JPS621399B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, A represents an N-acyl-α-aminocarboxy group) A novel 5-fluorouridine-5′-
This invention relates to ester derivatives and methods for producing the same. The 5-fluorouridine derivatives according to the present invention are all new substances created by the present inventors, and are used as pharmaceuticals, especially anti-cancer agents, anti-viral agents, etc.
It is a compound useful as an immunosuppressant and as an intermediate thereof. The N-acyl-α-aminocarboxy group that constitutes a part of the chemical structure of the 5-fluorouridine derivative according to the present invention is derived from the chemical structure of the corresponding N-acyl-α-aminocarboxylic acid. . Here, α-aminocarboxylic acid refers to a natural or synthetic amino acid, and examples of this α-amino acid include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, phenylalanine, Examples include tyrosine, tryptophan, proline, and oxyproline. Examples of acyl groups located at the N atom of α-aminocarboxylic acids include alkyl or aralkyloxycarbonyl groups such as ethoxycarbonyl and benzyloxycarbonyl; alkylcarbonyl groups having 1 to 10 carbon atoms such as methyl, ethyl, butyl, and nonyl. ;
Aroyl group such as benzoyl; phenylacetyl,
Examples include aralkylcarbonyl groups such as phenylpropionyl and benzoylthio lower alkylcarbonyl groups such as 2-(benzoylthio)propionyl. All of these novel 5-fluorouridine derivatives according to the present invention have excellent anti-malignant tumor activity. Examples of the results of examining this anti-malignant tumor effect in CDF ₁ mice are shown in Table 3 at the end of this specification. The 5-fluorouridine derivative according to the present invention is
It has an excellent anti-malignant tumor effect, and has an extremely large safety factor (maximum life extension rate dose/25% life extension rate dose), making it excellent in terms of safety. The 5-fluorouridine derivative according to the present invention is N
It can be obtained by bonding the carboxy group of -acyl-α-aminocarboxylic acid and the 5'-OH position of 5-fluorouridine through an ester bonding reaction and esterifying it. The method of this esterification itself is not well specified, either of the well-known esterification methods or their variations. N-acyl-α-aminocarboxylic acid, which is one of the starting materials, is obtained from a suitable acyl halide and α-aminocarboxylic acid that meet the purpose of the present invention according to a conventional method, and can be used in its original form. Alternatively, it can be converted into a reactive derivative such as a halide or anhydride thereof and then subjected to the reaction. In addition, 5-fluorouridine, which is the other starting material, is a known substance, and in order to prevent side reactions, its -OH at the 2' and 3' positions are usually protected with a protecting group by a conventional method. It is best to use this form for the reaction. The protecting group at that time is not specified,
Examples include alkylidene groups such as isopropylidene, ethoxyethylidene, and benzylidene. A preferred reaction method is to form an ester bond between N-acyl-α-aminocarboxylic acid and 2',3'-O-alkylidene-5-fluorouridine, and then remove the alkylidene group to obtain the target compound. In order to form an ester bond between N-acyl-α-aminocarboxylic acid and 2',3'-O-alkylidene-5-fluorouridine by this method, for example, by a conventional method, both are combined in a basic solution in an anhydrous solvent. The compound is reacted with a condensing agent at 40°C or lower in the presence of the condensing agent. In this case, an anhydrous aprotic solvent is used as the solvent, examples of which include benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, chloroform, monochloroethane, dichloroethane, trichloroethane, etc., ether,
Examples include tetrahydrofuran, dioxane, pyridine, and nitromethane. As the above basic compound, tertiary amines such as trialkylamine, pyridine, picoline, and lutidine, or inorganic bases such as sodium bicarbonate, sodium carbonate, and barium carbonate can be used, but when pyridine is used, it also serves as a solvent. It has the advantage that it can also be done. As a condensing agent, arylsulfonyl chloride such as p-toluenesulfonyl chloride, triisopropylbenzenesulfonyl chloride, methanesulfonyl chloride, alkylsulfonyl chloride, dicyclohexyl carbodiimide,
Thionyl chloride, phosphorus oxychloride, etc. can be used. The molar ratio of each substance used in the reaction is usually, for example, 1 mole of 2',3'-O-alkylidene-5-fluorouridine to 1 mole each of N-acyl-α-aminocarboxylic acid, basic compound, and condensing agent. ~3 moles. The reaction is carried out at 40°C or lower and is usually completed in 1 to 44 hours. The intermediate produced as a result of this condensation reaction is separated by an appropriate method and the alkylidene group is removed to obtain the desired compound. The reaction to remove the alkylidene group is carried out by a conventional method.
