JPS6134427B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for purifying crude 5-fluorouracil, and particularly to a method for purifying crude 5-fluorouracil obtained by decarboxylation of 5-fluoroorotic acid. 5-Fluorouracil

[Formula] is known to be 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 synthesis method using fluoroacetic ester as a raw material and a synthesis method of fluorinating uracil are known (Japanese Patent Publication No.
(See Publication No. 9578, Special Publication No. 50-25476, etc.)
However, the former method uses highly toxic raw materials and
The latter method has drawbacks such as a large number of synthesis steps and a low yield, and the latter method has the drawback that it is difficult to separate 5-fluorouracil and unreacted uracil, resulting in a low yield. Conventionally, it has not been possible to easily achieve a satisfactory yield. Previously we found that orotic acid

[Formula] is fluorinated to give 5-F fluoroorotic acid

The inventors discovered a method for producing 5-fluorouracil by producing [Formula] and then decarboxylating this 5-fluoroorotic acid, and filed a patent application. This method requires that the fluorination of orotic acid in the first step is easy and that 5-fluoroorotic acid can be obtained in high yield, that decarboxylation of 5-fluoroorotic acid is easy, and that orotic acid, 5-fluoroorotic acid, and This is an excellent method for producing 5-fluorouracil in a high yield because the acid and 5-fluorouracil have different properties such as water solubility and separation between the three or two of them is easy. However, the problem with this method is 5-
Crude 5- produced by decarboxylation of fluorotic acid
There is a problem that fluorouracil tends to be colored. 5-
Decarboxylation of fluoroorotic acid is carried out in water at a temperature above 120°C, preferably between 140 and 180°C, or at 200°C in an inert gas or in vacuum.
Since the reaction is carried out at a temperature above, 5-fluoroorotic acid or 5-fluorouracil is likely to be thermally decomposed and a small amount of a colored substance is likely to be mixed into 5-fluorouracil, which is expected to cause a coloring problem.
Used as pharmaceuticals or raw materials for their preparation5
- Since it is extremely problematic that fluorouracil is colored by impurities, there is a need to effectively remove this colored substance. The present inventor conducted various research studies on the purification method of crude 5-fluorouracil containing a colored substance, and as a result, this crude 5-fluorouracil was purified.
It has been found that a solution of fluorouracil can be effectively purified by adsorption treatment in a specific order using a specific combination of adsorbents. This particular adsorbent is essentially a combination of activated alumina and a cation exchange resin, which are typically packed into a column to form a packed bed, through which the crude 5-fluorouracil solution is passed.
The specific order is such that the treatment with activated alumina is performed before the treatment with the cation exchange membrane resin. That is, the present invention provides a method for purifying 5-fluorouracil, which comprises treating a solution of crude 5-fluorouracil obtained by decarboxylating 5-fluoroorotic acid with an adsorbent to remove the colored substances. This is a method for purifying 5-fluorouracil, characterized in that a combination of at least activated alumina and cation exchange resin is used as the agent, and the treatment with activated alumina is carried out before the treatment with the cation exchange resin. Crude 5-fluorouracil is obtained by decarboxylating 5-fluoroorotic acid as described above, and contains a trace amount of colored substances. pure 5-
Fluorouracil is white and non-white 5-
Fluorouracil is thought to contain some impurities. Since the purpose of purifying crude 5-fluorouracil in the present invention is to remove this impurity, it is not necessary to use only crude 5-fluorouracil obtained from decarboxylation of 5-fluoroorotic acid, as well as 5-fluorouracil obtained from the other methods mentioned above. - Crude 5- which is fluorouracil and contains trace amounts of colored substances
