JPS5943471B2 - 1-(2-tetrahydrofuryl)-5-fluorouracil - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 1-(2-tetrahydrofuryl)-5-fluorouracil.
The present invention relates to a method for producing 1-(2-tetrahydrofuryl)-5-fluorouracil by reacting fluorouracil and 2,3-dihydrofuran in the presence of an amine salt.

1-(2-tetrahydrofuryl)-5-fluorouracil is a well-known compound as an antitumor agent, antiviral agent, etc., and several methods are known for its production. .

For example, in British Patent No. 1168391, 5-
A method is described in which mercury salt of fluorouracil is reacted with 2-chlorotetrahydrofuran, and Japanese Patent Publication No. 49-10510 describes a method in which 2,4-bis(trimethylsilyl)-5-fluorouracil is reacted with 2-chlorotetrahydrofuran. It describes how to do this. Furthermore, in Pelky Patent No. 807556, 2, 4
A method for reacting -bis(trimethylsilyl)-5-fluorouracil with 2-acyloxytetrahydrofuran or 2-alkoxytetrahydrofuran is also described. However, in the first method, the 2-chlorotetrahydrofuran used in the reaction is an extremely unstable compound, so not only does the reaction have to be carried out at a low temperature of -60 to -10°C, but also 5-chlorotetrahydrofuran is an extremely unstable compound. Since mercury salt of fluorouracil is used, there is a risk of causing pollution problems. In the second method, not only is there an unavoidable industrial disadvantage due to the use of 2-chlorotetrahydrofuran, but also 5-fluorouracil is first converted into 2,4-bis(trimethylsilyl)-5-fluorouracil, which is easy to react. However, the complexity of the process and the increase in cost are unavoidable. Furthermore, the third method is not only similar to the second method in that it uses 2,4-bis(trimethylsilyl)-5-fluorouracil, but also 2-acyloxytetrahydrofuran and 2-alkoxytetrahydrofuran, which are usually 2- Since the compound is prepared from chlorotetrahydrofuran, it cannot be said to be an industrially advantageous method. As a result of repeated research aimed at improving the drawbacks of these known methods and devising an industrially advantageous method for producing 1-(2-tetrahydrofuryl)-5-fluorouracil, the present inventor discovered that the reaction accelerator By using amine salts as 5-fluorouracil, 2,
The present invention was completed by discovering that it easily reacts with 3-dihydrofuran to produce 1-(2-tetrahydrofuryl)-5-fluorouracil.

To give a more detailed explanation of the present invention, the reaction accelerator used in the present invention includes inorganic acid salts of organic amines or organic acid salts, such as methylamine, dimethylamine, triethylamine, viridine, vicoline, lutidine, Hydrochlorides, bromates, iodine, sulfates, benzenesulfonates, p-toluenesulfonates, acetates, trifluoroacetates, etc. of quinoline, dimethylaniline, etc. are suitable; Quaternary ammonium salts such as nium salts and tetramethylammonium salts can also be used.

The amount of amine salt used is based on 5-fluorouracil.
The molar ratio may be 0.01 or more. 5-Fluorouracil and 2
Although the reaction with 3-dihydrofurarane may be carried out without using a solvent, it is usually appropriate to carry out the reaction in a solvent in the presence of the above-mentioned amine salt.

Suitable reaction solvents include, for example, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoramide pyridine, pyricone, quinoline, and triethylamine. Generally, a solvent that dissolves 5-fluorouracil is suitable, but a solvent that does not dissolve 5-fluorouracil very well can also be used if the reaction is carried out with 5-fluorouracil in a suspended state. The reaction temperature is usually 0 to 20
0°C is sufficient. After the reaction is completed, the reaction solution is treated in a conventional manner to isolate 1-(2-tetrahydrofuryl)-5-fluorouracil.

According to the invention, 1-(2-tetrahydrofuryl)-5
- Fluorouracil can be easily produced with good yield.

The present invention will be specifically explained below with reference to Examples.

