JPS6157832B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antitumor agents. More specifically, the present invention relates to 5-fluorouracil derivatives having antitumor effects. 5-Fluorouracil (hereinafter abbreviated as 5-FU)
Although it is a widely used antitumor agent, it has drawbacks such as its strong toxicity, which limits its applicability, makes it difficult to use over a long period of time, and makes it difficult to administer orally. In recent years, as the incidence and mortality rate of malignant tumors such as cancer have increased, there is a need for antitumor agents that are highly effective, can be administered orally, and are less toxic. A lot of research is being carried out to overcome the above-mentioned drawbacks by modifying them. For example, 1-(2-tetrahydrofuryl)
-5-Fluorouracil [Product name: Futrafur (Taiho Pharmaceutical);
50-64281, 51-146482 and 53-
84981], 1-n-hexylcarbamoyl-5-fluorouracil [Mitsui Pharmaceutical;
148365], TAC-278 [Takeda Pharmaceutical; Japanese Patent Application Publication No. 1973-
18586, 53-53672 and 53-103480] are representative examples. The present inventors have completed the present invention as a result of intensive research aimed at developing a prodrug of 5-FU, improving its administration form, reducing side effects caused by itself or its metabolites, and improving its ability to reach tumor cells. It was time to do it. The compound of the present invention is represented by the following general formula. [In the formula, R ¹ and R ₂ are hydrogen or the formula:

[Formula] or

[Formula] (wherein R ³ and R ⁴ each represent hydrogen, hydroxy, trialkylsilyloxy, alkoxy, or cyano, and R ⁵ and R ⁶ each represent alkyl). However, the case where R ¹ and R ² are both hydrogen is excluded. ] In the above definition, alkoxy has 1 to 1 carbon atoms.
5 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, t-butoxy, pentyloxy,
Isopentyloxy, neopentyloxy, t-
Examples include pentyloxy. Trialkylsilyloxy is silyloxy having three same or different alkyl groups having 1 to 4 carbon atoms, and includes trimethylsilyloxy, triethylsilyloxy,
It means tripropylsilyloxy, dimethylethylsilyloxy, dimethylpropylsilyloxy, diethylmethylsilyloxy, methylethylpropylsilyloxy, dimethylbutylsilyloxy, dimethyl t-butylsilyloxy, and the like.
Alkyl means lower alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, and the like. The compounds () of the present invention may each have isomers, but these are also included within the scope of the present invention. The compound () of the present invention comprises 5-FU represented by the following general formula () and the general formula () or ().
It can be easily produced from the compound represented by using a known method. (In the formula, R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as above, and X represents a halogen.) More specifically, (A) 5-FU () is replaced with the compound () or ().
(The halogen shown in the formula represents chlorine, bromine or iodine) is reacted with an equimolar amount of 1-substituted-5 shown in the following general formula (Ia).
-FU is obtained as the main product. (B) Compound () or () in 5-FU ()
When the excess amount, theoretically 2 equivalents, is applied, the 1,3-disubstituted-
5-FU is obtained as the main product. (C) 1,3-di-substituted-5-FU obtained in (B) above
When formula (b) is hydrolyzed, the following general formula (
3-substituted-5-FU shown in c) is obtained. [In the formula, R ^1a and R ^2a each have the formula:

[expression] or

[Formula] (wherein R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as above). ] The reactions (A) and (B) are carried out in a suitable solvent under ice cooling. The solvent may be appropriately selected from aprotic solvents such as acetonitrile, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and hexamethylphosphoric triamide, with dimethylformamide being preferred. In order for the reaction to proceed smoothly, it is recommended to add a base to neutralize the hydrogen halide (HX) produced as a result of the reaction. As the base, organic bases such as pyridine and triethylamine, and inorganic bases such as sodium carbonate and potassium carbonate are preferred. The hydrolysis reaction in (C) is achieved by reacting aqueous ammonia in pyridine-ethanol, and only the substituent at the 1-position is selectively removed. Raw material () or () is a compound ()
Or from (), Org.Synth.Collect.Volume 5, 145
It can be manufactured according to the method on page 1. (In the formula, R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as above.) The compound ( ) of the present invention has excellent antitumor activity. The activity test is performed as described below to determine the effectiveness. (1) Effect on murine leukemia L1210 (test method) 10 ⁵ ascites cells of L1210 murine leukemia are diluted with physiological saline and injected intraperitoneally into 5-week-old BDF ₁ mice. 8-10 mice are used for the control group, and 6-7 mice are used for the experimental group. The test drug is administered intraperitoneally or orally for 5 consecutive days to the experimental group. (Determination of effectiveness) Calculate the survival rate (ILS) from the average survival days of each administration group and the average survival days of the control group according to the formula below. ILS (%) = Average survival days of the treated group - Average survival days of the control group / Average survival days of the control group x 100 Also, the dose at the time of maximum ILS (maximum effect dose) and the dose at time of ILS of 30% Calculate the chemotherapy index (CI) from the dose (minimum effective dose) according to the formula below. The larger this value is, the higher the safety is. CI=Maximum effect dose (mg/Kg)/Minimum effect dose (mg/Kg) (Test drug) A: 5-FU B: Futorafur C: 1-(3-oxo-6-cyano-1,3-
dihydro-1-isobenzofuranyl)-
5-FU D:3-(3-oxo-6-cyano-1,3-
dihydro-1-isobenzofuranyl)-
5-FU E: 1,3-bis(3-oxo-6-cyano-
1,3-dihydro-1-isobenzofuranyl)-5-FU F:1-(3-oxo-1,3-dihydro-1
-isobenzofuranyl)-5-FU G:3-(3-oxo-1,3-dihydro-1
-isobenzofuranyl)-5-FU

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[Table] (2) Effect on murine leukemia P388 (test method) 10 ⁶ P388 leukemia cells were intraperitoneally transplanted into 6-week-old BDF1 male mice, and the test drug was administered intraperitoneally for 5 consecutive days starting from the next day. Administer orally.
Nine to ten mice are used as a control group and six to seven mice are used as an experimental group. The effect is determined in the same way as (1). The test results are shown in Tables (2)-1 to (2)-4. (Result)

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[Table] ( ³ ) Effect on mouse Ehrlichi carcinoma cells (test method)
- The test drug is subcutaneously implanted into male mice, and the test drug is administered intraperitoneally or orally for 10 consecutive days starting the next day. Mice were aged 6 to 7 in both control and experimental groups.
use one. On day 15, kill the mice and excise the tumor to determine efficacy. The tumor index is expressed as a relative ratio of the tumor weight of the experimental group, with the resected tumor weight of the control group being 1.00. Further, the CI value is expressed as _LD50 / _ED50 . The test results are shown in Tables (3)-1 to (3)-4. (Result)

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[Table] (4) Effect on mouse Sarcoma 180 (test method) 5 x 10 ⁶ Sarcoma 180 tumor cells were incubated at 5 weeks of age.
The test drug is subcutaneously implanted into DS female mice, and the test drug is administered intraperitoneally or orally for 10 consecutive days starting the next day. Mice were aged between 6 and 6 for both control and experimental groups.
Nine animals were used, killed on the 11th day after the start of the test, and the tumors were excised, and the efficacy was determined in the same manner as in test method (3). The test results are shown in Tables (4)-1 to (4)-4. (Result)

