JP2514830B2 - Process for producing 5-alkynyl-1-β-D-ribofuranosylimidazol-4-carboxamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides compounds of the formula [I] [In the formula, R ¹ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a phenyl group, and R ² represents a hydrogen atom or a hydroxyl-protecting group. ] 5-Alkynyl-1-β-D represented by
-Ribofuranosyl imidazole-4-carboxamides.

[Conventional technology]

5-alkynyl-1-β-represented by the above formula [I]
D-ribofuranosyl imidazole-4-carboxamide is a novel compound developed by the present inventors and is expected to be developed as an antitumor agent (Japanese Patent Laid-Open No. 1-1999).
See 221388).

Conventionally, in the above formula [I], a compound in which R ¹ is a hydrogen atom is prepared by adding the following formula (A) compound to the formula (B) YC≡SCnZ ₃ (B) [wherein, Y is a silyl group and Z is A lower alkyl group is shown. ]
Was carried out by a method of reacting an ethynyltin compound represented by the following formula (C) compound, removing the silyl group of the following formula (C) compound after the reaction, and further removing the sugar moiety hydroxyl group if desired (see below) See the reaction formula).

[Wherein X is a halogen atom, R ² ′ is a protective group for a hydroxyl group, and Y is
And R ² has the same meaning as above. [Problems to be Solved by the Invention] In the above-mentioned conventional method, preparation of an ethynyltin compound to be reacted with a raw material compound (compound of formula (A)) is complicated, and the synthetic yield of the ethynyltin compound is low (around 50%). ), Not necessarily a satisfactory method.

Therefore, the present invention provides a more convenient 5-alkynyl-
The main object of the present invention is to provide a method for producing 1-β-D-ribofuranosylimidazole-4-carboxamide.

[Means for solving the problem]

The present inventors have found that the formula [II] [In the formula, R ¹ and R ² have the same meanings as described above. ] The new compound represented by the formula, 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile, was successfully synthesized.

In order to study the usefulness of the compound, further studies, be subjected to hydrolysis, which is commonly the compound in the preparation of the nitrile derivative (-CN) from the acid amide derivative (-CONH ₂₎ To easily give 5-alkynyl-
1-β-D-ribofuranosylimidazole-4-carboxamide can be prepared, and generally, in the hydrolysis reaction for preparing an acid amide derivative from a nitrile derivative, the acid amide derivative formed is further hydrolyzed to give a carboxylic acid derivative ( -COOH) is produced, but when 5-alkynyl-1-β-D-rifofurofuranosylimidazol-4-carbonitrile is used as a starting compound, 5-alkynyl-1-β- D-ribofuranosyl imidazole-4-carboxamide is the main product, 5-alkynyl-1-β-D-ribofuranosyl-4
-The present invention has been completed by discovering that carboxylic acids are rarely produced or only slightly produced.

That is, the present invention provides a compound represented by the formula [II]
Alkynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile was used as a starting compound, and the starting compound was subjected to a hydrolysis reaction to give a compound represented by the formula [I]
Acquiring alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide 5-
The present invention relates to a method for producing alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (hereinafter, sometimes abbreviated as the method of the present invention).

 Hereinafter, the method of the present invention will be described in detail.

The starting compound used in the method of the present invention is 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile represented by the above formula [II] (hereinafter, may be abbreviated as the starting compound). Wherein R ¹ and R ² are as defined above.

In more detail for R ¹ and R ^2, the method of the present invention is not in a manner limited by the type of R ¹ and R ^2, the formula of this order, R ¹ of the starting compound in the preparation purposes [ It is appropriately determined in the form corresponding to R ¹ in the compound represented by I]. R ¹ in the formula [II] in the case in particular order to obtain a compound R ¹ in the formula [I] is, for example a methyl group
Also, a compound having a methyl group may be used as a starting compound for the reaction of the present invention.

