JPS6247197B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the following general formula (), [In the formula, R is a group -L ₁ -O-R ₁ or a group -L ₁ -O-L ₂
-O-R ₁ (wherein L ₁ and L ₂ are the same or different and represent an alkylene group, and R ₁ represents an alkyl group)]
The present invention relates to a di-O-acetyl-5-fluorouridine derivative, a method for producing the same, and an antitumor agent containing the same as an active ingredient. 2'-deoxy-5-fluorouridine (hereinafter referred to as
FUDR) is a compound used as an anticancer drug. However, as a pharmaceutical
FUDR not only has the drawbacks of being extremely toxic and has a narrow safety margin, but also has the critical drawback in practical treatment that its administration route is limited to intra-arterial injection, that is, it cannot be administered orally. are forced to be subject to restrictions (Fujishisha's Desk Reference, p. 1387,
(1978). Previously, the mechanism of action of FUDR to express its anticancer effects was studied by C. Heidelberger (C.
Heidelberger et al. carried out vigorous research, and by chemically modifying FUDR, they discovered a FUDR derivative that does not have the above-mentioned drawbacks and has a stronger anticancer effect. Research has also been conducted on this topic. However, as one of such FUDR derivatives,
2′-deoxy-3′・5′-di-O-acetyl-5-
It was discovered that fluorouridine (hereinafter referred to as acetyl FUDR) has properties that suggest that it is difficult to be degraded in vivo and can be administered orally (Cancer Research, 23
Vol. 49 et seq., 1963). However, according to the results of experiments conducted regarding anticancer activity, acetyl FUDR has been evaluated as having no significant difference or even being less effective than FUDR (Biochemical Pharmacology, Vol. 14, 1605 Pages below, 1965
, Cancer Research, vol. 23, p. 420 et seq.
(1963), which is extremely unsatisfactory. Many studies have been conducted on FUDR derivatives, but their results are, for example,
Cancer Research, Vol. 30, as a correlation between the chemical structure and anticancer activity of FUDR and its derivatives.
Pages 1555-1556, summarized in 1970. In other words, through the elucidation of the mechanism of action of FUDR to express its anticancer effect, the three types of enzyme activities that have been found to be key to the expression of the effect are used as indicators, and the molecular structure of FUDR is used as an indicator for the expression of this effect. A diagram is shown and explained that shows which parts and what forms are required above, and it is clearly stated that N at position 3 on the pyrimidine nucleus of FUDR must not be substituted. There is. The present inventors have discovered that for acetyl FUDR derivatives,
As a result of intensive research aimed at enhancing its antitumor activity and reducing its toxicity, surprisingly, contrary to the above-mentioned findings, the N at position 3 on the pyrimidine nucleus of FUDR was replaced with a specific aroyl group. The present invention was completed by discovering that a novel compound of the substituted formula () has favorable effects. The present invention will be described in more detail as follows.
(), where R is a group -L ₁ -O-R ₁ or a group -L ₁ -O
-L ₂ -R ₁ (where L ₁ and L ₂ are the same or different and represent an alkylene group, and R ₁ represents an alkyl group), but preferred L ₁ and L ₂ are a methylene group, an ethylene group, and an alkyl group. Preferred examples of R ₁ include alkyl groups having 1 to 3 carbon atoms such as methyl group, ethyl group, and propyl group. Particularly preferable examples of R include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, an ethoxyethyl group, a propoxymethyl group, a propoxyethyl group, a methoxyethoxymethyl group, a methoxyethoxyethyl group, an ethoxyethoxyethyl group, and the like. The compound of formula () of the present invention can be produced, for example, by either of the following two methods. Method A General formula () for acetyl FUDR, A method of reacting benzoic acid halide represented by the formula (wherein, hal represents a halogen atom, and R has the meaning described above). Method B General formula (), 3-(Hydroxy-substituted benzoyl)-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine represented by the general formula (), R-hal () (in the formula, hal and A method of reacting an alkyl halide represented by (R has the meaning described above). The raw material halide used in Method A and Method B is particularly preferably chloride, and the molar ratio used is:
It is preferable to use 1 to 4 moles per mole of the other uridine derivative in each method. Methods A and B co-reactions are usually preferably carried out in organic solvents, in particular aprotic solvents such as ether, dioxane, chloroform, acetonitrile, pyridine, dimethylformamide, etc. in method A and in particular in method B. Preferably, aprotic solvents such as acetone and methyl ethyl ketone are used, respectively. In both methods A and B, the reaction is preferably carried out in the presence of a base; in method A, it is preferably carried out in the presence of an organic base, particularly an aromatic amine such as trialkylamine, pyridine, etc. is preferred. The base is usually used in an amount of 1 to 5 moles per mole of benzoic acid halide, but when the organic base itself is used as a solvent, a larger number of moles can be used. In addition, in method B, it is preferable to carry out in the presence of an inorganic base, particularly in the presence of sodium carbonate, potassium carbonate, etc. The base is an alkyl halide 1
It is preferable to use 0.5 to 3 moles per mole. The reaction proceeds under ice cooling or at the boiling temperature of the solvent, and the reaction time is preferably 30 minutes to several hours. The reaction product is isolated and purified by concentrating the liquid obtained by filtering the reaction mixture under reduced pressure and recrystallizing it or by chromatography to obtain the compound of the present invention. When obtained as a viscous oil, after dissolving in a small amount of ethanol, dimethyl sulfoxide, or a mixed solution of these,
The compound of the present invention can also be obtained as a solid by gradually pouring this into water while stirring. Next, the pharmacological tests conducted on the compound of the present invention thus obtained and the results thereof will be shown. Test method (a) Test for measuring antitumor activity Approx.
