Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
View Patent ↗The present invention provides (i) a process for preparing a 2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion of the lactone to nucleosides with potent anti-HCV activity, and their analogues, and (iii) a method to prepare the anti-HCV nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.
1. A compound of the following formula:
wherein R 3 and R 5 can be independently H, CH 3 , benzyl, 4-methoxybenzyl, trityl, trialkylsilyl, t-butyldialkylsilyl, t-butyldiphenylsilyl, tetraisopropyldisilyl (TIPDS), tetrahydropyranyl (THP), methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), or acyl;
alternatively, R 3 and R 5 are linked through —SiR 2 —O—SiR 2 — or —SiR 2 —, wherein R is a lower alkyl.
2. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, benzoyl, pivaloyl, 4-nitrobenzoyl, 3-nitrobenzoyl, 2-nitrobenzoyl, 4-chlorobenzoyl, 3-chlorobenzoyl, 2-chlorobenzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 2-methylbenzoyl, 4-phenylbenzoyl, benzyl, 4-methoxybenzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.
3. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, benzoyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.
4. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, or THP.
5. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, or TIPDS.
6. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, benzyl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, or TIPDS.
7. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , acetyl, or benzyl.
8. A compound of claim 1 , wherein R 3 and R 5 are each independently H, CH 3 , or acetyl.
9. A compound of claim 1 , wherein R 3 and R 5 are each independently H or CH 3 .
10. A compound of claim 1 , wherein R 3 and R 5 are H.
11. A compound of claim 1 , wherein R 3 and R 5 are CH 3 .
12. A compound of claim 1 , wherein R 3 and R 5 are acetyl.
13. A compound of claim 1 , wherein R 3 and R 5 are benzyl.
14. A compound of claim 1 , wherein R 3 and R 5 are acyl.
15. A compound of claim 1 , wherein R 3 and R 5 are linked through —SiR 2 —O—SiR 2 — or —SiR 2 —, and
wherein R is selected from among methyl, ethyl, n-propyl, and i-propyl.
16. A process for the preparation of the compound of claim 1 wherein R 5 is H and R 3 is Bz, comprising the steps of:
(a) reacting a compound of the formula, 39,
with an alkyl-2-bromopropionate in the presence of activated zinc in a solvent;
(b) adding an oxidizing agent to provide a ketone;
(c) fluorinating the product of step (b) to produce a fluorinated ketone;
(d) reducing the fluorinated ketone of step (c); and
(e) benzylating the product of step (d).
17. The process of claim 16 , wherein the solvent of step (a) is selected from the group consisting of diethyl ether and tetrahydrofuran.
18. The process of claim 16 , wherein the oxidizing agent of step (b) is selected from the group consisting of: an activated dimethylsulfoxide, a chromatic agent, a Dess-Martin periodione, and tetrapropylammonium perruthenate.