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[Table] As is clear from the above results, the compound () of the present invention has an excellent antitumor effect and can be used as an antitumor agent for humans or animals. In particular, treatment and prevention of metastasis of malignant tumors such as uterine cancer, esophageal cancer, skin cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer, bladder cancer, chorionic tumor, brain tumor, lymphosarcoma, and leukemia. is effective. In addition, since the effective dose range is relatively wide, it has the advantage that the dosage can be easily increased or decreased. The compounds of the present invention () can be administered orally or parenterally to humans or animals. For example, the compound () can be dissolved or suspended in a suitable injectable solvent (e.g., distilled water for injection, ethanol, glycerin, propylene glycol, olive oil, peanut oil, etc.) and administered intravenously, intramuscularly, or subcutaneously. Can be administered. When used as an injection, the compound () can be sealed in an ampoule as a solution or suspension, but it can also be stored in an ampoule or vial as a crystal, powder, microcrystal, lyophilized product, etc. It is preferable to prepare and use it. Additionally, a stabilizer may be added. The compound () may also contain pharmaceutical ingredients such as diluents (e.g. starch, sucrose, lactose, calcium carbonate, kaolin, etc.), lubricants (e.g. stearic acid, sodium benzoate, boric acid, silica, polyethylene glycol), etc. powder, tablets, granules, capsules, troches,
It can be formed into dry syrup and administered orally. When compound () is used for tumor treatment in adults,
It is usually administered orally at a daily dose of 500 mg to 10 g, 1 to 3 times a day. However, it is preferable to increase or decrease the dose as appropriate depending on the patient's age, medical condition, medical history, etc. Examples are shown below to clarify aspects of the present invention. Example 1 Production of 1-(3-oxo-6-cyano-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 5 g (31 mmol) of 3-oxo-6-cyano-1,3-dihydroisobenzofuran and 9.0 g (50 mmol) of N-bromosuccinimide were added to tungsten under reflux in 300 ml of a 1:1 mixture of carbon tetrachloride and benzene. By irradiating light with a lamp for about 3 hours to react, 1-bromo 3-oxo-6-cyano-1,
3-dihydroisobenzofuran is obtained. Without purification, this bromo compound was dissolved together with 4 g (31 mmol) of 5-FU in 40 ml of anhydrous dimethylformamide, and 4.3 ml (31 mmol) of triethylamine was added dropwise to the solution under ice-cooling and stirring. The reaction mixture was further stirred for 15 hours under ice cooling. The resulting precipitate is washed with a small amount of ice-cold anhydrous dimethylformamide, then three times with cold water, twice with cold methanol, and twice with ether to give 3.8 g of the title compound as a crude product. The liquid and washing liquid were combined and extracted with a mixture of ethyl acetate and acetonitrile (1:1). The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was dissolved in benzene-ethyl acetate (2:
1) Separate the mixed solution by silica gel column chromatography using a developing solvent to obtain an additional 1.2 g of the title compound. When both are combined and recrystallized from methanol, 4.81 g (yield 54%) of the title compound is obtained. Melting point 269-271℃ Elemental analysis Calculated value (as C ₁₃ H ₆ O ₄ N ₃ F): C, 54.37;
H, 2.11: N, 14.63; F, 6.61 Experimental value: C, 54.46; H, 2.37; N, 14.62;
F, 6.48 IR: ν ^KBr _nax 2240, 1779, 1734, 1714, 1687,
1674cm ^-1 UV: λ ^EtOH _nax nm (ε); 240.5 (10700), 24
7.5
(10700) NMR: δ ^d 6 ^-DMSO 7.5 (s, 1H), 7.74 (d,
J = 7Hz, 1H), 8.04 (s, 2H), 8.28 (s,
1H), 12.0 (broad, 1H). 1,3-bis(3-oxo-6-cyano-1,3-dihydro-
0.5 g (yield 3.6%) of 1-isobenzofuranyl)-5-fluorouracil is obtained. Example 2 1,3-bis(3-oxo-6-cyano-1,
