JPH0676433B2 - Process for producing 2'-deoxy-5-fluorouridine-diacyl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present inventor relates to a method for producing a diacyl derivative of 2'-deoxy-5-fluorouridine useful as an antitumor agent or an intermediate thereof.

A 3 ', 5'-diacyl derivative of 2'-deoxy-5-fluorouridine and a derivative in which the 3-position is also substituted have been synthesized as an antitumor agent with low toxicity and high activity.

[Conventional technology]

The above-mentioned derivative is synthesized by the acylation reaction of 2'-deoxy-5-fluorouridine.
The industrial production method of 5-fluorouridine has not been established, it is expensive and has not been widely used.

As a conventional method for producing a diacyl derivative of 2'-deoxy-5-fluorouridine, a method of reducing a 2'-halogen derivative (Japanese Patent Publication No. 55-40598) or a diacyl derivative of 2'-deoxyuridine in an organic solvent is used. There are known methods such as the action of fluorine gas (German Patent No. 95001 (1973)), but the reduction method requires several steps until the 2'-halogen compound, and fluorination in an organic solvent is large. Difficult to scale.

[Problems to be solved by the invention]

The inventors of the present invention have conducted extensive studies for the purpose of efficiently producing a diacyl derivative of 2'-deoxy-5-fluoro-uridine in a smaller number of steps, and as a result, industrially available fluorine of 2'-deoxyuridine An efficient production method by cyclization and acylation was found.

[Means for solving problems]

That is, the first aspect of the present invention is to react 2'-deoxyuridine with fluorine gas in an aqueous solution to give 2'-deoxy-5,
6-Dihydro-5-fluoro-6-hydroxyuridine is produced, and then the general formula R-CO-X [I] (wherein R is an aliphatic hydrocarbon group having up to 20 carbon atoms, or a substituted or unsubstituted A phenyl group, X represents an acyloxy group represented by RCO ₂ , or a halogen atom), or a carboxylic acid anhydride or halide represented by the general formula (Wherein R represents an aliphatic hydrocarbon group having up to 20 carbon atoms, or a substituted or unsubstituted phenyl group), and is a method for producing a 2'-deoxy-5-fluorouridine-diacyl derivative, The second aspect of the invention is 2'-
Deoxyuridine is fluorinated in an aqueous solution in the presence of a lower fatty acid or a salt thereof with fluorine gas, and then reacted with an anhydride or halide of a carboxylic acid represented by the above general formula [I]. A method for producing a deoxy-5-fluorouridine-diacyl derivative.

The 2'-deoxy-5,6-dihydro-5-fluoro-6-hydroxyuridine of the first invention has the following formula It can be easily obtained by reacting 2'-deoxyuridine with diluted fluorine gas in water. As a gas for diluting the fluorine gas, an inert gas such as nitrogen, helium or argon is used, and the fluorine concentration is 5 to 20 mol%.

Although the fluorination proceeds smoothly, the reaction temperature is 50 ° C. or less, preferably 0 to, in order to reduce the production of sugar-base bond cleavage by-products due to the strongly acidic medium after the fluorination reaction. Carry out under mild conditions at 25 ° C. Furthermore, fluorination in an aqueous solution containing one or more equivalents of carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate to capture HF generated by fluorination can also suppress the formation of by-products. . The concentration of 2'-deoxyuridine in the aqueous solution is not particularly limited, but if it is too low, the efficiency of the apparatus is poor and it is not industrial, and a range of 3% to 20% is recommended. The obtained reaction liquid is preferably neutralized in advance with calcium carbonate or the like so that it will not be decomposed by heating conditions during the subsequent isolation. 2'-Deoxy-5,6-dihydro-5-fluoro-6-hydroxyuridine is a white powder containing 1 mol of water of crystallization and a melting point of 40-45 ° C.

This compound further used an acid anhydride or acid halide up to 4 mol per 1 mol, and by heating, acylation and elimination of the 6-position --OH group easily proceeded. ′ -Deoxy-5-fluorouridine-diacyl derivative was obtained and then efficiently hydrolyzed to 2′-
Deoxy-5-fluorouridine can be obtained.