It is carried out in a solvent in the presence of an acid at a temperature below 40°C. Examples of acids used in this case include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and trifluoroacetic acid, and examples of solvents include protic solvents such as water, methanol, ethanol, formic acid, acetic acid, etc., or mixtures thereof. can be given. Depending on the case, aprotic solvents may be used in combination. The reaction time is usually 30 minutes to 20 hours. The target compound produced is purified by chromatography or the like. Next, examples related to manufacturing are listed. Example 1 5'-O-(N-benzyloxycarbonylmethionyl)-5-fluorouridine 940 mg (3.3 mmol) of N-benzyloxycarbonyl-L-methionine and 2',3'-O-ethoxyethylidene-5 -Fluorouridine 530mg
(1.7 mmol) was azeotropically dehydrated three times with 5 ml of anhydrous pyridine, then dissolved in anhydrous pyridine, 1.0 g (3.3 mmol) of triisopropylbenzenesulfonyl chloride (hereinafter abbreviated as TPS) was added, and the mixture was heated for 20 minutes at room temperature.
The mixture was stirred for hours to react. The solvent was distilled off under reduced pressure, and the residue was mixed with 100 ml of chloroform and 100 ml of water (this aqueous layer was kept at pH 7.5-8 using solid sodium carbonate).
The chloroform layer was dried over anhydrous sodium sulfate, filtered, and then chloroform was distilled off under reduced pressure. The residue was dissolved in 3 ml of chloroform, adsorbed on 20 g of silica gel, and developed with chloroform containing 1% methanol to give 5'-O-(N-benzyloxycarbonylmethionyl)-2',3'-O-.
Ethoxyethylidene-5-fluorouridine 970
I got mg. [Nuclear magnetic resonance spectrum (DMSO-
d6) δppm11.46 (bs, 1H, H ₃ ), 8.08 (d,
1H, H ₆ ), 7.30 (s, 5H, phenyl proton),
5.7 (bs, 1H, H ₁ '), 5.10 (s, 2H, O-benzylmethylene proton), 3.6 (bq, 2H, C-methylene proton), 2.6 (s, 3H, s-methyl proton), 1.2 ( m, 3H, C-methyl proton)]. Next, dissolve this ester in 15 ml of ethanol, add 3 ml of 90% formic acid aqueous solution and 7 ml of water, and leave at room temperature.
The reaction was allowed to proceed for 20 hours. After the reaction solution was distilled off under reduced pressure, the residue was dissolved in 3 ml of chloroform and silica gel 15
The desired 5'-O-N-benzyloxycarbonylmethionyl-5-fluorouridine was obtained by adsorbing it on 5'-O-N-benzyloxycarbonylmethionyl-5-fluorouridine and developing it with chloroform containing 3% methanol.
790 mg was obtained as a colorless caramel. Mass analysis value: 527 (M ⁺ ), 397, 398, 130 Elemental analysis (as C ₂₂ H ₂₆ N ₃ O ₉ FS) C H N analysis value: 49.85% 5.02% 7.94% Theoretical value: 49.85% 5.02% 7.94% Example 2 5-O-(N-decanoylmethionyl)-5-
Fluorouridine 1.00g (3.30mmol) of 2',3'-O-isopropylidene-5-fluorouridine and 2.00g (6.60mmol) of N-decanoylmethionine were dissolved in 7ml of anhydrous pyridine, followed by 2.00g (6.60mmol) of TPS. was added and allowed to react at room temperature for 44 hours. After evaporating the solvent under reduced pressure, the residue was distributed between 100 ml of chloroform and 100 ml of water (this aqueous layer was kept at pH 7.5 to 8 using solid sodium carbonate), and the chloroform layer was dried over anhydrous sodium sulfate and filtered. Thereafter, chloroform was distilled off under reduced pressure. The residue was dissolved in 5 ml of chloroform, adsorbed on 150 g of silica gel, and developed with chloroform containing 1% methanol.