3-dihydro-1-isobenzofuranyl)-5
-Manufacture of fluorouracil 5-FU1.67g (12.9 mmol) and 3-oxo-6-cyano-1,
1-bromo-3-oxo-6 synthesized from 4.16 g (25.8 mmol) of 3-dihydroisobenzofuran
-Cyano-1,3-dihydroisobenzofuran is dissolved in 28 ml of anhydrous dimethylformamide, and 4 ml (25.8 mmol) of triethylamine is added dropwise while cooling with ice and stirring. After stirring and reacting for an additional 17 hours under ice-cooling, the triethylamine bromate produced was removed and the mixture was washed with a small amount of ice-cooled dimethylformamide. The solution and washing solution were combined and dimethylformamide was distilled off under reduced pressure. The residue was separated and purified using silica gel chromatography using a benzene-ethyl acetate (2:1) mixture as the developing solvent, and then re-purified from ethyl acetate-ethanol. 2.95g of the title compound crystallized
(yield 51%). This is an approximately 1:1 diastereomeric mixture that is difficult to separate.
Melting point 200-215°C Example 3 Production of 3-(3-oxo-6-cyano-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 1,3-bis(3-oxo-6-cyano-1,
3-dihydro-1-isobenzofuranyl)-5-
Dissolve 4.48 g (10 mmol) of fluorouracil in 50 ml of pyridine-ethanol (1:(1) mixture, and add 1.2 ml of 28% ammonia water while stirring on ice.
After further stirring for 1.5 hours under ice cooling, the solvent was distilled off and the resulting residue was mixed with benzene-ethyl acetate (1:1).
Separate and purify the mixed solution using silica gel column chromatography using a developing solvent. The obtained product was recrystallized from methanol to obtain 1.22 g of the title compound (yield: 42
%). Melting point 277-281℃ Elemental analysis Calculated value (as C ₁₃ H ₆ O ₄ N ₃ F): C, 54.37;
H, 2.11; N, 14.63; F, 6.61. Experimental value: C, 54.57; H, 2.56; N, 14.31;
F, 6.28. IR: ν ^KBr _nax 2225, 1794, 1725, 1660cm ^-1 . UV: λ ^EtOH _nax nm (ε) 240.5 (18300), 248.
8
(17600) NMR: δ ^d 6 ^-DMSO 4.0 (broad, 1H), 7.84
(s, 1H), 7.92 (d, 1H, J=6Hz), 8.08
(s.2H), 8.30 (s, 1H). Example 4 Production of 1,3-bis(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 4.02 g (30.9 mmol) of 5-FU and 14.5 g (68 mmol) of 1-bromo-3-oxo-1,3-dihydroisobenzofuran (Org.Synth.Coll.Vol.,
V p145) and 60 ml of anhydrous dimethylformamide.
Dissolve triethylamine 9.6 in ice-cooled and stirred
ml (68 mmol) dropwise. Cool on ice for 1 hour.
After stirring for an additional hour at room temperature, the triethylamine hydrochloride formed was removed and washed with a small amount of cold dimethylformamide. The product obtained by distilling off dimethylformamide was separated by silica gel column chromatography using a mixture of benzene and ethyl acetate (2:1) as a developing solvent, and two types of title compounds having a diastereoisomeric relationship were obtained. A, 4.58g (yield 37%), title compound B, 2.25g
(Yield: 19%) and 3.14g of mixture of A and B (Yield: 26%)
%) was obtained. TLC Rf value (Merck silica gel 60F
-254, 0.25mm): A isomer, 0.28; B isomer,
0.28. Title compound, A isomer Melting point 258-261°C Elemental analysis Calculated value (as C ₂₀ H ₁₁ O ₆ N ₂ F): C, 60.92;
H, 2.81; N, 7.11 Experimental value: C, 60.73; H, 2.66; N, 6.97. IR: ν ^KBr _nax 1785, 1736, 1698, 1678 cm ^-1 . UV: λ ^EtOH _nax nm (ε); 228.5 (14100 ), 27
1
(6800). NMR: δ ^d 6 ^-DMSO 7.4-8.3 (m, 11H) Title compound, B isomer melting point 251-254°C Elemental analysis Calculated value (as C ₂₀ H ₁₁ O ₆ N ₂ F): C, 60.92;
H, 2.81; N, 7.11. Experimental value: C60.59; H, 2.63; N, 7.09. IR: ν ^KBr _nax 1770, 1738, 1690 cm ^-1 . UV: λ ^EtOH _nax nm (ε); 228.5 (21000) ,27
0
(10000). NMR: δ ^d 6 ^-DMSO 7.4-8.3 (m, 1H). When the mother liquor was separated by silica gel chromatography using a benzene-ethyl acetate (1:1) mixture as the developing solvent, a small amount of 1-(3-oxo-1,3-