However, considering the usefulness of 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide prepared by the method of the present invention, especially antitumor activity,
R ¹ is preferably a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, and specifically, the lower alkyl group or the hydroxy lower alkyl group has a carbon number.
An alkyl group having 10 or less, more preferably 4 or less carbon atoms, or a hydroxyalkyl group in which a hydroxyl group is substituted at any position of the alkyl group is suitable. R ² may be either a hydrogen atom or a hydroxyl-protecting group. The protective group for the hydroxyl group represented by R ² may be one commonly used as a protective group for the hydroxyl group of a nucleoside, for example, acetyl, chloroacetyl, dichloroacetyl,
Trifluoroacetyl, methoxyacetyl, propionyl, n-butyryl, (E) -2-methyl-2-butenoyl, isobutyryl, pentanoyl, benzoyl, o-
(Dibromomethyl) benzoyl, o- (methoxycarbonyl) benzoyl, p-phenylbenzoyl, 2,4,6-
Trimethylbenzoyl, p-trioil, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, α
-Acyl group such as naphthoyl, alkyloxymethyl group such as methoxymethyl, ethoxymethyl, n-propoxymethyl, substituted ethyl group such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, benzyl, phenethyl, 3-phenylpropy L, p-methoxybenzyl, p
Alkyl groups such as -nitrobenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl, α- or β-naphthylmethyl, α-naphthyldiphenylmethyl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran Pyranyl groups such as -4-yl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, silyl groups such as methyldi-t-butylsilyl, triisopropylsilyl, tetraisopropyldisiloxyl, ethylidene, propyldene, isopropylidene. Acetal or ketal type protecting groups such as lidene, benzylidene, cyclohexylidene, cyclopentylidene, methoxymethylidene, ethoxymethylidene, dimethoxymethylidene, methoxycarbonyl, Butoxycarbonyl, and the like can be exemplified alkyloxycarbonyl group such as t- butoxycarbonyl.

Specific examples of the present raw material compound include, for example, 5- (phenylethyn-1-yl) -1-β-D.
-Ribofuranosylimidazole-4-carbonitrile,
5-ethynyl-1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (1-propyn-1-yl) -1-β-D-ribofuranosylimidazol-4-
Carbonitrile, 5- (1-butyn-1-yl) -1-
β-D-ribofuranosylimidazol-4-carbonitrile, 5- (1-pentyn-1-yl) -1-β-D-
Ribofuranosylimidazole-4-carbonitrile, 5
-(1-hexyn-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (1-
Heptin-1-yl) -1-β-D-ribofuranosylimidazole-4-carbonitrile, 5- (1-octin-1-yl) -1-β-D-ribofuranosylimidazole-4-carbonitrile , 5- (1-nonin-1-yl) -1-β-D-ribofuranosylimidazol-4-
Carbonitrile, 5- (1-decyn-1-yl) -1-
β-D-ribofuranosylimidazol-4-carbonitrile, 5- (1-undecyn-1-yl) -1-β-D
-Ribofuranosylimidazole-4-carbonitrile,
5- (1-dodecin-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (3
-Methyl-1-butyn-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5-
(3,3-Dimethyl-1-propyn-1-yl) -1-β
-D-ribofuranosylimidazol-4-carbonitrile, 5- (3-methyl-1-pentyn-1-yl) -1
-Β-D-ribofuranosylimidazol-4-carbonitrile, 5- (4-methyl-1-pentyn-1-yl)
-1-β-D-ribofuranosylimidazole-4-carbonitrile, 5- (3-hydroxy-1-propyne-1
-Yl) -1-β-D-ribofuranosyl imidazole-
4-carbonitrile, 5- (3-hydroxy-1-butyn-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (4-hydroxy-1)
-Butyn-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (3,4-dihydroxy-1-butyn-1-yl) -1-β-D-ribofurano Cylimidazole-4-carbonitrile, 5- (3
-Hydroxy-1-pentyn-1-yl) -1-β-D
-Ribofuranosylimidazole-4-carbonitrile,
5- (4-hydroxy-1-pentyn-1-yl) -1
-Β-D-ribofuranosylimidazole-4-carbonitrile, 5- (5-hydroxy-1-pentyn-1-yl) -1-β-D-ribofuranosylimidazole-4-
Carbonitrile, 5- (3,4-dihydroxy-1-pentyn-1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (4,5-dihydroxy-1-pentyne- 1-yl) -1-β-D-ribofuranosylimidazol-4-carbonitrile, 5- (4-
Hydroxy-3-methyl-1-butyn-1-yl) -1
-Β-D-ribofuranosylimidazole-4-carbonitrile, 5- (6-hydroxy-1-hexyn-1-yl) -1-β-D-ribofuranosylimidazole-4-
Carbonitrile, 5- (4-hydroxy-1-hexyn-1-yl) -1-β-D-ribofuranosylimidazole-4-carbonitrile, 5- (3-methyl-5-hydroxy-1-pentyne- Examples thereof include compounds such as 1-yl) -1-β-D-ribofuranosylimidazole-4-carbonitrile, and compounds in which the sugar group hydroxyl groups of these compounds are protected by the above-mentioned protecting groups.

