JPH035388B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention obtains industrially high-grade 5-fluorouracil (5-FU) in high yield through direct fluorination reaction of uracil and fluorine gas, and also improves and simplifies the synthesis process. This paper relates to a method for converting uracil into a fluoride for various purposes. 5-Fluorouracil is used in large quantities as a chemotherapeutic drug for cancer treatment or as a raw material for the synthesis of antitumor substances derived from it, and a production method that is industrially economical and yields high is desired. . A known example of fluorinating uracil is to react uracil or a similar pyrimidine-based raw material with a mixed gas consisting of fluorine and an inert gas in a liquid medium that does not react with fluorine, and then to fluorinate the liquid medium from the reaction mixture. Many methods have been proposed to remove it. However, industrially, all of them still have problems with quality, yield, complicated processes, economic efficiency, etc.
It's not satisfying. The reason why these problems are not solved is that, for example, when fluorinating uracil in water, when trying to increase the reaction rate between uracil and fluorine gas, which has an extremely strong oxidizing power, for example, 5,5-difluoro- Decomposition products of uracil, which are perfluorinated side reaction products such as 6-hydroxy-6-hydrouracil, are likely to occur, and conversely, if the reaction is suppressed, unreacted uracil remains, so the most preferable reaction medium, inert gas, and temperature conditions are , the combination of _F2 gas concentrations has not always been found, and the intermediate 5-fluorohydrin (5-fluoro-6
The main reason for this is that side reactions occur due to complicated treatments during the dehydration conversion and isolation of -hydroxy-5,6-dihydrouracil) or its hydrated salt to 5-fluorouracil, which reduces the quality and yield. Overall, the present inventors believe that in order to solve the problem, a liquid that is less likely to cause a heterogeneous reaction in the fluorination reaction and in which the solubility of the fluorinated intermediate is low is used as the reaction medium. From experimental considerations, we have found that the most effective method is to separate the fluorinated intermediate as soon as possible after completion. Furthermore, we were able to find favorable conditions for the fluorination reaction temperature, inert gas, _F2 gas concentration, and conditions for stable conversion of the fluorinated intermediate to 5-fluorouracil, which are factors that indirectly contribute in this case. . By the method of the present invention, an amazingly high purity of 99.0% or more was obtained even with unpurified crude 5-fluorouracil. Water is the preferred reaction medium for uracil as a raw material from an economic standpoint, but the solubility of the raw material is low (0.36 g/100 ml, 20°C), yields are poor under mild reaction conditions, and high temperatures and high temperatures are required. There is a risk of explosion under the severe conditions of raw material concentration gas and high raw material concentration slurry. In order to avoid this, it has been proposed to use a medium such as trifluoroacetic acid or highly concentrated hydrofluoric acid (Japanese Patent Application Laid-open No. 51-149287, Japanese Patent Publication No. 54-3875), which have a high solubility of uracil. etc. are hydrosilicic acid aqueous solutions (H ₂ SIF ₆ aqueous solutions) that are widely used industrially, in large quantities, at low cost, and are easy to handle.
Even though the solubility of uracil is extremely low, if uracil is used as a medium, for example, a slurry with a uracil concentration of 30 wt%, an F ₂ /inert gas = 2/1 vol ratio, and a reaction temperature of 70°C can cause a heterogeneous reaction even under severe conditions. We have discovered a fact that creates an ideal situation that is completely different from conventional methods, in which no liquid phase or gas phase explosions occur. Although this fact does not wish to be bound by theoretical considerations, in an aqueous solution of hydrofluoric acid, the solubility of uracil is extremely low, so the liquid viscosity does not increase as in the case of water or hydrofluoric acid, and it becomes a gas-liquid. This is thought to be due to the fact that it does not inhibit contact and makes the reaction extremely gentle, and at the same time is itself extremely stable against fluorine gas over a wide concentration range. Generally, in direct fluorination, the stability of the system varies greatly depending on the type of medium, but it is surprising that uracil is extremely effective in an aqueous medium such as an aqueous solution of hydrosilicic acid, despite its poor solubility. . Table 1 shows the solubility of raw material uracil and intermediate 5-fluorohydrin hydrate in various aqueous media.