Ten million cells were implanted subcutaneously in the inguinal region of 5-week-old ICR male mice. After 24 hours, administration of compounds of the invention began. Administration was forcibly administered once a day for 7 days using an oral probe. The weight of each animal was measured every day immediately before administration. The compound of the present invention is polyethylene glycol
Polyethylene glycol 400 alone was administered to the control group in the same volume of 0.1 ml/10 g to each animal. The dosage of the compound of the present invention varies depending on the individual compound, but is generally in the range of 1 mg/Kg to 200 mg/Kg.
The compound of the invention was administered to one group of mice (consisting of 6 mice) at each dose step over 12 steps. Note that 18 mice were used in the control group. Eight days after transplantation, the mice were sacrificed by exsanguination under ether anesthesia, tumor tissues were removed, and tumor weights were immediately measured.
For each compound, the average tumor weight (this is referred to as T) and the average value of tumor weight in the control group (this is referred to as C) are determined for each dose, and the T/C value is 0.70 and 0.50. I read out the numerical value indicating . For evaluation of antitumor activity, T/C value is
It is considered to be somewhat effective if it is between 0.70 and 0.51, and effective if it is less than 0.50 (Applied Pharmacology, Vol. 7,
pp. 1277-1292, 1973). Therefore T/C0.70
Alternatively, the smaller the value of 0.50, the stronger the antitumor activity. (b) Test for measuring toxicity Judging from the effects of the compounds of the present invention, toxicity values were determined by the following test method, taking into account cumulative toxicity. Five-week-old ICR male mice were used in groups of 10 mice. Administration was forcibly administered once a day for 7 days using an oral probe. The weight of each animal was measured every day immediately before administration. The compound of the present invention was dissolved or suspended in polyethylene glycol 400, and the same volume of 0.1 ml/10 g was administered to each animal. The dosage of the compound of the present invention is
Varies depending on individual compound, but approximately 30mg/Kg
to 400 mg/Kg, and the dosage of the same compound was varied over five stages, and one group of mice was administered the compound of the present invention at each dosage stage. The animals were determined to be alive or dead on the 14th day after the end of administration, and LD ₁₀ was determined by the Richfield-Wilkoxon method. Results The test results of (a) and (b) above and the therapeutic coefficient (LD ₁₀ value/T/C0.50 value) calculated from these were used as the first
Listed in the table. [Table] From the results shown in the above table, it is clear that the compounds of the present invention have more preferable antitumor activity than known compounds. The clinical dosage of the compounds of the invention is preferably in the range of 50 to 1000 mg per day. As for the administration route, parenteral administration such as intravenous injection and intrarectal administration using suppositories is possible, but oral administration is preferable. The dosage form for oral administration is 10 to 500 mg per unit.
Tablets containing the compound of the present invention as an active ingredient,
Examples include capsules and liquids. In addition to the active ingredient, these tablets and capsules may contain the following commonly used ingredients, such as excipients such as lactose, corn starch, potato starch, microcrystalline cellulose, etc.
