JPH0523277B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivatives.

Conventional technology and its problems General formula [In the formula, X represents a halogen atom, a lower alkyl group, or a trifluoromethyl group. ] 3'-O-benzyl-2'-deoxy-
β-uridines have excellent anticancer effects and are useful compounds as antitumor agents.

Conventionally, as a method for producing uridines of the above general formula (), for example, the general formula [In the formula, X' represents a fluorine atom or a trifluoromethyl group. It is produced by benzylating the hydroxyl group of the sugar moiety of the compound represented by ] and then carrying out a reaction to remove the N-benzoyl group. For example, when benzylating a hydroxyl group in a sugar moiety, a method is known in which benzyl bromide is reacted in the presence of silver oxide, barium oxide, or mercury oxide (JP-A-59-216899, JP-A-60-61591). (see official bulletin). However, in the above method, when barium oxide or mercury oxide is used, benzylation hardly progresses, and therefore only a small amount of the target compound can be obtained. Furthermore, when silver oxide is used, benzylation progresses compared to when barium oxide and mercury oxide are used, but the desired 3′-O-
Benzyl-2'-deoxy-β-uridines could not be obtained selectively, and 5'-O-benzyl-2'-
It is only obtained as a mixture with deoxy-β-uridines, and therefore the yield of 3'-O-benzyl-2'-deoxy-β-uridines is inevitably low, and separation by column chromatography. This method is not suitable as an industrial production method because it requires operations and, in addition, silver oxide is expensive.

Means for Solving the Problems The present inventors have developed a new production method capable of producing 3'-O-benzyl-2'-deoxy-β-uridines of the above general formula () in an industrially advantageous manner. As a result of repeated research to develop the following, it was discovered that the intended purpose of the present invention could be achieved through the following general formula (). The present invention was completed based on this knowledge.

The present invention provides 2- represented by the following general formula ().
It concerns a deoxy-3-O-thiobenzoyl-D-ribofuranose derivative.

[In the formula, R ¹ represents a trityl group, a lower acyl group, a trialkylsilyl group, or a monohalogen-substituted benzoyl group. R ² represents a lower alkyl group. ] As used herein, lower acyl groups include acyl groups having 1 to 6 carbon atoms, specifically formyl, acetyl, propionyl, butyryl, pivaloyl,
Examples include hexanoyl group.

Trialkylsilyl groups include trimethylsilyl, triethylsilyl, tripropylsilyl,
Examples include tributylsilyl and tert-butyldimethylsilyl groups.

The monohalogen-substituted benzoyl group includes a benzoyl group substituted at one of the ortho, meta, or para positions with a fluorine atom, chlorine atom, bromine atom, or iodine atom, specifically, p-chlorobenzoyl, o Examples include -fluorobenzoyl, m-chlorobenzoyl, p-bromobenzoyl, and p-iodobenzoyl.

Examples of halogen atoms include fluorine atoms, bromine atoms,
Examples include iodine atoms.

Examples of lower alkyl groups include alkyl groups having 1 to 4 carbon atoms, specifically methyl, ethyl, propyl,
Examples include isopropyl and butyl groups.

The 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative () of the present invention can be easily produced, for example, by the method shown in the reaction formula below.

[In the formula, R ¹ and R ² are the same as above. ] That is, the 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative () is the known 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative (2).
-Deoxy-D-ribofuranose was derived by a known method, and the 5-position hydroxyl group of the compound () was protected with an appropriate substituent represented by R to obtain the compound (), and then a normal thiobenzoylation reaction was applied. Manufactured by

Here, compound () and compound () are known compounds or compounds easily produced by known methods [see Chem, Ber, 93, 2777 (1960)].

For example, a compound () in which R ¹ is a trialkylsilyl group is produced by reacting the corresponding compound () with a trialkylsilylating agent such as t-butyldimethylsilyl chloride. The reaction is usually carried out in a suitable solvent. The solvent used here is not particularly limited as long as it does not adversely affect the reaction, but specific examples include aprotic solvents such as benzene, ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, pyridine, and dimethylformamide. can be mentioned. The amount of t-butyldimethylsilyl chloride to be used is preferably about 1 to 2 times the mole of the compound (). A base is preferably present in the reaction system, and examples of such bases include sodium hydride, pyridine, trialkylamine, and imidazole. The amount of the base to be used is preferably about 1 to 5 times the mole of t-butyldimethylsilyl chloride, but if the base can also be used as a reaction solvent, it may be used in excess of the above number of moles. is also possible. The reaction temperature for the above reaction is not particularly limited, and can be appropriately selected from the range of usually ice cooling to the boiling point temperature of the solvent. The reaction proceeds suitably under ice cooling or around room temperature, and generally
It takes about 0.5 to 10 hours to complete.