As the acid anhydride, a linear or branched carboxylic acid anhydride such as acetic anhydride, propionic acid anhydride or isobutyric acid anhydride, and a cyclic anhydride such as succinic acid are used. In the latter case, a w-carboxy substituted acyl derivative is obtained. As the carboxylic acid halide, long-chain fatty acid halides such as acetyl chloride, acetyl bromide to capryl chloride and lauroyl chloride, and aromatic carboxylic acid halides such as benzoyl chloride and p-chlorobenzoyl chloride can be applied.

It is effective to add an organic base such as pyridine, substituted pyridine, N-alkylimidazole, trialkylamine, and N, N-dialkylcarboxylic acid amide to the reaction system, but the amount of the catalyst is 5 mol% of the catalyst. From the amount to the reaction solvent system, it is adopted as necessary. A solvent is not always necessary, but ethyl acetate, acetonitrile, THF or the like which can dissolve the raw material compound can be used. Although the reaction temperature is not particularly limited, it is carried out between room temperature and 120 ° C. Purification is performed by removing the reaction solution under reduced pressure and subjecting it to recrystallization or column chromatography separation.

The second aspect of the present invention is to add 2'-deoxyuridine in an aqueous solution,
A diacyl derivative of 2'-deoxy-5-fluorouridine is obtained by fluorinating with a fluorine gas in the presence of a lower fatty acid or a salt thereof to form an intermediate, and then reacting the intermediate with an anhydride or halide of a carboxylic acid. Is a method of manufacturing.

Although various solvents are used in fluorinating 2'-deoxyuridine, an aqueous solution is advantageous in view of solubility. The concentration of 2'-deoxyuridine in the aqueous solution is preferably 10% by weight or less. Fluorination is performed by diluting with an inert gas, nitrogen, helium, argon, etc.
It is performed by blowing 10% fluorine gas into the solution. As additives, formic acid, acetic acid, propionic acid, butyric acid, and other lower fatty acids having up to 4 carbon atoms, or their Li salts, Na
Alkali metal salts such as salts and K salts, alkaline earth metal salts such as Mg salts and Ba salts, and ammonium salts are used. The effect of this additive is that it captures hydrogen fluoride generated during fluorination and acts as a catalyst for the reaction in the next step, so that 1 mol or more is required relative to 2'-deoxyuridine, and usually 2 to 5 Used in double mole.

Fluorination proceeds without heating, but is carried out under mild conditions of 0 ° C. to room temperature in order to suppress cleavage of the sugar-base bond.
The progress of the reaction is monitored by high performance liquid chromatography, and when the raw material disappears, the introduction of fluorine gas is stopped. By this reaction, as shown by the following formula, 2'-deoxy-5,6-dihydro-5-fluoro-6-hydroxyuridine and 2'-deoxy-5,6-dihydro-5-fluoro-6-acyloxyuridine A mixture of

The production ratio of this mixture depends on the amount of the lower fatty acid or its salt added and the carbon number of the fatty acid. After the fluorination reaction is complete, the solvent is removed under reduced pressure and the mixture is dried.
The above-mentioned carboxylic acid anhydride or halide of the general formula [I] is added to the residue in an amount of 4 to 50 times the substrate, and the mixture is heated and stirred. The reaction is performed from room temperature to the boiling point of the carboxylic acid anhydride or halide, the time until the reaction is completed,
From the viewpoint of suppressing side reactions, the range of 50 ° C to 120 ° C is preferable. Follow the reaction by high performance liquid chromatography and stop heating when no change is observed. The acid anhydride and acid halide used in the present invention are the same as those used in the above-mentioned first invention, and it is also effective to add an organic base such as pyridine to the reaction system as in the first invention. Is. The product 2'-deoxy-5-fluorouridine 3 ', 5'-diacyl can be isolated by diluting the reaction solution with water, or removing the solvent under reduced pressure, and then adding water, and adding CHCl. Extract with a halogen-based solvent such as ₃ , CH ₂ Cl ₂ , CH ₂ Cl-CHCl ₂ , CHCl ₂ -CHCl ₂ . Slightly colored 2'-deoxy-5-fluorouridine-3 ', 5' upon evaporation of the solvent
-A diacyl product is obtained, which can be purified by recrystallization if desired.

This compound is useful as a carcinostatic agent etc. as it is, but by reacting with alkali hydroxide or ammonia in hydrous alcohol to perform deacylation to give 2'-deoxy-5-fluorouridine, 3 ', 5 It is also used as a raw material for a more effective anti-cancer drug in which the'-position is asymmetrically substituted.

