JPS6324992B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 5-fluorouracil, and more specifically, the present invention relates to a method for producing 5-fluorouracil, and more specifically, the present invention relates to a method for producing 5-fluorouracil, and more specifically, a method for producing 5-fluorouracil in a smooth and advantageous manner by a combination of a fluorination reaction in a solvent using orotic acid as a raw material, and pressure heating of a specific intermediate in water. The present invention relates to a novel method for producing oluracil. It has been known that 5-fluorouracil is useful as an antitumor agent or as a raw material for preparing other antitumor agents, and various methods for its synthesis have been proposed. For example, a synthetic method using fluoroacetic ester as a raw material (U.S. Patent No.
2802005, Japanese Patent Publication No. 36-9578, etc.), this method uses raw materials with extremely high toxicity, requires many synthesis steps, and has a low yield of the target product. There are some difficulties in industrial implementation. Furthermore, a method has been proposed in which 5-fluorouracil is produced by a fluorination reaction using uracil as a raw material and a fluorinating agent such as fluorine gas or hypofluorite. For example, see Japanese Patent Publication No. 50-25476, Japanese Patent Application Laid-Open No. 47-9127, Japanese Patent Application Laid-open No. 149287-1987, etc. Furthermore, there are also methods such as a method of reacting a cytosine compound with FOSO ₂ F as in JP-A-52-108990, or a method of fluorination and acid hydrolysis of a specific intermediate as in JP-A-53-18586. Proposed. Previously, the present inventors have discovered that 5-fluorouracil can be produced smoothly and advantageously by combining a fluorination reaction and a decarboxylation reaction using orotic acid as a raw material. Also, in such a method,
It has also been found that formic acid or water-containing formic acid is effective as a reaction medium for orotic acid and a fluorinating agent.
See Japanese Patent Application No. 52-70981, Japanese Patent Application No. 52-144009, Japanese Patent Application No. 52-156677, etc.
In these methods, 5-fluoroorotic acid is obtained by a fluorination reaction, and then the 5-fluoroorotic acid is decarboxylated and converted to 5-fluorouracil. In addition, in the fluorination reaction of orotic acid, the formula

[Formula] (However, X in the formula represents a nucleophilic group derived from the solvent) is produced. However, in the above method, the adduct is heated to produce 5-fluoroorotine. The idea was to convert it into an acid and further decarboxylate it. The present inventor has conducted various studies and studies on the method for producing 5-fluorouracil as described above, which includes a step of subjecting orotic acid to a fluorination reaction in a solvent. We have come to the interesting finding that 5-fluorouracil can be produced very smoothly and advantageously by directly pressurizing and heating such an intermediate in water without converting it into 5-fluoroorotic acid. That is, for example, it is possible to produce the intermediate as described above by fluorination reaction of orotic acid in a solvent, and extract the intermediate by distilling off the solvent and adding water, and the intermediate thus obtained. Aqueous solution 120~250
When heating to
cm ² ) while removing carbon dioxide gas. As a result, the intermediate is decarboxylated and converted to 5-fluorouracil. Furthermore, since the intermediate has a much higher solubility in water than the raw material orotic acid, it is very easy to separate the two. Thus, the present invention was completed based on the above findings, and involves reacting orotic acid with a fluorinating agent in a solvent to obtain the formula

