JPS6153352B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 5-fluorouracil derivative and a method for producing the same.

The 5-fluorouracil derivative of the present invention has the general formula (In the formula, R ₁ is a 2-tetrahydrothienyl group or 2
-tetrahydrothiophene-1-oxide group, _R2 represents hydrogen, 2-tetrahydrothienyl group or 2-tetrahydrothiophene-1-oxide group).

The compounds of the present invention are novel 5-fluorouracil derivatives and are useful as antiviral and antitumor agents.

Since 5-fluorouracil was revealed to have antitumor effects by Heidelberger et al. (Cancer Research, Vol. 18, p. 305,
(1958) and is widely used clinically as an antitumor agent. The present inventors have conducted intensive research to develop a 5-fluorouracil derivative having an excellent antitumor effect, and as a result, they have discovered that the compound of the present invention has an excellent antitumor effect.

The compound of the present invention is produced by the method shown in the following reaction formula.

(In the formula, A ₁ and A ₂ are lower alkyl groups, R ₃ is hydrogen or a 2-tetrahydrothienyl group, and R ₄ is hydrogen or a 2-tetrahydrothiophene-1-oxide group.) That is, 2.4 bis( tri-lower alkylsilyl)-
Compound () is produced by reacting 5-fluorouracil () with 2-acyloxytetrahydrothiophene (), and compound () is produced by oxidizing compound () with peracid.
is manufactured.

To explain in more detail the method for producing the compound () of the present invention, the compound () used as a starting material in the above method is a known compound, for example, obtained by heating and reacting hexa-lower alkyldisilazane and 5-fluorouracil. The excess hexa-lower alkyldisilazane in the reaction product may be distilled off in a nitrogen stream, and the resulting oily substance may be further fractionated to isolate the compound (), but this oily substance may be used as a raw material as it is. Good too. Compound (), which is the other raw material of the present invention, is also a known compound and is easily available (Journal of Organ Chemistry, Vol. 38, p. 2163, 1973).

The usage ratio in the reaction between compound () and compound () may be determined appropriately. For example, if compound () is used at a molar ratio of 1.5 times or less to compound (), 1-(2-tetrahydrothienyl) is formed. −
5-fluorouracil is advantageously obtained. Industrially, the ratio of compound () to compound () is approximately 1.0
It is preferable to use a molar ratio of ~1.3 times. Also, 1,3-bis(2-tetrahydrothienyl)-
In order to advantageously obtain 5-fluorouracil, it is preferable to use the compound () in a molar ratio of at least 2 times that of the compound (), and industrially, the molar ratio of the compound () is approximately 2.2 to 3.5 times that of the compound (). It is preferable to use

It is preferable to use a Lewis acid or an alkali metal iodide as a catalyst in this reaction. The use of a catalyst can lower the reaction temperature, shorten the reaction time, and increase the reaction yield.

Examples of the Lewis acid include stannic chloride, titanium tetrachloride, antimony pentachloride, and boron trifluoride, and stannic chloride is advantageously used. The amount of Lewis acid used varies widely, but industrially it is approximately 0.002 to
It is preferable to use twice the molar amount.

As the alkali metal iodide, lithium, sodium, potassium and other iodides are used, and sodium iodide is preferably used. The amount of alkali metal iodide to be used is about 0.1 to 10 times the mole of the compound (), and preferably about 0.5 to 5 times the mole in industrial terms.

The reaction temperature and reaction time of this reaction are not particularly limited, but if the reaction temperature is too high, the reaction product may decompose and the yield may decrease. When using alkali metal iodides, temperatures of room temperature to 200°C are advantageous.

Although this reaction can be carried out in the presence of a solvent or without a solvent, the use of a solvent is generally preferred since it can increase the reaction yield. The solvent used is preferably an anhydrous aprotic solvent, such as dichloromethane, dichloroethane, benzene, toluene,
Examples include acetonitrile and dimethylformamide. This reaction is preferably carried out in a nitrogen stream, and the progress of the reaction can be monitored by thin layer chromatography.

Next, the method for producing the compound () of the present invention will be described. It can be easily obtained by dissolving the compound () in an organic solvent, adding an organic peracid, stirring, and oxidizing. The organic solvent is preferably one that dissolves the compound () and is stable against oxidation, such as methylene chloride, chloroform, acetone, and the like. Preferred organic peracids include perbenzoic acid, m-chloroperbenzoic acid, and monoperphthalic acid. The organic peracid is preferably used in an amount of about 1 to 5 times, preferably about 1 to 3 times, the amount of compound (2). The reaction usually proceeds satisfactorily at 0 to 50°C. The progress of the reaction can be monitored by thin layer chromatography.

Next, the present invention will be explained with reference to Examples.

