JPH02117689A - Production of dideoxynucleosides - Google Patents

Abstract

PURPOSE:To simply produce the title compound in high selectivity by converting a specific nucleoside compound to a compound having a specific skeleton in a molecule and reducing the compound having the specific skeleton with hydrogen in a mixed solvent system in the presence of palladium using a base. CONSTITUTION:A nucleoside compound having a skeleton expressed by formula I (R<2> is H, 1-12C acyl, 6-18C aralkyl or silyl; B is purine base linking to saccharide residue in 9 position or pyrimidine base, imidazole base or triazole base each linking to the saccharide residue in 1-position) is converted to a compound having a skeleton expressed by formula II (R<1> is H or 1-12C acyl; X is halogen atom) or formula III, which is then subjected to addition of a base (preferably carbonate) and hydrogen reduction in a mixed solvent of an organic solvent (preferably acetonitrile) and water in the presence of a palladium catalyst to provide the aimed compound expressed by formula IV).

Description

[Detailed description of the invention] [Industrial application field] The present invention is useful as a medicine such as an antiviral agent.

The present invention relates to a method for producing 3'-dideoxynucleosides.

[Conventional technology]

2゛,3　-dideoxynucleosides are reduced with hydrogen in the presence of triethylamine using a palladium catalyst, and then deprotected to produce 2゛,3''-dideoxyadenosine as described below (J, Am, Chem,
Soc, 95.4025 (1973)) is known.

can be used as a medicine because it has an antiviral effect that can be used, for example, as an AIDS treatment drug (Japanese Patent Application Laid-Open No. 1986-1999).
Publication No. 280500 and J, Med, Chem, +
30, 440 (1987)). B represents a purine base bound to a sugar residue at the 9-position, and a pyrimidine bound to a pyrimidine at the 1-position.
, 3'-dideoxynucleosides [Problems to be Solved by the Invention] In the method of the above-mentioned document, a large amount of 3'-deoxyadeno as described below is produced as a by-product, and the 2',3'-dioxyadenosine and 3'-deoxyadenosine are produced as a by-product. The termination ratio with -deoxyadenosine reached as high as 40:4G, and it could not be said to be an industrially advantageous method.

Therefore, there has been a need for a method that can obtain 2°, 3°-dideoxynucleosides with high selectivity in an industrially efficient manner using starting materials that can be easily and inexpensively prepared.

[Means to solve the problem]

In order to solve the above problems, the present invention I74;l:,G
As a result of careful investigation, the following compound [1] deoxynucleoside °tJ'[111] was obtained with high selectivity and high yield. After converting the following compound OOH into the following compound (11), It was discovered that the following 2',3'-di by-product was significantly suppressed by reduction with hydrogen using a base in the presence of a palladium catalyst in a mixed solvent system with water, and based on this discovery, the present invention was developed. The invention was completed.

However, in the above formulas (1) to (IV), R1 represents a hydrogen atom or an acyl group having 1 to 12 carbon atoms, and R2 represents a hydrogen atom, an acyl group having 1 to 12 carbon atoms, (, acyl group having 1 to 12 carbon atoms,
12 alkyl group, aralkyl group or silyl group having 6 to 18 carbon atoms, X represents a halogen atom, B is a purine base bonded to the sugar residue at the 9-position, and is bonded at the 1-position. It represents a pyrimidine base, an imidazole base attached at the 1-position, or a triazole base attached at the 1-position.

Examples of the acyl group for R1 include an acetyl group, a propionyl group, and a benzoyl group.

Examples of the acyl group for R2 include acetyl group, propionyl group, benzoyl group, etc. Examples of alkyl group include methyl group, ethyl group, propyl group, etc., and examples of aralkyl group include benzyl group and phenylethyl group. , phenylpropyl group, etc. Examples of the halogen atom of X include chlorine, bromine, and iodine.

Examples of the purine base B include adenosine, guanosine, hypoxanthine, xanthine, 6-chloropurine, 6-mercaptopurine, 6-methylthiopurine, 2.6-dichloropurine, 2-chloropurine, 2.6-liamitsupurine, 2- Examples include amino-6 chloropurine and 2-aminopurine. Examples of the pyrimidine base include uracil, cytosine, thymine, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-
Examples of the imidazole base include 5-amino-4-imidazolecarboxamide, and examples of the triazole base include 1.2.4-)riazole-3-carboxamide. . If necessary, the amino group of the base moiety may be protected.

The compound (II) can be prepared, for example, by a method known per se (J
, ^rm, Chem, Soc,, 95.4025
(1973)) from the above compound (I).

The palladium catalyst is not particularly limited, but 1 to 10% palladium on carbon, either dry or containing water, is preferred.

The amount of palladium catalyst used is preferably about 1 to 10% in molar ratio to compound (II).

As the solvent, a mixed solvent of an organic solvent and water is preferable.
Examples of organic solvents include esters such as ethyl acetate, methyl acetate, and propyl acetate, hexane, heptane, benzene,
Hydrocarbons such as toluene, ethers such as dioxane, diethyl ether, and tetrahydrofuran, halogenated hydrocarbons such as chloroform and dichloromethane, alcohols such as methanol, ethanol, and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, acetonitrile, Examples include nitriles such as propionitrile. Among these, acetonitrile is particularly preferred. The mixing ratio of organic solvent and water is suitably about 1 to 10 by volume.

The concentration of the compound (It) dissolved in the solvent is preferably about 1 to 20%.

