JPH068282B2 - AICA-riboside analog and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention provides a compound useful for producing a carbocyclic analog of 2′-deoxypurine nucleoside, which has antiviral activity and is advantageous in the fields of genetic engineering or biochemistry. It is provided.

2. Description of the Related Art As an example of a carbocyclic analog of purine nucleoside, the general formula (A) In which Y'is adenine-9-yl [Chemica
Communications), 852 (1967)], or a compound in which Y'is hypoxanthin-9-yl [Chemical and.
Formal Bretain (Chemical & Pharmac
eutical Bulletin), 24 , 2624 (1976)] is known.
The above compounds are respectively carbocyclic analogs of adenosine and neusin (in the following description, the carbocyclic analog may be abbreviated as C-analog).

Problems to be Solved by the Invention Cyclopentanediol purine nucleoside analogues represented by Alisteromycin have already been proved to work effectively as substrates in various enzyme systems involving ordinary purine nucleosides [Journal・ Journal of Biochemistry, 73 , 94
5 (1973))].

Recently, C-analogs of purine nucleosides have attracted attention as antiviral agents [Science, 22
7 , 1296 (1985)]. On the other hand, those containing a C-analog of 2'-deoxypurine nucleotide in DNA have advantageous characteristics in genetic engineering as compared with those containing deoxyadenosine [Japanese Patent Application No. 59-73822 and Japanese Patent Application No. 5
9-258789 (JP-A-61-137887)].

However, deoxyguanosine C-analogs and guanosine C-analogs are still unexamined in many fields, and it is an important subject to synthesize and evaluate various C-analogs.

Means for Solving the Problems Under the circumstances as described above, the present inventors investigated various production methods for obtaining a novel and useful C-analog of 2′-deoxypurine nucleoside, and described below. 5-amino-4-carbamoyl- represented by the general formula [I]
It was found that the C-analog of 1-β-D-2'-deoxyribofuranosyl imidazole (hereinafter sometimes abbreviated as AICA riboside) is useful as an intermediate for producing the above-mentioned desired product, and the present invention It has been completed.

That is, the present invention provides (1) the general formula [I] (Wherein R ₁ and R ₂ represent an optionally protected hydroxyl group) and (2) the general formula [II] (In the formula, R ₁ and R ₂ represent an optionally protected hydroxyl group, and R ₃ represents hydrogen or an alkoxymethyl group)
Is a method of producing a compound of general formula [I], which comprises treating the compound represented by

In the compounds of the general formulas [I] and [II], when R ₁ and R ₂ are a hydroxyl protecting group, the protecting group is
Those that are stable under alkaline conditions are desirable. For example,
Alkylsilyl having 3 to 10 carbon atoms (eg, t-butyldimethylsilyl, etc.), tetrahydrofuranyl and tetrahydrofuranyl derivative having 4 to 7 carbon atoms, tetrahydropyranyl and tetrahydrapyranyl derivative having 5 to 8 carbon atoms (eg, Methoxytetrahydropyranyl), alkoxyalkyl having 3 to 10 carbon atoms (eg, ethoxyethyl,
Methoxyethyl, etc.), trityl and its substitution products (eg, monomethoxytrityl, dimethoxytrityl, etc.) and the like.

In the compound of the general formula [II], the alkoxymethyl group represented by R ₃ is generally one having a carbon number of 2 to 7, such as methoxymethyl, ethoxymethyl, propoxymethyl, phenoxymethyl, and the like. The methyl group is useful.

Alkali hydroxide can be preferably used in the above alkali treatment. For example, about 1M to 5M aqueous sodium hydroxide or potassium hydroxide solution, or an alkaline solution and a neutral water-soluble organic solvent (alcohols,
It can be carried out by heating in a mixed solution with dioxane) in the range of about 60 ° to 200 ° C. The reaction time at this time is usually about 10 minutes to 2 hours.

The compound of the general formula [II] used in the above reaction is obtained by converting the adenine ring of alisteromycin into a hypoxanthine ring [Chem. Pharmaceutical Bulletin (Chem.Pharm.Bull), 24 , 2624 (1976). ] If necessary, a hydroxyl group-protecting group represented by R ₁ and R ₂ is introduced into the obtained compound, and an alkoxymethyl group represented by R ₃ is introduced.

