Process for the preparation of phosphorothioate triesters

A process for the preparation of a deprotected oligonucleotide, oligonucleotide phosphorothioate or mixed oligonucleotide/oligonucleotide phosphorothioate which comprises:

• a) coupling a protected nucleoside or oligonucleotide H-phosphonate comprising a 3′ or 5′-H-phosphonate function with a protected nucleoside or oligonucleotide comprising a free 3′ or 5′-hydroxy function in the presence of a coupling agent thereby to form an H-phosphonate diester and, in situ, reacting the H-phosphonate diester with a sulfur transfer agent to produce a phosphorothioate triester, wherein the coupling reaction between the H-phosphonate and the alcohol, occurs in the presence of the sulfur transfer agent;
• and
• b) deprotecting the phosphorothioate triester produced in a) thereby to form a deprotected oligonucleotide, oligonucleotide phosphorothioate or mixed oligonucleotide, oligonucleotide/phosphorothioate.

A process for the synthesis of a deprotected oligonucleotide, said process comprising an assembly process in which a protected oligonucleotide is assembled, and a deprotection process in which the deprotected oligonucleotide is produced, the assembly process comprising coupling of a protected nucleoside or oligonucleotide H-phosphonate with a protected nucleoside or oligonucleotide comprising a free hydroxy function in the presence of a coupling agent thereby to form an H-phosphonate diester, characterised in that the coupling of the protected nucleoside or oligonucleotide H-phosphonate with the protected nucleoside or oligonucleotide comprising a free hydroxy function occurs in the presence of the sulfur transfer agent.

A process for the preparation of an H-phosphonate diester, which comprises coupling an H-phosphonate with an alcohol in the presence of a coupling agent, characterised in that the coupling reaction between the H-phosphonate and the alcohol occurs in the presence of the sulfur transfer agent.