Hereinafter, the present invention will be described in detail with reference to examples.

〔Example〕

Example 1 2'-Deoxyuridine (50.0 g, 0.22 mol) was dissolved in 1 liter of water, and 10% He diluted fluorine gas was passed at a flow rate of 140 ml / min while stirring vigorously, and the temperature was maintained at 3 to 5 ° C. The reaction was carried out. The reaction was monitored by high performance liquid chromatography, and it took 6 hours and 50 minutes until the raw materials disappeared. At this time
The F ₂ consumption was 0.236 mol. Calcium carbonate in the reaction solution
31 g was added and the mixture was stirred for 1.5 hours for neutralization, and the resulting white precipitate was filtered through Celite. 200 ml of ethanol was added to a viscous oily substance obtained by distilling off water at an internal temperature of 40 ° C. or lower under reduced pressure, and an insoluble white precipitate was separated by filtration. 2'-Deoxy-5,6-dihydro-5-fluoro-6-hydroxyuridine (-hydrate) which is a white solid when the solvent is removed from the filtrate under reduced pressure.
(Hereinafter, abbreviated as [III] H ₂ O) was obtained in an amount of 60.8 g. (98%).

Melting point 40 to 45 ° C ¹ H nmr (CD ₃ OD) δ 2.25 (m, 2H, 2′-CH ₂ ), 3.60 to 3.90 (m, 3H, 4′-CH, 5′-CH ₂ ), 4.35 (m , 1H, 3′-CH), 5.27 (m, 1H, 5′-CH), 5.55 (m, 1H, 6-CH), 6.20 (t, 1H, 1′-CH) ¹⁹ F nmr (CD ₃ OD ) −7.2 (d, J = 48Hz), −5.0 (d, J = 48Hz), 9.6 (d, J = 48Hz), 12.4 (d, J = 48Hz) ppm (CFCl ₃ standard) Elemental analysis analysis value C; 38.30, H; 5.38, N; 963% C 9 H 13 FN 2 O 6 · calculated for _{H 2 C; 38.40, H;} 5.12, N; reacted with pyridine and acetic anhydride part of 9.32% the compound 2 '
-Deoxy-3 ', 5'-diacetyl-5-fluorouridine induced high-performance liquid chromatography to find that 5-fluorouracil with cleaved sugar-base bond was
% Was included.

Examples 2-4 For fluorination of 2'-deoxyuridine in aqueous solution,
The reaction was carried out in the same manner as in Example 1 except that the fluorination temperature and conditions were as shown in Table 1.

The results are shown in Table 1.

Example 5 4.47 g (15.9 mmol) of [III] H ₂ O obtained in Example 1 was suspended in 40 g (0.39 mol) of acetic anhydride, and 120 mg of pyridine (1.56 mmo)
l) was added and the mixture was stirred at 100 ° C. for 15 hours. After concentrating the solvent under reduced pressure, the residue was recrystallized from ethanol and 2'-deoxy-3 ', 5'-diacetyl-5-fluorouridine [I
3.80 g (72.6%) of I] (R = CH ₃ ) was obtained.

mp 148-9 ° C ¹ H nmr (CDCl ₃ ) δ 2.15 (S, 6H), 2.2-2.8 (m, 2H), 4.3 (m, 3H), 5.2 (m, 1H), 6.3 (t, 1H), 7.65 (d, 1H, J = 6Hz) ¹⁹ F nmr (CDCl ₃ ) −164.88ppm (d, J = 5.9Hz), (CFCl ₃ standard) ir (KBr) ν 3500 1750,1700,1660,123cm ^-1 Implemented Examples 6-10 Compound [III] H ₂ O 1.00 g (3.6 mmol) was added with acetic anhydride 9.7 g.
(89 mmol) and suspended various organic bases in catalytic amounts (0.32 mmo
l) added and stirred at the given temperature. The same procedure as in Example-5 was repeated to give 2'-deoxy-3 ', 5'-diacetyl-5-.
Was obtained fluorouridine (II) (R = CH _3). The results are shown in Table 2.