Crystals of dihydro-1-isobenzofuranyl)-5-fluorouracil are obtained. Melting point: 290℃ or higher Elemental analysis Calculated value (as C ₁₂ H ₇ O ₄ N ₂ F): C, 54.97;
H, 2.69; N, 10.69; F, 7.24. Experimental value: C, 54.95; H.2.77; N, 10.38; F,
7.64. IR: ν ^KBr _nax 1798, 1715, 1686, 1670cm ^-1 . UV: λ ^EtOH _nax nm (ε); 227 (17400), 264
(10000) NMR: δ ^d 6 ^-DMSO 4.36 (broad, 1H), 7.5-8.2
(m, 4H), 7.56 (s, 1H), 7.67 (d, J=7
Hz, 1H). Example 5 Production of 3-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 1.5 g (3.8 mmol) of a mixture of two diastereoisomeric isomers of 1,3-bis(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil was added to 6 ml of pyridine. Dissolve in this 0.75ml of 28% ammonia water
Add 30 ml of ethanol and react at 60°C for 4.5 hours. The solvent was distilled off under reduced pressure and chloroform was added to the residue to obtain 671 mg of crude crystals of the title compound. This was recrystallized from methanol to obtain the title compound.
Obtain 483 mg (48% yield). Melting point 231-234 and 257-262°C Elemental analysis Calculated value (as C ₁₂ H ₇ O ₄ N ₂ F): C, 54.97;
H, 2.69; N, 10.69; F, 7.24. Experimental value: C, 55, 31; H, 2.66; N, 10.58;
F.7.17. IR: ν ^KBr _nax 1788, 1736, 1667 cm ^-1 . UV: λ ^EtOH _nax nm (ε); 227.5 (11100), 27
Five
(7200). NMR: δ ^d 6 ^-DMSO 3.0-6.5 (broad, 1H), 7.35
~8.05 (m, 4H), 7.76 (s, 1H), 7.88 (d, J
=6Hz, 1H). Example 6 Production of 1,3-bis(5-oxo-4,4-dimethyl-2,3,4,5-tetrahydro-2-furyl)-5-fluorouracil 3.9 g (30 mmol) of 5-FU and 11.6 g (60 mmol) of 2,2-dimethyl-4-bromobutyrolactone were dissolved in 150 ml of dimethylformamide, and 8.76 ml (63 mmol) of triethylamine was added under stirring under ice cooling. React for 17 hours at room temperature. The residue obtained by distilling off the solvent was separated by silica gel chromatography using a mixture of benzene and ethyl acetate (2:(1)), and recrystallized from acetone-ether to separate diastereoisomers. Title compound A isomer of species, 2.60 g
(24.6%) and title compound B isomer, 2.32 g (21.8
%), TLC Rf value (Merck silica gel 60F
-254, 0.25mm): A isomer, 0.46, B isomer,
0.34. Title compound, A isomer Melting point 255-256°C Elemental analysis Calculated value (as C ₁₆ H ₁₉ O ₆ N ₂ F): C, 54.23;
H, 5.40; N, 7.90; F, 5.36. Experimental value: C, 54.42; H5.44; N, 7.78; F,
5.63. IR: ν ^Nujol _nax 1800, 1780, 1730, 1705, 16
75 ^-1 . NMR: δ ^d 6 ^-DMSO 1.30-1.33 (m, 12H), 220
~ ^(T ― ⁶⁰⁾ 2.57 (m, 4H), 6.33 ~ 6.67 (m,
1H), 6.73-7.07 (m, 1H), 8.33 (d, J=7
Hz, 1H). Title compound, B isomer Melting point 194-195°C Elemental analysis Calculated value (as C ₁₆ H ₁₉ O ₆ N ₂ F): C, 54.23;
H, 5.40; N, 7.90; F, 5.36. Experimental value: C, 54.24; H, 5.32; N, 7.79;
F5.24. IR: ν ^{CHC 3} _nax 1795, 1735, 1680 cm ^-1 . NMR: δ ^{CDC 3} 1.26~1.67 (m, 12H), 2.13~
^(T ― ⁶⁰⁾ 3.00 (m, 4H), 6.27 to 6.63 (m, 1H),
6.77-7.10 (m, 1H), 7.50 (dJ=5Hz, 1H). Example 7 3-(5-oxo-4,4-dimethyl-2,
3,4,5-tetrahydro-2-furyl)-5
-Manufacture of fluorouracil 1,3-bis(3-oxo-4,4-dimethyl-1,3,4,5-tetrahydro-1-furanyl)-5-fluorouracil (two diastereoisomers) obtained in Example 6. Dissolve the crude product (mixture of isomers) in a mixture of 100 ml of pyridine and 200 ml of ethanol, add 5.1 ml of 28% aqueous ammonia, and react at 60°C for 4.5 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography using a benzene-ethyl acetate (2:1) mixture and recrystallized from acetone-ether to give 2.03 g (yield: 39.3% from 5-fluorouracil). ) to obtain the title compound. Melting point 194-195℃ Elemental analysis Calculated value (as C ₁₀ H ₁₁ O ₄ N ₂ F): C, 49.58,
H, 4.57; N, 11.56; F7.84. Experimental value: C, 49.07; H, 4.59; N, 11.20;
F, 8.17. IR: ν _nax ^(Nuj) 1760, 1720, 1660cm. NMR: δ ^d 6 ^-acetone 1.37 (s, 3H), 1.40
(s, ^(T ― ⁶⁰⁾ 3H), 2.47~2.77 (m, 2H), 6.80~
7.17 (m, 1H), 7.73 (d, J=5Hz, 1H). Examples 8-9 The compounds in Table 5 can be prepared in the same manner as in Example 1.

