JPH0425265B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-fluorouracil useful as an anticancer drug or an intermediate for its synthesis, and in particular to an improvement in the method for producing 5-fluorouracil by fluorinating uracil with fluorine gas. It is related to.

Various improvements have already been proposed for the method of producing 5-fluorouracil by fluorinating uracil with fluorine gas, but none of them can be said to be fully satisfactory industrially.

For example, uracil can be mixed with acetic acid, hydrogen fluoride anhydride,
A method of obtaining 5-fluorouracil by dissolving it in sulfuric acid etc. and reacting with fluorine gas (Japanese Patent Application Laid-Open No. 1983-25476)
The yield is extremely low. In addition, a method of introducing fluorine gas into an aqueous solution of uracil and reacting it (Tokuko Showa)
54-32790) has poor industrial practicality due to the low concentration of uracil in the reaction medium, and the yield is also unsatisfactory. A method of fluorinating uracil in trifluoroacetic acid or a highly concentrated fluoric acid aqueous solution using fluorine gas (JP-A-14287-14287,
-3875) uses expensive trifluoroacetic acid and hydrofluoric acid, requires refrigeration equipment to keep the reaction temperature low, and has disadvantages such as low purity of the obtained 5-fluorouracil. However, it lacks industrial practicality.

As a result of extensive research to eliminate these drawbacks of conventional methods, the present inventors have discovered an excellent industrial and practical method for obtaining 5-fluorouracil with extremely high yield and high purity. . That is, uracil is dispersed in a relatively dilute aqueous solution of fluoric acid and reacted directly with fluorine gas diluted with an inert gas such as nitrogen gas to form 5-fluoro-6-hydroxy-5,6-dihydrouracil hydrate. (below
After cooling the reaction solution and separating the crystallized FUOH ₂・H ₂ O, the resulting solution _is recycled for the _next fluorination reaction as a reaction solution (hereinafter referred to as reaction solution). ), FUOH ₂ H ₂ O can be obtained in extremely high yield;
By keeping the reaction temperature at a relatively high and limited value, extremely high purity FUOH ₂ .
H ₂ O is obtained and no by-product impurities remain in the reaction solution, so the reaction solution can be recycled for a long period of time, and uracil and fluorine gas are The present invention was completed by cleverly utilizing the hydrogen fluoride produced during the reaction in the presence of the hydrogen fluoride.

According to the conventional method (Japanese Patent Publication No. 54-3875) that uses a hydrofluoric acid aqueous solution as a reaction solution, when uracil is fluorinated in a hydrofluoric acid aqueous solution with fluorine gas,
If the hydrofluoric acid concentration is less than 50% by weight, the process efficiency will decrease, the proportion of unreacted uracil remaining, and the generation of by-products will be large, and at temperatures above 15°C, the yield will decrease and more by-products will be generated. However, it is said that a hydrofluoric acid concentration of 50 to 85% by weight and a reaction temperature of 15°C or less are essential. However, the present inventors set the reaction temperature to a relatively high temperature of 40 to 60 degrees Celsius, set the hydrofluoric acid concentration to a relatively high concentration of 20 to 40% by weight, and combined these with the circulating use of the reaction solution. It was discovered that 5-fluorouracil of extremely high purity can be obtained in good yield. In all conventional methods, 5-fluorouracil is obtained by distilling off the reaction solution, which always involves loss of solvent and energy for distillation, whereas in the method of the present invention, the reaction solution is simply distilled off to obtain 5-fluorouracil. After cooling and separating the crystallized FUOH ₂ H ₂ O, the filtrate is recycled for the reaction again, which eliminates the need for additional solvents other than water and improves the reaction rate during recycling. The concentration of hydrofluoric acid in the solution was determined by the crystallization
Hydrogen fluoride is carried out of the system together with attached water after FUOH ₂ H ₂ O is filtered, hydrogen fluoride is carried away by inert gas such as nitrogen gas that dilutes fluorine gas during the reaction, and uracil and fluorine gas are carried away. It has been found that the hydrogen fluoride produced during the reaction in the presence of water can be balanced at a certain concentration by adjusting the amount of uracil.

Based on these findings, the present inventors have introduced a new technical idea of recycling the reaction solution, which is not easily thought of in the common knowledge of organic chemical reactions where side reactions are likely to occur. Although this was considered impossible due to poor yield and purity, we have established a method that is extremely economical and has high practical value.

The present invention involves reacting uracil dispersed in a 20-40% by weight aqueous fluoric acid solution with fluorine gas diluted with an inert gas such as nitrogen gas at a temperature of 40-60°C.
The resulting reaction solution was cooled, and the resulting crystals of 5-fluoro-6-hydroxy-5,6-dihydrouracil hydrate were filtered off and dried at 80 to 100°C.
It is characterized in that 5-fluorouracil is produced by heating to 170 to 200°C to remove H ₂ O, and the filtrate is recycled to the above-mentioned reaction of uracil and fluorine gas.

The reason why a 20 to 40% by weight aqueous hydrofluoric acid solution is used in the method of the present invention is that uracil is added at 5 parts per 100 parts of the solution.
When carrying out a fluorination reaction at such a ratio, the concentration of hydrofluoric acid in the reaction solution to be recycled is automatically adjusted to a range of 20 to 40% by weight depending on the balance of hydrogen fluoride. Experience has shown that it stays within. This is different
The amount of reaction solution contained in FUOH ₂ H ₂ O, the amount of hydrogen fluoride contained in the fluorine gas used for the reaction,
It is difficult to clarify by theoretical calculations because it changes slightly depending on the amount of inert gas such as nitrogen gas that dilutes fluorine gas, but for example,
By using 15 parts of uracil per 100 parts and diluting the fluorine gas with an inert gas such as nitrogen gas, the concentration can be maintained at approximately 30% by weight. Of course, there is no argument that each time it is reused, it is necessary to add water that is insufficient to correspond to the reaction solution of FUOH ₂ .H ₂ O removed after filtration.