The introduction of the hydroxyl-protecting group can be carried out by a method known per se [eg, Canadian Journal of Chemistry (Can.J.Che
m.), 60 , 111 (1982)], and when it has the protecting group, it is convenient for purification after the ring-opening reaction of the hypoxanthine ring by the alkali treatment. For example, the introduction of this protecting group is carried out in an organic solvent such as pyridine, dimethylformamide, dichloromethane, chloroform, dioxane, ethyl ether, acetonitrile, dimethylsulfoxide, nitromethane, trityl-, methoxy-trityl-, dimethoxy-trityl-chloride or dimethyl. It is carried out by reacting an alkylsilyl chloride such as tert-butyl silyl chloride or vinyl ethers such as vinyl ethyl ether and dihydropyran.

Thus, after protecting the hydroxyl groups of R ₁ and R _2, the hydroxyl group at the 2'position is thiocarbonylated or converted to phenylthioacetic acid ester, and then radically 2'-deoxylated with an organic tin hydride. of organic chemistry (J.Org.Chem.), 47, 485
(1982) ”can be used.

Next, the introduction of the alkoxymethyl group represented by R ₃ is carried out according to the method described in, for example, “Journal of American Chemical Society (J. Am. Chem. Soc.), 24 , 2624 (1976)”. Can be implemented. The introduction of the present alkoxymethyl group can be performed by opening the hypoxanthine ring under relatively mild conditions, and can be easily removed in the subsequent treatment as compared with the case where R ₃ is a simple alkyl group. Is advantageous in. By the above method, the general formula [I
I] can be obtained.

The trityl group and various ether type hydroxyl group-protecting groups in the compound of the general formula [I] can be easily removed with an organic acid or various inorganic acids. The silyl-based hydroxyl group-protecting group can be eliminated with an acid, but it can be removed under more mild conditions by using tetrabutylammonium fluoride.

The compounds of general formula [I] of the present invention are useful as intermediates for the preparation of carbocyclic analogs of 2'-deoxypurine nucleosides. That is, the general formula [I]
The compound of formula [III] (In the formula, R ₁ and R ₂ have the same meanings as described above, and Y represents guanine-9-yl, isoguanine-9-yl or hypoxanthin-9-yl).

The above-mentioned purine ring formation can be carried out by utilizing a reaction method known in heterocyclic chemistry. For example,
A compound in which Y is hypoxanthin-9-yl in the general formula [III] can be obtained by the following method. That is, the compound of the general formula [I] is used in sodium alcoholate (eg, ethylate, methylate, tertiary butyrate, etc.) and various esters (eg, chain or branched fatty acid having 2 to 20 carbon atoms or 7 to 7 carbon atoms). 2-alkyl, 2-allyl substituted 2'by heating reaction with an aromatic carboxylic acid of 30 and an alcohol of an alcohol having 1 to 10 carbon atoms.
It can also be a C-analog of deoxyinosine or can be heated with formamide or formic acid to form a C-analog of 2'-deoxyinosine. After heating with phenylisothiocyanate or potassium xanthate in pyridine to give a C-analog of 2'-deoxy form of 2-mercaptoinosine, it is passed through a 2-halogen form (eg, chloro form, bromo form). It is also possible to use a 2-alkoxy form (eg, methoxy, ethoxy, butoxy form) or a 2-substituted amino form (eg, methylamino, dimethylamino, ethylamino, diethylamino, cyclohexylamino, morpholino form).

In the general formula [III], the compound in which Y is guanin-9-yl is obtained by the method of the 2'-deoxy C-analog of 2-mercaptoinosine [Chem.Pharm.Bull., 19 , 576].
(1971)] can be adopted. Further, according to the method described in [Nucleic Acids Research (Nucleic Acids Res.), 3 , 251 (1976)], for example, a compound of the general formula [I] is reacted with benzoyl isothiocyanate in acetone under boiling. Then, a methyl group is introduced into the obtained benzoylisothiourea derivative using methyl iodide in an acetone-potassium carbonate mixture or dimethylsulfate in an aqueous solution of sodium hydroxide, and further subjected to ring closure by heating in about 2 to 6N-sodium hydroxide. Methods can also be employed.

On the other hand, when the benzoyl / methylisothiourea compound is subjected to ring closure by heating with a relatively low-concentration alkaline solution, for example, about 0.1 to 1N sodium hydroxide, a compound of the general formula [III] in which Y is isoguanine-9-yl is obtained. .

Next, each hydroxyl-protecting group in the compound of general formula [III] can be removed by the same method as in the case of the compound of general formula [I].

