JPS626712B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to amino-5-fluorouracil derivatives and methods for producing the same.

The amino-5-fluorouracil derivative of the present invention is a new compound, and has the general formula [In the formula, R ₁ represents a lower acylamino group or an arylsulfonylamino group, and R ₂ represents hydrogen or an arylsulfonylamino group].

In the present invention, lower acylamino groups include:
Acylamino groups having 2 to 6 carbon atoms such as acetylamino group, propionylamino group, butyrylamino group, hexanoylamino group, etc., and arylsulfonylamino groups such as benzenesulfonylamino group, p-toluenesulfonylamino group, di-p-
Examples include toluenesulfonylamino group.

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

The compound of the present invention can be produced, for example, by the method shown below.

[In the formula, R represents hydrogen or an amino group, R ₃ represents a lower acyl group or an arylsulfonyl group, X represents a halogen atom, and (R ₄ CO) ₂ O represents an aliphatic carboxylic acid anhydride. R ₁ and R ₂ are the same as above. ] That is, first, 5-fluorouracil and an aminating agent such as hydroxylamine-O-sulfonic acid or O-mesitylenesulfonylhydroxylamine are reacted to form 3-amino-5-fluorouracil and/or 1,3-diamino-5. ―
N-amino-5-fluorouracil consisting of fluorouracil can be obtained.

In the above amination reaction, the aminating agent is used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles, per mole of 5-fluorouracil. The reaction solvent is not particularly limited as long as it does not participate in this reaction, but examples include aprotic polar solvents such as chloroform, dichloromethane, dichloroethane, nitromethane, and dioxane, water, and sodium carbonate.
A buffer such as sodium hydrogen carbonate may also be used. The reaction is usually carried out at a temperature of about 0 to 100°C, preferably about 0 to 30°C when carried out in an organic solvent, and preferably about 60 to 80°C when carried out in water. The reaction time is about 1 to 48 hours, but the reaction is usually completed in about 2 to 5 hours.

The reaction between N-amino-5-fluorouracil and lower acyl halide, arylsulfonyl halide, or aliphatic carboxylic acid anhydride is N-amino-5-fluorouracil.
This can be carried out after isolating 5-fluorouracil, but it can also be carried out without isolation.

In the reaction, lower acyl halide, arylsulfonyl halide or aliphatic carboxylic acid anhydride is preferably used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles, per mole of N-amino-5-fluorouracil. In addition, as dehydrohalogenation agents, tertiary amines such as triethylamine, trimethylamine, pyridine, and picoline, lower acyl halides,
It is generally preferable to use about 1 mole or more per mole of arylsulfonyl halide, and pyridine, picoline, etc. can also be used as a solvent. When reacting an aliphatic carboxylic acid anhydride, a tertiary amine may or may not be added.
The solvent is not particularly limited as long as it does not participate in the reaction, but examples include chloroform, dichloromethane, dichloroethane, nitromethane, dioxane, diethyl ether, acetone, dimethylformamide,
Examples include dimethyl sulfoxide and amines such as pyridine and picoline.

The reaction is usually carried out at a temperature of about 0 to 100°C, preferably about 0 to 30°C for reactions of lower acyl halides and arylsulfonyl halides, and about 60 to 80°C for reactions of aliphatic carboxylic anhydrides.

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

Example 1 3-amino-5-fluorouracil 1 g
(0.0069 mol) was dissolved in 20 ml of dioxane under heating, 2 ml of water and 4.4 g (0.028 mol) of butyric anhydride were added, and the mixture was stirred at 80°C for 12 hours.

The reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent: chloroform:ethanol = 4:1) to separate the product.
The eluate is separated and concentrated under reduced pressure, and the residue is recrystallized from ethanol to obtain 0.7 g of crystals of 3-butyrylamino-5-fluorouracil (yield: 47%).

Decomposition point 185-7℃ Elemental analysis As C ₈ H ₁₀ N ₃ O ₃ F Calculated value (%): C, 44.65; H, 4.68; ; N, 19.53 Actual value (%): C, 44.59; H, 4.78; ;N, 19.44 The eluate was fractionated and concentrated under reduced pressure to obtain oily 3-amino-1-butyryl-5-fluorouracil.

