CS264901B1 - Process for preparing 5'-chloro-5'-deoxy-5-fluorourine - Google Patents

Abstract

A method for preparing 5"-chloro-5'-deoxy-5- -fluorouridines, consisting in treating S^-chloro-S^-deoxyuridine, especially its diacetyl derivative, with fluorine in an acetic acid environment. The resulting 6-acetoxy-2',3"-di-O-acetyl- -5'-chloro-5'-deoxy-5-fluoro-5,6-dihydrouridine is isolated and further converted to 5'-chloro- -5'-deoxy-5-fluorouridine. The resulting product has a cancerostatic effect.

Description

The present invention provides a process for the preparation of 5'-chloro-5'-deoxy-5-fluorouridine, a biologically active substance with a high cancerostatic effect.

The substance prepared according to the present invention shows in tissue culture and animal experiments some advantageous properties, higher efficacy and lower toxicity than 5-fluorouracil, which is an indispensable drug in the treatment of cancer. It is referred to as a prodrug of 5-fluorouracil (J. Med. Chem. 25, 999, 1982) and was prepared by a multi-step synthesis from 5-fluorouridine (AO 199 949, 204 212, 204 213, 204 214). Attention was therefore paid to the method of preparation by direct fluorination, which could find technical application.

The present invention provides a process for preparing 5'-chloro-5'-deoxy-5-fluorouridine by direct fluorination of 5'-chloro-5'-deoxyuridine. The main advantage of this method is that all intermediate synthesis steps are performed with readily available nucleoside derivatives and the conversion to the fluorine derivative is performed in one reaction step at the end of the synthesis.

This minimizes economically demanding fluorine derivative operations. A further advantage of the process is the simple design which can be carried out in a conventional chemical laboratory equipped with an efficient fume hood, without the need for special equipment. The high yield of 5'-chloro-5'-deoxy-5-fluorouridine calculated on the starting 5'-chloro-5'-deoxyuridine, possibly uridine, represents a substantial economic advantage of this process over the known syntheses.

The present invention provides a process for the preparation of 5'-chloro-5'-deoxy-5-fluorouridine by converting 5'-chloro-5'-deoxyuridine, preferably its diacetyl derivative, with fluorine, preferably acetic acid, and further treating the desired 5'-chloro-5'-deoxy-5-fluorouridine with preferably methanolic sodium methoxide. The individual reaction intermediates are isolated. After completion of the fluorination, 6-acetoxy-2 ', 3'-di-O-acetyl-5'-chloro-5'-deoxy-5-fluoro-5,6-dihydrouridine is isolated by shaking between the organic solvent and water and, optionally, following chromatography. Said dihydroderivative is further converted with active methanolic sodium methoxide or with the action of an inorganic base, preferably sodium carbonate, 5'-chloro-5'-deoxy-5-fluorouridine. The fluorination product can be converted by treatment with triethylamine in ethanol, or by heating, optionally by sublimation to 2 ', 3'-diacetyl-5'-chloro-5'-deoxy-5-fluorouridine, followed by conventional removal of acetyl groups to 5'-chloro-5'- deoxy-5-fluorouridine.

In the treatment of any intermediate reaction step to the final 5'-chloro-5'-deoxy-5-fluorouridine, a wide range of inorganic bases, alkali alkoxides, alkali carbonates, alkali hydroxides, basic ion exchangers, ammonia can be used instead of methanolic sodium methoxide. The process of the present invention can generally be used for the electrophilic substitution of fluorine to pyrimidine nucleosides and analogues thereof, particularly uridine, 2'-deoxyuridine, but also fluorinated analogues such as 5-fluorouracil, 5-fluorouridine and the like.

In the following, the invention is illustrated in more detail by way of examples, without being limited thereto.

Example 1

To a solution of 23'-di-O-acetyl-5'-chloro-5'-deoxyuridine (hereinafter diaoethyl-5'-chloruridine, 3.47 g) in acetic acid (200 mL) was added fluorine gas (diluted with nitrogen). until the starting material is completely reacted (about 24 h). The solution was purged with nitrogen (30 min), evaporated in vacuo and 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, 1x with water, evaporated in vacuo and codistilled twice with toluene. The residue is dissolved in 80 ml of 0.15 M methanolic sodium methoxide and left at room temperature for 12 h. The solution was neutralized with an acidic ion exchanger and evaporated in vacuo. 2.3 g (82%) of 5'-chloro-5'-deoxy-5-fluorouridine (hereinafter referred to as 5'-chloro-5-fluorouridine), m.p. Mp 181-182 ° C.

CS 264 901 Bl

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. The solution was evaporated in vacuo and 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. It is then shaken vigorously with 10% sodium carbonate solution until all nucleoside derivative is shaken out of the ethyl acetate solution. The aqueous solution was neutralized with an acidic ion exchanger and evaporated in vacuo. 2.1 g (75%) of 5'-chloro-5-fluorouridine are obtained, m.p. Mp 181-182 ° C.

Example 3

A solution of the diacetyl 1-5'-chlorofuridine (3.47 g) in acetic acid (200 mL) was treated with fluorine until the starting material disappeared (about 24 h). The solution was 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. The ethyl acetate solution was evaporated in vacuo and chromatographed on silica gel with ethyl acetate-toluene 1: 1. The obtained 6-acetoxy-diacetyl-5'-chloro-5'-deoxy-5-fluoro-5,6-dihydrouridine. is dissolved in chloroform and triethylamine is added to the alkaline reaction. After 12 h, the reaction solution was shaken with 2 x 20 mL of water and evaporated in vacuo. The diacetyl-5'-chloro-5-fluorouridine obtained is converted to 5'-chloro-5-fluorouridine (1.74 g, 62%) by a conventional method, e.g. by methanolysis of acetyl groups, m.p. Mp 181-182 ° C.

Example 4

The 6-acetoxy-diacetyl-5'-chloro-5-fluoro-5,6-dihydrouridine prepared according to Example 3 is converted by heating at 140 ° C for 3 h to diacetyl-5'-chloro-5-fluorouridine followed by cleavage of the acetyl groups and 5'-chloro-5-fluorouridine (2.2 g, 78%), m.p. Mp 181-182 ° C.

Claims (1)

Process for the preparation of 5'-chloro-5'-deoxy-5-fluorouridine characterized in that 5'-chloro-5-deoxyuridine, in particular its diacetylderivative, is treated with fluorine in acetic acid, formed by 6-acetoxy-2 ', 3 1'-di-O-acetyl-5'-chloro-5'-deoxy-5-fluoro-5,6-dihydrouridine is isolated and further converted to 5'-chloro-5'-deoxy-5-fluorouridine.