JPS6037113B2 - New uracil derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N1-(3,〆-pitetrahydrofuran-2-yl)-5-fluorouracil, which is a new compound useful as a pharmaceutical, and a method for producing the same.

N1-3,2-bitetrahydrofuran-2-yl)-5
-Fluorouracil is a novel compound represented by the formula that has not yet been published in the literature, and is easily converted into 5-fluorouracil and NI-(2-tetrahydrofuryl)-5-fluorouracil in vivo.

Since 5-fluorouracil and NI-(2-tetrahydrofuryl)-5-fluorouracil are substances that have recently attracted attention as anti-malignant agents, they can be expressed by the formula (1).
According to the present invention, the compound of formula (1) is also useful as an anti-malignant tumor agent. 3-dihydrofuran in the presence of a catalyst and a proton-donating substance, and the reaction product produces NI-(3,Z-bitetrahydrofuran-1-yl)-
It can be easily produced by separating 5-fluorouracil.

2,4-bis(trimethylsilyl)-5-fluorouracil used as a starting material in the present invention can be easily produced by a known method of reacting hexamethyldisilazane with 5-fluorouracil. In addition, 2,3-dihydrofuran, which serves as the other starting material, can be used as a commercially available product as it is or after being purified. The amount of 2,3-dihydrofuran used at this time can vary within a fairly wide range, but in consideration of reaction yield and economy, it is usually 2,4-bis(trimethylsilyl).
-1.2 to 15.0 per mole of 5-fluorouracil
Selected within the molar range. Lewis acids, halogen molecules, and alkali metal iodine are used as catalysts in the method of the present invention. Examples of Lewis acids include stannic chloride,
Examples include aluminum chloride, titanium tetrachloride, silicon tetrachloride, antimony pentachloride, and boron trifluoride, with aluminum chloride and stannic chloride being particularly preferred. These may be used alone or in combination of two or more. Examples of halogen molecules include bromine, iodine, and mixtures thereof, but iodine is preferred in consideration of ease of handling, reaction yield, coloring of the product, etc. In addition, examples of alkali metal iodides include lithium iodide, sodium iodide, and potassium iodide, but lithium iodide and lithium iodide are particularly effective in terms of low reaction temperature and high reaction yield. Sodium uride is preferred. These may be used alone or in combination of two or more. The optimal amount of the catalyst used in the method of the present invention depends on the reaction temperature, reaction time, type of catalyst, etc., and cannot be determined unconditionally, but it is usually based on 2,4-bis(trimethylsilyl)-5-fluorouracil. , selected within the range of 0.1 to 80 mol%. In the method of the present invention, water is contained in the normally used solvent and acts as a proton-donating substance, so there is no need to add a proton-donating substance, but if desired, further proton-donating substances can be added. Substances can be added.

As this proton donor substance, any substance that can release brotons can be used, but water, alcohols such as methyl/ethanol, pro/gol, butanol, and organic Acids such as acetic acid,
Propionic acid is preferred.

This proton-donating substance is preferably used in a ratio of 0.1 to 2.0 mol per mol of 2,4-bis(trimethylsilyl)-5-fluorouracil, including the water present in the solvent and the additional amount. good. Solvents used in the method of the present invention include aprotic polar solvents such as acetonitrile, dimethylformamide and dimethyl oxide; esters such as ethyl acetate and ethyl propionate;
Examples include halogenated hydrocarbons such as rumethane, dichloroethane, and chloroform, and aromatic hydrocarbons such as benzene and toluene. The reaction temperature used varies depending on the type and amount of catalyst used, reaction time, etc.
Although it cannot be determined unconditionally, a relatively low temperature is used when organic acids or Lewis acids are used as the catalyst, and a relatively high temperature is used when an alkali metal bromide is used. Usually, this reaction temperature is selected within the range of 20 to 190 qo. In addition, the reaction time required at this time is 20
It ranges from minutes to 1 hour. In the reaction mixture thus obtained, in addition to N1-(3,2'-pitetrahydrofuran-2-yl)-5-fluorouracil, N1
Contains 1-(2-tetrahydrofuryl)-5-fluorouracil and 6-fluorouracil, which is an unreacted raw material.

To separate the target compound NI-3,2-bitetrahydrofuran-2-yl)-15-fluorouracil from this reaction mixture, a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid is added to By heating to 100℃,
After selectively decomposing only NI-(2-tetrahydrofuryl)-5-fluorouracil into 5-fluorouracil, it is treated with silica gel column chromatography.

The NI-(3,2-bitetrahydrofuran-2-yl)-5-fluorouracil thus separated may be further recrystallized from an alcoholic solvent such as methanol or ethanol, if desired. Can be purified. NI-(3,2'-bitetrahydrofuran-2-yl)-5-fluorouracil of the present invention has a melting point of 166.5
~1670 colorless crystalline substances, respectively in Figure 1 and
The ultraviolet absorption spectrum, infrared absorption spectrum, and nuclear magnetic resonance spectrum shown in FIGS. 2 and 3 are shown.

