JPS5927341B2 - Purification/separation method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a purification and separation method, and more particularly to a method for purifying and separating 5-fluorouracil with high purity from a mixture containing at least uracil and 5-fluorouracil.

5-Fluorouracil is a substance useful both as an anticancer agent itself and as a synthetic intermediate for other anticancer agents, and due to its nature, high purity is required.

Conventionally, it has been known that 5-fluorouracil is produced by reacting uracil dissolved or suspended in a liquid medium with fluorine or a similar fluorinating agent such as trifluoromethylhypofluorite. The crude product obtained by these reactions contains the desired 5-
In addition to fluorouracil, it usually contains by-products such as unreacted raw material uracil and perfluorinated products of uracil, so it is necessary to apply appropriate purification methods to increase the purity of 5-fluorouracil. .

However, in purifying such crude 5-fluorouracil, it is extremely difficult to separate uracil and 5-fluorouracil, and even the method of crystallizing crude 5-fluorouracil from water, which has been considered a relatively preferable purification method, has been difficult. It was almost impossible to remove uracil mixed in as an impurity. In other words, the reality is that no suitable method for separating uracil and 5-fluorouracil has been found so far. Therefore, in the above reaction, attempts have been made to increase the conversion rate of uracil to minimize the content of unreacted uracil in the crude product, but increasing the conversion rate of uracil reduces fluorination in the early stage of the reaction. As a result, although the amount of unreacted uracil decreases to some extent, the fluorination of 5-fluorouracil progresses even more, and by-products such as the difluoro form of uracil are produced, resulting in an improvement in the purity of 5-fluorouracil. Not only was the original purpose not achieved, but the yield was also reduced, which was an undesirable result.

As described above, it has been desired to develop a method that can remove unreacted uracil from crude 5-fluorouracil and obtain highly pure 5-fluorouracil, and as a result of intensive study, the present inventors found that Surprisingly, by crystallizing and separating a mixture containing uracil and 5-fluorouracil using an aqueous hydrofluoric acid solution as a solvent, uracil can be significantly removed from the mixture, resulting in highly pure 5-fluorouracil.
We have discovered the fact that fluorouracil can be obtained.

Such a fact is completely unexpected from the knowledge of the conventional crystallization separation method using water as a solvent. The present invention was completed based on the discovery of this fact, and its gist is that at least uracil and 5-5-
A method for purifying and separating 5-fluorouracil with high purity from the mixture, comprising dissolving a mixture containing fluorouracil in an aqueous hydrofluoric acid solution and crystallizing and separating 5-fluorouracil from the resulting solution.

According to the method of the present invention, it is possible to remove uracil from a mixture containing uracil and 5-fluorouracil and purify and separate high-purity 5-fluorouracil with ease and high yield, so that the conversion rate of uracil as described above can be achieved. As a result, the reaction time is shortened and the yield is improved due to a reduction in by-products.

Furthermore, in the method of the present invention, decolorization is carried out at the same time, eliminating the need for the decolorization step that was also necessary in the case of conventional crystallization separation using water. It has the advantage of greatly increasing processing power. The method of the present invention can be used in the purification and separation of mixtures containing uracil and 5-fluorouracil, but usually
It is used for the purification and separation of crude 5-fluorouracil produced by the fluorination of uracil.

Furthermore, when applying the fluorination reaction to crude 5-fluorouracil obtained by performing the fluorination reaction in an aqueous hydrofluoric acid solution, highly pure 5-fluorouracil can be obtained by directly crystallizing and separating the reaction solution. It is particularly advantageous because it allows Various methods can be employed to fluorinate uracil for the production of 5-fluorouracil, but generally uracil is fluorinated in a liquid medium (polar solvent such as water, acetic acid, trifluoroacetic acid, perfluoroacetone, etc.). Alternatively, a method may be used in which a similar fluorinating agent such as trifluoromethyl hypofluorite is reacted.