1.17 g of 5-fluorouridine was obtained as a colorless caramel. [Nuclear magnetic resonance spectrum (CDCl ₃ ) δ
ppm, 10.3 (bs, 1H, 3H), 7.70 (d, 0.5H,
H ₆ ), 7.60 (d, 0.5H, H ₆ ) 5.85 (bs, 0.5H,
H ₁ ′), 5.70 (bs, 0.5, H ₁ ′), 2.10 (s, 3H, methylthioproton), 1.61, 1.42 (s, s, 3H ×
2, isopropylidene methyl proton), 1.25
(bs, 14H, C-methylene proton), 0.90 (bt,
3H, C-methyl proton)]. Next, add 970 mg (1.65 mmol) of this ester to 90
% trifluoroacetic acid aqueous solution, and stirred and reacted at room temperature for 1 hour. The reaction solution was distilled off under reduced pressure, and the residue was dissolved in 5 ml of chloroform and adsorbed on 20 g of silica gel, and developed with chloroform containing 3% methanol to obtain the desired 5'-O-(N-decanoylmethionyl). )―
750 mg of 5-fluorouridine was obtained. mp133―
6℃ (isopropanol) Mass spectrometry: 547 (M ⁺ ), 418, 130, Elemental analysis (as C ₂₄ H ₃₈ N ₃ O ₈ SF) C H N analysis value: 52.74% 6.85% 7.81% Theoretical value: 52.64% 6.99 % 7.67% Example 3 5'-O-{N-(3-phenylpropionyl)
Methionyl}-5-fluorouridine N-(3-phenylpropion)methionyl
940 mg (3.35 mmol) and 600 mg (1.99 mmol) of 2′,3′-O-isopropylidene-5-fluorouridine
After dissolving in 20ml of anhydrous pyridine, 1.00g of TPS
(3.31 mmol) was added and reacted at room temperature for 4.5 hours.
When this reaction mixture was operated according to Examples 1 and 2, 5'-O-{N-(3-phenylpropionyl)methionyl 2',3'-O-isopropylidene-
350 mg of 5-fluorouridine was obtained as a colorless caramel. [Nuclear magnetic resonance (CDCl ₃ ) δppm,
7.54 (d, 0.5H, H ₆ ), 7.44 (d, 0.5H, H ₆ ),
7.21 (s, 5H, phenyl proton), 5.71 (d,
0.5H, H ₁ ′), 5.58 (d, 0.5H, H ₁ ′), 2.03 (s,
3H, thiomethyl proton), 1.55, 1.34 (s,
s, 3H×2, isopropylidene methyl proton)]. Add 440 mg (1.20 mmol) of the ester obtained above to
It was dissolved in 2 ml of 90% trifluoroacetic acid aqueous solution and reacted for 1 hour at room temperature. This reaction mixture was prepared in Example 1.
and 2, the desired 5′-O-{N
-(3-phenylpropionyl)methionyl}-
300 mg of 5-fluorouridine was obtained as a colorless caramel. Mass spectrometry: 525 (M ⁺ ), 394, 130, Elemental analysis (as C ₂₃ H ₂₈ N ₃ O ₈ FS) C H N analysis value: 52.64% 5.56% 8.11% Theoretical value: 52.56% 5.37% 8.00% Example 4 5′-O-(N-pentanoylmethionyl)-5
-Fluorouridine N-pentanoylmethionine 3.00g
(12.9 mmol) and 1.94 g (6.44 mmol) of 2',3'-O-isopropylidene-5-fluorouridine were azeotropically dehydrated with anhydrous pyridine, and then
5.50 g (18.2 mmol) of TPS was dissolved in 40 ml and reacted at room temperature for 25 hours. When this reaction mixture was treated according to Examples 1 and 2, 1.39 g of 5'-O-(N-(pentanoylmethionyl)-2',3'-O-isopropylidene-5-fluorouridine) was obtained as colorless caramel. [Nuclear magnetic resonance (CDCl ₃ ) δ
ppm, 7.62 (d, 0.5H, H ₆ ), 7.42 (d, 0.5H,
H ₆ ) 5.77 (bd, 0.5H, H ₁ ′), 5.62 (bd, 0.5H,
H ₁ ′), 2.07 (s, 3H, thiomethyl proton),
1.56, 1.36 (s, s, 3H x 2, isopropylidene methyl proton), 0.90 (bt, 3H, C-methylene proton)]. Ester obtained above 1.01g (1.95mmol)
was dissolved in 4 ml of chloroform, 20 ml of 90% trifluoroacetic acid aqueous solution was added, and the mixture was reacted at room temperature for 1.5 hours. This reaction mixture was treated according to Examples 1 and 2 to obtain 840 mg of 5'-O-(N-pentanoylmethionyl)-5-fluorouridine as a colorless caramel. Mass spectrometry: 477 (M ⁺ ), 347, 130, Elemental analysis (as C ₁₉ H ₂₈ N ₃ O ₈ SF) C H N analysis value: 47.61% 5.97% 8.52% Theoretical value: 47.79% 5.91% 8.80% Example 5 5'-O-(N-benzyloxycarbonylprolyl)-5-fluorouridine N-benzyloxycarbonyl-L-proline
3.30g (13.2mmol), 2',3'-O-isopropylidene-5-fluorouridine 2.00g (6.6mmol)
Dissolve in 14 ml of anhydrous pyridine, then add 4.00 g of TPS.
