Process for the preparation of oligonucleotides

1. A process for the synthesis of an oligonucleotide in which an oligonucleotide is assembled on a swellable solid support using the phosphoramidite approach in the presence of a solvent and an activator, wherein, the solvent and swellable support are selected such that a swell ratio of from 5 to 20 is achieved, swell ratio being calculated according to the formula:

Swell

⁢

⁢

Ratio

=

Vol

final

-

Vol

initial

Vol

initial

wherein

Vol final is the final volume occupied by the swellable support after full swelling; and

Vol initial is the initial dry bed volume of the swellable support, the activator being selected from the group consisting of i) compounds having the chemical formula (1):

wherein p is 0 or an integer from 1 to 4; X is O or S; and R for each occurrence is a substituent selected from the group consisting of halo groups, aliphatic groups, —NR 1 R 2 , —OR 3 , —OC(O)R 3 , —C(O)OR 3 , cyano, aryl groups, heterocyclyl groups, —CHO, —COR 3 , —NHCOR 3 , aralkyl groups, and —SR 13 , wherein R 11 and R 12 are each, independently, —H, an aliphatic group, an aryl group, an aralkyl group; or together with the nitrogen to which they are attached form a 5 or 6-membered heterocyclic ring; and R 13 is an aliphatic group, an aryl group, or an aralkyl group; or two adjacent R groups taken together with the carbon atoms to which the are attached form a six membered saturated or unsaturated ring; and ii) salts formed between a compound of chemical formula (1) and an organic base.

2. A process according to claim 1 , wherein the activator is the N-methylimidazobe, pyridine or 3-methylpyridine salt of a compound of formula (1) wherein X is O and p is 0.

3. A process according to claim 1 , wherein the swellable support comprises functionalised polystyrene, partially hydrolysed polyvinylacetate or poly(acrylamide).

4. A process according to claim 1 , wherein the process comprises coupling a nucleoside phosphoramidite with a nucleoside or oligonucleotide comprising a free hydroxy group.

5. A process according to claim 4 , wherein the nucleoside phosphoramidite is a deoxyribonucleside-3′-phosphoramidite or ribonucleside-3′-phosphoramidite.

6. A process according to claim 4 , wherein the nucleoside or oligonucleotide comprising a free hydroxy group comprises a free 5′-hydroxy group.

7. A process according to claim 4 , wherein the nucleoside or oligonucleotide comprising a free hydroxy group is attached to the solid support by a cleavable linker.

8. A process according to claim 1 , wherein the solvent is dimethylformamide, N-methylpyrrolidinone, dichloromethane, tetrahydrofuran or pyridine.

9. A process according to claim 1 , wherein the assembled oligonucleotide is cleaved from the solid support.

10. A process for the synthesis of an oligonucleotide which comprises coupling a nucleoside phosphoramidite with a nucleoside or oligonucleotide comprising a free hydroxy group in the presence of an activator, wherein:

a) the nucleoside or oligonucleotide comprising a free hydroxy group is attached to a swellable solid support by a cleavable linker, said swellable support being selected from the group consisting of functionalized polystyrene, partially hydrolyzed polyvinylacetate and poly(acrylamide);

b) said activator is a salt formed between an organic base and a compound having the chemical formula:

wherein p is 0 or an integer from 1 to 4;

R for each occurrence is a substituent selected from the group consisting of halo groups, aliphatic groups, —NR1R2, —OR3, —OC(O)R3, —C(O)OR3, cyano, aryl groups, heterocyclyl groups, —CHO, —COR3, —NHCOR3, aralkyl groups, and —SR13, wherein R11 and R12 are each, independently, —H, an aliphatic group, an aryl group, an aralkyl group; or together with the nitrogen to which they are attached form a 5 or 6-membered heterocyclic ring; and R13 is an aliphatic group, an aryl group, or an aralkyl group; or two adjacent R groups taken together with the carbon atoms to which they are attached form a six membered saturated or unsaturated ring; and X is O or S;

the process employing a solvent which swells the solid support selected from the group consisting of dimethylformamide, N-methylpyrrolidinone, dichloromethane, tetrahydrofuran and pyridine.

11. A process according to claim 10 , wherein the activator is the N-methylimidazole, pyridine or 3-methylpyridine salt of a compound of formula (1) wherein X is O and p is 0.