JPS6045196B2 - Method for producing 1-(2-tetrahydrofuryl)uracils - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an industrially advantageous method for purifying 1-(2-tetrahydrofuryl)uracils.

Among the compounds obtained by the present invention, 1-(2-tetrahydrofuryl)-5-fluorouracil is an excellent anticancer agent that is already commercially available.

Many methods for producing these compounds have been developed in the past, and the following two methods can be cited depending on the type of reaction.

(1) Mercury or silicon derivatives of uracils and 2-
A method for condensing substituted tetrahydrofurans.

(UK Patent No. 1168391, Pelkey Patent No. 807
No. 556, JP-A-51-828) J(2) Method of condensing uracils and 2-substituted tetrahydrofurans.

(JP-A-49-127981, JP-A-51-5218
The above method (1) requires a step to convert uracils into active derivatives, and especially when mercury is used, many post-treatment steps are essential to avoid pollution. be. Furthermore, when using silicon derivatives, it is necessary to set anhydrous conditions because hexamethyldisilazane and trimethylsilyl chloride used in silicon derivative synthesis are expensive, and silyl derivatives of uracils are unstable in water. There are many disadvantages from an industrial standpoint. Method (2) is superior to method (1) because it does not require converting uracils into active derivatives, but one reactant, 2-substituted tetrahydrofuran, is
- It is generally derived from dihydrofuran. For example, 2-chlorotetrahydrofuran is obtained by a low-temperature addition reaction of 2●5-dihydrofuran and hydrogen chloride;
Monoacetoxytetrahydrofuran is obtained by the addition reaction of 2●3-dihydrofuran and acetic acid. Furthermore 2-t
-Butoxytetrahydrofuran is obtained by the addition reaction of 2,3-dihydrofuran and t-butanol in the presence of a catalytic amount of hydrogen chloride. In this way, method (2) is
When procuring 2-monosubstituted tetrahydrofuran as a reactant, a step of deriving 2-substituted tetrahydrofuran from 2,3-dihydrofuran is required, and the 2-halogenotetrahydrofurans that are commonly used in the past are extremely unstable. This method is disadvantageous for industrial use. In view of these circumstances, the present inventors have conducted extensive research into an advantageous industrial production method that does not have these drawbacks, and as a result, the present inventors have found that 2,3-dihydrofuran can be produced without the need for a process for producing 2-substituted tetrahydrofuran. This led to the completion of the present invention, which allows for the direct use of molecule as a reactant.

That is, the present invention General formula (1) (However, X is a hydrogen or halogen atom.

) is reacted with 2,3-dihydrofuran to form a compound of the general formula (■) (where X is hydrogen or a halogen atom).

) is a method for producing 1-(2-tetrahydrofuryl)uracils. The reaction formula of the present invention is as follows.

(However, X is hydrogen or a halogen atom.

) The present invention will be explained in detail below. Compound (1) which is a raw material of the present invention includes uracil, 5-fluorouracil, and 5-chlorouracil [J. Am. Chem. SOc.
,? , 3146, (1954)], 5-bromouracil [J. Org. Chem. , Illusion, 11, (1959)]
, 5-iodouracil [J. BiOl. , Chem. ,
dan, 30飄 (1906)] etc. are used.

2,3-dihydrofuran as a reactant is stable at normal temperature and pressure, and can be stored for a long period of time if stored at a low temperature. It can also be easily purified by distillation. By the method of the present invention (
■) No by-products other than those produced. This means that when ordinary Lewis acids such as aluminum chloride, tin chloride, and boron fluoride are used as catalysts, by-products are produced in addition to 1-(2-tetrahydrofuryl)uracils. By using the halides of magnesium, lithium, potassium, etc. or mixtures thereof of the present invention instead,
This is because the formation of the above-mentioned by-products is not observed. To carry out the present invention, compound (1) and 2,3-dihydrofuran may be heated in a polar solvent, but from an industrial perspective, it is desirable to heat them in the presence of a catalyst in order to accelerate the reaction rate.

As a result of various studies, the present inventors found that the reaction temperature was 30~
It has been found that a temperature of 200°C, preferably 60-150°C is suitable. N-N-dimethylformamide, N-N-dimethylacetamide, dimethyl sulfoxide, etc. are excellent as solvents, but mixtures of these solvents with hexamethylphosphoramide or crown ethers in appropriate proportions are also preferred. gives the yield. The catalysts used include organic bases such as triethylamine, pyridine, and quinuclidine, and halides, oxides, and hydroxides such as lithium, sodium, potassium, magnesium, calcium, copper, aluminum, iron, tin, and zinc. The halides of magnesium, lithium, potassium, or mixtures thereof, which are soluble in solvents, exhibit particularly excellent catalytic activity. For example, these halides,
Magnesium chloride, lithium chloride, potassium iodide,
Among these, magnesium chloride or magnesium bromide not only exhibits excellent catalytic activity in the present invention, but also prevents the formation of by-products and converts 1-(2 -tetrahydrofuryl) uracils are formed, it is particularly preferred to use magnesium chloride or magnesium bromide as catalyst.
The amount of catalyst used is based on 1 mole of raw material uracils,
It is sufficient if it is 0.001 mol or more, but industrially it is 0.05 mol or more.
It is desirable to use it in a proportion of ~0.1 mole.