(13.2 mmol) was added, and the mixture was stirred and reacted at room temperature for 3 hours. When this reaction mixture was treated according to Examples 1 and 2, 3.00 g of 5'-O-(N-benzyloxycarbonylprolyl)-2',3'-O-isopropylidene-5-fluorouridine was obtained. Ta. [Nuclear magnetic resonance spectrum (CDCl ₃ , TMS), δppm,
10.0 (bs, 1H, H ₃ ), 7.35 (bs, 6H, phenyl proton and H ₆ ), 5.85 (bs, 0.5H, H ₁ ′) 5.75
(bs, 0.5H, H ₁ ′), 5.20 (s, 2H, benzyl methylene proton), 3.60 (bt, 2H, -N-methylene proton) 2.1 (m, 4H, C-methylene proton), 1.60 (s, 3H, isopropylidene methyl proton), 1.40 (s, 3H, isopropylidene methyl proton)]. Then 3.06g of the ester obtained above
(5.74 mmol) in 12 ml of 90% trifluoroacetic acid aqueous solution
The mixture was stirred and reacted at room temperature for 1.5 hours. This reaction mixture was treated according to Examples 1 and 2.
1.63 g of 5'-O-(N-benzyloxycarbonylprolyl)-5-fluorouridine was obtained. Melting point 137-144° (isopropanol) Mass spectrometry value: 493 (M ⁺ ), 358, 130, Elemental analysis (as C ₂₂ H ₂₄ N ₃ O ₉ F) C H N analysis value: 53.44% 4.89% 8.59% Theoretical value :53.55% 4.90% 8.52% Example 6 5'-O-(N-benzyloxycarbonylvalyl)-5-fluorouridine N-benzyloxycarbonyl-L-valyl
3.51 g (13.98 mmol) and 2',3'-O-isopropylidene-5-fluorouridine 2.72 g
(9.00 mmol) was azeotropically dehydrated with anhydrous pyridine, then dissolved in 50 ml of anhydrous pyridine and TPS5.40 g
(17.82 mmol) was added and reacted at room temperature for 20 hours. When this reaction mixture was treated according to Examples 1 and 2, 5'-O-(N-benzyloxycarbonylvaline)-2',3'-O-isopropylidene-
3.62 g of 5-fluorouridine was obtained as a colorless caramel. [Nuclear magnetic resonance spectrum (CDCl ₃ ,
TMS), δppm, 7.40 (s and d, 6H, phenyl proton and H ₆ ), 5.63 (d, 1H, H ₁ '), 5.18
(s, 2H, benzylmethyl proton), 5.0 (m,
2H, H ₂ ′ and H ₃ ′), 4.4 (bs, 4H, H ₅ ′, H ₄ ′ and N-methine proton), 2.2 (m, 1H, C-methine proton), 1.58, 1.46 (s, s , 3H×2, isopropylidene methyl proton), 0.92 (d,
d, 6H, isopropylmethyl proton)]. Next, 3.49 g of the ester obtained above was dissolved in 4 ml of chloroform, 10 ml of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was reacted at room temperature for 3 hours. When this reaction mixture was treated according to Examples 1 and 2,
2.11 g of 5'-O-(N-benzyloxycarbonylvalyl)-5-fluorouridine was obtained as a colorless caramel. Mass analysis value: 495 (M ⁺ ), 365, 130 Elemental analysis (as C ₂₂ H ₂₆ N ₃ O ₉ F・H ₂ O) C H N analysis value: 51.56% 5.25% 7.82% Theoretical value: 51.46% 5.50% 8.18% Example 7 5'-O-(N-benzyloxycarbonylphenylalanyl)-5-fluorouridine 3.00 g (10.0 mmol) of N-benzyloxycarbonyl-L-phenylalanine and 2',3'- O-isopropylidene-5-fluorouridine 1.50g
After dissolving (5.00 mmol) in 40 ml of anhydrous pyridine,
3.00 g (10.0 mmol) of TPS was added and stirred at room temperature for 2 hours to react. This reaction mixture was then treated according to the methods of Examples 1 and 2 to provide 5'-O-(N
-benzyloxycarbonylphenylalanyl)
2.80 g of -2',3'-O-isopropylidene-5-fluorouridine was obtained as a colorless caramel.
