Process for the preparation of phosphorothioate triesters
First Claim
1. In process for the preparation of a phosphorothioate triester which comprises coupling an H-phosphonate with an alcohol in the presence of a coupling agent thereby to form an H-phosphonate diester, and subsequently, reacting the H-phosphonate diester with a sulfur transfer agent thereby to form a phosphorothioate triester, the improvement wherein the coupling reaction between the H-phosphonate and the alcohol is carried out in the presence of the sulfur transfer agent which is later used to form the triester.
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Accused Products
Abstract
A process for the synthesis of a phosphorothioate triester is provided. The process comprises the coupling of an H-phosphonate with an alcohol in the presence of a solution comprising both a coupling agent and a sulfur transfer agent. Preferably, the H-phosphonate and alcohol are protected nucleosides or oligonucleotides.
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Citations
30 Claims
- 1. In process for the preparation of a phosphorothioate triester which comprises coupling an H-phosphonate with an alcohol in the presence of a coupling agent thereby to form an H-phosphonate diester, and subsequently, reacting the H-phosphonate diester with a sulfur transfer agent thereby to form a phosphorothioate triester, the improvement wherein the coupling reaction between the H-phosphonate and the alcohol is carried out in the presence of the sulfur transfer agent which is later used to form the triester.
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15. A process for the preparation of a deprotected oligonucleotide, oligonucleotide phosphorothioate or mixed oligonucleotide/oligonucleotide phosphorothioate which comprises:
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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. - View Dependent Claims (16, 17, 18, 19, 20, 21)
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- 22. 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.
- 27. 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.
Specification