After completion of the reaction, in order to isolate and purify 1-(2-tetrahydrofuryl)uracils, the reaction solution is concentrated to dryness under reduced pressure.
Crude crystals can be easily obtained by dissolving the residue in a water-insoluble organic solvent, preferably chloroform, filtering off raw materials insoluble in the organic solvent, washing the filtrate with water, and drying with sodium sulfate. Furthermore, if necessary, white crystals can be easily obtained in good yield by recrystallizing the residue from ethyl acetate. As mentioned above, this reaction is extremely simple to carry out, and unreacted uracils can be easily recovered.

Next, the method of the present invention will be explained by giving examples.

Example 1 In a flask equipped with a reflux condenser and a stirrer, 5-
Fluorouracil 1.0y (7.7 mmol) and magnesium chloride 73.3m9 (0.77 mmol) were mixed in N-N
-Dissolved in 10 ml of dimethylformamide, added 0.8 f (11.4 mmol) of 2,3-dihydrofuran and 12
Stir at 0°C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, 25 mt of chloroform was added to the residue to dissolve it, and the raw material 5-fluorouracil insoluble in chloroform was filtered off. The filtrate was washed with water and dried over sodium sulfate. When chloroform was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate, Mpl66-16
1.1y (71%) of white crystals of 8 vinegar are obtained. This compound was confirmed to be 1-(2-tetrahydrofuryl)-5-fluorouracil by a blending test with known compounds and a comparison of infrared absorption spectra. The chloroform washing water was dried under reduced pressure, combined with the chloroform-insoluble matter, and recrystallized from water to recover 0.2 Da (20%) of 5-fluorouracil. Example 2 1.0 g (7.7 mmol) of 5-fluorouracil and 73.3 m9 (0.77 mmol) of magnesium chloride were mixed with N
・Dissolved in 10ml of N-dimethylformamide, 2.3
After adding 540 mg (7.7 mmol) of 2,3-dihydrofuran and stirring at 120°C for 1 hour, 540 mg (7.7 mmol) of 2,3-dihydrofuran was added.
0 m9 was added and the reaction was further carried out at 120°C for 3 hours.

The post-treatment was carried out in the same manner as in Example 1, and 1-(2-tetrahydrofuryl)-5-fluorouracil 1.2-f (79.1
%) was obtained. Example 3 1.0 y (7.7 mmol) of 5-fluorouracil, 32.6 m9 (0.77 mmol) of lithium chloride and 1.28 g (7.7 mmol) of potassium iodide were dissolved in N-N-
Dissolved in 10mt of dinomethylformamide, added 0.8y (11.6 mmol) of 2,3-dihydrofuran, and
After reaction at 200C for 5 hours. Treated in the same manner as in Example 1,
1.3y (83%) of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained.

5 Reference Example 1 5-fluorouracil 1.0y (7.7 mmol), 2
・Dissolve 0.8 g (11.6 mmol) of 3-dihydrofuran and 78.5 m9 (0.77 mmol) of triethylamine in 10 m1 of N●N-dimethylformamide.9
The reaction was carried out at 130° C. for 5 hours and post-treated in the same manner as in Example 1 to obtain 1-(2-tetrahydrofuryl)-5-fluorouracil 0.96V (62%).

Example 4 1.0 y (7.7 mmol) of 5-fluorouracil and 85.7 wL9 (0.89 mmol) of magnesium chloride were dissolved in 10 ml of N.N-dimethylacetamide, and 0.8 f (11.6 mmol) of 2,3-dihydrofuran was dissolved. The mixture was reacted at 120° C. for 3 hours, and treated in the same manner as in Example 1 to obtain 855 m9 (55%) of 1-(2-tetrahydrofuryl)-5-fluorouracil.

Example 5 1.12y (10 mmol) of uracil and 85.8m9 (0.89 mmol) of magnesium chloride were dissolved in 10 mL of N-N-dimethylformamide, and 0.9y (12 mmol) of 2,3-dihydrofuran was added. The reaction was carried out at 120°C for 3 hours, and post-treated in the same manner as in Example 1 to obtain MplOO°C.
1-(2-tetrahydrofuryl)uracil 1.3y(
72%).

Example 6 1.0 g (7.7 mmol) of 5-fluorouracil and 142 mg (a) of anhydrous magnesium bromide. 77 mmol) was suspended in 20 ml of dioxane, 1.08 y (15.4 mmol) of 2●3-dihydrofuran was added, and the mixture was stirred at 120° C. for 1 hour in a sealed tube.

After the reaction, insoluble magnesium bromide is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure.

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, X
represents a hydrogen or halogen atom. ) in the presence of a catalyst selected from halides of magnesium, lithium, and potassium 2
・General formula (II) for reacting 3-dihydrofuran ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) (However, X is hydrogen,
Or represents a halogen atom. ) A method for producing 1-(2-tetrahydrofuryl)uracils.