This substance is easily decomposed in the living body and converted into 5-fluorouracil and N1-(2-tetrahydrofuryl)-5-fluorouracil, so it can be used in medicine, especially as an anti-malignant octopus preparation.

Next, the present invention will be explained in more detail with reference to Examples. Note that the production rate of the target product in each example was calculated based on the results of high performance liquid chromatography. Example 1 55 g of 2,4-bis(trimethylsilyl)-5-fluorouracil, 96 g of 2,3-dihydrofuran, and anhydrous aluminum chloride2. The female was dissolved in 0.8 parts acetonitrile containing 1.8 parts water and stirred at an oil temperature of 85°C for about 4 hours (reaction rate 22%).

After the reaction, the mixture is neutralized with IN caustic soda, and the acetonitrile is distilled off under reduced pressure. 0.5 ml of water is added to the concentrated solution, and the pH is adjusted to 4.0 with hydrochloric acid. After stirring at 80q0 for 6 hours, a large amount of 5-fluorouracil was precipitated when the mixture was left at 5°C overnight. After separating and removing 5-fluorouracil,
After extracting 3 times with 200% dichloromethane and washing with water,
Dry with E-nitrogen and remove dichloromethane under reduced pressure to obtain an oily substance.

It was subjected to silica gel column chromatography, eluted with chloroform-ethanol (5:1), concentrated, and recrystallized from ethanol to obtain the desired NI-(3,2'-bitetrahydrofuran-2-yl)-5-fluorouracil 8. .6g (
Yield: 16%). Melting point: 164.5-165.5q
o Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value: 53.3 5.6
10.4 Actual value; 53.2 5.3 10.
2UV; enter spell o (m one) 270 (go = 8.974) I
R; Hiyakubukuro (Ken-1) 3.600-3.200, 1,7
20, 1.460, 1400, 1360, 1260 Example 2 The procedure was carried out in exactly the same manner as in Example 1 except that iodine was used instead of anhydrous aluminum chloride (reaction rate 26%).
) Target product NI-(3,2'-pitetrahydrofuran-2
-5-fluorouracil 10. Pine (yield 19%
).

Melting point: 165.5-166.5℃ Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value; 53.3 5.6 10
．． 4 Actual measurement value; 53.1 5.6 10.3UV; ^
Inquiry o (m French) 2m m;Shi profit revealing skin-1) 3600-3200, 1720,
1460, 1400, 1360, 1260 Example 3 In Example 1, sodium iodide* was used instead of anhydrous aluminum chloride, and the reaction temperature was 100°C in a pressurized reaction pot. %), target NI
-(3,2'-bitetrahydrofuran-2-yl)-5
-Fluorouracil 4. Obtain the key (9% yield).

Melting point: 165.5-166.5°C Elemental analysis value (C, 2 days, as 4F of 5N) C (%) days (%) N (%) Calculated value: 53.5 5.6 10.
4 Actual measurement: 52.9 5.4 10.2UV: Enter the Cabinet.

(m France) 2701R: Le Obi Mai (enemy-1) 3600-32
00,1720,1460,1400,1360,12
60 Example 4 Example 2 was carried out under exactly the same conditions except that 10 ml of ethyl alcohol was added instead of 1.8 ml of water (reaction rate 24%).
) Target product NI-(3,2'-bitetrahydrofuran-2
-5-fluorouracil 8. Thigh (yield 16%)
get.

Melting point: 165-165.5℃ Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value; 53.3 5.6 10
．． 4 Actual measurement value; 52.9 5.4 10.2UV; Irifugatsu Saru o (m〃) 270 1R: Le Egu (G-1) 3600-3200, 1720
, 1460, 1400. 1360, 1260 Example 5 The same conditions as in Example 1 except that 4 acetic acids were added instead of 1.8' of water, the reaction temperature was 65oo instead of 85oo, and the reaction time was 7 hours. (reaction rate 14%) to obtain the target product NI-(3,2'-bitetrahydrofuran-2-yl)-5-fluorouracil5. (yield 10%).

Melting point: 165-165.500 Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value: 53.3 5.6 10
．． 4 Actual measurement value: 52.9 5.7 10.5UV; illuminated.

(m1) 2701R; Re band shadow (skin-1) 3600-32
00,1720,1460,1400,1360,12
60 Example 6 In Example 4, the amount of 2,3-dihydrofuraso was changed to 260
The reaction was carried out under the same conditions except that 0.6% of chloroform was used as the reaction solvent (reaction rate 18%), and the target product NI-(3,2'-bitetrahydrofuran-2-yl) was obtained.
5.9 g (yield 11%) of -5-fluorouracil is obtained.

Melting point: 166-166.500 Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value; 53.3 5.6 10
．． 4 7.0 Actual value; 53.5 5.5 10.2
6.7UV; Irimusaru o (m French) 2701R: Hikama bag (skin-1) 3600-3200, 1720, 1460
, 1360, 1260, Example 7 Example 6 was carried out under exactly the same conditions except that 0.7 kg of benzene was used as the reaction solvent (yield 14%).
2'-bitetrahydrofuran-2-yl)-5-fluorouracil4. Shigeru (yield 9%) is obtained.