Example 11 [III] H ₂ O 1.01 g (3.56 mmol) of anhydrous propion 12.4 g
(65.4 mmol) and 4-dimethylaminopyridine 39 mg (0.
32 mmol) was stirred at 70 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, the residue was adsorbed on silica gel column chromatography, and the eluate of benzene-methanol (5: 1) was recrystallized from ethanol-benzene to give 2'-deoxy-3 ', 5'-diene. Propionyl-5-fluorouridine [I
0.78 g (61%) of white crystals of I] (R = C ₂ H ₅ ) were obtained.

mp from 78 to 78.5 ° C. Example 12 (III) _{H 2 O 1.00g (3.55mmol),} 14.0g isobutyric anhydride
(88.6mmol), 4-dimethylaminopyridine 39mg (0.32mm
ol) was stirred at 70 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, the residue was separated by silica gel column chromatography, and 2'-deoxy-3 ', 5'-diisobutyl-5-fluorouridine was added to 1.05 from the eluate of chloroform-ethanol (60: 1). g (77%) was obtained.

mp 120 to 121.5 ° C Example 13 [III] H ₂ O 1.02 g (3.6 mmol) and succinic anhydride 8.9 g (89 mm
ol) and 39 mg (0.32 mmol) of 4-dimethylaminopyridine were stirred under reflux in 17 ml of ethyl acetate for 5 hours. After removing the solvent, the product was separated by silica gel column chromatography, and 3 ', 5'-bis (3-carboxypropionyl) -2'-deoxy-5-fluorouridine [II] (R = CH ₂ CH ₂ COOH) 1.
Obtained 15 g (73%). ¹ H nmr (heavy acetone) δ 2.10 to 2.70 (m, 10H), 4.10 to 4.50 (m, 3H), 5.10 to 5.40 (m, 1H), 6.25 (t, 1H, J = 6Hz) 7.75 (d, 1H) , J = 6.8Hz) 4.90 to 6.10 (brood) ¹⁹ F nmr (heavy acetone) −166.27ppm (d, J = 6.8H
z), (CFCl ₃ standard) ir (Neat) 3500 3250,1740,1490,1290,1180 …… c
m ^-1 Example 14 [III] H ₂ O 1.18 g (4.2 mmol) was dissolved in pyridine 24 ml,
Caprylyl chloride 4.76 (29.3 mmol) was added dropwise with stirring at 0 ° C. The solution was kept at 95 ° C. and stirred for 5 hours. The reaction mixture was poured into water, extracted with chloroform, washed with diluted sulfuric acid, 1% aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was separated by column chromatography on silica gel, and chloroform-n-hexane (1:
1) from the eluate 2'-deoxy-3 ', 5'-dicaprylyl-5-fluoro uridine (II) _{(R = (CH 2) 6} CH 3) 1.35g (65% as an oil) was obtained. ¹ H nmr (CDCl ₃ ) δ 0.90 (t, 6H, J = 6Hz), 1.10 to 2.00 (m, 20H), 2.00 to 2.90 (m, 6H), 4.10 to 4.70 (m, 3H), 5.10 to 5.40 ( m, 1H), 6.35 (t, 1H, J = 6Hz), 7.70 (d, 1H, J = 6.4Hz), 9.90 to 10.70 (brood S, 1H) ¹⁹ F nmr (CDCl ₃ ) −164.62ppm (d, J = 6.4Hz), (CFCl ₃ standard) ir (KBr) 3240,3120,2960,2890,1740,1480,137
0,1280,1180,1120Cm _-1 EXAMPLE 15-20 [III] H ₂ O1.0g a (3.6 mmol) was dissolved in pyridine 24 ml,
21.6 mmol of acyl halide was added and the reaction and treatment were carried out under the same conditions as in Example-14 to obtain 2'-deoxy-3 ', 5'-diacyl-5-fluorouridine [II].

The results are summarized in Table 3.

Example-21 2.02 g (8.80 mmol) of 2'-deoxyuridine and 1.44 g (17.6 mmol) of sodium acetate were dissolved in 40 ml of water, and 10% He diluted fluorine gas was passed at 3 to 5 ° C with stirring. When the reaction was traced by liquid chromatography, it was 11 mmol.
The disappearance of the raw materials was observed at the point of passing through F ₂ . The reaction solution
Search with ¹⁹ F nmr −7.2 ppm (d, 48 Hz) (CFCl ₃
2) -deoxy-5,6-dihydro-5-fluoro-
The peak of 6-hydroxyuridine is -8.6ppm (d, 48Hz)
A peak of 2'-deoxy-5,6-dihydro-5-fluoro-6-acetoxyuridine was observed at a ratio of 67:33.

