Purification method and composition of 5-perfluorodihydrouracil compound

Abstract

To provide a method for efficiently purifying a 5-perfluorodihydrouracil compound while suppressing the generation of corrosive gases.SOLUTION: A purification method and a composition of a 5-perfluorodihydrouracil compound represented by the general formula (2) in the figure are used. The method comprises: reacting an α-substituted fluorine-containing acrylic acid with urea in the presence of acetic anhydride to obtain a reaction mixture containing the 5-perfluorodihydrouracil compound; heating the reaction mixture, at a temperature equal to or higher than 40°C and lower than 70°C, in the presence of an aqueous mineral acid solution in an amount of 0.80 to 1.30 molar equivalents relative to the by-produced acetylurea; and then cooling it for recrystallization.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for purifying a 5-perfluorodihydrouracil compound. The 5-perfluorodihydrouracil compound is not only a compound that may have physiological activity itself, but also an industrially useful compound that can be induced into pharmaceuticals such as anticancer agents and antiviral agents.

Background Art

[0002] As a method for purifying a 5-perfluorodihydrouracil compound, a method is known in which α-substituted acrylic acid and urea are reacted in the presence of acetic anhydride, and the by-produced acetylurea is removed by recrystallization from ethanol (Patent Document 1).

[0003] Furthermore, as a method for purifying a 5-perfluorodihydrouracil compound, a method is known in which α-substituted acrylic acid and urea are reacted in the presence of acetic anhydride, and the by-produced acetylurea is treated with a mineral acid (for example, Patent Document 2). The method of Patent Document 2 has problems that the crystallization temperature is high and the decomposition of the 5-perfluorodihydrouracil compound proceeds, and the yield is as low as 64-67%.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] As a result of intensive studies on a method for purifying a 5-perfluorodihydrouracil compound, the inventors of the present invention have found that the 5-perfluorodihydrouracil compound may decompose upon heating in a neutral solvent such as ethanol used in Patent Document 1, generating hydrofluoric acid. When a significant amount of a corrosive gas such as hydrofluoric acid is generated, it may cause corrosion of the contacting reactor, and there is a problem that suppression of its generation becomes necessary. Also, even in the mineral acid used in Patent Document 2, the 5-perfluorodihydrouracil compound decomposes to generate hydrofluoric acid at a relatively high temperature, for example, 80°C, and there is a problem that suppression of its generation becomes necessary, as in the case of Patent Document 1.

[0006] An object of the present invention is to provide a method for purifying a 5-perfluorodihydrouracil compound while suppressing the generation of a corrosive gas and purifying it efficiently.

Means for Solving the Problems

[0007] As a result of intensive studies, the inventors of the present invention have found that by reducing the temperature during recrystallization, the generation of hydrofluoric acid can be suppressed, and by adjusting the equivalent amount of the mineral acid to an appropriate range, the 5-perfluorodihydrouracil compound can be purified efficiently, thus completing the present invention.

[0008] That is, the present invention relates to the following gist. [1] α-Substituted fluorine-containing acrylic acid and urea represented by the following general formula (1)

Chemical formula

Chemical formula

[0009] According to the present invention, a 5-perfluorodihydrouracil compound useful as a pharmaceutical intermediate can be efficiently purified while suppressing the generation of corrosive gases in its production. [Brief Description of the Drawings]

[0010]

Figure 1

[0011] One aspect of the present invention relates to a method for purifying a 5-perfluorodihydrouracil compound. Each term and detail will be described below.

[0012] <Reaction mixture containing a 5-perfluorodihydrouracil compound> In the purification method of the present invention, a reaction mixture containing a 5-perfluorodihydrouracil compound can be obtained by reacting an α-substituted acrylic acid and urea in the presence of acetic anhydride as described in Patent Document 1 and Patent Document 2.

[0013] <Acetylurea> In the purification method of the present invention, acetylurea is an impurity generated when an α-substituted acrylic acid and urea are reacted in the presence of acetic anhydride as described in Patent Document 1 and Patent Document 2. The generated acetylurea cannot be easily separated by operations such as recrystallization and is known to inhibit the reaction in subsequent steps (Patent Document 2), so it is desirable to remove it during purification.

[0014] <Mineral acid> In the purification method of the present invention, a mineral acid is necessary for efficiently purifying the 5-perfluorodihydrouracil compound. Although the detailed mechanism of action is unknown, it is considered that it can selectively form a complex with acetylurea, which is a main impurity, to improve water solubility. Without being limited to the following examples, examples of the mineral acid include, for example, hydrochloric acid, nitric acid, phosphoric acid, aluminum sulfate, ammonium chloride, or sulfuric acid. Hydrochloric acid and sulfuric acid are preferred in terms of relatively low cost, and hydrochloric acid is particularly preferred because of its good yield.

[0015] In the purification method of the present invention, the amount of the mineral acid used is preferably 0.40 to 2.00 molar equivalents, more preferably 0.60 to 1.50 molar equivalents, and even more preferably 0.80 to 1.20 molar equivalents, based on the molar equivalent of acetylurea contained in the reaction mixture containing the 5-perfluorodihydrouracil compound. When the amount of the mineral acid is small, there is a possibility that acetylurea may be mixed in. When the amount of the mineral acid is large, not only the recovery rate of the 5-perfluorodihydrouracil compound decreases, but also a large amount of waste may be generated.

