JPS6244557B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing nucleosides. Many of the various nucleosides have strong physiological activity and are widely used as medicines, agricultural chemicals, and intermediates thereof. The present inventors conducted extensive research to find a new method for producing nucleosides, and found that this objective could be achieved by using an onium salt of a certain nitrogen-containing aromatic compound, and thus arrived at the present invention. That is, the gist of the present invention is to prepare a nucleoside, which is characterized in that a benzoxazolium salt and a nucleoside base are reacted in the presence of a tertiary amine, followed by treatment with triethyloxonium tetrafluoroborate, and then a sugar is reacted. It depends on the manufacturing method. The present invention will be explained in detail below. Examples of benzoxazolium salts include 3-
Examples include ethyl-2-chlorobenzoxazolium tetrafluoroborate. Examples of the nucleoside base include benzimidazole, 5,6-dimethylbenzimidazole, and theophylline. Examples of tertiary amines include triethylamine and 2,6-dimethylpyridine. Examples of sugars include 1-hydroxy sugars such as 2,3,
4,6-tetra-O-acetyl-β-D-glucopyranose (hereinafter abbreviated as "A"), 2,3,5-
Examples include tri-O-benzoyl-β-D-ribofuranose (hereinafter abbreviated as "B"). The amount of benzoxazolium salt used is approximately equimolar to the nucleoside base. The amount of tertiary amine used is approximately equimolar to the benzoxazolium salt. The reaction of the benzoxazolium salt with the nucleoside base is carried out in an inert solvent such as a halogenated hydrocarbon such as dichloroethane. The amount of inert solvent is about 1 to 10 per mole of nucleoside base. The reaction temperature is usually about room temperature to 100°C. The reaction time is usually about 1 to 10 hours.
The reaction mixture is used as it is in the next reaction without any particular purification. The amount of triethyloxonium tetrafluoroborate used is approximately equimolar to the benzoxazolium salt. For the treatment with triethyloxonium tetrafluoroborate, it is sufficient to add the inert solvent solution of triethyloxonium tetrafluoroborate to the reaction mixture and stir for several hours to about a day. The treatment with triethyloxonium tetrafluoroborate is, for example, to remove chlorine ions remaining in the reaction mixture as ethyl chloride. If this operation is not performed, the desired nucleoside will not be obtained and the product will be contains only chlorosugar. At this stage, it is thought that an adduct is formed in which, for example, the hydrogen atom bonded to the nitrogen atom of the nucleoside base and the 2-position chlorine atom of the benzoxazolium salt are dehydrochlorinated. Approximately equimolar amounts of the nucleoside base and sugar are used to react for the production of nucleosides. The reaction mixture treated with triethyloxonium tetrafluoroborate is used in an amount of about 1.5 times the mole of this mixture of nucleoside base and sugar. The reaction between the nucleoside base and the sugar is carried out in the inert solvent. The amount of inert solvent is about 5 to 20 per mole of sugar. Reaction temperature is usually room temperature ~
The temperature is 100°C and the reaction time is about 1 to 24 hours. After the reaction is completed, the desired nucleoside can be purified and isolated by post-treatment according to a conventional method for nucleoside synthesis. According to the method of the present invention, nucleosides can be produced in high yield under mild conditions such as low reaction temperature, and furthermore, heavy metal catalysts and acid catalysts are not required, and the method has great industrial significance. EXAMPLES The present invention will be described in more detail with reference to Examples below, but the present invention is not limited by the Examples unless it exceeds the gist thereof. Example 1 2-chloro-3-ethylbenzoxazolium tetrafluoroborate 404 under argon atmosphere
mg (1.5 mmol) and benzimidazole 177
A suspension of triethylamine (1.5 mmol) in dichloroethane (3 ml) was cooled to -23°C, and triethylamine 151
mg (1.5 mmol) in dichloroethane (2 ml) is added dropwise. After heating the reaction mixture at 60° C. for 5 hours, it is cooled to room temperature and a solution of 285 mg (1.5 mmol) of triethyloxonium tetrafluoroborate in dichloroethane (2 ml) is added dropwise. After stirring the reaction solution overnight, 2,3,4,6-tetra-O
-Acetyl-β-D-glucopyranose 348mg
(1.0 mmol) and triethylamine 151 mg
(1.5 mmol) in dichloroethane (4 ml) was slowly added dropwise at room temperature and stirred for 2 hours. After removing dichloroethane under reduced pressure, separation was performed by thin layer chromatography (silica gel) (methylene chloride:methanol, 100:3), 2, 3, 4,
91 mg (yield 20%) of 6-tetra-O-acetyl-β-D-glucopyranosylbenzimidazole and 301 mg (yield 67%) of cyclic acetal are obtained. Example 2 2-chloro-3-ethylbenzoxazolium tetrafluoroborate 404 under argon atmosphere
mg (1.5 mmol) and benzimidazole 177
A suspension of triethylamine (1.5 mmol) in dichloroethane (3 ml) was cooled to -23°C, and triethylamine 151
mg (1.5 mmol) in dichloroethane (2 ml) is added dropwise. After heating the reaction mixture at 60° C. for 5 hours, it is cooled to room temperature and a solution of 285 mg (1.5 mmol) of triethyloxonium tetrafluoroborate in dichloroethane (2 ml) is added dropwise. After stirring the reaction solution overnight, 2,3,4,6-tetra-O
-Acetyl-β-D-glucopyranose 348mg
(1.0 mmol) and 2,6-lutidine 161 mg
(1.5 mmol) in dichloroethane (4 ml) was slowly added dropwise at room temperature and stirred for 2 hours. After removing dichloroethane under reduced pressure, separation was performed by thin layer chromatography (silica gel) (methylene chloride:methanol, 100:3), 2,3,
4,6-tetra-O-acetyl-β-D-glucopyranosylbenzimidazole 32 mg (yield 7
%) and 400 mg of cyclic acetal (yield 89%). Example 3 A solution of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (1.5 mmol) and benzimidazole (1.5 mmol) in 1,2-dichloroethane (hereinafter abbreviated as DCE) (3 ml),
Triethylamine (1.5 mmol) in DCE (2
ml) solution at −23°C under an argon atmosphere,
It was then heated to 60°C for 5 hours. After cooling, triethoxyoxonium tetrafluoroborate (1.5
A solution of 2 mmol) in DCE (2 ml) was added and stirred overnight. A (1.0 mmol) was added to this reaction mixture.
and DCE of benzimidazole (1.0 mmol)
(3 ml) solution and dimethoxyethane (4 ml) were added, and the mixture was stirred at 60°C for 10 hours. Remove the solvent under reduced pressure,
When the residue was separated using silica gel chromatography, it was found that 2,3,4,6-tetra-O-acetyl-
β-D-glucopyranosylbenzimidazole
Obtained with a yield of 73%. Examples 4 to 6 The same procedure as in Example 3 was repeated except that the types of sugar and nucleoside base were changed to those shown in Table 1, and the products shown in Table 1 were produced in the yields shown in Table 1. Obtained.

[Table] In the table, "Ac" represents an acetyl group, "Bz" represents a benzoyl group, and "Me" represents a methyl group.

Claims (1)

[Claims] 1. A method for producing a nucleoside, which comprises reacting a benzoxazolium salt and a nucleoside base in the presence of a tertiary amine, followed by treatment with triethyloxonium tetrafluoroborate, and then reacting with a sugar.