JPH0136837B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1-β-D-arabinofuranosyl-(E)
-5-(2-halogenovinyl)uracil (hereinafter 5
- Abbreviated as Halogenovinylara U. ).

5-halogenovinylaraU has remarkable antiviral activity and is a compound useful as a medicine such as an antiviral agent. (Refer to Japanese Patent Application Laid-Open No. 56-87599).

The present invention is based on the general formula [] [In the formula, R ¹ , R ² and R ³ are the same or different and represent hydrogen or a protective group, and A represents hydrogen or a cation. ] 1-β-D-arabinofuranosyl-5-(2-carboxyvinyl)uracil (hereinafter abbreviated as 5-carboxyvinylara-U) or its salt is subjected to a halogenation and decarboxylation reaction, and the general formula [] [In the formula, R ¹ , R ² , R ³ have the same meanings as above, and
indicates halogens such as bromine, chlorine, and iodine. ] Provides a method for producing 5-halogenovinylara U represented by the following.

Hereinafter, the reaction of the present invention will be specifically explained.

The raw material 5-carboxyvinylara U is represented by the above general formula []. In the formula, R ¹ , R ² ,
When R ³ is a protecting group, the protecting group is a protecting group commonly used in nucleoside chemistry;
Not particularly limited. Specific examples include acyl groups such as acetyl, butyryl, isobutyryl, and benzoyl, as well as benzyl groups, trityl groups, and pyranyl groups. Also, in the formula, A
is hydrogen or a cation, and examples of the cation include cations that form salts soluble in the reaction solvent, such as sodium, potassium, silver, and lead. It is preferable that the raw material compound is subjected to the reaction in a form soluble in the reaction solvent. For example, when water is used as a reaction solvent, it is preferable to use it as a potassium salt or a sodium salt.

Although this compound is a new compound, it can be easily synthesized, for example, by the method shown in Reference Examples. In other words, the general formula [] [In the formula, R ¹ , R ² , and R ³ are protecting groups. 1 represented by ]
-β-D-arabinofuranosyl-5-halogenowyl and an acrylic acid alkyl ester are reacted in the presence of a tertiary organic amine phosphine and a palladium catalyst, preferably in a polar solvent to form the general formula [] [In the formula, R ¹ ′, R ² ′, and R ³ ′ have the same meanings as above,
R ⁴ represents an alkyl group derived from an acrylic acid alkyl ester. This is a method of obtaining a 5-alkoxycarboxyl vinyl compound represented by the following formula and further subjecting it to a hydrolysis reaction.

The types of protecting groups for the compound [] in this first reaction are the same as the types of protecting groups for R ¹ , R ² and R ³ described above. Further, as the alkyl group of the acrylic acid alkyl ester, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl are preferable. Tertiary amines include trimethylamine, triethylamine, tri-n-butylamine, N,N-dimethylpropylamine, tetramethylenediamine, etc.; phosphines include trimethylphosphine, triethylphosphine,
Tertiary phosphine such as tri-n-butylphosphine, tribenzylphosphine, triphenylphosphine, tri-p-anisylphosphine, tri-o-tolylphosphine, methyldiphenylphosphine, diethyltolylphosphine, etc. As the palladium catalyst, palladium acetate, palladium chloride, etc. can be used. Although this reaction may be carried out without a solvent, it is preferably carried out in a polar solvent such as tetrahydrofuran, dioxane, acetic acid, or acetonitrile. The reaction conditions are usually room temperature to reflux temperature, and the reaction is completed in several hours to several tens of hours.

Further, the hydrolysis reaction of the 5-alkoxycarbonylvinyl compound may be carried out by a conventional method, and a method using either a base catalyst or an acid catalyst may be used.
As the base catalyst, sodium hydroxide, potassium hydroxide, ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, etc. can be used. As the acid catalyst, hydrochloric acid, sulfuric acid, acetic acid, or formic acid can be used.

The halogenation and decarboxylation of the method of the present invention is carried out by a method in which a halogenating agent acts on a conventional carboxylic acid or a salt thereof.

As the halogenating agent, those capable of liberating atomic halogen in the reaction system can be used. Such halogenating agents include N-halogenosuccinimides such as N-bromosuccinimide, N-iodosuccinimide, and N-chlorosuccinimide; N-halogenoacetamides such as N-bromoacetamide; Chlorophthalic acid imide, N
- N-halogenophthalimides such as bromophthalimide, N-halogenosulfonamides such as N-dichlorophenylsulfonamide, t-
t-butyl hypohalide such as butyl hypochloride, t-butyl hypobromide, bromine,
Atomic halogens such as chlorine and iodine can be used. Among these, N-halogenosuccinimide is particularly preferred.

The reaction solvent should be appropriately selected depending on the solubility and stability of the halogenating agent and the solubility of the raw material compound. Although it cannot be specified unconditionally, it is usually water, N,N-dimethylformamide, N,N-
An amide solvent such as dimethylacetamide or formamide may be used alone, a mixed solvent, or a water-containing solvent. In particular, when using N-halogenosuccinimide or atomic bromine, iodine, chlorine, etc., anhydrous N,N-dimethylformamide or N,N-dimethylacetamide is particularly preferred.

Although the reaction conditions are not particularly limited, the reaction is usually completed in several hours at room temperature to 80°C.