Melting point: 166.5-167.500 Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value; 53.3 5.6 10
．． 4 Actual measurement value; 53.1 5.4 10.5UV: Entering bee.

(Mount M) 270m; Le obi drum (Gaga-1) 3600-320
0,1720,1460,1400,1360,126
0, Example 8 The same conditions as in Example 1 were used except that 3.5 g of antimony pentachloride was used instead of aluminum chloride and the reaction time was 6 hours (yield 17%).
-(3,2'-bitetrahydrofuran-2-yl)-5
-Fluorouracil6. Obtain the gunwale (yield 12%).

Melting point: 166.5-166.0q○ Elemental analysis value (C, 2
Day, 5N204F) C (%) Day (%) N (%) Calculated value; 53.3 5.6 10.4 Actual value; 53.
6 5.4 10.3UV; ^ Manifested form o (m Buddha) 2
70 m: Le Obiai (Arc-1) 3600-3200, 1720,
1460, 1400, 1360, 1260 Example 9 The reaction was carried out under exactly the same conditions as in Example 1, except that 1.5 g of iodine was added as a catalyst in addition to aluminum chloride, and 6.5 g of methyl alcohol was added instead of water. 8.6 g (yield 16%) of the target product NI-(3,2'-bitetrahydrofuran-2-yl)-5-fluorouracil was obtained.

Melting point: 165.5-166.500 Elemental analysis value (C, 2 days, as 5N204F) C (%)
Day (%) N (%) Calculated value; 53.3 5.6 10
．． 4 Actual measurement value; 53.4 5.6 10. I UV; Entering o(my) 270 1R; Hiki-mai (Arc-1) 3600-3200, 1720
,1470,1400,1360,1260

[Brief explanation of the drawing]

Figure 1 is the ultraviolet absorption spectrum of the compound of the present invention, Figure 2 is the infrared absorption spectrum, and Figure 3 is the nuclear magnetic resonance spectrum.Figure 1Figure 2Figure 3

Claims (1)

[Claims] 1 N^1-(3,2'-bitetrahydrofuran-2-yl)-5-fluorouracil represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼. 2 2,4-bis(trimethylsilyl)-5-fluorouracil shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and 2,3-dihydrofuran shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ are reacted in the presence of a catalyst and a proton-supplying substance, and the reaction product is N^1-(3,2-bitetrahydrofuran-
A method for producing a novel uracil derivative, which comprises isolating 2-yl)-5-fluorouracil. 3. The method according to claim 2, wherein the catalyst is at least one selected from Lewis acids, halogen molecules, and alkali metal iodides. 4. The method according to claim 3, wherein the Lewis acid is at least one selected from stannic chloride, aluminum chloride, titanium tetrachloride, silicon tetrachloride, antimony pentachloride, and boron trifluoride. 5. The method according to claim 3, wherein the halogen molecule is at least one selected from lithium iodide, sodium iodide, and potassium iodide. 6. The method according to claim 3, wherein the alkali metal iodide is at least one selected from lithium iodide, sodium iodide, and potassium iodide. 7 The amount of catalyst used is 2,4-bis(trimethylsilyl)
The method according to claim 2, wherein the amount is 0.1 to 80 mol % based on -5-fluorouracil. 8 The amount of 2,3-dihydrofuran per mole of 2,4-bis(trimethylsilyl)-5-fluorouracil,
The method according to claim 2, wherein the amount is 1.2 to 15.0 mol. 9. The method according to claim 2, wherein the proton supplying substance is water. 10. The method according to claim 2, wherein the proton supplying substance is an alcohol. 11. The method according to claim 10, wherein the alcohol is at least one selected from methanol, ethanol, propanol, and putal. 12. The method according to claim 2, wherein the proton supplying substance is an organic acid. 13. The method according to claim 12, wherein the organic acid is at least one of acetic acid and propionic acid. 14 The amount of proton supplying substance used was 0 per mole of 2,4-bis(trimethylsilyl)-5-fluorouracil.
．． The method according to claim 2, wherein the amount is 1 to 2.0 mol. 15. The method according to claim 2, wherein the reaction is carried out at a temperature in the range of 20 to 190°C. 16. The method according to claim 2, wherein the reaction is carried out for 20 minutes to 15 hours. 17 The reaction product is treated under mineral acid acidic conditions to produce N^1-
(2-Tetrahydrofuryl)-5-fluorouracil is selectively decomposed to 5-fluorouracil, and N^1-3
, 2'-bitetrahydrofuran-2-yl)-5-fluorouracil. 18. The method according to claim 17, wherein the mineral acid is at least one selected from hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. 19. The method according to claim 17, wherein the treatment is carried out at a temperature in the range of 30 to 100°C.