Method for the preparation of D-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative
3R-carboxylate enantiomer derivative of formula (III) can be prepared easily and selectively by the method of the present invention, and a highly pure D-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative can be prepared efficiently from the compound of formula (III) as an intermediate.
1. A method for preparing a 2,2-difluoro-2-deoxy-1-oxoribose derivative of formula (I), comprising the steps of:
(i) reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain a compound of formula (IV) having the 3-hydroxy group protected by a biphenylcabonyl group;
(ii) reacting the compound of formula (IV) with a base in a mixed solvent essentially comprising water and isolating a resulting 3R-carboxylate enantiomer of formula (III) by filtration;
(iii) reacting the compound of formula (III) with an acid to obtain a 5-hydroxy-1-oxoribose derivative of formula (II); and
(iv) protecting the 5-hydroxy group of the compound of formula (II) with R 3 :
wherein,
R is
R 1 is methyl or ethyl;
R 2 C 1-3 alkyl;
r 3 is benzoyl or
R 4 is phenyl or substituted phenyl; and
M is sodium or potassium.
2. The method of claim 1 , wherein the biphenylcarbonyl group of step (i) is 2-biphenylcarbonyl or 4-biphenylcarbonyl.
3. The method of claim 1 , wherein the mixed solvent essentially comprising water used in step (ii) is a mixture of water and an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, acetone, methylisobutylketone, methylethylketone, methanol, ethanol, propanol, isopropanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylacetate and a mixture thereof
4. The method of claim 1 , wherein the base used in step (ii) is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and a mixture thereof.
5. The method of claim 4 , wherein the base used in step (ii) is potassium carbonate.
6. The method of claim 1 , wherein the acid used in step (iii) is selected from the group consisting of 1 to 12 N HCl, 1 to 9 N H 2 SO 4 , methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid.
7. The method of claim 6 , wherein the acid used in step (iii) is 12 N HCl.
8. The method of claim 1 , wherein the acid used in step (iii) is employed in an amount ranging from 1.1 to 1.5 equivalents based on the compound of formula (II).