[Formula] (However, X in the formula is a nucleophilic group originating from the solvent or
5-fluorouracil is produced by heating the intermediate under pressure in water without separating it as 5-fluoroorotic acid. This provides a new method for producing oluracil. According to the method of the present invention, it can be carried out at a relatively lower temperature than when converting to 5-fluoroorotic acid and then converting it to 5-fluorouracil by thermal decarboxylation. For example, heating decarboxylation of 5-fluoroorotic acid in a vacuum or _N2 stream requires a temperature of 230°C or higher, and in sulfolane, triethylene glycol dimethyl ether, etc., a temperature of 200°C or higher is required. A temperature below 180℃ is sufficient.
Furthermore, advantages are recognized in terms of operation, and 5-fluorouracil can be obtained in good yield. Furthermore, post-treatment is easier than when 5-fluoroorotic acid is heated and decarboxylated in a high-boiling organic solvent. Furthermore, the method of the present invention has advantages such as easy separation and recovery of unreacted orotic acid, and raw material orotic acid is inexpensive and easily available. It can be said that In the present invention, the raw material orotic acid is
Although it can be employed in various forms, a monohydrate is usually preferably employed in consideration of availability and other factors. Of course, a form of orotic acid that is not a hydrate may also be employed. Such orotic acid is first reacted with a fluorinating agent. As a fluorinating agent,
Fluorine gas is usually used, but other hypofluorites (CF ₃ OF), xenon fluoride (XeF ₂ )
etc. may also be adopted. Therefore, when using fluorine gas, it is desirable to dilute it with an inert gas in order to avoid rapid progress of the reaction. For example, about 0.3 to 50 times the amount of fluorine gas, preferably 0.5
Good results can be obtained by diluting with ~10 times the amount of nitrogen gas. The reaction of orotic acid and fluorinating agent is carried out in a solvent. That is, it is desirable to use a liquid solvent that is inert to the fluorinating agent such as fluorine gas under the fluorination reaction conditions of the present invention. for example,
Trifluoroacetic acid, water, hydrofluoric acid, sulfuric acid, formic acid, acetic acid, perfluoroalcohols, etc. can be used alone or in mixtures as liquid solvents, but polar solvents are preferably used. Therefore, in order to achieve smooth progress of the reaction, it is desirable to disperse orotic acid as uniformly as possible in a liquid solvent. It is desirable to force them. The operation and conditions for the reaction using the fluorinating agent are preferably selected depending on the type of fluorinating agent and other factors. For example, when using fluorine gas, it is preferable to dilute it with an inert gas as described above, and the reaction temperature varies depending on the solvent used, but it is -50°C to +100°C, especially -10°C to +70°C. It is preferable to adopt a certain degree and moderately suppress the introduction rate of fluorine gas. Fluorine gas is applied at a rate of about 0.5 to 5,000 ml/min per mole of raw material orotic acid.
Preferably, the solution is diluted with 5 times the amount of inert gas before introduction. In addition, by using hypofluorite as a fluorinating agent, the reaction temperature can be increased from -80℃ to +
It is also possible to lower the temperature to around 30°C. In the fluorination process of the present invention, orotic acid reacts with fluorine gas in a solvent, and in most cases the formula (X in the formula is OH or CF ₃ COO, CH ₃ COO,
It is observed from the infrared absorption spectrum and NMR spectrum that an intermediate product (adduct) represented by F (indicating a nucleophilic group resulting from the solvent) is formed. This adduct is highly soluble in water, alcohol, and other solvents, and therefore, after removing the fluorination reaction solvent, it is easy to dissolve the adduct by adding, for example, water to the resulting solid reaction mixture. It is possible to separate it from unreacted orotic acid.
The adduct is relatively stable at room temperature, but by heating the adduct to 90°C or higher in a suitable solvent, for example water, or heating the solid to about 100 to 160°C in air, it can be converted to the following formula: It quickly becomes 5-fluoroorotic acid. In the present invention, it is important to fluorinate orotic acid in a solvent as described above to produce a specific intermediate, and then convert the intermediate to 5-fluorouracil by heating under pressure in water. Therefore, separation of 5-fluoroorotic acid from the intermediate is not performed. As a solvent for the fluorination reaction, various solvents can be used as described above, but it is usually preferable to use a water-containing solvent, and specifically, formic acid and trifluoroacetic acid are preferable. It is. Therefore, 0.5 to 1000 parts of water per 100 parts by weight of solvent.
Parts by weight, preferably 1 to 100 parts by weight, may be employed. In particular, it is preferable to use 50 parts by weight or less of water per 100 parts by weight of the solvent. In addition, in the fluorination reaction, the dilution ratio of orotic acid with the solvent (total amount of water and solvent when water is included) is usually 1 to 1 mol of solvent per 1 mole of orotic acid.
About 1000 mol, preferably about 10 to 100 mol is employed. said intermediate

