Solution phase synthesis of oligonucleotides
A process for the synthesis in solution phase of a phosphorothioate triester is provided. The process comprises the solution phase coupling of an H-phosphonate with an alcohol in the presence of a coupling agent to form an H-phosphonate diester. The H-phosphonate diester is oxidised in situ with a sulfur transfer agent to produce the phosphorothioate triester. Preferably, the H-phosphonate and alcohol are protected nucleosides or oligonucleotides. Oligonucleotide H-phosphonates which can be used in the formation of phosphorothioate triesters are also provided.
1 - 13 . (canceled)
14 . A process for introducing a group of formula —S-A into an H-phosphonate diester moiety, comprising: reacting a substrate comprising an H-phosphonate diester moiety with a sulfur transfer agent selected from the group consisting of
a) compounds of formula:
wherein A represents an aryl, methyl, substituted alkyl or alkenyl group;
b) compounds of formula:
wherein A represents an aryl, methyl, substituted alkyl or alkenyl group; and
c) compounds of formula:
wherein A represents a methyl or alkenyl group.
15 . A process according to claim 14 , wherein the sulfur transfer agent is selected from the group consisting of
16 . A process according to claim 14 or claim 15 , wherein the H-phosphonate diester is an oligonucleotide H-phosphonate diester.
17 . A process according to claim 16 , wherein the oligonucleotide H-phosphonate diester is a protected oligonucleotide H-phosphonate diester.
18 . A process according to claim 17 , further comprising one or more subsequent deprotection steps, thereby producing a deprotected oligonucleotide.
19 . A process for the preparation of an oligonucleotide, an oligonucleotide phosphorothioate or a mixed oligonucleotide/oligonucleotide phosphorothioate, said process comprising: introducing a group of formula —S-A into an H-phosphonate diester moiety by the process according to claim 14 .
20 . A process according to claim 19 , wherein the sulphur transfer agent is selected from the group consisting of
21 . A compound of formula:
wherein A represents an aryl, methyl, substituted alkyl or alkenyl group.
22 . A compound according to claim 21 , wherein A represents a phenyl group or a —CH 2 CH 2 AN group.
23 . A compound according to claim 22 , wherein A represents a phenyl group and the phenyl group is unsubstituted or is substituted by a halo or alkyl group.
24 . A compound of formula:
25 . A compound of formula:
wherein A represents an alkenyl group.