[Table] Examples 10 to 11 The compounds shown in Table 6 can be produced in the same manner as in Example 2.

【table】

[Table] Example 12 The compound of Example 11 is hydrolyzed with tetra-n-butylammonium fluoride to obtain the following compound. Isomer A IR: ν ^KBr _nax 1777, 1740, 1696, 1686 cm ^-1 UV: λ ^EtOH _nax nm (ε) 262.5 (26400), 312
(3600), 290 (sh). NMR: δ ^d 6 ^-DMSO 6.85-7.95 (m, 9H). mp.200～212℃ Isomer B IR: ν ^KBr _nax 1777, 1727, 1672mm ^-1 . UV: λ ^EtOH _nax nm (ε) 2.63 (20400), 311
(8500), 291 (sh). NMR: δ ^d 6 ^-DMSO 6.55-7.85 (m.9H). mp.172-174°C Example 13 The following compound can be produced in the same manner as in Example 3. IR: ν ^{CHC 3} _nax 1780, 1741, 1696 cm ^-1 . UV: λ ^EtOH _nax nm (ε) 256 (18000). NMR: δ _{CDC 3-DMSO(2} : ₁₎ 0.27 (s, 6H),
0.96 (s, 9H), 6.8-7.2 (m, 2H), 7.52 (d,
1H), 7.69 (s, 1H), 7.74 (d, 1H), 12.0
(br, 1H). Example 14 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil (1) Reaction using triethylamine in dimethylformamide-5-FU 13g (0.1 mol) and 1
16.9 g (0.1 mol) of -chloro-3-oxo-1,3-dihydroisobenzofuran is dissolved in 195 ml of anhydrous dimethylformamide, and 13.9 ml (0.1 mol) of triethylamine is added dropwise while stirring under ice cooling. After returning to room temperature and reacting for an additional 15 hours,
Add the reaction mixture to 1 liter of ice water with stirring. Stir for an additional 30 minutes under ice cooling, filter the resulting crystalline product, and wash three times with 200 ml each of water. The obtained crystals were dried to yield 22.8g (yield 87
%) of the title compound. (2) Reaction using triethylamine in acetonitrile - 1.3 g (10 mmol) of 5-FU was suspended in 26 ml of acetonitrile, and 1-chloro-
3-oxo-1,3-dihydroisobenzofuran 1.69 (10 mmol) and triethylamine
Add 1.39 ml (10 mmol) and stir at room temperature for 15 hours. After pouring the reaction mixture into 130 ml of ice water and stirring well, the formed crystal product was collected.
Wash with water and acetonitrile, then dry.
2.26 g (86% yield) of the title compound are obtained. (3) Reaction using potassium carbonate in dimethyl sulfoxide - 26 g (0.2 mol) of 5-fluorouracil and 33.7 g (0.2 mol) of 1-chloro-3-oxo-1,3-dihydroisobenzofuran are dissolved in 260 ml of anhydrous dimethyl sulfoxide. Then, 27.6 g (0.2 mol) of anhydrous potassium carbonate was added while stirring on ice and allowed to react for about 1 hour. Then, 1.3 g of ice water containing 200 ml of 1N hydrochloric acid was added to the reaction mixture with stirring. After stirring for a further approximately 30 minutes, the crystalline product formed is filtered and washed five times with 200 ml each of water and twice with 200 ml of methanol. The obtained crystals are dried to obtain 48.0 g (yield 92%) of the title compound, 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil. Melting point: 290℃ or higher (recrystallized from dimethyl sulfoxide-methanol)

Claims (1)

[Claims] 1. A 5-fluorouracil derivative represented by the following general formula. [In the formula, R ¹ and R ² are each hydrogen or the formula: [Formula] or [Formula] (wherein, R ³ and R ⁴ are each hydrogen, hydroxy, trialkylsilyloxy, alkoxy, or cyano, and R ⁵ and Each R ⁶ represents an alkyl group. However, the case where R ¹ and R ² are both hydrogen is excluded. ]