As a binder, gum arabic, gelatin, hydroxypropylcellulose, potato starch, etc. are used; as a lubricant, magnesium stearate, talc, etc.; as a disintegrant, carboxymethyl cellulose calcium, potato starch, corn starch, etc. are used. For the liquid preparation, commonly used dissolving agents, suspending agents, etc. can be used, but it is particularly preferable to use polyethylene glycol 200 to 600. Next, an example will be given and explained. Example 1 3-{2-(2-methoxyethoxy)benzoyl}-2'-deoxy-3', 5'-di-O-acetyl-5-fluorouridine: 2'-deoxy-3', 5'- di-O-acetyl-5
- To a solution of 5.0 g (0.015 mol) of fluorouridine and 7 ml of triethylamine in 50 ml of dry dioxane, 4.5 g (0.021 mol) of 2-(2-methoxyethoxy)benzoyl chloride is added dropwise under ice-cooling and stirring. After leaving in a cold place overnight, react at room temperature for 5 hours with occasional shaking. The precipitated triethylamine hydrochloride is removed, and the solvent is distilled off from the solution under reduced pressure. The residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and then the sodium sulfate is removed. The solvent was distilled off from the solution under reduced pressure, and the target product was separated using column chromatography (Wakogel, C-200; eluent: chloroform), followed by preparative thin layer chromatography (Kieselgel).
GF ₂₅₄ , type 60; Separated and purified with developing solvent chloroform:methanol = 39:1) to yield 6.9g of oily substance.
(90.1%). Elemental analysis value C ₂₃ H ₂₅ FN ₂ O As ₁₀ Theoretical value (%): C, 54.33; H, 4.96; N, 5.51 Actual value (%): C, 54.12; H, 4.85; N, 5.63 UVλ ^EtOH _nax nm : 259 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.66
(d, H ₆ ), 6.26 (broad-t, H ₁ ′), around 2.4 (m, H ₂ ′), 5.16 to 5.32 (m, H ₃ ′), 4.22 to
4.44 (m, H ₄ ′, H ₅ ′), 2.15 (S, OCOC
H ₃ ), 2.08 (S, OCOC H ₃ ), 3-substituted benzoyl moiety: 8.10 (d, d, H ₆ ), 7.59 (t,
d, H ₄ ), 7.08 (t, H ₅ ), 6.95 (d, H ₃ ),
4.13 ₍ broad-t, _CH3OCH2CH2O- ), _3.60
(broad-t, CH ₃ OC H ₂ CH ₂ O-), 3.31 (S,
C H ₃ OCH ₂ CH ₂ O-) Example 2 3-(4-ethoxymethoxybenzoyl)-2'-
Deoxy-3', 5'-di-O-acetyl-5-fluorouridine: 3-(4-hydroxybenzoyl)-2'-deoxy-3', 5'-di-O-acetyl-5-fluorouridine 0.95 g (0.002 mol) in 20 ml of dry acetone
0.6 g of potassium carbonate is added, and 0.6 g of chloromethyl ethyl ether is added dropwise while stirring under reflux. When one of the raw materials, 3-(4-hydroxybenzoyl-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine) disappears in thin layer chromatography, the reaction is stopped and the mixture is cooled. , insoluble matter was removed, the liquid was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (Kieselgel GF ₂₅₄ , type
60;Developing solvent chloroform:methanol=
99.1), the resulting oil was dissolved in a small amount of ethanol-dimethyl sulfoxide, poured into ice water with stirring to form a powder, and dried over phosphorus pentoxide in a desiccator. Melting point 59−85
