초록

This invention presents novel methods for synthesizing phosphorothioate oligonucleotides, using support-bound phosphoramiditese. Novel intermediates useful in the methods are also provided.

대표청구항 ▼

[ What is claimed is:] [1.] A method for synthesizing a phosphorothioate oligonucleotide on a solid phase support comprising the steps of:reacting a phosphordiamidite of Formula I: [ STR 10 ]wherein:R.sub.1 is a protecting group;R.sub.2 and R.sub.3 are dialkylamino having up to 12 carbon atoms, or m

[ What is claimed is:] [1.] A method for synthesizing a phosphorothioate oligonucleotide on a solid phase support comprising the steps of:reacting a phosphordiamidite of Formula I: [ STR 10 ]wherein:R.sub.1 is a protecting group;R.sub.2 and R.sub.3 are dialkylamino having up to 12 carbon atoms, or morpholino;B is a nucleosidic base;R.sub.6 is halogen, O-alkyl, O-alkylamino, O-alkylalkoxy, amino protected O-alkylamino, --O-alkyl-N(H)-alkyl, --O-alkyl-N-imidazolyl, or a polyether of the formula --O(--CH.sub.2 -CH.sub.2 --O---).sub.m -alkyl where m is 1 to about 10;with a support-bound synthon of Formula II: [ STR 11 ]wherein:R.sub.4 is a linker connected to a solid support;R.sub.5 is a phosphoryl protecting group;n is 0 to 100;to form a support-bound phosphoramidite of Formula III: [ STR 12 ]reacting said support-bound phosphoramidite of Formula III with a reagent of formula H--OR.sub.5 to displace said R.sub.2 with said --OR.sub.5, and to form thereby a support-bound phosphite of Formula IV: [ STR 13 ]treating the support-bound phosphite with a sulfurizing agent to form a protected phosphorothioate; anddeprotecting the protected phosphorothioate to form a further support-bound synthon of Formula V: [ STR 14 ] [13.] A compound of formula: [ STR 15 ] rein:B is a nucleosidic base;R.sub.1 is a protecting group;R.sub.2 is dialkylamino having up to 12 carbon atoms, or morpholino;R.sub.4 is a linker connected to a solid support;R.sub.5 is a phosphoryl protecting group;R.sub.6 is halogen, O-alkyl, O-alkylamino, O-alkylalkoxy, amino protected O-alkylamino, --O-alkyl-N(H)-alkyl, --O-alkyl-N-imidazolyl, or a polyether of the formula --O(--CH.sub.2 -CH.sub.2 --O--).sub.m -alkyl where m is 1 to about 10; andn is 1 to about 100. The compound of claim 13 wherein n is from 15 to 25. The compound of claim 13 wherein R.sub.2 is diisopropylamino or morpholino. The compound of claim 15 wherein the phosphoryl protecting group is cyanoethyl. The compound of claim 13 wherein the phosphoryl protecting group is 4-cyano-2-butenyl or diphenylmethylsilylethyl. The compound of claim 13 wherein n is 1 to 30.