Example 2 9 g (0.069 mol) of 5-fluorouracil in 2N
-Dissolve in 340 ml of sodium hydroxide, and add dropwise 38 g (0.34 mol) of hydroxylamine-O-sulfonic acid dissolved in 170 ml of cold water. Then add the reaction solution
Heat and stir at 80°C for 4 hours. After 4 hours, the reaction solution was neutralized with hydrochloric acid, concentrated under reduced pressure, ethanol was added to the residue, and extracted under heating. After concentrating the ethanol solution, dry the residue, and then add 100ml of pyridine.
After dissolving in the solution, 7.2 g (0.038 mol) of p-toluenesulfonyl chloride was added and stirred overnight at room temperature. After concentrating the reaction solution, the residue was added to ice water with vigorous stirring to remove the precipitate. After drying, silica gel column chromatography (developing solvent, chloroform:ethanol = 4:1) is performed to separate the product.

The eluate was separated and concentrated under reduced pressure, and the residue was dried to obtain 1.7 g of powdered 3-(di-p-toluenesulfonyl)amino-5-fluorouracil (yield 5.4%).
I got it.

Decomposition point 98℃ Elemental analysis C ₁₈ H ₁₆ N ₃ O ₆ S ₂ Calculated value (%): C, 47.68; H, 3.56; N, 9.27 Actual value (%): C, 47.64; H, 3.66; N , 9.25 The eluate was collected and concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the first crystalline 1,3-di-
1.9 g (yield 5.9%) of crystals of p-toluenesulfonylamino-5-fluorouracil were obtained.

Melting point 224-227°C Elemental analysis As C ₁₈ H ₁₇ N ₄ O ₆ S ₂ F Calculated value (%): C, 46.15; H, 3.66; N, 11.96 Actual value (%): C, 46.13; H, 3.58; N, 12.05 1,3-di-p-toluenesulfonylamino-
After obtaining 5-fluorouracil, the liquid was concentrated,
The residue was recrystallized from ethanol to obtain 2.9 g (yield: 14%) of 3-p-toluenesulfonylamino-5-fluorouracil crystals.

Decomposition point 228℃ Elemental analysis C ₁₁ H ₁₀ N ₃ O ₄ As SF Calculated value (%): C, 44.15; H, 3.37; N, 14.04 Actual value (%): C, 44.01; H, 3.23; N, 13.92 Example 3 13 g (0.1 mol) of 5-fluorouracil was added to 1M sodium carbonate-sodium hydrogen carbonate (PH9) 300
ml, add 15 g (0.13 mol) of hydroxylamine-O-sulfonic acid, and stir at 80°C for 2 hours. After 2 hours, the reaction solution was concentrated under reduced pressure, and ethanol was added to the residue for extraction under heating. After treating the ethanol extract with activated carbon, it is concentrated and the residue is dried. Next, after dissolving this in 140 ml of pyridine,
-Toluenesulfonyl chloride 10.3g (0.054
mol) and stir overnight. After concentrating the reaction solution, pour the residue into ice water with vigorous stirring to remove the precipitate. This precipitate was recrystallized from ethanol to give 9.7 g of crystals of 3-p-toluenesulfonylamino-5-fluorouracil (yield: 32
%) was obtained. Decomposition point: 228℃~

Claims (1)

[Claims] 1. General formula _{Amino- _}
5-Fluorouracil derivative. 2. A general method characterized in that the reaction product obtained by reacting 5-fluorouracil and an aminating agent is then reacted with one selected from lower acyl halides, aliphatic carboxylic acid anhydrides, and arylsulfonyl halides. formula _{Amino- _}
A method for producing a 5-fluorouracil derivative. 3 General formula A general formula characterized by reacting [R is hydrogen or an amino group] with one selected from lower acyl halides, aliphatic carboxylic acid anhydrides, and arylsulfonyl halides. _{Amino- _}
A method for producing a 5-fluorouracil derivative.