The present invention can also be used to purify fluorouracil. Since crude 5-fluorouracil is a water-soluble compound, it is usually treated as an aqueous solution. However, the solution is not limited to an aqueous solution, and an inorganic or organic solvent that dissolves 5-fluorouracil and is inert to it can also be used. Treatment with the specific adsorbent of the present invention is usually carried out by passing a solution of crude 5-fluorouracil through an adsorbent packed in a column or the like. There are other methods that have not been conventionally used for adsorbent treatment, such as adding an adsorbent to a solution of crude 5-fluorouracil, stirring it, and filtering it after the treatment to separate the purified 5-fluorouracil solution from the adsorbent. Various methods can also be used. However, the method of forming an adsorbent packed bed in a column is easy to operate, and is especially easy to perform when adsorption treatment is performed many times as described below. This is the most preferred method.
A method of passing the crude 5-fluorouracil solution through this packed bed will be shown below as an example, but it goes without saying that other methods may be used depending on the case. When activated alumina and cation exchange resin are used as adsorbents, the use of these alone may not be sufficiently effective, in which case it is desirable to use these together with other adsorbents.
When the degree of coloration of crude 5-fluorouracil is relatively low, a combination of activated alumina and a cation exchange resin may be sufficient, but it is usually preferable to use these together with activated carbon or porous polymer beads. That is, the treatment before the treatment with a cation exchange resin can be carried out using a combination of activated carbon and activated alumina as an adsorbent, or activated alumina and optionally activated carbon can be used, a cation exchange resin can be used, and then porous This method uses polymer beads. When activated alumina and activated carbon are used together in the first stage, they can be used in combination, but it is usually appropriate to use them separately, preferably using activated alumina in the first stage and activated carbon in the second stage. It is. The activated alumina and/or activated carbon primarily adsorb and remove colored substances, and the cation exchange resin primarily removes metal ion impurities that may or may not cause coloring. The porous polymer beads adsorb and remove minute amounts of colored substances that remain unadsorbed in the treatment using activated alumina and, if necessary, activated carbon. Since the adsorption amount of these porous polymer beads is small, this method is effective in treatment after most of the colored substances have been removed, and adsorption treatment with porous polymer beads is performed before treatment with activated alumina. I don't like that. However, after the treatment with activated alumina or optionally in combination with activated carbon, treatment with porous polymer beads may also be carried out before the cation exchange resin treatment. In summary, the preferred embodiment of the treatment in the present invention is based on activated alumina → cation exchange resin, activated alumina → activated carbon → cation exchange resin, activated alumina → cation exchange resin → porous polymer beads, activated alumina → activated carbon It is a combination of → cation exchange resin → porous polymer beads. Note that crude 5-fluorouracil can be purified by recrystallization, sublimation, or other methods other than the adsorbent treatment before being treated with the adsorbent of the present invention, and further purified after the purification of the present invention. It can also be precisely refined. The purpose of the former purification is to remove colored substances, but it is mainly performed to remove relatively large amounts of unreacted substances and impurities. When forming a packed bed of the above adsorbent in the column,
Of course, there is a method of packing different adsorbents into different columns and combining the columns, as well as a method of combining two or more types of adsorbents into one.
It can also be packed into one column. However, even if different types of adsorbents are packed in the same column, it is preferable to use them by forming separate packed beds. Activated alumina is porous aluminum oxide that is sometimes called γ-alumina, alumina gel, etc. Its surface area is usually 100 to 600 m ² /g, and its main component is γ-type alumina. Various types of activated carbon commonly used for decolorization can be used, but activated carbon having a surface area of 100 m ² /g or more is generally preferred. The cation exchange resin is −SO ₃ H, −