Isolation and purification of the target compound from the reaction solution can be carried out by conventional methods, such as chromatography methods such as adsorption chromatography using silica gel or adsorption resin as a carrier, ion conversion chromatography, recrystallization. The purification method may be carried out by appropriately selecting and applying known purification methods such as methods and combining them.

Hereinafter, the present invention will be explained in more detail with reference to Examples, and a method for synthesizing the raw material compounds will be shown as a reference example.

Example 1 70g of potassium acetate and 5% of water heated to 60℃
After adding and dissolving 109.7 g of -carboxyvinylara U, 74.2 g of N-bromosuccinimide was added over 15 minutes, and the mixture was further heated at 60°C for 1 hour. After the reaction was completed, it was adsorbed onto a 5-column of absorption resin Diaion HP20 (trade name; manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with 20% ethanol. The eluted fraction of the target compound was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from water to obtain 51.7 g of crystals of 5-bromovinylara-U. (Yield 42.4%).

Melting point: 195℃ (decomposed) Elemental analysis value: as C ₁₁ H ₁₃ N ₂ O ₆ Br Calculated value: C, 37.84; H, 3.75: N, 8.02% Actual value: C, 37.94; H, 3.56; N, 8.01 % Example 2 After dissolving 50 g of 5-carboxyvinylara U in 500 ml of N,N-dimethylformamide, 34 g of N-bromosuccinimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from water to give crystals of 5-bromovinylara U34.
I got g. (yield 61.3%).

Example 3 50 g of 5-carboxyvinylara U was dissolved in 500 ml of N,N-dimethylacetamide, heated to 100°C, 25.5 g of N-chlorosuccinimide was added little by little, and the mixture was further heated for 30 minutes. After diluting the reaction solution with 2.4 parts of water, it was adsorbed on a Diaion HP20 column (800 ml) and eluted with 5 parts of 10% ethanol. The eluted fractions of the target compound were collected, concentrated to dryness under reduced pressure, and the residue was recrystallized from water to obtain 12.5 g of crystals of 5-chlorovinyla-U (yield: 25.8%).

Melting point: 223-224℃ ( _{decomposition} ) Elemental analysis value _{: C11H13N2O6C1} Calculated value: C, _43.36 ; H, 4.30; N, 9.19% Actual value: C, 43.29; H, 4.17; , 9.44% Example 4 After dissolving 25 g of 5-carboxyvinylara U in 250 ml of N,N-dimethylacetamide, it was heated to 70°C, 21.5 g of N-iodosuccinimide was added, and the mixture was further heated for 5 hours. After diluting the reaction solution to 1.5 with water, it was adsorbed on a Diaion HP20 column (500 ml), and 20% ethanol 5, 30% ethanol 3.2
It was eluted. The eluted fractions of the target compound were collected and concentrated to dryness under reduced pressure. The obtained residue was recrystallized from water to obtain 3.8 g of crystals of 5-iodovinylara-U.

Melting point: 170-175℃ (decomposition) Ultraviolet absorption spectrum: λ ^H2O _nax 298, 253 nm Elemental analysis value: C ₁₁ H ₁₃ N ₂ O ₆ I Calculated value: C, 33.35; H, 3.31; N, 7.07% Actual value :C, 33.33; H, 3.13; N, 6.96% Reference example 1-β-D-arabinofuranosyl-5-iodo-2',3',5'-triacetyluracil 421g, methyl acrylate 300ml, triethylamine 150 ml, 22.5 g of triphenylphosphine and 19.1 g of palladium acetate were added to 1.36 g of tetrahydrofuran, and the mixture was heated under reflux for 3 hours with stirring. After cooling the reaction solution, 1.5 g of chloroform was added and stirred, insoluble matter was filtered off, and the mixture was concentrated to dryness under reduced pressure. Ethanol was added to the resulting residue to make 2, and after cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1-β-D-arabinofuranosyl-5-methoxycarbonylvinyl-2',3' , 213 g of 5'-triacetyluracil crystals were obtained.

After dissolving 10 g of the above compound in 2.5 g of 0.1N sodium hydroxide solution, the solution was left at room temperature for 4 hours, the reaction solution was adjusted to pH 7.0, concentrated under reduced pressure to 250 ml, and cooled overnight. The precipitated crystals were collected by filtration and recrystallized from water to obtain 5.99 g of 5-carboxyvinylara U crystals.

Melting point: 272-273℃ Ultraviolet absorption spectrum: λ ^0.05N-HC1 _nax 301,
267nm (shoulder) Elemental analysis value: C ₁₂ H ₁₄ N ₂ O ₈ Calculated value: C, 45.87; H, 4.49; N, 8.91% Actual value: C, 45.87; H, 4.37; N, 8.78%

Claims (1)

[Claims] 1. General formula [] [In the formula, R ¹ , R ² and R ³ are the same or different and represent hydrogen or a protective group, and A represents hydrogen or a cation. ] 1-β-D-arabinofuranosyl-5-(2-carboxyvinyl)uracil or a salt thereof is subjected to a halogenation-decarboxylation reaction to obtain the general formula [] [In the formula, R ¹ , R ² , R ³ have the same meanings as above, and
indicates halogen. ] 1-β-D-
1-β- characterized by obtaining arabinofuranosyl-(E)-5-(2-halogenovinyl)uracil
A method for producing D-arabinofuranosyl-(E)-5-(2-halogenovinyl)uracil. 2. 1-β-D-arabinofuranosyl-(E)-5-(2-halogenovinyl ) Production method of uracil.