In the method of the present invention, R ¹ in the compound represented by the general formula [I] to be prepared from the above-mentioned starting compounds is used.
The compound having R ¹ corresponding to may be used as the starting compound in the method of the present invention.

This starting material compound can be prepared, for example, by the following reaction steps.

[In the formula, R ¹ and R ² have the same meanings as described above, R ² ′ represents a hydroxyl-protecting group, and X represents a halogen atom. That is, a protecting group is introduced into the sugar group hydroxyl group of 5-amino-1-β-D-ribofuranosylimidazole-4-carbonitrile (compound (A)) (first step), and the 5-position of the base moiety is halogenated. (2nd step) and introducing an alkynyl group at the 5-position of the base moiety (3rd step).

(Step 1) The introduction of a protective group into compound (A) may be carried out according to a method commonly used for the protective group to be used. For example, in the case of introducing an acyl group as a protective group, compound (A)
A reaction solvent (for example, pyridine, picoline, diethylaniline, etc.) is used with 3 to 15 times mol of an acylating agent (an acid anhydride or acid chloride corresponding to R ² ′) per mol.
Basic solvent such as tributylamine, triethylamine or a mixed solvent of the basic solvent and acetonitrile, dimethylformamide, dimethylacetamide, formamide, chloroform, methane dichloride, dioxane, tetrahydrofuran, dimethylaminopyridine, etc., at a reaction temperature of 0 to It can be carried out by reacting at 50 ° C. for 1 to 30 hours.

(Step 2) The halogenation reaction at the 5-position of the base moiety is a halogenation reaction via a diazonium compound, and is, for example, Nair and Rich.
It can be carried out according to the method of Ardson (see J. Org. Chem., 45 , 3969-3974 (1980)).

Specifically, as the halogenating agent, tribromomethane for bromination and diiodomethane for iodination can be used, and these halogenating agents also act as reaction solvents. Then, the halogenation reaction is carried out in the amount of 2 to 30 times mol of alkyl nitrite with respect to compound B and 1 mol of compound B (eg, isoamyl nitrite, butyl nitrite, etc.)
Can be dissolved in a halogenating agent and reacted at 50 ° C. to solvent reflux temperature for 10 minutes to 30 hours.

(Third Step) The introduction of the alkynyl group to the 5-position of the base moiety is carried out by, for example, compound (C) and formula (D) HC≡CR ¹ ′ (D) [wherein R ¹ ′ is a silyl group or a lower alkyl group, A hydroxy lower alkyl group and a phenyl group are shown. ] It can carry out by the method of making the acetylene derivative represented by these react.

In the above formula (D), the silyl group of R ¹ ′ includes trimethylsilyl, t-butyldimethylsilyl, methyldi-t-
Examples thereof include silyl groups used in the usual synthesis of organic compounds such as butylsilyl and tripropylsilyl.

The selection of the acetylene derivative used in this step depends on the type of R ¹ of the compound to be prepared when R ¹ in the compound of the formula [I] to be prepared is other than a hydrogen atom.
A compound having R ¹ ′ may be selected, and when R ¹ is a hydrogen atom, a compound having R ¹ ′ is a silyl group may be selected.

Examples of the reaction solvent include triethylamine, tributylamine, trioctylamine, N, N, N ', N'-
Tetramethyl-1,8-naphthalenediamine, dimethylaniline, diethylaniline, a basic solvent such as pyridine alone or the basic solvent and acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, tetrahydrofuran, A mixed solvent with dioxane or the like can be used.

The reaction between the compound (C) and the acetylene derivative proceeds efficiently in the presence of a palladium catalyst, and examples of the palladium catalyst include bis (acetonitrile) palladium dichloride, bis (triphenylphosphine) palladium dichloride and bis (benzo). Nitrile) palladium dichloride, tetra (triphenylphosphine)
Palladium or the like can be used.

