JPS6048508B2 - 5-Fluoro-6-hydroxy-6-carboxy-5,6-dihydrouracil and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new compound, 5-fluoro-6-hydroxy-6-carboxy-5,6-dihydrouracil, and a method for producing the same.

) Organic fluorine compounds containing one to several fluorine atoms in their molecules are widely used in the fields of medicine, agrochemicals, etc. due to their unique physiological activity. For example, it is known that 5-fluorouracil is useful as an antitumor agent or as a raw material for the preparation of other antitumor agents, and various methods for its synthesis have been proposed. The present inventor has obtained the following interesting findings in the process of continuing various studies and examinations on the synthesis method of 5-fluorouracil using orotic acid as a raw material.

That is, we discovered that when orotic acid is reacted with fluorine gas in the presence of water at a relatively low temperature, a new compound useful as an intermediate for the synthesis of fluorine-containing compounds such as 5-fluorouracil is produced. . And this new compound! 5 was confirmed to be 5-fluoro-6-hydroxy-6-carboxy-5,6-dihydrouracil. For example, by heating an aqueous solution of the novel compound of the present invention at 130° C. or higher, 5-fluorouracil, an antitumor agent, can be easily formed. The structural formula of the compound of the present invention is as follows.

The "°F cough magnetic resonance spectrum of this compound showed a tablet at the chemical shift δ = 209.1 ppm, and its binding constant was JHF = 49.8 Hz (Cc
e3F standard), the chemical shift of F is due to C1F, and the fact that the signal is a tablet indicates that H is present on the same carbon. In addition, the analysis results of the "°C nuclear magnetic resonance spectrum are as follows, when the C nucleus is numbered as in the above structural formula and the chemical shifts are listed: C2: 152.1ppmC4: 166.4pp
m C5: 86.5 ppm C6: 80.4 ppm C7: 168.7 ppm Since the compound of the present invention is decomposed by heating, it has no melting point or boiling point.

Also, the solubility in water (per 100g of water) is
58 g at 15°C), 73 g at 40°C, orotic acid (0.04 g at 150°C), 5-fluoroorotic acid (0.4 g at 15°C), 5-fluorouracil (15
1g at °C). Further, the results of thermal analysis of the compound of the present invention are shown in the attached drawings. In the accompanying drawings, A corresponds to adsorbed water desorption and B corresponds to D to melting, volatilization, and decomposition of 5-fluorouracil, respectively.

The compound of the present invention can be produced smoothly and advantageously by reacting it with a fluorinated gas or the like in the presence of orotic acid.

Various forms of orotic acid can be employed, but monohydrates are usually preferably employed in consideration of availability and other factors. Of course, the non-hydrate form of orotic acid 5
It can also be adopted in It is desirable to use fluorine gas after diluting it with an inert gas to avoid rapid progress of the reaction. For example, good results can be obtained by diluting fluorine gas with about 0.3 to 5 times the amount of nitrogen gas, preferably 0.5 to 10 times the amount of nitrogen gas. The reaction between orotinhydric acid and fluorine gas is preferably carried out in a solvent. For example, trifluoroacetic acid, water, hydrofluoric acid, sulfuric acid, formic acid, acetic acid, perfluoroalcohols, etc. can be used alone or as a mixture as a liquid solvent, but it is preferable to use a polar solvent.
Yes. 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, and for example, it is desirable to react it with fluorine gas in the form of a solution or suspension. The reaction temperature varies depending on the solvent used, but is -10°C to +70°C)
In particular, it is preferable to adopt a temperature of about 5 to 50°C and appropriately control the introduction rate of fluorine gas.

Fluorine gas is 20 to 5000 per mole of orotic acid.
It is preferable that the inert gas is diluted with about 0.5 to m times the amount of inert gas and introduced at a rate of about mι/min. Note that by using trifluoromethylhypofluorite or the like instead of fluorine gas, it is also possible to lower the reaction temperature to about -80°C to +30°C. In the present invention, it is preferable to carry out the reaction between orotic acid and fluorine gas in the presence of water in a liquid solvent, but usually a water-containing solvent is employed.