EXAMPLES Hereinafter, the present invention will be described more specifically by showing Reference Examples and Examples.

Example 1 9-[(1R, 2S, 3R, 4R) -4-methyl-2-
Synthesis of hydroxy-3,6- (tetraisopropyldisiloxanyl) dioxy-cyclopentan-1-yl] hypoxanthine C-analog of inosine [Compound of general formula (A) in which Y'is hypoxanthin-9-yl ] (10 g, 37.5 mmol)
Dissolve in 200 ml of anhydrous DMF, 1,3-dichloro-1,
1,3,3-Tetraisopropyldisiloxane (13 ml, 41
mmol) and imidazole (11.3 g, 165 mmol) were added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was added dropwise to water 2 and the resulting precipitate was collected by filtration, washed with water, then quickly washed with diethyl ether, dried, and then a white powdery compound (17.2 g)
Got Further, a part was recrystallized from dichloromethane to obtain crystals. mp135-138 ° C.

Example 2 9-[(1R, 2S, 3R, 4R) -4-methyl-2-
Benzoylthiocarbonyloxy-3,6- (tetraisopropyldisiloxanyl) dioxycyclopentane-
Synthesis of 1-yl] hypoxanthine The compound (11.2 g, 22.3 mmol) obtained in Example 1 was dissolved in 300 ml of anhydrous acetonitrile, and dimethylaminopyridine (15.
8g, 53.5mmol) and phenoxythiocarbonyl chloride (5
g, 29 mmol) was added and the mixture was stirred at room temperature for 7 hours. The residue obtained by removing the solvent under reduced pressure was dissolved in 250 ml of chloroform, and a 0.5 M potassium dihydrogen phosphate solution (250 ml x
It was washed with 2), washed with water (200 ml), dried (anhydrous sodium sulfate) and concentrated under reduced pressure to obtain a yellow syrupy substance.

Silica gel chromatography (90g, solvent; CHCLl)
Purification with ₃ and CHCl ₃ / MeOH = 60/1) gave a pale yellow glassy compound (13.0 g).

NMR (60MHz, CDCl ₃ ) δppm: 1.0-1.23 (28H, m), 2.13-2.4
3 (3H, m, H4 ' , H5'), 3.93-4.10 (2H, m, H 6 '), 4.80-5.
20 (2H, m, H ₁ ′, H ₃ ′), 6.00-6.20 (1H, m, H ₂ ′), 7.03-
7.50 (5H, m), 7.87 (1H, s), 8.13 (1H, s) Example 3 9-[(1R, 3S, 4R) -4-Methyl-3,6-
Synthesis of (tetraisopropyldisiloxanyl) dioxy-cyclopentan-1-yl] hypoxanthine To the compound (13.0 g, 20 mmol) obtained in Example 2 was added 30 ml of anhydrous toluene, and the mixture was concentrated under reduced pressure. Then, it was dissolved in 30 ml of anhydrous toluene, and nitrogen gas was bubbled for 20 minutes. After adding tributyltin hydride (11 ml, 40 mmol), while heating to 80 ° C, α, α′-
Azobisisobutyronitrile (AIBN) crystal (820m
g) was added. After heating with stirring for 3 hours, the solvent was removed under reduced pressure and the resulting oil was subjected to silica gel chromatography (8
0 g, solvent; CHCl ₃ and CHCl ₃ / MeOH = 60/1 to 30/1) to obtain a colorless glassy compound (10.4 g).

Further, a part thereof was recrystallized from ethanol to obtain colorless needle crystals. mp200-202 ℃.

NMR (60MHz, CDCl ₃ ) δppm: 0.93-1.20 (28H, s), 1.97-2.
53 (5H, m, H ₂ ′, H ₄ ′, H ₅ ′), 3.80-4.07 (2H, m,
H ₆ ′), 4.43-5.27 (2H, m, H ₁ ′, H ₃ ′), 7.87 (1H, s), 8.
20 (1H, s) Example 4 9-[(1R, 3S, 4R) -4- (monomethoxytrityloxy) methyl-3-hydroxyl-cyclopentan-1-yl]-(1-methoxy-methylhypoxanthine ) The compound (9.8 g, 19.8 mmol) obtained in Example 3 was dissolved in 240 ml of anhydrous dioxane, sodium hydride (880 mg, 21.8 mmol) was quickly added under ice-cooling stirring, and the mixture was returned to room temperature and stirred for 1.5 hr. Subsequently, methoxymethyl chloride (2 ml, 21.8 mmol) was quickly added under ice cooling, and stirring was continued at room temperature for 3 hours.