The pH of the aqueous solution was 5.1. The solvent was concentrated to dryness under reduced pressure at 40 ° C or below, and 22.4 g (219 mmo of acetic anhydride was added to the residue.
l) was added and the mixture was stirred at 75 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, water and methylene chloride were added, the methylene chloride extract layer was dried and concentrated, and then recrystallized from ethanol to give 2'-
Deoxy-3 ', 5'-diacetyl-5-fluorouridine [II] a (R = CH ₃₎ was obtained 2.56g (88.4%).

mp 148 to 149 ° C ¹ H nmr (CDCl ₃ ) δ 2.15 (S, 6H), 2.2 to 2.8 (m, 2H), 4.3 (m, 3H), 5.2 (m, 1H), 6.3 (t, 1H), 7.65 (d, 1H, J = 6Hz), ¹⁹ F nmr (CDCl ₃ ) −164.88ppm (d, J = 5.9Hz), (CFCl ₃ standard) Examples 22 to 28 Implemented by adding salts of various fatty acids Under the same conditions as in Example 21,
2'-Deoxyuridine was fluorinated and reacted with a fatty acid anhydride to obtain 2'-deoxy-3 ', 5'-diacyl-5-fluorouridine [II].

The results are shown in Table 4.

Reference Example 1 15.55 g (0.389 mol) of sodium hydroxide was added to ion-exchanged water 20
It was dissolved in 0 ml, mixed with 500 ml of ethanol and cooled with ice. While stirring, 2'-deoxy-3 ', 5'-diacetyl-5-
Fluorouridine [II] (R = CH ₃ ) 42.18g (0.128mo
l) was added and stirred at room temperature for 3.5 hours to give a clear solution. 20 g of acetic acid was added for neutralization, and the reaction solution was concentrated under reduced pressure. 500 ml of water was added to the residue to dissolve it, 100 ml of cation exchange resin IR 120-B was added, and the mixture was left for 1 hour. After the resin was filtered off, the same amount of cation exchange resin was added again and the same operation was performed, and the filtrate was evaporated to dryness under reduced pressure. The white solid obtained was recrystallized from ethanol to give 24.80 g (78.9%) of 2'-deoxy-5-fluorouridine.

mp 149.5 to 150.5 ° C degree of illumination [α ▲] ²⁵ _D ▼ + 37.3 ° (C = 1.06, H ₂ O) [Effect of the invention] The present invention is useful as an antitumor agent or the like 2′-deoxy-5-fluoro. A method for producing a uridine-diacyl derivative, which uses industrially easily available 2'-deoxyuridine as a raw material,
By fluorinating with a fluorine gas in a system in which water is present, carboxylic acid anhydride or halide is allowed to act on the obtained intermediate, and the desired product can be efficiently obtained.

Claims (2)

[Claims] 1. A method of reacting 2'-deoxyuridine with fluorine gas in an aqueous solution to obtain 2'-deoxy-5,6-dihydro-5-
Fluoro-6-hydroxyuridine is produced, and then the general formula R-CO-X [I] (In the formula, R is an aliphatic hydrocarbon group having up to 20 carbon atoms, or a substituted or unsubstituted phenyl group, and X is A general formula characterized by reacting an anhydride or a halide of a carboxylic acid represented by RCO ₂ or an acyloxy group represented by RCO ₂ or a halogen atom) (Wherein R represents an aliphatic hydrocarbon group having up to 20 carbon atoms, or a substituted or unsubstituted phenyl group), and a method for producing a 2'-deoxy-5-fluorouridine-diacyl derivative 2. 2'-Deoxyuridine is fluorinated with fluorine gas in the presence of a lower fatty acid or a salt thereof in an aqueous solution, and then the compound of the general formula R-CO-X [I] (wherein R represents 20 carbon atoms). Up to an aliphatic hydrocarbon group, or a substituted or unsubstituted phenyl group, X is an acyloxy group represented by RCO ₂ , or a carboxylic acid anhydride or halide represented by General formula (Wherein R represents an aliphatic hydrocarbon group having up to 20 carbon atoms, or a substituted or unsubstituted phenyl group), and a method for producing a 2'-deoxy-5-fluorouridine-diacyl derivative