Also, does the existing compound (n) have a? When a base is added to a mixed solvent system of 8 medium and water and hydrogen reduction is carried out in the presence of a palladium catalyst, the target compound (1) can be obtained with high purity.

Examples of the base used include organic bases such as triethylamine, tripropylamine, tributylamine, pyridine, piperidine, and pyrrolidine, and inorganic bases.

Preferably, an inorganic base is used.

As the inorganic base, carbonate, hydrogen carbonate, hydroxide, acetate, ammonia or a mixture thereof is selected. Specific examples include sodium carbonate, sodium acetate, sodium hydrogen carbonate, sodium hydroxide, ammonium carbonate, ammonium acetate, and the like. Among these, a mixed system of sodium carbonate and sodium acetate is particularly preferred.

At this time, the pH of the reaction system is maintained at 9 to 11 using the above-mentioned base.

The table below shows the results of measuring the relationship between the solvent and base used, the reaction product, and the yield.

The starting compound (n) used was one in which R1 was an acetyl group, Rt was an acetyl group, X was a bromine atom, and B was an adenine.

28〃 Same as above 3 ' NatCOz(1,1)4 ^
cO [! Shi II! ONatω3(3,1)(5jl) 5b htsu II Et2N (1,4)6
〃 〃 7 11tO only Na, α)! (3,1)5
7 f39.6 10.05 2 G
9.4 4.35 3.5 Ta, 3 3. (
i lo 3 60.5 2.410
l 50.7 1.45 3 51.2
1.5 a: As the raw material compound (I summer), the actual reaction solution (not purified from adenosine) was used.

b: Known method (J, Am, Chem, Soc, +
95.4025 (1973)) MeCN Niacetonitrile NaIC0, : Sodium carbonate Ac0Na : Sodium acetate Ac0EL : Ethyl acetate IhO : Water MeOH : Methanol EtJ :) The ethylamine reaction product was tracked by high-resolution liquid chromatography. As shown in the table above, the solvent is preferably a mixture of water and an organic solvent. Also, as in Experiment No. 1.2, when the bases are sodium carbonate and sodium acetate, and their mixed molar ratios (relative to compound (U)) are 1.1 and 2.2, (1)/(IV) The production ratio is extremely high at 6 to 10, and both the yield and the ratio are far superior to those of Experiment No. 115, which was conducted using a known method.

2'', 3°-dideoxynucleosides useful as pharmaceuticals such as antiviral agents usually have R2 as a hydrogen atom. Therefore, if R2 is protected with an acyl group, etc., the The desired compound can be obtained by deprotection using a method and purification using a chromatography or crystallization method.

〔Example〕

Hereinafter, the method of the present invention will be specifically explained with reference to Examples.

Production of 2',3'-dideoxyadenosine 9-(2,5-0
-Diacetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine 1 g (2.41 mmol)
and 5% palladium carbon 256■ containing 50% water,
1.2 d of 20% sodium carbonate and 4 d of sodium acetate
35 ml was added, and the mixture was stirred at room temperature for 2 hours while blowing hydrogen.

The reduction reaction was completed in 2 hours, and 5"-acetyl-2',
The yield of 3′-dideoxyadenosine was 73.5%, 2”
The molar ratio of the 3'-dideoxy form and the 3'-deoxy form was 6.0.

After filtering off the catalyst, the mixed solution of water and acetonitrile was concentrated under reduced pressure. The residue was adjusted to pH 12 with an aqueous sodium hydroxide solution.
and stirred at room temperature for 1 hour. Then, adjust the pH with hydrochloric acid.
Adjusted to a. This solution was mixed with synthetic adsorption resin SP-207.
After purification, the product was cooled and crystallized using i4mt (manufactured by Mitsubishi Kasei ■). After drying, 0.39 μm (1 mmol, yield 69.2%) of 2°, 3°-dideoxyadenosine was obtained.

[Effects of the Invention] By the method of the present invention, 2',3'-dideoxynucleosides can be produced quickly and highly selectively.

Claims (2)

[Claims] (1) Nucleoside compound having the following skeleton in the molecule [
I 〕 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼〔 I 〕 A compound that has the following skeleton in the molecule [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II ] In a mixed solvent system of organic solvent and water,
Formula [III] ▲ Mathematical formula, chemical formula, which is characterized by reduction by hydrogen using a base in the presence of a palladium catalyst.
There are tables, etc. ▼ [III] Method for producing 2',3'-dideoxynucleosides having the skeleton shown in the molecule. However, in the above formula, R^1 is a hydrogen atom or a carbon number of 1 to 1.
2 represents an acyl group, R^2 is a hydrogen atom, and has 1 or more carbon atoms.
It represents an acyl group having 12 carbon atoms, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 6 to 18 carbon atoms, or a silyl group. X represents a halogen atom. B represents a purine base bound to the sugar residue at the 9-position, a pyrimidine base bound to the 1-position, an imidazole base bound to the 1-position, or a triazole base bound to the 1-position. (2) The production method according to claim (1), characterized in that carbonate, hydrogen carbonate, hydroxide, acetate, ammonia, or a mixture thereof is added as the base. (3) Acetonitrile or acetonitrile is added as the organic solvent. (4) The manufacturing method according to claim (1), which uses ethyl acetate. (4) The manufacturing method according to claim (1), which uses sodium carbonate, sodium acetate, or a mixture thereof as the base.