JPS6111226B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the general formula (1) The present invention relates to a 5-fluorouracil derivative represented by the formula (wherein R ¹ and R ² are the same as those stated in claim (1)) and a method for producing the same.

The present inventors have synthesized many useful compounds as derivatives of 5-fluorouracil, and as a result of further research, the compound represented by formula (1)
The present inventors have discovered that these compounds have excellent anticancer activity, and have completed the present invention.

R ³ in the general formula (3) (ClCH ₂ SR ³ hereinafter abbreviated as chloride (3)) represents a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. can give. Therefore, the compounds of formula (3) include chloromethylmethylsulfide, chloromethylethylsulfide, chloromethylpropylsulfide, chloromethylisopropylsulfide, chloromethylbutylsulfide, and chloromethylhexyl. Examples include sulfides.

To carry out the production method of the present invention, 5-fluoro-2,4-bis-trimethylsilyloxypyrimidine and chloride (3) may be allowed to react. A solvent may or may not be used.

The reaction temperature ranges from room temperature to about 120°C, preferably from 30 to 80°C. The reaction time varies depending on conditions such as reaction temperature, but when the reaction is carried out at 70°C, the reaction is completed within one hour.

Although the reaction of the present invention proceeds without a catalyst, it is preferable to use an acidic catalyst such as tin tetrachloride, iron chloride, titanium tetrachloride, or aluminum chloride.

After the reaction, for example, add ethanol to decompose the catalyst, remove the solvent, add an organic solvent such as dichloromethane or chloroform, and water, shake, and dry and concentrate the organic solvent layer to obtain the target compound. I can do that.

The target compound is 1-methylthiomethyl-
5-fluorouracil, 1-ethylthiomethyl-
5-fluorouracil, 3-methylthiomethyl-
5-fluorouracil, 1-propylthiomethyl-5-fluorouracil, 1-butylthiomethyl-5-fluorouracil, 1-hexylmethyl-
Examples include 5-fluorouracil, -3-ethylthiomethyl-5-fluorouracil, 1,3-bis-methylthiomethyl-5-fluorouracil, 1,3-bis-ethylthiomethyl-5-fluorouracil, and the like.

These compounds have been found to have anticancer activity against murine leukemia L-1210, and are novel and useful compounds.

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

Example 1 5.49 g (0.02 mol) of 5-fluoro-2,4-bis-trimethylsilyloxypyridine and 2.21 g (0.02 mol) of chloromethylethyl sulfide were mixed and heated to 70°C, and the mixture was stirred. While stirring, 5.21 g (0.02 mol) of tin tetrachloride was added dropwise over 10 minutes. After dropping, stir for 20 minutes, cool and add ethanol.
Add 20ml of dichloromethane after drying the whole.
It was dissolved in 100ml and washed with water. The dichloromethane layer was then concentrated, and the precipitated crystals were filtered, washed with ether, and dried to give 1-ethylthiomethyl-5.
- A yield of 2.65 g (65.1%) of fluorouracil was obtained. Melting point 148-149℃. Elemental analysis: Experimental value: C,
40.87; H, 4.20; F, 9.10; N, 13.48.
Calculated value as C ₇ H ₉ FN ₂ O ₂ S (MW204.219):
C, 41.17: H, 4.44; F, 9.30; N, 13.72. Infrared absorption spectrum is 3190, 3170, 2860, 1730,
1675, 1430, 1382, 1360, 1252, 1241, 1134,
It has absorption at 928, 771, and 704 cm ^-1 .

The nuclear magnetic resonance absorption spectrum (solvent CDCL ₃ ) is
δ=1.31 (3H, t, J=7Hz, CH ₃ ), 2.64
(2H, q, J=7Hz, CH ₂ ), 4.86 (2H, s,
_CH2S ), 7.53 (1H, d, J=6Hz, _C6 -H),
9.92 (1H, broad, _N3 -H).

Example 2 5.49 g (0.02 mol) of 5-fluoro-2,4-bis-trimethylsilyloxypyrimidine and 1.93 g (0.002 mol) of chloromethylmethyl sulfide were added.
2.3 tin tetrachloride dissolved in 30 ml chloroform at 40 °C
ml (0.02 mol) was added dropwise. After 30 minutes, 7 ml of ethanol was added dropwise to terminate the reaction. 18.1 g of an oily substance obtained by drying the reaction mixture was added to silica gel (C-
200) Separation was performed by column chromatography to obtain 1.66 g (yield: 43.6%) of 1-methylthiomethyl-5-fluorouracil. Melting point 147-148℃. Elemental analysis:
Experimental values are C, 37.69; H, 3.70; F, 9.73; N,
14.66.

Calculated values for C ₆ H ₇ FN ₂ O ₂ S (MW190, 192): C, 37.89; H, 3.71; F, 9.99; N,
14.73. Infrared absorption spectrum: 3180, 3030,
2840, 1775, 1735, 1690, 1670, 1488, 1432,
1381, 1350, 1295, 1250, 1234, 1127, 1003,
756, 711 cm ^-1 . Nuclear magnetic resonance absorption spectrum (solution〓〓〓〓〓
Medium: heavy acetone), δ2.23 (3H, s, CH ₃ ), 4.88
(2H, s, CH ₂ ), 7.87 (1H, d, C ₆ -H),
10.50 (1H, broad, N3 _- H). Furthermore, 0.06 g (yield 1.2%) of 1,3-bis-methylthiomethyl-5-fluorouracil was obtained as another product. Elemental analysis in candy form: Experimental value; C, 38.25; H, 4.41;
F, 7.38; N, 10.95. C ₈ H ₁₁ FN ₂ O ₂ S ₂ (MW250,
168): C, 38.40; H, 4.43;
F, 7.59; N, 11.19.

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Claims (1)

[Claims] 1 General formula (1) (In the formula, R ¹ represents a lower alkylthiomethyl group, and R ² represents a hydrogen atom or the same lower alkylthiomethyl group as R ^1. ) A 5-fluorouracil derivative represented by the following. 2. The 5-fluorouracil derivative according to claim 1, which is 1-methylthiomethyl-5-fluorouracil. 3. The 5-fluorouracil derivative according to claim 1, which is 1-ethylthiomethyl-5-fluorouracil. 4. The 5-fluorouracil derivative according to claim 1, which is 1,3-bis-ethylthiomethyl-5-fluorouracil. 5 5-Fluoro-2,4-bis-trimethylsilyloxypyrimidine and a chloride represented by the general formula (2) Cl-CH ₂ SR ³ ...(2) (in the formula, R ³ represents a lower alkyl group). General formula (1) characterized by (In the formula, R ¹ represents a lower alkylthiomethyl group, and R ² represents a hydrogen atom or the same lower alkylthiomethyl group as R ^1. ) A method for producing a 5-fluorouracil derivative represented by the following formula.