[Nuclear magnetic resonance spectrum (CDCL ₃ , TMS), δ
ppm, 7.39 and 7.3 (s and m, 11H, phenyl proton and H ₆ ), 5.68 (d, 1H, H ₁ '), 5.15
(s, 2H, O-benzylmethylene proton),
3.15 (d, 2H, C-benzyl proton), 1.58,
1.37 (s, s, 3H x 2, isopropylidene methyl proton)]. 1.20 g of this obtained ester was dissolved in 5 ml of 90% trifluoroacetic acid aqueous solution and stirred at room temperature for 30 minutes to react. This reaction mixture was treated according to Examples 1 and 2 to obtain 940 mg of 5'-O-(N-benzyloxycarbonylphenylalanyl)-5-fluorouridine as a colorless caramel. Mass analysis value: 543 (M ⁺ ), 414, 130, Elemental analysis (as C ₂₆ H ₂₆ N ₃ O ₉ F) C H N analysis value: 57.34% 4.83% 8.00% Theoretical value: 57.46% 4.82% 7.73% Implementation Examples 8 to 16 Corresponding N-acyl-α-aminocarboxylic acids and
The following compound was obtained using 2',3'-O-isopropylidene-5-fluorouridine. 5'-O-(N-phenylacetylmethionyl)
-5-fluorouridine, 5'-O-(N-benzoylglycyl)-5-fluorouridine, 5'-O-(N-decanoylglycyl)-5-fluorouridine, 5'-O-{N -(n-pentanoylglycyl)}-5-fluorouridine, 5'-O-{N-(2-benzoylthiopropionyl)glycyl}-5-fluorouridine, 5'-O-(N-benzyloxycarbonyl -S
-benzylcysteinyl)5-fluorouridine) 5'-O-(N-benzyloxycarbonylglycyl)-5-fluorouridine, 5'-O-(N-benzyloxycarbonyltryptophanyl)-5-fluoro The chemical shift values of the nuclear magnetic resonance spectra of uridine, 5'-O-(N-benzyloxycarbonylseryl)-5-fluorouridine, and each 5-fluorouridine-5'-ester obtained in Examples 1 to 16 are It is shown in Table 1.

【table】

[Table] Example 17 5'-O-(N-butyrylvalyl)-5-fluorouridine 5'-O-(N-benzyloxycarbonylvalyl)-2',3'-O- obtained in Example 6 Isopropylidene-5-fluorouridine 2.20g
(4.11 mmol) in isopropyl alcohol solution (93.5 ml), 3.7% (wt/wt) hydrogen chloride-isopropyl alcohol solution (3.80 g) and 10% palladium-carbon (1.60 g) were added, and the mixture was heated at room temperature and pressure in a hydrogen stream. Stirred for 3 hours. After the reaction, the catalyst was separated and the solvent was distilled off under reduced pressure. 5'-O-valyl-2',3'-O-isopropylidene-5-fluorouridine hydrochloride obtained as a residue was dissolved in dichloromethane (30 ml), and 0.83 g (7.76 mmol) of 2,6-lutidine was dissolved.
added. Cool this solution on ice and add butyryl chloride.
A solution of 0.41 g (3.85 mmol) in dichloromethane (10
ml) was added dropwise. Ice water (25 ml) and chloroform (40 ml) were added to the reaction mixture, and the organic layer was separated.