Synthetic resins such as polystyrene resins, phenolic resins, and acrylic resins have spherical or granular shapes that have cation exchange groups such as CH ₂ SO ₃ H, -COOH, and phenolic OH groups, and in the present invention, these commercially available products can be used. Porous polymer beads are spherical or granular porous synthetic resin bodies made of, for example, polystyrene, acrylic resin, phenolic resin, or other thermoplastic or thermosetting resins. The purified 5-fluorouracil solution is usually concentrated to precipitate 5-fluorouracil crystals, which are then separated and recovered. Alternatively, 5-fluorouracil can be obtained by completely removing the solvent by evaporation.
In addition, various methods can be used to remove the solvent and obtain purified 5-fluorouracil. The method of the present invention is very effective in removing colored substances, provides a completely uncolored product in a short processing time, has low loss of 5-fluorouracil, and has low purification costs. EXAMPLES The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples. Example 1 40 g of orotic acid hydrate (C ₅ H ₄ N ₂ O ₄・H ₂ O) and 400 g of 88% formic acid aqueous solution were charged into a reactor made of SUS316L with an internal volume of 1, and fluorine gas ( A mixed gas of 28 ml/min) and nitrogen gas (112 ml/min) was blown in to carry out the reaction at a temperature of 10°C. After 6 hours of reaction, 200 ml of water was added to the solid residue obtained by distilling off the solvent at 50°C under reduced pressure to dissolve the intermediate, and the unreacted orotic acid was removed by filtration.
2.1 g was separated to obtain an intermediate aqueous solution. Next, add 200 ml of this intermediate aqueous solution to SUS316L with an internal volume of 300 ml.
The mixture was placed in a manufactured autoclave, heated, and held at 155° C. for 2 hours while removing carbon dioxide gas generated so that the pressure within the system was 5 kg/cm ² . After 2 hours, the autoclave was cooled to 10° C. and left for 3 hours to obtain 21.2 g of yellow 5-fluorouracil crystals. This crude 5-fluorouracil was heated and dissolved in warm water to make a 3.5% aqueous solution, and while kept at 60℃, γ-
The mixture was passed through a purification tube with an inner diameter of about 2 cm filled with 20 g of alumina (AC-11 manufactured by Sumitomo Chemical Co., Ltd.) and 15 ml of cation exchange resin (PK212 manufactured by Mitsubishi Chemical Co., Ltd.) at a flow rate of 100 ml/hr. When a liquid equivalent to 20 g of 5-fluorouracil was treated, the purified liquid that had passed through the purification tube was slightly colored yellow. 430nm of 1% aqueous solution of 5-fluorouracil obtained by cooling the purified liquid
When the transmittance was measured using a 10 mm cell, it was 99.5%. Example 2 A 3.5% aqueous solution of crude 5-fluorouracil obtained by reacting in the same manner as in Example 1 was heated at 60°C, and 20 g of γ-alumina and 10 g of activated carbon (8 to 12 meshes) were added at a flow rate of 100 ml/hr. , cation exchange resin 15ml
Decolorization and purification were performed by sequentially passing through a column with an inner diameter of 2 cm packed with . After processing 35g of crude 5-fluorouracil, approximately 1 of the purified liquid was concentrated to 300ml, and pure white 5-fluorouracil crystals were obtained.
26.5g was obtained. Example 3 50 g of the slightly yellow colored 5-fluorouracil obtained in Example 1 was added to about 1.5 g of water and dissolved by heating to obtain a 5-fluorouracil aqueous solution. Next, while keeping this at 60℃, 20ml of porous polymer beads (HP20 manufactured by Mitsubishi Kasei Corporation) were added.
Decolorization and purification were carried out by passing the sample through a column packed with at a flow rate of 100 ml/hr. Approx.
After heating and concentrating to 400 ml, the mixture was allowed to stand at room temperature, yielding 43 g of white crystals of 5-fluorouracil.

Claims (1)

[Scope of Claims] 1. A 5-fluorouracil solution comprising treating a solution of crude 5-fluorouracil obtained by decarboxylating 5-fluoroorotic acid with an adsorbent to remove the colored substance.
A method for purifying 5-fluorouracil, characterized in that a combination of at least activated alumina and a cation exchange resin is used as an adsorbent, and the treatment with activated alumina is performed before the treatment with the cation exchange resin. Method. 2. The method for purifying 5-fluorouracil according to claim 1, wherein the solution of crude 5-fluorouracil is an aqueous solution. 3. The method for purifying 5-fluorouracil according to claim 1, characterized in that the treatment is carried out by passing a solution of crude 5-fluorouracil through a packed bed of adsorbent.