The reaction to obtain compound () from compound () is
For example, it can be carried out in the same manner as a conventional esterification reaction using a thiobenzoylating reagent such as thiobenzoyl chloride or phenyl dithiobenzoate. Specifically, it varies depending on the type of thiobenzoylation reagent used, but for example, when thiobenzoyl chloride is used, the reaction is as follows.

The reaction to obtain compound () from compound () is
It is usually carried out in a suitable solvent. The solvent used here is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of conventionally known solvents can be used. Specifically, benzene, ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, Conventional aprotic solvents such as pyridine, dimethylformamide, etc. can be used. The amount of thiobenzoyl chloride used is 1 to 1 mole of compound ().
The amount is preferably about 3 moles. Further, it is preferable that a base be present in the reaction system, and examples of such a base include preferably organic bases such as sodium hydride, pyridine, and trialkylamine. The amount of the base to be used is preferably about 1 to 5 moles per mole of thiobenzoyl chloride, but if the base can also be used as a reaction solvent, it may be used in an amount exceeding the above number of moles. Of course it is possible. The reaction temperature for this reaction is not particularly limited, but is usually in the range of ice cooling to the boiling temperature of the solvent, preferably ice cooling to around room temperature. The reaction time is generally about 0.5 to 10 hours.

Further, when phenyl dithiobenzoate is used as the thiobenzoylating reagent, the reaction is as follows.

The reaction to obtain compound () from compound () is
It is usually carried out in a suitable solvent. The solvent used here is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of conventionally known solvents can be used. Specifically, the same conventional aprotic solvents as mentioned above can be used. . The amount of phenyl dithiobenzoate used is compound ()
The amount is preferably about 1 to 3 moles per mole. Further, it is preferable that a base similar to the above be present in the reaction system. Among these bases, sodium hydride is preferred. The amount of the base to be used is preferably about 0.5 to 5 mol per 1 mol of compound (). The reaction temperature for this reaction is not particularly limited, but the reaction usually proceeds well in the range of ice cooling to the boiling temperature of the solvent, preferably around room temperature. The reaction time is generally about 10 minutes to 10 hours.

The target compound of the present invention obtained by the above method is:
It can be isolated and purified by commonly known separation and purification means, such as recrystallization and column chromatography.

The 2-deoxy-3-O-thiobenzoyl-D-ribofuranose represented by the general formula () of the present invention can be prepared as a pharmaceutically useful compound according to the method shown below.
It can be derived from 3'-O-benzyl-2'-deoxy-β-uridines ().

First, as shown in the reaction formula below, the 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative () of the present invention is subjected to a condensation reaction with a pyrimidine derivative () to form a 3'- O-thiobenzoyl-2'-deoxy-β-
A uridine derivative is produced.

[In the formula, R ¹ , R ² and X are the same as above. ] 2-deoxy-3-O-thiobenzoyl-D-
The reaction between the ribofuranose derivative () and the pyrimidine derivative () is usually carried out in a suitable solvent in the presence of a catalyst. As the solvent used here, a wide variety of conventionally known solvents can be used as long as they do not adversely affect the reaction, and specific examples include benzene, ether, tetrahydrofuran, dioxane, methylene chloride, 1,2-dichloroethane, and chloroform. , acetone, acetonitrile, dimethylformamide and the like can be used. As the catalyst, it is preferable to use trialkylsilyl perfluoroalkanesulfonates such as trimethylsilyltrifluoromethanesulfonate and triethylsilyltrifluoromethanesulfonate. The amount of the above catalyst used is usually 0.5~
The amount is preferably about 5 molar equivalents, preferably about 1 to 3 molar equivalents. The ratio of compound () to compound () to be used is not particularly limited, but it is generally preferable to use the latter in an amount of about 0.5 to 2 molar equivalents to the former. Although the reaction temperature for the above reaction varies depending on the type of solvent used and cannot be generalized, it is preferable to carry out the reaction at a temperature above the freezing point and below room temperature. Although the reaction time is not particularly limited, the reaction is generally completed within 10 hours.