[Table] It is well known that fluorine forms stable complex ions with various elements in water. In addition to H ⁺ ₂ SiF ^-- ₆ , fluorine-containing complex ionic acids include H ⁺ BF ^- ₄ , H ⁺ ₂
TiF _--6 , H ⁺ ₂ ZrF ^-- ₆ , H ⁺ PF ^- ₆ , etc. are also available industrially at 40 to 70
It is used synthetically in a concentration range of less than % by weight. Even if uracil is directly fluorinated using these acids as a medium, unlike the case where glacial acetic acid is used as a medium, the reaction does not take place directly, and complex ions do not bind to uracil molecules in either case. As shown in Table 1, H ₂ SiF ₆ aqueous solution has the lowest solubility and is stable against organic substances, and unlike H ₂ ZrF ₆ and H ₂ TiF ₆ , ZrF ₄ and
Since non-volatile components such as TiF ₄ do not remain,
Among the fluorine-containing complex ionic acids, only the H ₂ SiF ₆ aqueous solution can be said to be practical. The selection of such an aqueous hydrosilicic acid solution cannot be expected at all from the known conditions of direct fluorination. When fluorinating uracil using an aqueous solution of hydrosilicic acid as a medium, local ignition may occur if the concentration of hydrosilicic acid is extremely low.
If the concentration exceeds 40%, it is completely stable even if other conditions are severe, while if the concentration exceeds 40%, the vapor pressure of silicon tetrafluoride (SiF ₄ ), which is a partial pressure component of the liquid, becomes high.
The reaction efficiency of fluorine is also poor, and the liquid composition of the medium is likely to change, which is disadvantageous, and the concentration range is limited to 10 to 40%, but a range of 15 to 25% is particularly convenient. If the reaction temperature is higher than 70°C, the production of difluoro compounds increases even in the hydrosilicic acid aqueous solution, impairing the quality of the product. On the other hand, if the temperature is lower than 40°C, the crystal grain size of the intermediate 5-fluorohydrin hydrate after the reaction is extremely small and solid-liquid separation is difficult, and many impurities remain. Therefore, the practically preferred fluorination temperature is limited to a range of 40 to 70°C. The fact that the fluorination temperature is within this range means that there is no need to cool it down to a low temperature range that requires a refrigerator, unlike in industrially known methods, and in this respect it is extremely economical. In addition, the problem of crystal grain size in particular greatly influences economic efficiency and the quality of 5-fluorouracil. When the reaction is completed at a relatively high temperature of 40 to 70°C, the crystal grain size of the intermediate 5-fluorohydrin hydrate is large and solid-liquid separation is easy, and the amount of mother liquor accompanying the solid is small. Even without washing with water, the product does not decompose during the subsequent conversion to 5-fluorouracil. Washing with water during solid-liquid separation is a factor that greatly reduces product yield. Phenomenologically, crystals with larger grain sizes have higher quality. Regarding the concentration of uracil in the medium, as mentioned above, in the case of an aqueous solution of hydrosilicic acid, a heterogeneous reaction does not occur even if the slurry concentration is high, so it can be made as high as possible in terms of equipment, and it can be added intermittently during the reaction. However, in order to maintain economic efficiency and good gas-liquid contact,
A range of 10 to 30% by weight is practical. It is a well-known fact that fluorine is diluted with an inert gas in order to directly control fluorination, but nitrogen is often used industrially because it is inexpensive. However, the inventors have discovered that hydrogen fluoride gas (HF) can also be used equally as nitrogen gas for the direct fluorination of uracil. Originally, HF is a by-product in the system during fluorination and has no negative effect on the reaction, but HF in the inert gas dissolves in the medium, When the HF concentration in the liquid increases, the solubility of the intermediate 5-fluorohydrin hydrate increases, resulting in a decrease in yield during solid-liquid separation. On the other hand, fluorine gas is used industrially by directly introducing the generated gas into the fluorination system through HF molten salt electrolysis.
30vol% of HF is entrained in the molten salt depending on its vapor pressure, and is usually removed using a cold trap, sodium fluoride trap, etc. However, as mentioned above, withdrawal from HF
Since there is no need for this, it can be used as is, and is economically advantageous. Based on these facts, in a system using an aqueous solution of hydrosilicic acid as a reaction medium, the HF concentration in nitrogen is 5 to 20 mol%, F ₂ /inert gas = 1/2 to
Limited to a range of 5 mol ratios. Furthermore, as shown in Table 1, the solubility of the intermediate 5-fluorohydrin hydrate in an aqueous solution of hydrosilicic acid decreases with the acid concentration, greatly increasing the recovery rate of solid-liquid separation. Since organic substances such as pyrimidine compounds are subject to decomposition if kept at high temperatures and in the presence of acids for long periods of time, it is most desirable to efficiently shorten the fluorination time and quickly perform solid-liquid separation. In other words, 5-fluorinated 5-fluorohydrin hydrate in the medium
It can be said that avoiding the heat dehydration treatment of fluorouracil and the subsequent heat distillation treatment of a large amount of medium will lead to good results. The figure shows differential thermal analysis data of the intermediate 5-fluorohydrin hydrate. In the drawings, T means a temperature curve, DTA means a differential thermal analysis curve, and TG means a thermogravimetric curve. From this figure, it can be seen that the dehydration temperature changes as follows. After the fluorination reaction, the crystals separated using a method such as a centrifugal separator or pressure filter are placed in a general dryer such as a shelf-type static dryer and dried in the air for 170 min.
5-Fluorouracil can be easily obtained by heat treatment at ~190°C. In this case, there are no particular restrictions on the type of equipment and no special gas atmosphere is required, but as a general precaution, it is best to use a solid-liquid separator with a small amount of residual mother liquor and a uniform heat distribution for drying. Of course. Even crude 5-fluorouracil can be analyzed by high-performance liquid chromatography if the treatment temperature is limited to 180±5°C and heat-treated for a specified period of time.
Purities of 99.0% to 99.8% are easily obtained. Even if hydrosilicic acid remains attached to the crystals,
It will not evaporate and remain in the product as volatile components such as SiF ₄ , HF, H ₂ O, etc., and will not have any adverse effect on the quality of 5-fluorouracil. Even in a system using an aqueous solution of hydrosilicic acid as a medium, an amount of the intermediate corresponding to the solubility remains in the mother liquor after separation of the intermediate 5-fluorohydrin hydrate, reducing the yield. By adding silicon oxide corresponding to the absorbed HF, it can be easily regenerated as an aqueous solution of hydrosilicic acid and recycled to the reaction medium, and as shown in Example 7 below, the yield of 5-fluorouracil in a single cycle can be improved. It can be greatly improved. 6HF+SiO ₂ →H ₂ SiF ₆ +2H ₂ O Examples and comparative examples are shown to specifically explain the method of the present invention. Example 1 A slurry liquid in which 1.5 kg of uracil was dispersed in 5 kg of an aqueous solution of hydrosilicic acid with a concentration of 20% by weight was continuously and vigorously stirred until the HF concentration in nitrogen was 7 mol%.
Inert mixed gas and fluorine gas F ₂ /N ₂ = 1/
The reaction medium is diluted to a 3 mol ratio and allowed to pass through, and the reaction medium is externally cooled with water to maintain the temperature of the reaction medium in the range of 45±5° C. until no absorption of 255 mμ of uracil is observed in the ultraviolet absorption spectrum. Thereafter, the reaction mixture was slowly cooled to -8°C and thoroughly separated into solid and liquid using a centrifugal dehydrator. About 2.74 kg of the obtained undried product was spread on a Teflon dish and placed in a tray-type static plate set at 180±5°C. The mixture was placed in a dryer and thermally decomposed for 12 hours to obtain 1.24 kg of crude product. This crude 5-fluorouracil has a melting point of 281-283
℃, infrared absorption analysis also agreed with literature values. Ultraviolet absorption analysis was also consistent. High performance liquid chromatography analysis showed 99.3% of 5-fluorouracil and 0.28% of impurity difluoro compound. The yield from uracil was 70.7%. Examples 2 to 6 and Comparative Examples 1 to 3 Table 2 shows the results of experiments conducted under different reaction conditions using the same scale, equipment, and operation as in Example 1. A comparative example shows a case where water was used as the medium. Both intermediate 5
- The thermal decomposition treatment of fluorohydrin hydrate was carried out under the same conditions as in Example 1. Example 7 The mother liquor obtained by solid-liquid separation using a centrifugal dehydrator in Example 3 had a composition of 18.2% H ₂ SiF ₆ and 7.4% HF, and about 4.5 kg was recovered. This mother liquor is transferred to a polyethylene beaker equipped with a stirrer, and 167 g of silicon dioxide powder (SiO ₂ ) is gradually added thereto, causing reaction and dissolution with a slight heat generation. After this, stirring was continued for about 2 hours, and 1580 g of purified water was added to make ₆ 20% H ₂ SiF liquids. A slurry liquid in which 1.5 kg of uracil was dispersed in 5 kg of the slurry was treated in the same manner as in Example 3 to obtain 1.58 kg of 5-fluorouracil with a purity of 99.2% and a difluoro impurity of 0.30% (HPLC analysis). yield
90.5% (crude product equivalent).