A suitable amount of uracil is 5 to 20 parts per 100 parts of the reaction solution. If more than 20 parts are used, foaming and ignition phenomena tend to occur during the fluorination reaction, making it difficult to control the reaction. If it is less than 5 parts, the efficiency is poor and economical, and the most preferable range is 10 to 15 parts. In this case, the hydrofluoric acid concentration of the reaction solution is automatically maintained within the range of 25-35% by weight.

The reaction temperature is preferably 40 to 60°C, particularly preferably 45 to 50°C. At this temperature, 5-fluorouracil with a purity of 99% or more can be obtained after passing through the thermal decomposition step described below, but at a temperature lower than 40° C., the purity decreases and a purification step such as recrystallization is required, which is not preferable.

Furthermore, when the reaction solution is recycled, there is an adverse effect of accumulation of impurities. A decrease in yield and purity is observed even at temperatures exceeding 60°C.

In addition, even when the reaction solution is used repeatedly, there is no question that it is necessary to carry out fluorination under these various conditions.

According to the method of the present invention, the by-products produced during the reaction are probably only substances that are highly volatile and insoluble in the fluoric acid aqueous solution, and are caused by the inert gas such as nitrogen gas used to dilute the fluorine gas during the reaction. Almost no by-products were observed to accumulate in the reaction solution, and the purity of the 5-fluorouracil produced was maintained extremely well even after repeated use several dozen times.

By cooling the reaction solution that has completed the fluorination reaction, FUOH ₂ ·H ₂ O is crystallized. Since the solution is recirculated, the cooling temperature is not particularly important, but it goes without saying that the lower the temperature, the better. The practical range is -10 to 0°C. Crystallized and separated FUOH ₂・
H ₂ O is dried at 80-100°C and then thermally decomposed at 170-200°C to produce 5-fluorouracil.

As described above, although the present invention is in an area that was previously thought to be impossible industrially, it skillfully selects and combines the concentration and reaction temperature of the reaction solution, and furthermore, it By introducing a new technical idea of cyclical use, we have provided a highly economical and practical method that can obtain high-yield, highly-purified 5-fluorouracil, which was not possible with conventional methods. be. The advantages of the present invention are summarized as follows.

Very high purity 5-fluorouracil is obtained.

A high yield can be achieved by recycling the reaction solution.

There is no loss of energy or solvent due to distillation of the reaction solution.

Since hydrogen fluoride, a by-product of the reaction, is used in the reaction solution, nothing other than water is necessary.

The amount of uracil used in the reaction solution is large and the efficiency is high.

The present invention will be specifically described below with reference to Examples.

Example 1 1.3 kg of uracil was dispersed in a 25% by weight aqueous hydrofluoric acid solution (prepared from the filtrate after cycling the reaction solution 5 times), and the temperature of the solution was raised to 45°C while stirring vigorously. 0.7 kg of fluorine gas diluted with nitrogen gas (F ₂ /N ₂ = 1/3 mol) was passed through the tube while maintaining the temperature. After the reaction was completed, the resulting solution was cooled to -5°C, the crystallized FUOH ₂ H ₂ O was filtered, dried at 90°C, and thermally decomposed at 180°C to give 1.33 kg (yield 88%) of 5
-Fluorouracil was obtained.

Liquid chromatography confirmed that the purity was 99.8%, and infrared absorption spectrum analysis confirmed that it was the same as the standard 5-fluorouracil.

Example 2 1.7 kg of uracil was dispersed in a 35% by weight aqueous hydrofluoric acid solution (prepared from the filtrate after cycling the reaction solution 20 times), and the solution temperature was raised to 50°C while stirring vigorously. 0.9 kg of fluorine gas diluted with nitrogen gas (F ₂ /N ₂ = 1/3 mol) was passed through the tube while maintaining the temperature. After the reaction, the obtained solution was processed in the same manner as in Example 1 to obtain 1.70Kg (yield: 86%), purity: 99.0%.
5-fluorouracil was obtained.

Comparative Example A reaction was carried out under exactly the same conditions as in Example 1, except that a freshly prepared 25% by weight aqueous hydrofluoric acid solution was used, and 0.85 kg (yield 57%) of 5-fluorouracil with a purity of 99.4% was obtained.

In Example 1 and Comparative Example, reactions were carried out under exactly the same conditions, except for whether or not the reaction solution was recycled. In Example 1,
The yield is good because the reaction solution is recycled, whereas in the comparative example, the yield is low because the reaction solution is not recycled and a new reaction solution is used. This also shows that circulating use of the reaction solution is an essential condition of the present invention.

Claims (1)

[Claims] 1. Uracil dispersed in a 20-40% by weight aqueous fluoric acid solution is reacted with fluorine gas diluted with an inert gas such as nitrogen gas at a temperature of 40-60°C, and the resulting reaction solution is cooled, The generated 5-fluoro-6-
After filtering the crystals of hydroxy-5,6-dihydrouracil hydrate and drying them at 80-100℃,
5- by heating to ℃ to remove _H2O .
A method for producing 5-fluorouracil, which comprises producing fluorouracil and recycling the filtrate in the above reaction between uracil and fluorine gas.