Obtain 0.6 g (58.8%) of white powder at °C. Elemental analysis value C ₂₃ H ₂₅ FN ₂ O As ₁₀ Theoretical value (%): C, 54.33; H, 4.96; N, 5.51 Actual value (%): C, 54.03; H, 4.83; N, 5.36 UVλ ^EtOH _nax nm : 282.5 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.86
(d, H ₆ ), 6.37 (broad-t, H ₁ ′), around 2.4 (m, H ₂ ′), around 5.3 (m, H ₃ ′), 4.28 to 4.50
(m, H ₄ ′, H ₅ ′), 2.17 (S, OCOC H ₃ ), 2.10
(S, OCOC H ₃ ), 3-substituted benzoyl moiety:
7.98 (d, H ₂ , H ₆ ), 7.21 (d, H ₃ , H ₅ ),
5.36 (s, CH ₃ CH ₂ OC _H2 O−), 3.78 (q,
CH ₃ C H ₂ OCH ₂ O−), 1.23 (t, C H _3
CH2OCH2O- ) Example 3 3-(3 _- ethoxymethoxybenzoyl)-2'-
Deoxy-3'.5'-di-O-acetyl-5-fluorouridine: A white powder with a melting point of 44-55°C was obtained in a yield of 23.3% in the same manner as in Example 2. Elemental analysis value C ₂₃ H ₂₅ FN ₂ O As ₁₀ Theoretical value (%): C, 54.33; H, 4.96; N, 5.51 Actual value (%): C, 54.36; H, 4.91; N, 5.36 UVλ ^EtoH _nax nm :261 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.66
(d, H ₆ ), 6.16 (broad-t, H ₁ ′), around 2.3 (m, H ₂ ′), around 5.16 (m, H ₃ ′), 4.14 to 4.40
(m, H ₄ ′, H ₅ ′), 2.11 (S, OCOC H ₃ ), 2.04
(S, OCOC H ₃ ), 3-substituted benzoyl moiety:
7.14-7.60 (m, aromaticH), 5.17 (S,
C ₂ H ₅ OC H ₂ O−), 3.67 (q, CH ₃ C H ₂ OC H ₂ O
-), 1.20 (t, CH ₃ CH ₂ O-CH ₂ O-) Example 4 3-(2-ethoxymethoxybenzoyl)-2'-
Deoxy-3'.5'-di-O-acetyl-5-fluorouridine: After reaction in the same manner as in Example 2, the reaction mixture was treated in the same manner as in Example 1 to obtain an oily product in a yield of 52.0%. Elemental analysis value C ₂₃ H ₂₅ FN ₂ O As ₁₀ Theoretical value (%): C, 54.33; H, 4.96; N, 5.51 Actual value (%): C, 54.47; H, 5.12; N, 5.69 UVλ ^EtoH _nax nm :258 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.40
(d, H ₆ ), 6.06 (broad-t, H ₁ ′), around 2.3 (m, H ₂ ′), around 5.04 (m, H ₃ ′), 4.04 to 4.30
(m, H ₄ ′, H ₅ ′), 2.08 (s, OCOC H ₃ ), 2.02
(S, OCOC H ₃ ), 3-substituted benzoyl moiety:
6.80~7.82 (m, aromaticH), 5.00 (s,
C ₂ H ₅ OC H ₂ O-), 3.50 (q, CH ₃ C H ₂ OCH ₂ O
-), 1.14 (t, C H ₃ CH ₂ OCH ₂ O-) Example 5 3-{4-(2-methoxyethoxy)methoxybenzoyl}-2'-deoxy-3'・5'-di-O- Acetyl-5-fluorouridine: An oily substance was obtained in the same manner as in Example 4 with a yield of 12.1%. Elemental analysis value C ₂₄ H ₂₇ FN ₂ O ₁₁ Theoretical value (%): C, 53.53; H, 5.05; N, 5.20 Actual value (%): C, 53.29; H, 5.16; N, 5.26 UVλ ^EtoH _nax nm :277 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.78
(d, H ₆ ), 6.30 (broad-t, H ₁ ′), around 2.5 (m, H ₂ ′), around 5.25 (m, H ₃ ′), 4.20 to 4.40
(m, H ₄ ′, H ₅ ′), 2.18 (s, OCOC H ₃ ), 2.10
(s, OCOC H ₃ ), 3-substituted benzoyl moiety:
7.90 (d, H ₂ , H ₆ ), 7.14 (d, H ₃ , H ₅ ),
5.34 (S _{, CH3OC2H4OCH2O-} ) _{, 3.44-3.90}
(m, CH ₃ OC H ₂ C H ₂ OCH ₂ O−), 3.36 (S, C
H ₃ OCH ₂ CH ₂ O−) Example 6 3-(3-propoxymethoxybenzoyl)−
2′-deoxy-3′・5′-di-O-acetyl-5
-Fluorouridine: 2'-deoxy-3', 5'-di-O-acetyl-5
