1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivatives and process for the preparation thereof
View Patent ↗1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) having the 3-hydroxy group protected with a biphenylcarbonyl group is a solid which can be easily purified by a simple procedure such as recrystallization, and therefore, it can be advantageously used as an intermediate in the preparation of gemcitabine in a large scale. Further, the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) can be prepared with high stereoselectivity using the compound of formula (V) as an intermediate.
1. A 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) in a solid form:
wherein,
R 1 is benzoyl or
R 2 is hydrogen, cyano, halogen, carboalkoxy, nitro, C 1-2 alkoxy, C 1-2 alkyl or dialkylamino; and
X is Cl, Br or I.
2. The derivative of claim 1 , wherein R 2 is hydrogen.
3. The derivative of claim 1 , wherein the β-anomer content is 0.5% or less.
4. A method for preparing the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I), comprising the steps of
(i) reducing a 1-oxoribose compound of formula (II) to obtain a lactol compound of formula (III);
(ii) reacting the compound of formula (III) with a halophosphate compound of formula (IV) in the presence of a base to obtain a 1-phosphate furanose derivative of formula (V); and
(iii) reacting the compound of formula (V) with a halide source, followed by recrystallizing the resulting product to obtain the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I):
wherein, R 1 , R 2 and X have the same meanings as defined in claim 1 ; and R 3 is methyl, ethyl or phenyl.
5. The method of claim 4 , wherein the base used in step (ii) is selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine.
6. The method of claim 5 , wherein the base used in step (ii) is triethylamine.
7. The method of claim 4 , wherein the halide source used in step (iii) is selected from the group consisting of HCl/acetic acid, HBr/acetic acid, HBr/propionic acid, a trialkylsilyl halide, a lithium halide, a sodium halide, a cesium halide, a potassium halide, tetraalkylammonium halide and a mixture thereof.
8. The method of claim 7 , wherein the halide source used in step (iii) is selected from the group consisting of 30% HBr/acetic acid, 30% HBr/propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride and a trimethylsilyl chloride-lithium bromide mixture.
9. The method of claim 4 , wherein the recrystallization in step (iii) is carried out using a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, water and a mixture thereof.
10. The method of claim 9 , wherein the recrystallization in step (iii) is carried out using isopropanol or an isopropanol-water mixture.
11. The method of claim 4 , wherein the derivative of formula (I) is obtained in a purity of 99.5% or more.
12. A 1-phosphate furanose derivative of formula (V):
wherein,
R 1 is benzoyl or
R 2 is hydrogen, cyano, halogen, carboalkoxy, nitro, C 1-2 alkoxy, C 1-2 alkyl or dialkylamino; and
R 3 is methyl, ethyl or phenyl.