Example 1 1.30 g of 5-fluorouracil and 1.94 g of hexamethyldisilazane are stirred at 150-160°C for 4 hours.
After the reaction, excess hexamethyldisilazane is distilled off under a reduced pressure of 20 mmHg at a temperature below 100°C in a nitrogen stream. The resulting oily 2,4-bis(trimethylsilyl)
-5-Fluorouracil was dissolved in 10 ml of acetonitrile, 1.46 g of 2-acetoxytetrahydrothiophene and 1.50 g of sodium iodide were added, and the mixture was stirred at 50-60°C in a nitrogen stream for 2 hours. After the reaction, the solvent was concentrated under reduced pressure, and the residue was mixed with 3 ml of water and 100 ml of dichloromethane.
Add and stir. The dichloromethane layer is separated, dried over magnesium sulfate (anhydrous), and then concentrated. The concentrated residue was recrystallized from ethanol to obtain white crystals of 1-
1.0 g of (2-tetrahydrothienyl group)-5-fluorouracil is obtained. mp190℃ Elemental analysis value (as C ₈ H ₉ N ₂ FSO ₂ ) C H N analysis value (%) 44.56 4.17 12.66 Calculated value (%) 44.44 4.20 12.95 Example 2 2,4-bis(trimethylsilyl)-5-fluorouracil Dissolve 2.74 g in 10 ml of dry dichloromethane and add 1 ml of 0.05M stannic chloride-dry dichloromethane solution. Next, 3.65 g of 2-acetoxytetrahydrothiophene was added to dry dichloromethane.
Add the solution dissolved in 10ml dropwise at below 20℃, then
Stir at ~25 °C for 3.5 h. After the reaction, add 1.75 g of sodium carbonate suspended in 5 ml of ice water to the reaction solution and stir well. After standing, the dichloromethane layer was separated and further washed with an aqueous sodium carbonate solution.
Wash with water and dry with magnesium sulfate (anhydrous).
After drying, it was concentrated, and the residue was recrystallized from ethanol to obtain 1.3 g of 1,3-bis(2-tetrahydrothienyl)-5-fluorouracil as white crystals.
mp148℃ Elemental analysis value (as C ₁₂ H ₁₅ N ₂ FS ₂ O ₂ ) C H N Analysis value (%) 47.82 5.11 9.25 Calculated value (%) 47.67 5.00 9.26 Example 3 1-(2-tetrahydrothienyl)- Dissolve 2.16 g of 5-fluorouracil in 50 ml of dichloromethane, add a dichloromethane solution of 2.03 g of m-chloroperbenzoic acid under ice cooling, and stir overnight. Collect the white precipitated crystals, wash the crystals thoroughly with dichloromethane, and then recrystallize from ethanol to obtain the white crystal 1-
1.54 g of (2-tetrahydrothiophene-1-oxide)-5-fluorouracil is obtained.
mp236~7℃ Elemental analysis value (as C ₈ H ₉ N ₂ FSO ₃ ) C H N Analysis value (%) 41.55 3.90 11.82 Calculated value (%) 41.38 3.91 12.06 Test example 1 Sarcoma 180 (solid) growth inhibition test ICR The above tumor cells were implanted subcutaneously in the left sore of a type of mouse, and 24 hours later, the tumor cells were injected once a day for 7 consecutive days.
(2-Tetrahydrothienyl)-5-fluorouracil was dissolved in a 5% aqueous solution of gum arabic and administered orally at a dose of 10 ml/Kg (0.45 mmol/Kg). On day 10, all mice are sacrificed, solid tumors are removed, and the average tumor weight is measured. The average tumor weight of the mice was measured in the same manner except that a 5% gum arabic aqueous solution was administered to the control group at a dose of 10 ml/Kg. The tumor suppressive effect (average tumor weight of drug administration group/average tumor weight of control group) is 0.62.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is a 2-tetrahydrothienyl group or 2
A 5-fluorouracil derivative represented by -tetrahydrothiophene-1-oxide group, _R2 represents hydrogen, 2-tetrahydrothienyl group or 2-tetrahydrothiophene-1-oxide group. 2. The 5-fluorouracil derivative according to claim 1, wherein R ₁ is a 2-tetrahydrothienyl group, and R ₂ is hydrogen or a 2-tetrahydrothienyl group. 3 R ₁ is 2-tetrahydrothiophene-1-
The 5-fluorouracil derivative according to claim 1, wherein the oxide group, R2 _, is hydrogen or a 2-tetrahydrothiophene-1-oxide group. 4. The 5-fluorouracil derivative according to claim 1, wherein _R2 is hydrogen. 5. The 5-fluorouracil derivative according to claim 1 or 4, wherein R ₁ is a 2-tetrahydrothienyl group and R ₂ is hydrogen. 6. 5 according to claim 2, wherein R ₁ and R ₂ are each a 2-tetrahydrothienyl group.
-Fluorouracil derivatives. 7 General formula Uracil derivatives represented by (in the formula, A ₁ represents a lower alkyl group) and the general formula A general formula characterized by reacting a 2-acyloxytetrahydrothiophene derivative represented by (wherein A ₂ represents a lower alkyl group) A method for producing a 5-fluorouracil derivative represented by the formula (wherein R ₃ represents hydrogen or a 2-tetrahydrothienyl group). 8 General formula Uracil derivatives represented by (in the formula, A ₁ represents a lower alkyl group) and the general formula (In the formula, A ₂ represents a lower alkyl group) is reacted with a 2-acyloxytitrahydrothiophene derivative represented by the general formula A general formula characterized by obtaining a 5-fluorouracil derivative represented by (in the formula, R ₃ represents hydrogen or a 2-tetrahydrothienyl group) and then oxidizing it with a peracid. (wherein R ₄ represents hydrogen or 2-tetrahydrothiophene-1-oxide group)
Method for producing fluorouracil derivatives. 9 General formula A general formula characterized by oxidizing a 5-fluorouracil derivative represented by (in the formula, R ₃ represents hydrogen or a 2-tetrahydrothienyl group) with a peracid. (wherein R ₄ represents hydrogen or 2-tetrahydrothiophene-1-oxide group)
Method for producing fluorouracil derivatives. 10 Claim 7, characterized in that the reaction between the uracil derivative and the 2-acyloxytetrahydrothiophene derivative is carried out in the presence of a Lewis acid.
or the manufacturing method described in paragraph 8. 11. The production method according to claim 7 or 8, characterized in that the reaction between the uracil derivative and the 2-acyloxytetrahydrothiophene derivative is carried out in the presence of an alkali metal iodide.