- 4.6 g (0.02 mol) of 3-propoxymethoxybenzoyl chloride is added dropwise to a solution of 5.0 g (0.015 mol) of fluorouridine and 10 ml of triethylamine in 100 ml of dry dioxane under ice-cooling and stirring. Thereafter, the mixture is stirred and reacted at room temperature for 1 hour at 40 to 60°C for 4 hours. After the reaction, the same procedure as in Example 1 was carried out to obtain 2.0 g (25.5%) of an oil. Elemental analysis value C ₂₄ H ₂₇ FN ₂ O As ₁₀ Theoretical value (%): C, 55.17; H, 5.21; N, 5.36 Actual value (%): C, 55.32; H, 5.44; N, 5.53 UVλ ^EtoH _nax nm :257 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.82
(d, H ₆ ), 6.30 (broad-t, H ₁ ′), around 2.4 (m, H ₂ ′), around 5.3 (m, H ₃ ′), 4.24 to 4.50
(m, H ₄ ′, H ₅ ′), 2.16 (s, OCOC H ₃ ), 2.08
(s, OCOC H ₃ ), 3-substituted benzoyl moiety:
7.28-7.70 (m, aromaticH), 5.28 (S,
C ₃ H ₇ OC H ₂ O−), 3.64 (t, CH ₃ CH ₂ C H ₂
OCH ₂ O−), 1.63 (q, d, CH ₃ C H ₂
CH ₂ OCH ₂ O−), 0.92 (t, CH _{3
CH2CH2CH2O-} ) Examples 7 to 15 The compounds _of Examples 7 to 15 were synthesized in the same manner as _in Example 6. The results are shown in Table 2. [Table] [Table] Example 16 3-{2-(2-ethoxyethoxy)benzoyl}-2'-deoxy-3', 5'-di-O-acetyl-5-fluorouridine: 2'-deoxy- 3′・5′-di-O-acetyl-5
- 5.4 g (0.024 mol) of 2-(2-ethoxyethoxy)benzoyl chloride is added dropwise to a solution of 6.0 g (0.018 mol) of fluorouridine and 7.3 g (0.072 mol) of triethylamine in 40 ml of dry dioxane under ice-cooling and stirring. . Then 30 minutes at room temperature, 50
Stir and react at ~60°C for 2 hours. The precipitated triethylamine hydrochloride was removed, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and water, 0.01
Wash with a specified aqueous sodium hydroxide solution, then with water, and dry with anhydrous sodium sulfate. The sodium sulfate was removed, the liquid was concentrated under reduced pressure, the residue was separated and purified by column chromatography (Wako Gel C-200; eluent: chloroform), and the resulting oil was dissolved in a small amount of dimethyl sulfoxide. Pour into ice water while stirring, remove the precipitated powder,
Dry and powder over phosphorus pentoxide in a dessicator.
Obtain 7.2g (76.6%). Elemental analysis value: C ₂₄ H ₂₇ FN ₂ O as ₁₀ Theoretical value (%): C, 55.17; H, 5.21; N, 5.36 Actual value (%): C, 55.27; H, 5.37; N, 5.36 UVλ ^EtoH _nax nm: 259.5 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.43
(d, H ₆ ), 6.08 (broad-t, H ₁ ′), around 2.40 (m, H ₂ ′), 5.00 to 5.16 (m, H ₃ ′), 4.08 to
4.30 (m, H ₄ ′, H ₅ ′), 2.08 (S, OCOC H
₃ ), 2.00 (S, OCOC H ₃ ), 3-position substituted benzoyl moiety: 7.82 (d, d, H ₆ ), 7.34 (t,
d, H ₄ ), 6.80 (t, H ₅ ), 6.75 (d, H ₃ ),
3.99 (t, C ₂ H ₅ OCH ₂ C H ₂ O−), 3.51 (t,
C ₂ H ₅ OC H ₂ CH ₂ O−), 3.36 (q, CH ₃ C H ₂ O
-), 1.13 (t, CH3CH2O- ) Examples _17-18 Compounds of Examples _17-18 were synthesized in the same manner as in Example 16. The results are shown in Table 3. [Table] [Table] Example 19 3-[4-{2-(2-ethoxyethoxy)ethoxy}benzoyl]-2′-deoxy-3′・5′-di-O-acetyl-5-fluorouridine: 2′-deoxy-3′・5′-di-O-acetyl-5
- 6.6 g of 4-{2-(2-ethoxyethoxy)ethoxy}benzoyl chloride is dissolved in 30 ml of dioxane solution containing 3.9 g (0.012 mole) of fluorouridine and 9.5 g (0.094 mole) of triethylamine.