The above condensation reaction gives priority to 3'-O-thiobenzoyl-2'-deoxy-α-uridine derivatives.
A 3'-O-thiobenzoyl-2'-deoxy-β-uridine derivative () can be obtained.

The pyrimidine derivative () used in the above reaction can be prepared using known methods such as JP-A-50-105673.
It is manufactured according to the method described in the publication.

3′- expressed by the general formula () obtained above
O-thiobenzoyl-2'-deoxy-β-uridine derivatives can be desulfurized and then subjected to a deprotection reaction, or deprotected and then desulfurized and reduced to produce 3'-O- which is useful as a pharmaceutical. derived from benzyl-2'-deoxy-β-uridines ().

Desulfurization reduction is usually carried out in a suitable solvent using a suitable reducing agent. As the reducing agent, for example, lithium aluminum hydride-aluminum chloride,
In addition to sodium boron hydride-boron trifluoride, catalytic reduction catalysts such as Raney-nickel catalysts can be used, and Raney-nickel catalysts are particularly preferred. The amount of such a catalyst to be used is usually about 1 to 50 times the weight of the compound to be reduced, preferably about 5 to 20 times the weight of the compound to be reduced. As the solvent, a wide range of conventionally known solvents can be used as long as it does not adversely affect the reaction, and specific examples include ether, tetrahydrofuran, methylene chloride, chloroform, acetone,
Examples include conventional aprotic solvents such as acetonitrile and dimethylformamide, and alcohols such as methanol and ethanol. The reaction can be carried out under cooling, at room temperature, or under heating, but is usually about -50 to 100°C, preferably -30°C to
The reaction proceeds suitably at around room temperature and is generally completed within 10 hours.

Deprotection reactions include alcoholysis, aminolysis, ammonolysis, and
Acid hydrolysis, mild catalytic reduction, etc. are widely applicable.

When the protecting group R is a trityl group or a t-butyldimethylsilyl group, acid hydrolysis is particularly desirable, and usually a mineral acid such as hydrogen chloride, a Lewis acid such as aluminum chloride, an organic acid such as trifluoroacetic acid, etc. The deprotection reaction is carried out in the presence of water, an alcohol such as methanol, an organic acid such as acetic acid, or a mixed solvent thereof. The reaction temperature for this reaction is not particularly limited, but is preferably about 0 to 50°C, and the reaction is generally completed within 10 hours.

When the protecting group R is a lower acyl group or a monohalogen-substituted benzoyl group, potassium hydroxide,
In the presence of inorganic metal hydroxides such as sodium hydroxide and barium hydroxide, inorganic carbonates such as potassium carbonate and sodium carbonate, ammonia and organic amines such as toethylamine, water, alcohols such as methanol, and ethers. , halogenated hydrocarbons, aprotic polar solvents such as dimethylformamide,
Alternatively, it is preferable to carry out the deprotection reaction in a mixed solvent thereof. The reaction temperature for this reaction is not particularly limited, but is preferably about 0 to 50°C, and the reaction is generally completed within 10 hours.

When the protecting group R is a trialkylsilyl group other than t-butyldimethylsilyl group, it can be easily deprotected with water.

The compound () obtained by the above method can be isolated and purified by commonly known separation and purification means, such as recrystallization, column chromatography, etc.

Effects of the Invention As mentioned above, the 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative represented by the above general formula () of the present invention is useful as a 3'-O-benzyl-2'- It is useful as an intermediate for synthesizing deoxy-β-uridines (). When the compound of the present invention is used, the target compound can be produced in a simple manner with good yield and at low cost.

Examples Production examples of the compounds of the present invention are listed as Examples, and then 3'-O-thiobenzoyl-2'-deoxy-β-
Production example of uridine () and its usefulness as a medicine
A production example of 3'-O-benzyl-2'-deoxy-β-uridine () is listed as a reference example.

The analysis results of nuclear magnetic resonance spectra of the compounds obtained in each Example and each Reference Example are shown, and all of these are δ values measured in DMSO-d ₆ using TMS as an internal standard.