%-sodium hydrogen carbonate (50 ml x 2) and water (50 ml x 2). After drying the organic layer (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (2.54 x 7.0 cm,
Separation and purification with chloroform-carbon tetrachloride 1:1, chloroform-methanol 99:1) gave 5′-O-
(N-butyrylvalyl)-2',3'-O-isopropylidene-5-fluorouridine 1.00g (54.6
%) was obtained as an amorphous powder. H ¹ -NMR (CDCl ₃ ) δppm7.43 (1H, d,
H ₆ ) 6.19 (1H, d, amide proton), 5.57
(1H, d, H ₁ '), 1.55 (3H, s, isopropylidene methyl proton), 1.35 (3H, s, isopropylidene methyl proton). To 1.00 g (2.12 mmol) of 5′-O-(N-butyrylvalyl)-2′,3′-O-isopropylidene-5-fluorouridine obtained above was added 90% trifluoroacetic acid aqueous solution (20 ml) at room temperature. The mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel column chromatography (1.0 x 20 cm, chloroform-methanol 97:3).
0.71 g of 5'-O-(N-butyrylvalyl)-5-fluorouridine (amorphous powder) was obtained. Elemental analysis (as C ₁₈ H ₂₆ N ₃ O ₈ F) C H N analytical value: 49.94 6.20 9.36 Theoretical value: 50.11 6.07 9.74 Example 18 5′-O-(N-propionylbaryl)-5-fluorouridine Example 5′-O-valyl-2′,3′- obtained in 17
3.57 g (8.16 mmol) of O-isopropylidene-5-fluorouridine hydrochloride was dissolved in dichloromethane (130
ml), 1.92 g of 2,6-lutidine
(17.95mmol) is added. Then, a dichloromethane solution (20 ml) containing 0.83 g (8.97 mmol) of propionyl chloride was added dropwise to the mixture under ice-cooling and stirring. After washing the reaction solution with water (100 ml) and drying the organic layer (Na ₂ SO ₄ ),
Concentrate under reduced pressure. The residue was chromatographed on silica gel (column size 3 x 10 cm, developing solvent 1-4
% methanol in chloroform), and 5'-O-(N-propionylvalyl)-
2.49 g (66.6%) of 2',3'-O-isopropylidene-5-fluorouridine was obtained. NMR ( _CDCl3 )
δppm0.90(d) and 0.95(d) (6H, isopropyl methyl proton), 1.18 (3H, t, methyl proton), 1.58 (s) and 1.37 (s) (6H, isopropylidene methyl proton), 2.30 (3H , m, methine proton, methylene proton), 5.88 (1H, d,
H ₁ ′), 6.12 (1H, d, NH), 7.42 (1H, d, C ₆
-H), 9.30 (1H, b, amide proton) 2.00 g (4.38 mmol) of the ester obtained above
was dissolved in 90% trifluoroacetic acid aqueous solution (10 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (column size 3 x 12, developing solvent chloroform containing 1-4% methanol) to obtain 5'-O
1.55 g of -(N-propionylvalyl)-5-fluorouridine was obtained as an amorphous powder. Elemental analysis (as C ₁₇ H ₂₄ N ₃ O ₈ F) C H N analysis value 47.38 5.51 10.42 Theoretical value 48.92 5.79 10.07 Example 19 5′-O-[N-Tigrilbaryl]-5-fluorouridine Obtained in Example 17 5′-O-baryl-2′,3′-
O-isopropylidene-5-fluorouridine hydrochloride 2.20 g (5.03 mmol) and 2,6-lutidine 1.35
Dissolve g (12.6 mmol) in methylene chloride (80 ml) and add 0.89 g of tiglyl chloride under ice cooling.
(7.5 mmol) in methylene chloride (3 ml) was added dropwise. After the dropwise addition was completed, the reaction solution was stirred at room temperature for 4 hours, and then added to a 2% aqueous solution of potassium carbonate (70%
ml), and the methylene chloride layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [φ3×20cm,
Developing solvent chloroform-carbon tetrachloride (1:1),
chloroform, chloroform containing 0.5% methanol] to obtain 5'-O-(N-tigrylbaryl)-2',3'-O-isopropylidene-
1.89 g of 5-fluorouridine was obtained. NMR (CDCl ₃ ) δppm7.55 (d, 1H, H ₆ ), 6.4
(m, 2H, vinyl proton, amino proton),
5.70 (bs, 1H, H ₁ '), 1.84 (s, vinyl methyl proton), 1.78 (d, vinyl methyl proton),
1.55 (s) and 1.36 (s) (6H, isopropylidene methyl proton), 0.96 (d, 6H, isopropyl methyl proton). 90% of the obtained ester 1.65g (3.42mmol)
The mixture was dissolved in an aqueous trifluoroacetic acid solution (10 ml) and stirred at room temperature for 1.5 hours. After distilling off the reaction solution under reduced pressure, the residue was subjected to silica gel column chromatography (φ
3 x 12cm, separated and purified using chloroform (developing solvent, chloroform containing 3% methanol).