Example 1 2.59 ml of 5-fluorouracil and 0.4 f1 of p-toluenesulfonic acid were dissolved in 50 ml of pyridine, and 1.5 ml of 2,3-dihydrofuran was added, and the mixture was heated on an oil bath.
The reaction was carried out at 120°C for 6 hours.

Further, 3 ml of 2,3-dihydrofuran was added in four portions, and the reaction was allowed to proceed for 15 hours. After the reaction was completed, pyridine was distilled off from the reaction solution, and 100 ml of chloroform was added to the residue to dissolve it, followed by filtration with P to decompose insoluble matter. After washing the p solution with water and drying it, chloroform was distilled off and concentrated.
The precipitated crystals were collected by P. The crystals were washed with a small amount of ether and dried to produce 1-(2-tetrahydrofuryl)-5.
-Fluorouracil 2.09 was obtained. The melting point of this crystal was 167-168°C, and its infrared absorption spectrum matched well with that of the standard product. The previously separated chloroform insoluble matter was washed with water to remove the raw material 5-fluorouracil 0.
．． 679 were recovered.

The yield of the target compound based on the consumed 5-fluorouracil was 71%. Example 2 5-fluorouracil 2.59 and pyridine hydrochloride 2
．． 49 was dissolved in 50 ml of pyridine, and 4.5 ml of 2,3-dihydrofuran was added in 4 portions for 20 hours, and the reaction was carried out on an oil bath at 120°C.

When a small amount of the reaction solution was collected and the progress of the reaction was examined by thin layer chromatography, it was found that the target compound was 90%, unreacted 5-fluorouracil was 5%, and by-products were 50%! ). The reaction solution was treated in the same manner as in Example 1 to obtain 1
-(2-tetrahydrofuryl)-5-fluorouracil 2.69 was obtained. The yield of the target compound was 70% based on the initially used 5-fluorouracil. Example
3 5-fluorouracil 1,39 and tetramethylammonium chloride 0.69 in dimethylformamide 20
m1, then 2,3-dihydrofuran 2.25
m1 was added thereto, and the reaction was carried out at 150° C. for 9 hours in an autoclave.

After the reaction, dimethylformamide was distilled off from the reaction solution, chloroform and a small amount of water were added to the residue, stirred, and filtered through P to separate insoluble materials. The chloroform layer of the solution was dried and concentrated, and the precipitated crystals were collected. The crystals were washed with ether and dried to produce 1-(2-tetrahydrofuryl).
-5-fluorouracil 0.859 was obtained. Melting point 165
~168℃. 0.59 of 5-fluorouracil, a raw material, was recovered from the previously separated chloroform-insoluble matter. The yield of the target compound based on consumed 5-fluorouracil is:
It was 69%. Example 4 1.39 of 5-fluorouracil and 1.89 of N,N-dimethylaniline acetate were dissolved in 15 m of dimethylformamide.
1, then 1.5 ml of 2,3-dihydrofuran
was added and reacted at 140°C for 20 hours.

After the reaction, dimethylformamide was distilled off from the reaction solution, and 50 ml of ethanol containing 1 acetic acid (:Fk) was added to the residue.
was added and heated for 30 minutes. Next, ethanol was distilled off, and chloroform and water were added to the residue and stirred. After separating the chloroform layer and drying it, chloroform was distilled off and 1(2-tetrahydrofuryl)-5-
1.59 fluorouracil was obtained. First used 5-
The yield of the target compound based on fluorouracil was 75%. Example 5 1.39% of 5-fluorouracil and 0.419% of triethylamine hydrochloride were dissolved in 15ml of dimethylformamide, and then 3d of 2,3-dihydrofuran was added and reacted in an autoclave at 150°C for 16 hours.

Claims (1)

[Claims] 1-1, characterized in that 5-fluorouracil and 2,3-dihydrofuran are reacted in the presence of an amine salt.
A method for producing (2-tetrahydrofuryl)-5-fluorouracil.