Example 1 Production of 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-trityl-D-ribofuranose 2-deoxy-1-O-methyl-5-O-trityl-D- 7.8 g (0.02 mol) of ribofuranose is dissolved in 40 ml of tetrahydrofuran, 0.48 g (0.02 mol) of sodium hydride is added at room temperature, and the mixture is stirred for 30 minutes. Then phenyl dithiobenzoate
Add 5.06 g (0.022 mol) and stir at room temperature for 30 minutes. Add 50 ml of benzene and 50 ml of water, separate the benzene layer, wash with water, and dry with Glauber's salt. After distilling off the solvent, the resulting residue was subjected to silica gel chromatography and petroleum ether-benzene (1:
1v/v) Oily 2-deoxy-1-
O-methyl-3-O-thiobenzoyl-5-O-
Trityl-D-ribofuranose 9.07g (yield 89
%).

NMR spectra 3.24 and 3.34 (3H, s, -OCH ₃ ) 4.3-4.5 (1H, m, H ⁴ ) 5.16-5.3 (1H, m, H ³ ) 5.8-6.0 (1H, m, H ¹ ) 7.15-8.2 (20H, m, aromatic H) Example 2 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-(p-chlorobenzoyl)
-Production of D-ribofuranose 4.44 g (0.03 mol) of 2-deoxy-1-O-methyl-D-ribofuranose was dissolved in 30 ml of pyridine, and 5.25 g of p-chlorobenzoyl chloride was added under ice cooling.
(0.03 mol) was added dropwise and stirred for 2 hours. After pyridine was distilled off under reduced pressure, the residue was dissolved in methylene chloride,
Wash with water, dry with Glauber's salt, and distill off the solvent. Add 40ml of tetrahydrofuran to this oily residue and dissolve it.
Add 0.72 g (0.03 mol) of sodium hydride under ice cooling, stir for 30 minutes, and add phenyl dithiobenzoate.
Add 6.9 g (0.03 mol) and stir for 1 hour under ice cooling. Add 80 ml of benzene and 80 ml of water to the reaction mixture, separate the benzene layer, wash with water, and dry with Glauber's salt. After evaporating the solvent, the resulting residue was subjected to silica gel chromatography, and oily 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-(p-chloro benzoyl)
-D-ribofuranose 5.86 g (yield 48%) is obtained.

NMR spectra 4.36-4.76 (3H, m, ^H4 and ^H5 ) 5.14-5.36 (1H, m, ^H1 ) 5.82-6.20 (1H, m, ^H3 ) 7.16-8.20 (9H, m, aromatic H) Example 3 Production of 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-acetyl-D-ribofuranose 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5 -O-trityl-D-ribofuranose 10.2g (0.02mol) in 0.1N hydrochloric acid-methanol
Dissolve in 100ml and stir at room temperature for 30 minutes. After adding 10 ml of pyridine to this solution and stirring at room temperature for 10 minutes, the solvent was distilled off under reduced pressure. 10 ml of acetic anhydride and 30 ml of pyridine are added to the resulting residue, and the mixture is stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, water and chloroform are added to the resulting residue, and the chloroform layer is separated, washed with water, and then dried with Glauber's salt.
After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography, and oily 2-deoxy-1-O-methyl-3 was extracted from the chloroform eluate.
-O-thiobenzoyl-5-O-acetyl-D-
5.46 g of ribofuranose (yield 88%) is obtained.

NMR spectrum 2.05 (3H, s, CH ₃ CO−) 4.14-4.32 (2H, m, H ⁵ ) 4.38-4.62 (1H, m, H ⁴ ) 5.10-5.40 (1H, m, H ¹ ) 5.68-6.16 ( 1H, m, ^H3 ) 7.10-8.22 (5H, m, aromatic H) Example 4 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-(t-butyldimethylsilyl) -Production of D-ribofuranose 14.8 g (0.1 mol) of 2-deoxy-1-O-methyl-D-ribofuranose is dissolved in 60 ml of dimethylformamide and cooled to 0°C. 15 g (0.22 mol) of imidazole and 16.5 g (0.11 mol) of t-butyldimethylsilyl chloride were added to this solution,
Stir at 0°C for 3 hours. After distilling off dimethylformamide under reduced pressure, extraction is performed with benzene, and the extract is washed with water and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of anhydrous tetrahydrofuran.
dissolve in The solution is cooled to 0° C., 3.64 g (0.11 mol) of sodium hydride is added and stirred for 30 minutes. Then 25.3g of phenyldithiobenzoate
(0.11 mol) and stirred at 0°C for 20 minutes.
Benzene and water are added to this solution, and the benzene layer is separated, washed with water, dried over Glauber's salt, and the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and benzene-acetone (98:
2v/v) Oily 2-deoxy-1-
O-methyl-3-O-thiobenzoyl-5-O-
18.9 g (yield 72%) of (t-butyldimethylsilyl)-D-ribofuranose is obtained.