1.08 g of 5'-O-[N-thigrivalyl]-5-fluorouridine was obtained as a colorless caramel-like substance. Elemental analysis (as C ₁₉ H ₂₆ N ₃ O ₈ F・0.5H ₂ O) C H N analysis value 50.13 5.93 9.32 Theoretical value 50.44 6.01 9.29 Example 20 5′-O-(N-hexanoylbaryl)-5- Fluorouridine 4.00 g of 5'-O-(N-benzyloxycarbonyl-valyl)-2',3'-O-isopropylidene-5-fluorouridine obtained in Example 6
(7.48 mmol) isopropyl alcohol solution (110 ml), 3.7% (wt/wt) hydrogen chloride-isopropyl alcohol solution (6.90 g), and 10% palladium-carbon (2.50 g) were added. I stirred for hours. The catalyst was separated and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (60 ml), and 1.70 g (15.9 mmol) of 2,6-lutidine was added. Cool this solution on ice and add 1.04 g of hexanoyl chloride.
(7.97 mmol) in dichloromethane (10 ml) was added dropwise (30 min). Ice water (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (40 ml x 3). The organic layer was washed with 0.5% potassium carbonate (50 ml x 4) and water (50 ml x 4), and then dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel column chromatography (2.54 x 10.0 cm, chloroform-carbon tetrachloride 2:1) to obtain 5'-O
-(N-hexanoyl-valyl)-2',3'-O-
Isopropylidene-5-fluorouridine 2.24g
(60%). H ¹ -NMR (CDCl ₃ ) δppm7.45 (1H, d,
H ₆ ), 6.32 (1H, d, amide proton), 5.60
(1H, bs, H ₁ ′) 1.54 (isopropylidene methyl proton), 1.34 (isopropylidene methyl proton). 5′-O-(N-hexanoyl-
Valyl)-2',3'-O-isopropylidene-5-
90% in fluorouridine 2.21g (4.42mmol)
Add trifluoroacetic acid aqueous solution (23 ml) and stir at room temperature.
Stir for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (2.0×
30 cm, separated and purified with chloroform-methanol 97:3) to produce 5'-O-(N-hexanoylvalyl-
1.13 g of 5-fluorouridine was obtained as an amorphous powder. Elemental analysis (as C ₂₀ H ₃₀ N ₃ O ₈ F・0.5H ₂ O) C H N analysis value 51.67 6.46 9.00 Theoretical value 51.27 6.56 8.96 Mass analysis value: 459 (M ⁺ ), 330, 130 Example 21 5' -O-(N-pentanoyl-tyrosyl)-5
-Fluorouridine A solution of 7.00 g (38.6 mmol) of L-tyrosine in 2N aqueous sodium hydroxide (38.5 ml), an ethyl ether solution (50 ml) of 6.0 g (50 mmol) of pentanoyl chloride, and a 2N aqueous solution of sodium hydroxide (26
ml) was stirred and simultaneously added dropwise (30 minutes) while maintaining the pH between 9 and 11 at 5°C. After further stirring at room temperature for 2 hours, 2N sodium hydroxide (5 ml) was added to the reaction solution and heated at 70°C for 10 minutes. The reaction solution was cooled to -10°C, and 9.87 g (58 mmol) of benzyloxycarbonyl chloride and 2N sodium hydroxide solution (20.5 ml) were added dropwise at the same time with vigorous stirring. After the reaction, 3N-hydrochloric acid was added to adjust the pH to 3. The precipitated white precipitate was collected and recrystallized from chloroform to give N-pentanoyl-O-benzyloxycarbonyl-tyrosine.
