JPS6044313B2 - Method for producing 1,3-bis(2'-tetrahydrofuryl)-5-fluorouracil - Google Patents

Description

[Detailed description of the invention] ゛.

. As shown by 0-0, one molecule of 5-fluorouracil contains 2
By adding 2,3-dihydrofuran to the molecule, 1,3-
The present invention relates to a method for producing bis(2'-tetrahydrofuryl)-5-fluorouracil.

In the present invention, 5-fluorouracil and 2,3-dihydrofuran in a molar ratio of 2 or more are reacted in a polar solvent to obtain the desired 1,3-bis(2'-1,3-dihydrofuran). It relates to a method for producing bis(2'-tetrahydrofuryl)-5-fluorouracil, and more specifically, it is a method for obtaining (2'-tetrahydrofuryl)-5-fluorouracil in a good yield in the following reaction formula O. It is not an essential requirement of the present invention to use a molar ratio of 2 or more of 2,3-dihydrofuran.

To give a more detailed explanation of the present invention, the polar solvent used in the present invention includes dimethylformamide,
It is convenient to use dimethylacetamide, dimethylsulfoxide, pyridine, picolines, etc. that can dissolve 5-fluorouracil well. In addition, a reaction accelerator is used to facilitate the reaction. Lewis acids are used as reaction accelerators, such as aluminum chloride, titanium tetrachloride, tin tetrachloride, zinc chloride, ferric chloride, cupric chloride, ferrous chloride,
Metal chlorides such as cuprous chloride, palladium chloride, platinum chloride, etc., or their corresponding bromides or fluorides, and pyridine, picolines, lutidines, quinolines, alkylamines, anilines, etc. combinations with organic bases such as glycine, alanine, and β
- Amino acids such as alanine, lysine, proline, etc., aminobenzene carboxylic acids or sulfonic acids such as anthranilic acid, m-aminobenzoic acid, p-aminobenzoic acid, orthanilic acid, methanic acid, sulfanilic acid, etc., nicotinic acid , heterocyclic carboxylic acids or sulfonic acids such as isonicotinic acid, quinoline carboxylic acid, pyrazine carboxylic acid, pyridine sulfonic acid, etc., oxyheterocyclic compounds such as oxypyridine, oxypyrimidine, oxypyrazole, oxyquinoline, etc. Examples include boron fluoride, activated carbon, diatomaceous earth, acid clay, and alumina. This reaction usually takes 10
The reaction is carried out at 0°C to the boiling point of the reaction solution.

In the present invention, since a Lewis acid is used as a reaction accelerator, there is no need to heat it to a high temperature exceeding the boiling point of the polar solvent used as a reaction solvent, and the reaction can be carried out substantially at atmospheric pressure. does not need to be sealed and can be opened to atmospheric pressure. Ru.

Although the reaction time varies depending on other reaction conditions, several hours to more than ten hours is usually sufficient. The completion of the reaction is confirmed by developing the reaction solution by thin layer chromatography. After the reaction is completed, the solvent, 2,3-dihydrofuran, etc. are distilled off from the reaction solution under reduced pressure. The residue contains small amounts of 5-fluorouracil, 1-(2″-tetrahydrofuryl)-
5-fluorouracil, 1,3-bis(2''-tetrahydrofuryl)-5-fluorouracil containing a reaction accelerator, etc. By extracting this using an appropriate solvent and recrystallizing it, 1,3- Bis(2-tetrahydrofuryl)-5-fluorouracil can be purified and separated.1,3-bis(7-tetrahydrofuryl)-5-fluorouracil produced by the present invention can be purified and separated under acidic or basic conditions. can be hydrolyzed to 1-(2″-tetrahydrofuryl)-5-fluorouracil.

This compound is useful as an antitumor agent. below,
The present invention will be specifically explained with reference to Examples.

Example 1 52.0y of 5-fluorouracil and 5.5g of anhydrous aluminum chloride were dissolved in 200' of pyridine, and 2
・Add 92.0f of 3-dihydrofuran and on an oil bath・13
The mixture was heated to 0°C and the reaction was carried out for 3 hours.

The black and colored residue obtained by concentrating the reaction solution under reduced pressure was dissolved in chloroform 1.5e, and the chloroform layer was diluted to 10%.
It was washed twice with 200 ml of aqueous sodium chloride solution and 200 ml of water, and then washed with 200 ml of dilute hydrochloric acid and 200 ml of water. Silica gel for chromatography 50y in the chloroform layer
The mixture was decolorized by adding anhydrous sodium sulfate, dehydrated, and filtered.
The crystals precipitated by concentrating the extract were collected overnight to obtain 75.6y of 1,3-bis(2″-tetrahydrofuryl)-5-fluorouracil. Yield 70%. Melting point 103-106°C.
. Example 2 2.6 g of 5-fluorouracil and 0.2 nicotinic acid
5q was dissolved in 30 ml of dimethylformamide, 7.0 y of 2,3-dihydrofuran was added thereto, and the reaction was carried out for 8 hours under reflux.

Claims (1)

[Claims] 1 1,3-bis(1,3-bis(
Method for producing 2'-tetrahydrofuryl)-5-fluorouracil.