NMR spectra 0.05 (6H, s, Si(CH ₃ ) ₂ ) 0.84 (9H, d, (CH ₃ ) ₂ C-) 1.95-2.62 (2H, m, H ² ) 3.29 and 3.31 (3H, s, CH ₃ O-) 3.54-7.96 (2H, m, ^H5 ) Reference example 1 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-trityl-2'-deoxy-β-
Production of uridine 5.1 g (0.01 mol) of 2-deoxy-1-O-methyl-3-O-thiobenzoyl-5-O-trityl-D-ribofuranose was dissolved in 50 ml of acetonitrile and heated to -40 to -45°C. 2.45g (0.011mol) of trimethylsilyltrifluoromethanesulfonate
and 2,4-bis-(trimethylsilyloxy)-
5-trifluoromethylpyrimidine 3.24g (0.01
mol) and stirred at the same temperature for 30 minutes. The reaction solution was neutralized with a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the chloroform layer was washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography, and the fraction eluted with chloroform-acetone (97:3v/v) showed 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-triphenylmethyl-
2'-deoxy-β-uridine 5.83g (yield 89%)
get.

NMR spectrum 3.40 (2H, m, H ⁵ ′) 6.04 (1H, m, H ³ ′) 6.22 (1H, t, H ¹ ′) 6.50 (1H, m, H ⁴ ′) 7.2-8.3 (20H, m, Aromatic H) 8.22 (1H, m, H ⁶ ) 12.02 (1H, s, NH) Reference example 2 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-acetyl-2'-deoxy- β−
Production of uridine 3.1 g (0.01 mol) of 2-deoxy-5-O-acetyl-1-O-methyl-3-O-thiobenzoyl-D-ribofuranose was dissolved in 50 ml of acetonitrile and heated to -40 to -45°C. 2.45g (0.011mol) of trimethylsilyltrifluoromethanesulfonate
Add and stir at the same temperature for 15 minutes. 3.24 g (0.01 mol) of 2,4-bis-(trimethylsilyloxy)-5-trifluoromethylpyrimidine was added to this solution at -40 to -45°C, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed with water, dried with Glauber's salt, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography, and the fraction eluted with chloroform-acetone (95:5v/v) was extracted with 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-acetyl-2'- Deoxy-β-uridine 3.94g (yield 86
%).

NMR spectrum 2.04 (3H, s, CH ₃ CO−) 2.58 to 2.86 (2H, m, H ² ′) 4.37 (2H, d, H ⁵ ′) 4.50 to 4.70 (1H, m, H ⁴ ′) 5.82 to 6.40 (1H, m, H ³ ′) 6.24 (1H, t, H ¹ ′) 7.34-8.24 (5H, m, aromatic H) 8.16 (1H, q, H ⁶ ) 11.96 (1H, brs, NH) Reference example 3 5-Fluoro-3'-O-thiobenzoyl-5'-
Production of O-acetyl-2'-deoxy-β-uridine 2,4-bis-(trimethylsilyloxy)-5
-2,4 instead of trifluoromethylpyrimidine
-Bis-(trimethylsilyloxy)-5-fluoropyrimidine 2.74 g (0.01 mol) was used, but the same operation as in Reference Example 2 was carried out, and 5-fluoro-3'-O-thiobenzoyl-5'-O- Acetyl-2'-deoxy-β-uridine 3.47g (yield 85
%).