The reaction conditions are as follows: in the presence of a catalytic amount of a palladium catalyst in the above reaction solvent, 1 to 3 moles, preferably 1 to 2 moles, of an acetylene derivative relative to 1 mole of compound (C), and a reaction temperature of 50 to 150. It can be carried out by reacting at 0 ° C, preferably 90 to 110 ° C for 1 to 30 hours.

When R ¹ ′ of the compound thus obtained is a silyl group, the silyl group is removed, and if necessary, the hydroxyl-protecting group represented by R ² ′ is removed to give the starting compound of the formula [I] obtain.

The removal of the silyl group and the protecting group may be carried out by an ordinary method. For example, the removal of the silyl group is carried out by acidic hydrolysis using hydrochloric acid-tetrahydrofuran-water, alkaline hydrolysis using methanol / ammonia, treatment with ammonium fluoride and the like. can do. When an acyl group is used as the protective group for the hydroxyl group represented by R ² ′, it can be removed by alkaline hydrolysis with methanol / ammonia, concentrated ammonia or the like.

The raw material compound thus obtained can be isolated and purified by a usual nucleoside isolation and purification means (for example, various chromatography methods such as adsorption or ion exchange, recrystallization method, etc.). .

When isolation and purification of the reaction product is required after completion of each of the above reaction steps, the usual isolation and purification means for nucleosides (for example, adsorption or ion exchange chromatography, recrystallization method, etc.) can be used in the same manner as the starting compound. ) Can be appropriately combined and implemented.

In the method of the present invention, the present raw material compound prepared as described above is subjected to a hydrolysis reaction and represented by the above formula [I].
5-alkynyl-1 to obtain -alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide
The present invention relates to a method for producing -β-D-ribofuranosylimidazole-4-carboxamide.

The hydrolysis reaction of the method of the present invention is a hydrolysis reaction employed in the preparation of an acid amide derivative from a nitrile derivative, specifically, an acidic hydrolysis reaction, a neutral hydrolysis reaction, and an alkaline hydrolysis reaction. It may be any hydrolysis reaction, preferably a neutral hydrolysis reaction or an alkaline hydrolysis reaction, and more preferably an alkaline hydrolysis reaction.

More specifically explaining the alkaline hydrolysis reaction, sodium hydroxide, potassium hydroxide, in the presence of a base such as ammonium hydroxide (or ammonia), the starting compound and hydrogen peroxide 10 ~ 50 ℃, preferably The hydrolysis reaction of the method of the present invention can be carried out by reacting at room temperature for 1 minute to 10 hours.

The reaction solvent may be any one that dissolves the starting material compound and the compound to be prepared and does not interfere with the reaction of the present invention, and specifically, an alcoholic solvent such as methanol or ethanol can be used.

The thus-obtained 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide is a usual nucleoside isolation and purification means (for example, various chromatographic methods such as adsorption or ion exchange, and recrystallization method). Can be appropriately combined and isolated and purified.

〔The invention's effect〕

The method of the present invention can easily and efficiently yield 5-alkynyl-1-β-D-ribofurano by subjecting 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile to a hydrolysis reaction. Ciliimidazole-4-carboxamide can be prepared. Therefore, 5-ethynyl-1- in which R ¹ in the above formula [I] is an ethynyl group.
β-D-ribofuranosylimidazole-4-carboxamide can also be prepared by an extremely simple method without using an ethynyltin compound as in the conventional method.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to Reference Examples and Examples.

〔Example〕

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

Reference Example Synthesis of 5-alkynyl 1-β-D-ribofuranosylimidazole-4-carbonitrile [formula [II], R ¹ = phenyl or hydrogen atom, R ² = hydrogen atom] 5-amino-1- (2 , 3,5-Tri-O-acetyl-
10.88 g (29.7 mmol) of β-D-ribofuranosyl) imidazole-4-carbonitrile was dissolved in 150 ml of diiodomethane in an oil bath at 100 ° C., and further 15 ml of isoamyl nitrite was added and reacted for 30 minutes. After the reaction, the reaction solution was developed on a silica gel column (3.6 × 36 cm) and eluted with 1 to 4% ethanol-chloroform to obtain a fraction containing the target compound, which was recrystallized from ethanol to give 5-iodo-1- (2,3,5
-Tri-O-acetyl-β-D-ribofuranosyl) imidazole-4-carbonitrile (9.86 g, yield 69.6%) was obtained.

