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 method for the preparation of a 2′-deoxy-2′-fluoro-2′-C-methyl-β-D-ribofuranosyl nucleoside of the following formula:
wherein the base is:
wherein R 2 and R 4 are independently H, OH, NH 2 , or OR′;
R′ is an optionally substituted straight, branched, or cyclic alkyl of C 1 -C 12 ;
Y is N or CH;
the method comprising the following steps:
(a) reacting a nucleoside intermediate of the following formula:
wherein the protected base is the base protected by a protecting group, wherein the protecting group is benzoyl;
wherein R 3 and R 5 are each independently tetrahydropyranyl, methyl, ethyl, benzyl, p-methoxybenzyl, benzyloxymethyl, phenoxymethyl, methoxymethyl, ethoxymethyl, mesyl, tosyl, trifluoroacetyl, or trichloroacetyl,
with diethylaminosulfur trifluoride or bis(2-methoxyethyl)aminosulfur trifluoride to yield a fluorinated intermediate of the following formula:
(b) deprotecting the R 3 and R 5 groups of the product of step (a) by treatment with a boron trihalide to yield an intermediate of the following formula:
(c) saponifying the product of step (b) to yield the desired nucleoside.
2. The method of claim 1 , wherein the boron trihalide of step (b) is selected from boron trifluoride, boron trichloride, boron tribromide or boron triiodide.
3. The method of claim 1 , wherein the saponification of step (c) is done with a metal alcoholate in alcohol.
4. The method of claim 3 , wherein the metal alcoholate in alcohol is sodium methoxide in methanol.