(0.024 mol) was added dropwise under ice-cooling and stirring. after that,
React at room temperature for 30 minutes and at 50-60°C for 1.5 hours, shaking occasionally. After the reaction, the precipitated triethylamine hydrochloride is removed, and the solvent is distilled off from the solution under reduced pressure. The residue is dissolved in chloroform, washed with water, 0.01N aqueous sodium hydroxide solution, and finally water, and dried over anhydrous sodium sulfate. After removing the sodium sulfate, the solvent is distilled off from the solution under reduced pressure. The residue was subjected to column chromatography (Wakogel C-200; eluent: chloroform) to decompose the target product, and then preparative thin layer chromatography (Kieselgel GF ₂₅₄ type 67;
Separation and purification using a developing solvent chloroform:methanol=39:1) yielded 1.0 g (14.7%) of an oily substance. Elemental analysis value: C ₂₆ H ₃₁ FN ₂ O ₁₁ Theoretical value (%): C, 55.12; H, 5.52; N, 4.94 Actual value (%): C, 55.40; H, 5.27; N, 5.06 UVλ ^EtoH _nax nm: 287.5 NMR (CDCl ₃ ) δ (ppm): Uridine moiety: 7.76
(d, H ₆ ), 6.30 (brad-t, H ₁ ′), around 2.4 (m, H ₂ ′), 5.16 to 5.34 (m, H ₃ ′), around 4.4 (m, H ₄ ′, H ₅ ′), 2.17 (S, OCOC H ₃ ),
2.09 (s, OCOC H ₃ ), 3-substituted benzoyl moiety: 7.90 (d, H ₂ , H ₆ ), 7.02 (d, H ₃ ,
H ₅ ), 3.20-4.35 (m, CH ₃ C H ₂ OC H ₂ C H ₂ OC
H ₂ C H ₂ O−), 1.22 (t, CH ₃ CH ₂ O−)

Claims (1)

[Claims] 1 General formula (), [In the formula, R is a group -L ₁ -O-R ₁ or a group -L ₁ -O-L ₂
-O-R ₁ (wherein L ₁ and L ₂ are the same or different and represent an alkylene group, and R ₁ represents an alkyl group)]
O-acetyl-5-fluorouridine derivative. 2'-deoxy-3'-2' according to claim 1, wherein L ₁ and L ₂ are alkylene groups having 1 to 3 carbon atoms, and R ₁ is an alkyl group having 1 to 3 carbon atoms. 5'-di-O-acetyl-5-fluorouridine derivative. 3 General formula (), [In the formula, R is a group -L ₁ -O-R ₁ or a group -L ₁ -O-L ₂
-O-R ₁ (wherein L ₁ and L ₂ are the same or different and represent an alkylene group, and R ₁ represents an alkyl group)]
An antitumor agent containing an O-acetyl-5-fluorouridine derivative as an active ingredient. 4 2'-deoxy-3'/5'-di-O-acetyl-, wherein L ₁ and L ₂ are alkylene groups having 1 to 3 carbon atoms, and R ₁ is an alkyl group having 1 to 3 carbon atoms. The antitumor agent according to claim 3, which contains a 5-fluorouridine derivative as an active ingredient. 5 2′-deoxy-3′・5′-di-O-acetyl-
5-fluorouridine has the general formula (), [In the formula, hal represents a halogen atom, R represents a group -L ₁ -
O-R ₁ or the group -L ₁ -O-L ₂ -O-R ₁ (where L ₁
and L ₂ are the same or different and represent an alkylene group,
The general formula () is characterized by reacting a benzoic acid halide represented by R ₁ represents an alkyl group), 2'-deoxy-3',5'-di-O-acetyl-5 represented by (in the formula, R has the above-mentioned meaning)
- A method for producing a fluorouridine derivative. 6. The method according to claim 5, wherein benzoic acid chloride in which hal is a chlorine atom is used, and the reaction is carried out in dioxane in the presence of triethylamine at 60° C. under ice cooling. 7 General formula (), 3-(hydroxy-substituted benzoyl)-
2′-deoxy-3′・5′-di-O-acetyl-5-
Fluorouridine has the general formula (), R-hal () [In the formula, hal is a halogen atom, R is a group -L ₁ -O-
R ₁ or the group -L ₁ -O-L ₂ -O-R ₁ (where L ₁ and
General formula () characterized by reacting an alkyl halide represented by [L ₂ is the same or different and represents an alkylene group and R ₁ represents an alkyl group]; 2'-deoxy-3',5'-di-O-acetyl-5 represented by (in the formula, R has the above-mentioned meaning)
- A method for producing a fluorouridine derivative. 8. The production method according to claim 7, wherein an alkyl chloride in which hal is a chlorine atom is used, and the reaction is carried out under heating and reflux in acetone in the presence of potassium carbonate.