In the formula, X is a nucleophilic group or an OH group derived from the solvent. In many cases, water is contained in the raw material or solvent, and in a preferred embodiment of the present invention, a water-containing solvent is employed, so the main component of the intermediate is one in which X is an OH group. In addition, when formic acid, acetic acid, trifluoroacetic acid, hydrofluoric acid, sulfuric acid, etc. are used as solvents,

【formula】

【formula】

[Formula] -F, -HSO ₄ and other intermediates are also produced. In the present invention, the fluorination reaction is carried out as described above.
A specific intermediate can be produced by carrying out the reaction at a temperature of 100°C or lower, particularly at about -15°C to +40°C. Of course, a small amount of 5-fluoroorotic acid may be produced as a by-product together with a specific intermediate. Accordingly, in the present invention, such an intermediate is directly converted to 5-fluorouracil by heating under pressure in water without separating it as 5-fluoroorotic acid. When the intermediate is heated under pressure in water, carbon dioxide gas is produced as a by-product due to decarboxylation, and the pressure in the system increases. There are no particular limitations on the conditions for pressure heating, but if the temperature is too low, the reaction rate will be low, and if the temperature is too high, a decomposition reaction will occur and the yield of 5-fluorouracil will decrease. Heating is carried out at a temperature of about 140 to 180 degrees Celsius, preferably about 140 to 180 degrees Celsius, while removing by-product carbon dioxide so that the pressure in the system is about 2 to 17 Kg/cm ² , preferably about 3 to 9 Kg/cm ² . It is desirable to do so. Since the intermediate is highly soluble in water,
Usually, 1 part by weight or more of water per 1 part by weight of the intermediate,
It is preferable to use about 2 to 8 parts by weight. Using too much water will be disadvantageous in terms of heating economy, and if too little water is used, for example, if the saturated solubility of the intermediate is significantly increased, it may be difficult to achieve uniform pressure heating. becomes disadvantageous. Under such conditions, for 0.1 to 10 hours, preferably 0.5
Pressure heating for about 4 hours is sufficient. In the present invention, after the fluorination reaction in the solvent, the intermediate can be easily extracted by adding water to the reaction mixture obtained by distilling off the solvent, and it can be smoothly and advantageously separated from unreacted orotic acid. be able to.
Of course, the unreacted orotic acid separated in this way can be recovered and reused. Then,
The intermediate extracted into water is subjected to the pressure heating described above in the form of its aqueous solution. For example, the intermediate aqueous solution is placed in a pressure-resistant container made of stainless steel, Hastelloy, etc., and heated to 140 to 180°C. For example, 150℃
In the case of decarboxylation, it is preferable to extract the generated carbon dioxide gas at a gauge pressure of 5 kg/cm ² or more. When the generation of carbon dioxide gas is almost no longer observed, it means that the decarboxylation reaction has ended; however, in order to obtain an appropriate amount of water, heating may be continued to evaporate the water. After the reaction is completed, crude 5-fluorouracil is obtained as crystals by cooling the container. The crude 5-fluorouracil thus obtained is
Although it has a fairly high purity and little coloring,
It can be made into a pure product by recrystallizing it from a solvent such as water or alcohol, and it is also possible to further increase the purity and make it into white crystals by decolorizing and purifying it with activated carbon, ion exchange resin, γ-alumina, etc. be. Next, embodiments of the present invention will be described in more detail, but it goes without saying that the present invention is not limited by such explanations. Example 1 A reactor made of SUS-316L with an internal volume of 1 was charged with 40 g of orotic acid monohydrate (C ₅ H ₄ N ₂ O ₄ H ₂ O) and 400 g of a formic acid aqueous solution with a formic acid concentration of 88% by weight. A mixed gas of fluorine gas (28 ml/min) and nitrogen gas (112 ml/min) was blown into the mixture while stirring, and the reaction was carried out at a temperature of 10°C. After 6 hours of reaction, remove the solvent under reduced pressure.
The solid residue obtained by distillation at 50°C,
200 ml of water was added to dissolve the intermediate, and 2.1 g of unreacted orotic acid was separated and removed by filtration.
An aqueous intermediate solution was thus obtained. This intermediate
Analysis by NMR revealed that the intermediate of structural formula A and the intermediate of structural formula B were contained in an A/B ratio of 19/1.