【table】 [Brief explanation of the drawing]

The drawing shows differential thermal analysis data of 5-fluorohydrin hydrate, an intermediate produced in a liquid medium during the fluorination reaction.

Claims (1)

[Claims] 1. Uracil is reacted with fluorine gas at a temperature of 40 to 70°C in a medium consisting of an aqueous solution of hydrosilicic acid with a concentration of 10 to 40% by weight, and the resulting precipitated product is solid-liquid separated. and the separated solid product from 170 to 190
1. A method for producing 5-fluorouracil, which comprises producing 5-fluorouracil by thermal decomposition treatment in air at .degree. 2. The method for producing 5-fluorouracil according to claim 1, which uses a slurry liquid in which the concentration of uracil in the medium is 10 to 30% by weight. 3 Fluorine gas is mixed with hydrogen fluoride concentration in nitrogen of 5
~20 mol of inert gas mixture, F ₂ /inert gas =
The method for producing 5-fluorouracil according to claim 1, wherein the 5-fluorouracil is used after being diluted to a 1/2 to 5 mol ratio. 4. Silicon oxide is dissolved in the mother liquor obtained by solid-liquid separation of the precipitated product after fluorination and regenerated as an aqueous solution of hydrofluoric acid with a concentration of 10 to 40% by weight, which is recycled as a reaction medium. A method for producing 5-fluorouracil according to item 1.