12.80g (82.9%) was obtained. ¹ H―NMR (DMSO―d ₆ ) δppm8.06 (1H, d,
amide proton), 7.42 (5H, s, phenyl proton), 7.30(d) and 7.11(d) (2H, and 2H), 5.26
(2H, s, benzyl methylene proton). 5.30 g of O-benzyloxycarbonyl-N-pentanoyl-tyrosine obtained above
(13.3 mmol) of TPS4.0 in pyridine (50 ml)
g (13.2 mmol) and 2.10 g (6.95 g) of 2',3'-O-isopropylidene-5-fluorouridine were added thereto and left at room temperature for 16 hours. The solvent was distilled off under reduced pressure, benzene (140 ml) was added to the residue, and 3% aqueous sodium hydrogen carbonate solution (100 ml x 4) and water (100 ml x
4). After drying the organic layer with Na ₂ SO ₄ and concentrating under reduced pressure, the residue was separated and purified by silica gel column chromatography (2.54 x 15.0 cm; developing solvent: chloroform-carbon tetrachloride 1:1 chloroform), and 5' -O-(O-benzyloxycarbonyl-N-pentanoyltyrosyl 2',3'-O-isopropylidene-5-fluorouridine 1.80g
(37.9%). ^1H -NMR ( _CDCl3 ) δppm7.39 (s, phenyl proton), 6.36 (1H, m, amide proton),
5.62 (1H, d, H ₁ '), 1.51 and 1.30 (methyl of isopropylidene). 5-fluorouridine-5′-O obtained above
- To a solution of 1.70 g (2.49 mmol) of the ester derivative in isopropyl alcohol (20 ml) was added 10% palladium-carbon (400 mg), and the mixture was stirred in a hydrogen stream at room temperature and pressure for 2 hours. The catalyst was separated and the solvent was distilled off under reduced pressure. The residue was separated and purified using silica gel column chromatography (2.54 x 10.0 cm, chloroform-methanol 98:2) to obtain 5′-O-(N-
Pentanoyl-tyrosinyl)-2',3'-O-isopropylidene-5-fluorouridine 1.10g
(80.5%). ₁ H-NMR (CDCl ₃ : CD ₃ OD (v/v) 5:
1) δppm6.96 (2H, d), 6.70 (2H, d),
5.70 (1H, d, H ₁ '), 1.55 (3H, s, isopropylidene methyl proton), 1.35 (3H, s, isopropylidene methyl proton). 5′-O-(N-pentanoyl-) obtained above
tyrosinyl)-2',3'-O-isopropylidene-
90 in 5-fluorouridine 1.10g (2.00mmol)
%-Trifluoroacetic acid aqueous solution (12.0ml) was added,
Stir for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and the residue was separated and purified using silica gel column chromatography (2.0 x 30 cm, chloroform-methanol 96:4).
465 mg of -(N-pentanoyl-tyrosinyl)-5-fluorouridine was obtained as an amorphous powder. Elemental analysis (as C ₂₃ H ₂₈ N ₃ O ₉ F) C H N analytical value 53.94 5.49 8.20 Theoretical value 54.22 5.54 8.25 Examples 22 to 33 Corresponding N-acyl-α-aminocarboxylic acid and
The following compound was obtained using 2',3'-O-isopropylidene-5-fluorouridine. 5'-O-(N-benzyloxycarbonylalanyl)-5-fluorouridine 5'-O-(N-butyrylalanyl)-5-fluorouridine 5'-O-(N-pentanoylalanyl)-5-
Fluorouridine 5'-O-(N-ethyloxycarbonylvalyl)-5-fluorouridine 5'-O-(N-acetylbaryl)-5-fluorouridine 5'-O-(N-pentanoylvalyl)-5 -Fluorouridine 5'-O-(N-benzyloxycarbonylisoleucyl)-5-fluorouridine 5'-O-(N-benzyloxycarbonylleucyl)-5-fluorouridine 5'-O-(N- Propionylphenylalanine)-5-fluorouridine 5'-O-(N-pentanoylphenylalanine)-5-fluorouridine 5'-O-(N-propionyltyrosyl)-5-
Fluorouridine 5'-O-(N-propionylmethionyl)-5
-Fluorouridine Table 2 shows the chemical shift values of the nuclear magnetic resonance spectra of each of the -5-fluorouridine-5'-esters obtained in Examples 17 to 33.

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula (In the formula, A is an N-acyl-α-aminocarboxy group.) A 5-fluorouridine-5'-ester derivative represented by: 2 A general formula characterized by forming an ester bond between N-acyl-α-aminocarboxylic acid and 5-fluorouridine through an esterification reaction, (In the formula, A is an N-acyl-α-aminocarboxy group.) A method for producing a 5-fluorouridine-5'-ester derivative represented by the following formula.