5-iodo-1- (2,3,5-tri-O-acetyl-
477 mg of β-D-ribofuranosyl) imidazole-4-carbonitrile and 18 mg (5 mol%) of bis (benzonitrile) palladium dichloride were placed in a sealed tube, and argon gas was bubbled to dissolve acetonitrile. Add 0.16 ml (1.2 mmol) of triethylamine and 1.2 mol of acetylene derivative (phenylethyne or trimethylsilylethyne),
The reaction was carried out in an oil bath at 100 ° C. After the reaction, the reaction solution was filtered through Celite, washed with ethanol, and then purified with a silica gel column.

The compound obtained above was dissolved in a mixed solvent of ammonium / methanol and reacted at room temperature for 4 to 12 hours. After the reaction, the solvent was distilled off, and the obtained residue was purified by a silica gel column to obtain the target compound. The identification data of the obtained compound are shown in Table 1.

Example 1 5- (phenylethyn-1-yl) -1-β-D-ribofuranosylimidazole-4-carbonitrile 10 mg
(0.03 mmol) ammonium-methanol (1: 1 V / V)
Dissolve it in 4 ml, add 0.2 ml of hydrogen peroxide to it, and let it stand at room temperature.
The reaction was stirred for 30 minutes. After the reaction, the solvent was distilled off, and the residue was eluted with a 5-20% ethanol-chloroform solution through a silica gel column (1.8 × 35 cm) to give 5- (phenylethyn-1-yl) -1-β-D-. Ribofuranosyl imidazole-4-carboxamide (8.4 mg, yield 79.6%) was obtained.

Melting point (mp) 168~169 ℃ Elemental analysis _{C 17 H 17 N 3 O 5} · 1 / 4H 2 O Calculated C58.70%, H5.07%, N12.08% Found C58.71%, H5. 05%, N 11.93% Example 2 5-ethynyl-1- (2,3,5-tri-O-acetyl-
Synthesis of β-D-ribofuranosyl) imidazole-4-carboxamide 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile 127 mg (0.51 mmol) in ammonia-methanol (1: 1) mixed solvent 6 ml. After dissolution, 0.5 ml of hydrogen peroxide was added thereto, and the mixture was reacted with stirring at room temperature for 45 minutes. After the reaction, the solvent was distilled off, and the residue was adsorbed on a silica gel column, eluted with a 5-10% ethanol-chloroform mixed solvent, and crystallized from ethanol to give 5-ethynyl-.
White crystals of 1-β-D-ribofuranosylimidazole-4-carboxamide were obtained.

mp 182-185 ° C. Elemental analysis C ₁₁ H ₁₃ N ₃ O ₅ Calculated C49.44%, H4.90%, N15.72% Found C49.45%, H4.95%, N15.62% said crystalline The whole amount was further added to a mixed solvent of anhydrous acetonitrile 4 ml, demethylaminopyridine 5 mg, triethylamine 0.28 ml, and acetic anhydride 0.19 ml, and the mixture was reacted with stirring at room temperature for 30 minutes, and further with methanol 1 ml and reacted for 5 minutes. After the reaction, the solvent was distilled off, and the residue was passed through a silica gel column (1.8 x 10c
m), and eluted with 50 to 25% hexane-ethyl acetate eluent to give 5-ethynyl-1- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) imidazole-4-.
154 mg (yield 77.0%) of carboxamide was obtained.

Claims (3)

(57) [Claims] 1. A formula [I] [In the formula, R ¹ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group or a phenyl group, and R ² represents a hydrogen atom or a hydroxyl group-protecting group. ] 5-Alkynyl-1-β- represented by
A method for producing D-ribofuranosylimidazole-4-carboxamide, which comprises the step of formula [II] [In the formula, R ¹ and R ² have the same meanings as described above. ] Represented by 5
5-alkynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile as a starting compound, the starting compound is subjected to a hydrolysis reaction to obtain the compound of the above formula [I] 5- Process for producing alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide. 2. The method for producing 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide according to claim 1, wherein the hydrolysis reaction is an alkaline hydrolysis reaction. 3. The method for producing 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamide according to claim 1, wherein the hydrolysis reaction is an alcal hydrolysis reaction using hydrogen peroxide.