided.
Claims19
A method for synthesizing a phosphorothioate oligonucleotides on a solid phase support comprising the steps of:
- reacting a phosphordiamidite of formula:
- 10
- wherein:
- R1 is a protecting group;
- R2 and R3 are dialkylamino or morpholino;
- B is a nucleosidic base;
- R6 is halogen, O-alkyl, O-alkylamino, O-alkylalkoxy, protected O-alkylamino, O-alkylaminoalkyl, O-alkyl imidazole, or a polyether of the formula (O-alkyl)m, where m is 1 to about 10;
- with a support-bound synthon of formula:
- 11
- wherein:
- R4 is a linker connected to a solid support;
- R5 is a phosphoryl protecting group;
- n is 0 to 100;
- to form a support-bound phosphoramidite of formula:
- 12
- protecting the support-bound phosphoramidite, thereby forming a support-bound phosphite of formula:
- 13
- sulfurizing the support-bound phosphite to form a protected phosphorothioate;
- and
- deprotecting the protected phosphorothioate to form a further support-bound synthon wherein n is increased by 1.
17 more elements
3 The method of claim 1 wherein at least one of R2 and R3 is diisopropylamino.
A compound of formula:
- 14
- wherein:
- B is a nucleosidic base;
- R1 is a protecting group;
- R2 is dialkylamino or morpholino;
- R4 is a linker connected to a solid support;
- R5 is a phosphoryl protecting group;
- R6 is halogen, O-alkyl, O-alkylamino, O-alkylalkoxy, protected O-alkylamino, O-alkylaminoalkyl, O-alkyl imidazole, or a polyether of the formula (O-alkyl)m, where m is 1 to about 10;
- and
- n is 1 to about 100.
7 more elements
Dependencies are inferred from the claim text.