CS264903B1 - Process for preparing 5-fluorouridine - Google Patents

Abstract

A method for preparing 5-fluorouridine, consisting in treating triacetyluridine with fluorine in acetic acid to form 6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine, which is converted to 5-fluorouridine after isolation. The resulting product has a cancerostatic effect.

Description

The subject of the invention is a process for the preparation of 5-fluorouridine, a biologically highly active substance, in cancer chemotherapy.

The present invention provides a process for the preparation of 5-fluorouridine by reacting triacetyluridine by reaction with fluorine in acetic acid to give 6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine which is isolated in pure form and further converted preferably in one reaction step to 5-fluorouridine.

The advantage of this process is that the final product is obtained in high purity and high yield. The fluorination product is isolated by shaking between organic solvent and water, and possibly subsequent chromatography. The dihydroderivative obtained can be converted to 5-fluorouridine by the action of inorganic bases, alkali hydroxides, carbonates, alkoxides, basic ion exchangers, ammonia. The dihydroderivative can also be converted by treatment with organic bases, e.g. triethylamine, or by heating to triacetyl-5-fluorouridine, followed by cleavage of the acetyl groups by conventional methods to 5-fluorouridine.

In the following, the invention is explained in more detail in the examples without being limited thereto

He did

To a solution of triacetyluridine (3.7 g) in acetic acid (200 mL) was added fluorine (diluted with nitrogen) for 24 h. The reaction solution, after reacting the starting material, was purged with nitrogen (30 min), evaporated in vacuo and codistilled 2 times with acetic acid and 2 times with ethanol. The residue was dissolved in ethyl acetate (200 mL) and shaken with water to remove the acidic reaction (6 x 20 mL). The ethyl acetate solution was evaporated in vacuo and co-distilled twice with toluene. The residue (6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine) was dissolved in 80 ml of 0.15 M methanolic sodium methoxide and left at room temperature for 12 h. The solution was neutralized with acidic ion exchanger, filtered and evaporated in vacuo. 2.15 g (82%) of 5-fluorouridine are obtained, m.p. 183-185 ° C.

Example 2

A solution of triacetyluridine (3.7 g) in anhydrous acetic acid (200 mL) was saturated with fluorine until the starting material was reacted (30 h). The solution was evaporated in vacuo, codistilled twice with acetic acid and 2x with ethanol. The residue was dissolved in ethyl acetate (200 mL) and shaken 3x with 5% sodium bicarbonate solution and 1x with water. The ethyl acetate solution was then shaken vigorously with 10% sodium carbonate solution until the nucleoside derivative was removed from the ethyl acetate solution. The aqueous solution was neutralized with an acidic ion exchanger, filtered and evaporated in vacuo. 2.02 g (78%) of 5-fluorouridine are obtained, m.p. 183-185 ° C.

Example 3

Triacetyluridine (3.7 g) was converted to 6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine according to Example 1. The dihydroderivative was dissolved in chloroform (200 mL) and triethylamine was added until alkaline. After 12 h, the chloroform solution was shaken with 3x20 mL of water and evaporated in vacuo. The residue is chromatographed on silica gel with ethyl acetate-toluene 4: 1. 2.91 g (75%) of triacetyl-5-fluorouridine are obtained, which is converted in a conventional manner, by cleavage of acetyl groups, to 5-fluorouridine (1.86 g, 71%), m.p. 183-185 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 5-fluorouridine characterized in that triacetyluridine is treated with fluorine in acetic acid to give 6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine which is converted to 5-fluorouridine after isolation.