[0016] In the purification method of the present invention, the method of adding the mineral acid is not particularly limited, and any of the following methods may be used: adding a salt and water, adding an aqueous solution of the mineral acid, or adding the reaction mixture to an aqueous solution of the mineral acid. It is appropriately determined according to the shape of the reactor and the piping equipment.

[0017] <Recrystallization> In the purification method of the present invention, the heating temperature for recrystallization can be carried out at 40°C or higher and less than 70°C, preferably 50°C or higher and less than 65°C. If the reaction temperature is less than 40°C, acetylurea may not dissolve sufficiently, and the purification efficiency may decrease. Further, if it exceeds 70°C, decomposition of the 5-perfluoroalkyldihydrouracil derivative occurs, the recovery rate decreases, and in addition, the hydrogen fluoride acid by-produced by the decomposition may cause corrosion of the reactor.

[0018] <Composition consisting of 5-perfluorodihydrouracil compound and acetylurea> In the present invention, in the composition consisting of the 5-perfluorodihydrouracil compound and acetylurea, the amount of acetylurea is preferably 0.001 to 0.30 parts by mass, more preferably 0.001 to 0.10 parts by mass, and particularly preferably 0.001 to 0.01 parts by mass, based on 100 parts by mass of the 5-perfluorodihydrouracil compound. When a large amount of acetylurea is contained, when bromination or the like is carried out on the 5-perfluorodihydrouracil compound to derivatize it, the reaction may be inhibited and the yield may decrease.

Examples

[0019] The present invention will be specifically described by the following examples, but the present invention is not limited only to these examples.

[0020] In addition, in this example, the compound (2-1) refers to 5-trifluoromethyldihydrouracil in which the number of carbon atoms of Rf in the general formula (2) is 1.

[0021] In the analysis, the following equipment was used. Gas chromatography (GC): GC-2025 manufactured by Shimadzu Corporation Gas chromatograph mass spectrometer (GC-MS): GCMS-QP2010Plus manufactured by Shimadzu Corporation

[0022] <Measurement (analysis) conditions for the amount of acetylurea by liquid chromatography (HPLC)> Model used: Agilent 1220 Infinity LC manufactured by Agilent Technologies Column: TSK-gel (registered trademark) ODS-80TM Eluent: 0.1% phosphoric acid water / acetonitrile = 1:9 Sample concentration: Dissolved in the above eluent and adjusted to 0.02 wt% Flow rate, injection volume, column temperature: 1 mL / min, injection volume 10 μL, column temperature 40 °C Detector: UV (225 nm) Acetylurea concentration (wt%): A mixed composition in which the compound (2-1), acetylurea, and the charging ratios are 1, 2, 3, 4, and 5 times was dissolved in the eluent and analyzed by HPLC. Using the peak area (a) of the compound (2-1) and the peak area (b) of acetylurea, the calibration curve for the peak area ratio and mass ratio of each component is shown in Fig. 1. From Fig. 1, the calibration curve showed good linearity with a correlation coefficient of 0.99. Therefore, accurate quantification of the acetylurea concentration is possible in HPLC analysis.

[0023] [Reference Example 1] [Chemical formula] Synthesis of Reaction Mixture Containing Compound (2-1) In a 500 ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer, a vacuum pump and a cooling device, 200 g (1.96 mol) of acetic anhydride and 64.3 g (1.07 mol) of urea were taken under a nitrogen atmosphere, and while maintaining the reaction temperature at 90-95 °C, a solution consisting of 60.0 g (0.43 mol) of α-trifluoromethylacrylic acid (purity 95.3%) and 200 g (1.96 mol) of acetic anhydride was added dropwise over 1 hour. After the start of the reaction, the pressure inside the system was reduced, and 309 g of the distillate containing acetic anhydride was recovered. 50 g of methanol was added, and the pressure inside the system was reduced to recover 58 g of the distillate, thereby obtaining 219 g of a reaction mixture containing compound (2-1) (containing 0.64 mol of acetylurea).

[0024] [Example 1] In a 100 ml four-necked flask equipped with a stirrer, a thermometer and a cooling device, 34.9 g of the reaction mixture containing compound (2-1) obtained in Reference Example 1 (containing 0.10 mol of acetylurea) and 30.28 g of hydrochloric acid with a concentration of 10 wt% (0.09 mol of hydrogen chloride) were taken, and while stirring, the temperature of the solution was raised to 60 °C. After holding at 60 °C for 1 hour, the temperature of the solution was cooled to 10 °C for recrystallization, and the crystals and the filtrate were separated by filtration. The crystals were dried to obtain 18.8 g of compound (2-1). The crystal and the filtrate were analyzed by HPLC. The results are shown in Table 1.

[0025] [Examples 2, 3] The procedure was the same as in Example 1 except that the mineral acid equivalent was changed. The results are shown in Table 1.

