Phosphitylation process
View Patent ↗A process for the phosphitylation of an alcohol or thiol with a phosphitylation agent in the presence of an activator is provided. The activator has the formula: wherein p is 0 or an integer from 1 to 4 and R for each occurrence is a substituent. Preferably X 7 is O and p is 0. The activator is commonly employed as a salt complex with an organic base. Preferred alcohols or thiols include nucleosides and oligonucleotides. The process is particularly suited for the synthesis of phosphoramidites.
1. A process for the phosphitylation of an alcohol or thiol with a phosphitylation agent in the presence of an activator, characterised in that the activator has the formula 1:
wherein p is 0 or an integer from 1 to 4, R for each occurrence is a substituent, and X 7 is O or S.
2. A process according to claim 1 , wherein X 7 is O and p is 0.
3. A process according to claim 1 or 2 , wherein the compound of formula 1 is employed as a salt complex with an organic base.
4. A process according to claim 3 , wherein the organic base is selected from the group consisting of pyridine, 3-methylpyridine, and N-methylimidazole.
5. A process according to claim 3 , wherein the alcohol or thiol is a nucleoside or oligonucleotide comprising a free hydroxy or thiol group.
6. A process according to claim 5 , wherein a nucleoside comprising a free 3′-hydroxy group is phosphitylated.
7. A process according to claim 3 , wherein the phosphitylation agent has the general chemical formula:
R 13 —X 6 —PX 4 X 5
wherein R 13 represents a phosphorus protecting group, X 6 represents O or S, X 4 and X 5 , which may be the same of different, represent leaving groups.
8. A process according to claim 7 , wherein R 13 represents a substituted or unsubstituted aliphatic or aralkyl group or a substituted or unsubstituted aromatic group, X 6 is O and X 4 and X 5 each independently represent —NR 14 R 15 , wherein R 14 and R 15 each independently represents a C 1-6 alkyl, group, or R 14 and R 15 are joined, together with the N to which they are attached, to form a 5-7 membered ring.
9. A process according to claim 8 , wherein the phosphitylating agent is selected from the group consisting of O-β-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite, O-β-cyanoethyl-N,N,N′,N′-tetramethylphosphorodiamidite, O-β-cyanoethyl-N,N,N′,N′-tetraethylphosphorodiamidite, bis (N,N-diisopropylamino)-2-methyltrifluoroacetylamino-ethoxyphosphine, bis (N,N-diisopropylamino)-2-diphenylmethylsilylethoxyphosphine and O-β-cyanoethyl-bis (N-morpholino) phosphorodiamidite.
10. A process for the preparation of a compound of formula:
which comprises reacting a compound of formula:
with a compound of formula:
NCCH 2 CH 2 O—P(N(R 16 ) 2 ) 2
in the presence of an activator, where the activator comprises a compound of formula:
and an organic base, wherein R 4 is an alcohol protecting group, R 5 is —H, —F —OR 6 , —NR 7 R 8 , —SR 9 , or a substituted or unsubstituted aliphatic group, such as methyl or allyl, R 6 for each occurrence is —H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl, an alcohol protecting group, or —(CH 2 ) q —NR 11 R 12 , R 7 and R 8 are each, independently, —H, a substituted or unsubstituted aliphatic group, or an amine protecting group or R 7 and R 8 taken together with the nitrogen to which they are attached are a heterocyclyl group, R 9 is —H, a substituted or unsubstituted aliphatic group, or a thiol protecting group, R 11 and R 12 are each, independently, —H, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group or an amine protecting group or R 11 and R 12 taken together with the nitrogen to which they are attached form a heterocyclyl group, q is an integer from 1 to about 6, B is —H, a natural or unnatural nucleobase, protected nucleobase, protected natural or unnatural nucleobase, heterocycle or a protected heterocycle and R 16 represents a C 1-6 alkyl group, preferably an isopropyl group.
11. A process according to claim 10 , wherein the organic base is selected from the group consisting of pyridine, 3-methylpyridine, and N-methylimidazole.
12. A process according to claim 10 or 11 , wherein R 5 is H, OMe or OCH 2 CH 2 OMe.
13. A process according to claim 10 or 11 , wherein R 4 is an acid-labile protecting group and R 5 is OR 6 wherein R 6 is a base labile protecting group or a silyl protecting group.