NMR spectrum 2.08 (3H, s, CH ₃ CO−) 2.50–2.80 (2H, m, H ² ′) 4.24–4.62 (3H, m, H ⁴ ′ and H ⁵ ′) 5.84–6.04 (1H, m, H ³ ') 6.10~6.40 (1H, m, ^H1 ') 7.30~8.24 (5H, m, aromatic H) 8.06 (1H, d, ^H6 ) 11.94 (1H, brs, NH) Reference example 4 5-tri Fluoromethyl-3'-O-thiobenzoyl-5'-O-(p-chlorobenzoyl)-2'-
Production of deoxy-β-uridine 2-deoxy-1-O-methyl-5-O-(p
-chlorobenzoyl)-3-O-thiobenzoyl-D-ribofuranose (4.07 g (0.01 mol)) was dissolved in 50 ml of acetonitrile and heated to -40 to -45°C to form trimethylsilyltrifluoromethanesulfonate.
Add 2.45 g (0.011 mol) and stir at the same temperature for 15 minutes. Add 2,4- to this solution at -40 to -45℃.
3.24 g (0.01 mol) of bis-(trimethylsilyloxy)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed with water, dried with Glauber's salt, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography, and from the chloroform-acetone (95:5v/v) eluate,
4.55 g (yield: 82%) of 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-(p-chlorobenzoyl)-2'-deoxy-β-uridine is obtained.

NMR spectra 2.70-2.96 (2H, m, ^H2 ') 4.50-4.86 (3H, m, ^H4 ' and ^H5 ') 6.02-6.36 (2H, m, ^H1 ' and ^H3 ') 7.30-8.24 ( 9H, m, aromatic H) 8.13 (1H, q, H ⁶ ) 11.90 (1H, brs, NH) Reference example 5 5-trifluoromethyl-3'-O-benzyl-
Production of 2'-deoxy-β-uridine 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-trimethyl-2'-deoxy-β-
6.58 g (0.01 mol) of uridine is dissolved in 50 ml of 0.1N hydrochloric acid-methanol and stirred at room temperature for 30 minutes. Neutralize with saturated aqueous sodium bicarbonate solution and extract with chloroform. The extract was washed with water, dried with Glauber's salt, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 20 ml of tetrahydrofuran, added at -20°C to a suspension of 66 g of Raney nickel in 80 ml of tetrahydrofuran, and stirred at the same temperature for 1 hour. After separating the Raney-nickel, the solvent was distilled off under reduced pressure.
The resulting residue was recrystallized from chloroform and
5-trifluoromethyl-3'-, melting point 158-159°C
O-benzyl-2'-deoxy-β-uridine3.26
g (yield 84%).

Reference example 6 5-trifluoromethyl-3'-O-benzyl-
Production of 2'-deoxy-β-uridine 5-trifluoromethyl-3'-O-thiobenzoyl-5'-O-(p-chlorobenzoyl)-2'-deoxy-β-uridine 5.55 g (0.01 mol) Dissolve in 10 ml of tetrahydrofuran and incubate at -20℃.
Add 55.5 g of nickel to a suspension of 60 ml of tetrahydrofuran and stir at the same temperature for 1 hour. After separating the Raney-nickel, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 140 ml of 1% potassium carbonate-methanol solution and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from chloroform to give 2.85 g of 5-trifluoromethyl-3'-O-benzyl-2'-deoxy-β-uridine with a melting point of 158-159°C. (yield 74%).

Reference Example 7 Production of 5-fluoro-3'-O-benzyl-2'-deoxy-β-uridine 5-fluoro-3'-O-thiobenzoyl-5'-
O-acetyl-2'-deoxy-β-uridine 4.08
g (0.01 mol) was dissolved in 10 ml of tetrahydrofuran, added at -20°C to a suspension of 40.8 g of Raney-nickel in 50 ml of tetrahydrofuran, and stirred at the same temperature for 1 hour. After separating the Raney-nickel, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 100 ml of saturated ammonia-methanol solution and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from chloroform to a melting point of 137.
5-Fluoro-3'-O-benzyl- at ~138°C
2'-deoxy-β-uridine 2.49g (yield 74%)
get.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a trityl group, a lower acyl group, a trialkylsilyl group, or a monohalogen-substituted benzoyl group. R ² represents a lower alkyl group. ] A 2-deoxy-3-O-thiobenzoyl-D-ribofuranose derivative represented by: