CS264904B1 - Nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil and a process for their preparation - Google Patents

Abstract

Nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil of the general formula I where R = 2,3,5-tri-O-acetylribosyl, 2,3-di- -O-acetyl-5-deoxyribosyl, 2, 3-di~O-acetyl-5- -chloro-5-deoxyribosyl and their economical preparation. These derivatives enable the production of highly pure 5-fluorouracil cancerostatics with high yields.

Description

These compounds have not been described in the scientific or patent literature yet and represent a new class of substances with potentially high biological, especially carcinostatic, activity.

The present invention provides novel nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil of formula I. Another aspect of the invention is a process for the preparation of nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil of formula I. by converting the corresponding uracil nucleoside derivative, preferably acetylated, such as triacetyluridine, diacetyl-5'-deoxyuridine, diacetyl-5'-chloruridine, into a 6-acetoxy-5-fluoro- compound by treatment with fluorine, preferably acetic acid. 5,6-dihydrouracil of the formula I and is isolated preferably by shaking between an organic solvent and water, optionally by chromatography and crystallization.

An advantage of the preparation process of the present invention is that the reaction can be carried out in a conventional chemical laboratory equipped with an efficient fume hood, without requiring special equipment. The high yield of said process is another advantage. It is an essential advantage of the present invention that the methods disclosed herein are applicable to pyrimidine nucleosides and nucleobases and analogs thereof, including 5-fluorine derivatives such as uracil, 5-fluorouracil, 5-fluorouridine, 2-deoxyuridine, 2-deoxy- 5-Fluorouridine. The novel 6-acetoxy-5-fluoro-5,6-dihydrouracil derivatives prepared according to the present invention can be converted into 5-fluorouracil derivatives in a simple manner, even in one reaction step, and are therefore important starting materials for their preparation. In this way, 5-fluorouracil and its derivatives can be prepared, drugs indispensable in cancer chemotherapy.

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

Γ k k 1 and d 1

To a solution of triacetyluridine (3.7 g) in acetic acid (200 mL) was added fluorine (24 h). After reacting. The reaction solution was purged with nitrogen (30 min), evaporated in vacuo and codistilled twice with acetic acid and ethanol. The residue was dissolved in ethyl acetate (200 mL) and shaken with water to remove the acidic reaction (6x20 mL). The ethyl acetate solution was evaporated in vacuo and codistilled with toluene. 4.22 g (94%) of 6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine are obtained, m.p. Mp 140-145 ° C.

Example 2

To a solution of diacetyl-5'-chloruridine (3.47 g) in acetic acid (200 mL) was added fluorine to react the starting material (30 h). The solution was purged with nitrogen (30 min), evaporated in vacuo and codistilled with acetic acid and ethanol. The residue was dissolved in ethyl acetate (200 mL), shaken with 3 x 5% sodium bicarbonate solution, 1 x water and evaporated in vacuo and chromatographed on a silica gel column with ethyl acetate-toluene 1: 1. 3.19 g (75%) of 6-acetoxy-diacetyl-5'-chloro-5-fluoro-5,6-dihydrouridine are obtained, m.p. 138-142 ° C.

CS 264 904 Bl

Example 3

To a solution of diacetyl-5'-deoxyuridine (3.12 g) in acetic acid (200 mL) was added fluorine to react the starting material. The solution was then purged with nitrogen, evaporated in vacuo and codistilled with acetic acid and ethanol. The residue was dissolved in ethyl acetate (200 mL) and shaken with water to remove the acidic reaction. Evaporation in vacuo gave 3.75 g (96%) of 6-acetoxy-diacetyl-5'-deoxy-5-fluoro-5,6-dihydrouridine. Crystallization from 2-propanol gave the title compound, m.p. M.p. 148-151 ° C.

Example 4 of Example 1 is dissolved by standing and the solution is neutralized with 5-fluorouridine, m.p.

6-acetoxy-triacetyl-5-fluoro-5,6-dihydrouridine prepared according to 0.15 M methanolic sodium methoxide solution (80 mL). After 12 h it was acidic exchanger and evaporated in vacuo. 2.39 g (91%) of 184-185 ° C are obtained.

Claims (2)

SUBJECT OF THE INVENTION Nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil of the general formula I wherein R = 2,3,5-tri-O-acetylribosyl, 2,3-di-O-acetyl-5-deoxyribosyl, 2 3-di-O-acetyl-5-chloro-5-deoxyribosyl 2. A process for the preparation of the nucleoside derivatives of 6-acetoxy-5-fluoro-5,6-dihydrouracil of the formula I according to claim 1, characterized in that the acetylated uracil derivative is reacted with fluorine in acetic acid.