【formula】

[Formula] Next, add this intermediate aqueous solution to an internal volume of 300ml.
Place it in a SUS-316L autoclave and heat it.
The system was maintained at 155° C. for 2 hours while removing generated carbon dioxide so that the pressure within the system was 5 kg/cm ² . 2
After some time, almost no carbon dioxide gas was generated, so the autoclave was cooled to 10°C and left for 5 hours, yielding 21.2g of yellow 5-fluorouracil crystals.
Obtained. This is based on consumed orotic acid.
This corresponds to a yield of 75%. Example 2 The fluorination reaction and dissolution separation treatment of orotic acid were carried out in the same manner as in Example 1, except that trifluoroacetic acid was used instead of formic acid, and the intermediates of structural formula A and structural formula C were obtained by A/C. An aqueous intermediate solution containing a 6/4 ratio was obtained. When this intermediate aqueous solution was heated under pressure in the same manner as in Example 1, 20.2 g of 5-fluorouracil (yield 72% based on consumed orotic acid) was obtained. Examples 3 to 6 The same procedure as in Example 1 was conducted except that the intermediate aqueous solution was heated under pressure under the conditions shown in Table 1 below. The results are summarized in Table 1 below.

[Table] * Consumed orotic acid standard Examples 7 to 9 The results of decarboxylation after fluorination were performed in the same manner as in Example 1, except that fluorination was performed under the conditions shown in Table 2 below. It is shown in Table 2 below.

【table】

Claims (1)

[Claims] 1 Orotic acid and a fluorinating agent are reacted in a solvent to form a compound of the formula [Formula] (where X in the formula is a nucleophilic group or
5-Fluorouracil is produced by producing an intermediate of Manufacturing method of fluorouracil. 2. The manufacturing method according to claim 1, which uses fluorine gas as the fluorinating agent. 3. The manufacturing method according to claim 1, which uses hypofluorite as the fluorinating agent. 4. The manufacturing method according to claim 2, which uses fluorine gas diluted with an inert gas as the fluorinating agent. 5. The manufacturing method according to claim 1, wherein the reaction between orotic acid and the fluorinating agent is carried out in a water-containing solvent. 6. The manufacturing method according to claim 1 or 5, wherein the solvent is formic acid. 7. The manufacturing method according to claim 1 or 5, wherein the solvent is trifluoroacetic acid. 8. The manufacturing method according to claim 1, wherein a hydrate of orotic acid is used as the orotic acid. 9 Reaction between orotic acid and fluorinating agent at -50℃ to +
The manufacturing method according to claim 1, which is carried out at a temperature of 100°C. 10. The manufacturing method according to claim 1, wherein the intermediate is heated under pressure in water at a temperature of 120 to 250°C. 11 Fluorine gas per mole of orotic acid 20~
The manufacturing method according to claim 2 or 4, wherein the reaction is carried out by introducing at a rate of 5000 ml/min. 12 Pressurize and heat the intermediate in water from 1 to 40 kg/cm ²
The manufacturing method according to claim 1 or 2, which is carried out under pressure. 13. The production method according to claim 1, wherein the intermediate aqueous solution obtained by extracting the intermediate from the fluorination reaction mixture with water is heated under pressure.