In particular, the method of invention completed by the present applicants (Japanese Patent Publication Publication No. 1983-
3875) is recommended from the viewpoint of industrial production efficiency. Therefore, in the most preferred embodiment of the present invention, uracil dissolved or suspended in a 50 to 85% by weight aqueous hydrofluoric acid solution is added to uracil at a temperature of 15° C. or below and above the freezing point of the hydrofluoric acid aqueous solution. and the resulting reaction mixture is heated to a temperature higher than the above reaction temperature and from room temperature to
An example of a method is to obtain a hydrofluoric acid aqueous solution of crude 5-fluorouracil by heating to about 80°C, and then to cool this solution as it is to crystallize and separate 5-fluorouracil. In the method of the present invention, the solvent used for crystallizing 5-fluorouracil is not particularly limited as long as it is an aqueous hydrofluoric acid solution, but an aqueous hydrofluoric acid solution having a concentration of 30 to 85% by weight is more preferably used.

When the hydrofluoric acid concentration is lower than 30% by weight, it is difficult to achieve sufficient separation of uracil, and when it is higher than 85% by weight, the vapor pressure increases rapidly, making it difficult to handle due to equipment problems. Moreover, crystallization is usually performed by cooling. The cooling temperature can be below the dissolution temperature of the raw material mixture, but it is preferable to use a temperature below room temperature because the recovery rate of 5-fluorouracil improves as the temperature decreases, and temperatures below the freezing point of the solvent used cannot be used. EXAMPLES The present invention will be described in more detail below with reference to Examples and Comparative Examples.

% is weight %. Examples 1 to 7 and Comparative Examples 1 to 2 Under the predetermined conditions shown in Table 1, crude 5-fluorouracil was completely dissolved in an aqueous hydrofluoric acid solution, and the resulting solution was cooled to crystallize 5-fluorouracil. After separation, the mixture was separated and dried to obtain white crystals of purified 5-fluorouracil.

The results are shown in Table 1. For comparison, almost the same operation as above was performed using water as a solvent, and the results are also listed in Table 1.

However, in this case, the obtained crystals were colored. The composition ratios of crude and purified 5-fluorouracil are the results of analysis using a liquid chromatograph (the same applies hereinafter).

Examples 8-9 20 equipped with stirrer, cooler, gas inlet and thermometer
A 10% solution of raw material uracil in a 65% hydrofluoric acid aqueous solution was placed in a 0 ml flask made of Daiflon resin (trifluorochloroethylene resin manufactured by Daikin Industries, Ltd.), and the temperature was maintained at -5°C. While stirring, fluorine gas diluted with nitrogen gas was passed through.

Claims (1)

[Claims] 1. A mixture containing at least uracil and 5-fluorouracil is dissolved in an aqueous hydrofluoric acid solution, and from the resulting solution, 5-fluorouracil is dissolved.
- A method for purifying and separating 5-fluorouracil with high purity from the aforementioned mixture, which comprises crystallizing and separating fluorouracil. 2. The method according to item 1 above, wherein the hydrofluoric acid aqueous solution has a concentration of 30 to 85% by weight. 3. The method according to item 1 above, wherein 5-fluorouracil is crystallized by cooling the obtained solution. 4. The method according to item 3, wherein the temperature is below room temperature and above the freezing point of the hydrofluoric acid aqueous solution. 5. The method according to item 1 above, wherein the mixture containing at least uracil and 5-fluorouracil is a reaction mixture obtained by reacting uracil with fluorine or trifluoromethylhypofluorite in a liquid medium, with the liquid medium removed. . 6. The reaction solution obtained by reacting uracil with fluorine in a 50 to 85% by weight aqueous hydrofluoric acid solution at a temperature below 15°C and above the freezing point of the aqueous hydrofluoric acid solution is heated once above the reaction temperature and from room temperature to room temperature. A method for purifying and separating 5-fluorouracil with high purity from the reaction solution, which comprises heating the reaction solution to 80° C., cooling the obtained reaction solution as it is, and crystallizing and separating 5-fluorouracil.