For example, per 1 part by weight of a solvent such as formic acid or trifluoroacetic acid, 0.5 to 10 parts by weight of water, preferably 1 to 100 parts by weight of water.
Parts by weight may be employed. In particular, it is preferable to use 5 parts of water or less per 10 parts of solvent. In addition, in the fluorination reaction, the dilution ratio of orotic acid with a water-containing solvent (total amount of water and solvent) is usually 1 mole of orotic acid/1 mole of solvent.
~1000 mol, preferably. In most cases, about 10 to 100 moles are employed. As mentioned above, the compound of the present invention has a much higher solubility in water than the raw material orotic acid, so after the fluorination reaction in a solvent, water can be easily added to the reaction mixture obtained by distilling off the solvent. It can be extracted and decomposed smoothly and advantageously with unreacted orotic acid.

Of course, the unreacted orotic acid separated in this way can be recovered and reused. As is clear from the results of the thermal analysis described above, the compound of the present invention thus obtained has 5
-It is useful as a synthetic intermediate for fluoroorotic acid, 5-fluorouracil, etc.

For example, the compound of the present invention extracted into water as described above,
By applying pressure and heating in the form of its aqueous solution, 5
- Can be converted to fluorouracil. That is, an aqueous solution of the compound of the present invention is placed in a pressure-resistant container made of stainless steel, Hastelloy, or the like, and heated to 140 to 180°C. For example, when heating at 150°C, decarboxylation can be easily achieved by extracting the generated carbon dioxide gas at a gauge pressure of 5 kg/cm or more. Of course, the compound of the present invention may be converted into 5-fluoroorotic acid, and then heated and decarboxylated to obtain 5-fluorouracil. 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 Orotic acid hydrate (C5H.N2O) was placed in a SUS-316L reactor with an internal volume of 11.

．． 350 formic acid containing 40 g (H2O) and 12% water by weight
Pour 1 ml of fluorine gas (28 ml/min) while stirring.
Blow a mixed gas of and nitrogen gas (112 mι/min),
The reaction was carried out at a temperature of 8-15°C. 5. After time reaction,
Unreacted orotic acid is separated by adding 200 ml of water to the solid residue obtained by removing the solvent under reduced pressure while keeping the solvent at a temperature below 45° C., stirring well, and filtering.

The filtrate is placed in a rotary evaporator and the water is distilled off under reduced pressure to give a tan solid. Furthermore, by drying at 50°C under reduced pressure, 39.1g
of solid was obtained. When the obtained solid was analyzed by ゛゜F nuclear magnetic resonance spectrum, infrared absorption spectrum, etc.,
The main component (95
% or more).

35.1 g of this solid (containing some adsorbed water) was dissolved in 150 mι of water containing a small amount of formic acid, and an SU with an internal volume of 300 mι was dissolved.
The autoclave was placed in an S-316L autoclave, heated, and maintained at 155°C for 2 hours while removing the generated carbon dioxide so that the pressure in the system became 5k9/d. 2 hours later,
Almost no carbon dioxide gas was generated, so the autoclave was cooled to 10 DEG C. and left to stand for 2 hours, yielding 19.4 g of yellow 5-fluorouracil crystals.

Brief explanation of the drawings The attached drawings show the results of thermal analysis of the compounds of the present invention.
A shows endothermic peaks corresponding to changes in the state of the five compounds of the present invention and changes due to chemical reactions.

Claims (1)

[Scope of Claims] 1 5-fluoro-6-hydroxy-6-carboxy-5,6-dihydrouracil represented by the formula ▲ Numerical formula, chemical formula, table, etc. are available▼. 2. 5 characterized by reacting orotic acid with fluorine gas in the presence of water to produce a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
-fluoro-6-hydroxy-6-carboxy-5,
Method for producing 6-dihydrouracil. 3. The method according to claim 2, wherein the fluorination reaction is carried out in a formic acid solvent containing 5-20% by weight of water. 4. The production method according to claim 2 or 3, wherein the fluorination reaction is carried out at a temperature of 5-50°C. 5. The manufacturing method according to claim 2, wherein orotic acid hydrate is used as orotic acid. 6. The manufacturing method according to claim 2, which uses fluorine gas diluted with an inert gas.