[0026] [Comparative Examples 1, 2] The procedure was the same as in Example 1 except that the mineral acid equivalent was changed. The results are shown in Table 1.

[0027]

Table 1

[0028] From Examples 1 and 2 and Comparative Examples 1 and 2, it can be seen that a mineral acid equivalent of 0.8 molar equivalents or more is effective in removing acetylurea. Also, when heating and holding at 60°C for 1 hour, it can be seen that no hydrogen fluoride acid is generated.

[0029] [Example 3] A reaction mixture containing compound (2-1) obtained by the same operation as in Reference Example 1 (4 g, containing 0.012 mol of acetylurea), 1.6 g of tap water, and 1.0 g of hydrochloric acid with a concentration of 10% by weight (0.0032 mol of hydrogen chloride) were separately placed in a Teflon (registered trademark) reaction tube and heated at a predetermined temperature for 24 hours. After the heating was completed, the mixture was separated by filtration, and the filtrate was 19 analyzed by 19F NMR to calculate the concentration (M) of hydrogen fluoride acid in the filtrate. The results are shown in Table 2.

[0030] [Comparative Examples 3 to 5] The same procedure as in Example 4 was carried out except that the heating temperature was changed. The results are shown in Table 2.

[0031]

Table 2

[0032] From Example 3 and Comparative Examples 2 to 4, when the reaction mixture containing compound (2-1) is heat-treated with hydrochloric acid, no hydrogen fluoride acid is generated at 60°C, but hydrogen fluoride acid is generated after 24 hours at 70°C or higher, and it can be seen that there is a risk of corrosion of glass equipment.

[0033] [Example 4] 5 g of tap water and 2.24 g of a reaction mixture containing compound (2-1) (containing 10 mmol of acetylurea) were added to a 20 mL vial. Then, 0.98 g (10 mmol) of 95% sulfuric acid was added, and the mixture was heated to 60°C. After heating and holding for 1 hour, it was cooled to 10°C, and the mother liquor and crystals were separated by filtration. The crystals of the obtained compound (2-1) were dried, and the yield was calculated. The results are shown in Table 3.

[0034] [Example 5] The procedure was the same as in Example 6 except that nitric acid was used instead of sulfuric acid. The results are shown in Table 3.

[0035] [Table 3]

[0036] From Examples 5 to 6, it can be seen that this purification method is applicable not only to hydrochloric acid but also to other mineral acids such as sulfuric acid and nitric acid.

[0037] [Example 6] [Chemical Formula] Synthesis of Reaction Mixture Containing Compound (3) 20 g of the reaction mixture containing compound (2-1) obtained by the same operation as in Example 1 was dissolved in 350 g of a 3.1% aqueous HBr solution and heated to 90 °C to dissolve the crystals. While stirring, 21 g (1.2 equivalents) of bromine was added dropwise over 4 hours. After the addition, the mixture was heated and stirred for 4 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were filtered off and dried to obtain a mixture containing compound (3). The crystals were analyzed by HPLC. The results are shown in Table 1. The yield was calculated from the weight of the dried crystals.

[0038] [Comparative Example 6] The procedure was the same as in Example 8 except that the reaction mixture containing compound (2-1) obtained by the same operation as in Comparative Example 1 was used. The results are shown in Table 4 below.

[0039] [Table 4]

[0040] From Example 7 and Comparative Example 6, it can be seen that when using the highly purified compound (2-1) purified by this purification method, there is no inhibition of the reaction by acetylurea, so the next step can be carried out efficiently. [Industrial Applicability]

[0041] The 5-perfluorodihydrouracil compound obtained by the present invention is expected to be used as an industrially useful compound that can be induced into pharmaceuticals such as anticancer agents and antiviral agents.

Claims

1. The following general formula (1): 【Chemical Formula 6】 (In general formula (1), Rf represents a perfluoroalkyl group having 1 to 5 carbon atoms.) The α-substituted fluorine-containing acrylic acid and urea represented by the formula are reacted in the presence of acetic anhydride, and the resulting following general formula (2): 【Chemical Formula 7】 (In general formula (2), Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms.) A method for purifying a 5-perfluorodihydrouracil compound, wherein a reaction mixture containing the 5-perfluorodihydrouracil compound represented by the formula is heated at 40 °C or higher and lower than 70 °C in the presence of an aqueous solution of a mineral acid in an amount of 0.80 to 1.30 molar equivalents relative to the by-produced acetylurea, and then cooled and recrystallized.

2. The purification method according to claim 1, wherein the mineral acid is selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid.

3. The purification method according to claim 1, wherein the mineral acid is selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, and sulfuric acid, and the addition amount of the mineral acid is 0.80 to 1.30 molar equivalents relative to the acetylurea contained in the reaction mixture containing the 5-perfluorodihydrouracil compound.

4. The following general formula (2): 【Chemical Formula 8】 (In general formula (2), Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms.) A composition comprising 100 parts by mass of the 5-perfluorodihydrouracil compound represented by the formula and 0.001 to 0.30 parts by mass of acetylurea.

Images