After removing the solvent under reduced pressure, the obtained oily substance was dissolved in 20 ml of chloroform, and 0.1 M triethyl bicarbonate (TEAB) buffer solution (pH 7.5, 100 ml × 2) was further washed with water (2
(00 ml), dried (anhydrous sodium sulfate) and concentrated under reduced pressure to obtain a syrup-like substance. _C18 silica gel chromatography (φ5.3 × 7.0 cm, solvent: acetone water, 55% -80%)
And purified to obtain a colorless glassy compound (8.5 g).

This compound (8.0 g) in 32 ml of tetrahydrofuran (THF)
The resulting solution was added with tetrabutylammonium fluoride trihydrate (TBAF / 3H ₂ O) (10 g), and the mixture was stirred at room temperature for 0.5 hr. The solvent was removed under reduced pressure to obtain an oily substance of 100 m
After dissolving in 1 l of water and washing with diethyl ether (100 ml × 2), tetrabutylammonium salt was removed on Dowex-50 (pyridine type, 60 ml) resin. This passing solution and a resin washing solution (240 ml) were combined and concentrated, and the residue was azeotropically distilled three times with pyridine to dehydrate it. This is dissolved in 100 ml of pyridine and monomethoxytrityl chloride (MMTrCl)
(5.4 g) was added, and the mixture was stirred at 37 ° C for 4 hr. The oily substance obtained by removing the solvent under reduced pressure was washed with 0.1 M-TEAB buffer (50
ml) and CHCl ₃ (100 ml), and the organic layer is washed with water (100 m
l), dried (anhydrous sodium sulfate) and concentrated under reduced pressure, and azeotroped with toluene to obtain a colorless syrupy substance. on the other hand,
The 0.1 M-TEAB buffer solution and the water washing solution were combined and concentrated to recover the compound that was not monomethoxytritylated.
This compound was concentrated, purified on HP-20 resin (190 ml, solvent; water and 30% aqueous methanol), concentrated, and subjected to pyridine azeotropy to perform monomethoxytritylation in the same manner as above. Purification of the target compound thus obtained in this example was performed by silica gel chromatography (80 g, solvent; CHCl ₃ / MeOH = 100/1, 60/1, 50/1), and the both compounds were colorless. A glassy compound (6.1 g) was obtained. Further, a part thereof was dissolved in dichloromethane and added dropwise into n-hexane to obtain a white powder.

NMR (60 MHz, CDCl ₃ ) δppm: 1.87-2.70 (5H, m, H ₂ ′,
H ₄ ′, H ₅ ′), 3.20-3.40 (2H, m, H ₆ ′), 3.43 (3H, s, C H ₃
OCH ₂ ), 3.80 (3H, s), 4.30-4.57 (1H, m, H ₃ ′), 4.87-5.10
(1H, m, H ₁ ′), 5.47 (2H, s, CH ₃ OC H ₂ -N), 6.73-6.97 (2H,
m), 7.17-7.53 (12H, m), 7.73 (1H, s), 7.98 (1H, s) Example 5 1-[(1R, 3S, 4R) -4- (monomethoxytrityloxy) methyl-3 -Hydroxyl-cyclopentan-1-yl]-(4-carbamoyl-5-aminoimidazole) The compound (6.1 g, 10.7 mmol) obtained in Example 4 was dissolved in 490 ml of ethanol and added under heating under reflux. Warmed 13
0 ml of 5M aqueous sodium hydroxide solution was added rapidly and reflux was continued for another 40 minutes. After removing the solvent under reduced pressure, the oily substance obtained was dissolved in 200 ml of chloroform and washed with water (100 ml
X2), followed by washing with 0.1 M TEAB buffer (100 ml x
2), further washed with saturated saline (100 ml), dried (anhydrous sodium sulfate) and concentrated under reduced pressure to obtain a syrup-like substance.
Silica gel chromatography (90 g, solvent; CHCl ₃₎
/ MeOH = 100/1 to 20/1) and colorless glassy compound (3.
2g) was obtained. Further, a part thereof was dissolved in chloroform and dropped into n-pentane with stirring to obtain a white powdery compound.

Elemental analysis value (%) C ₃₀ H ₃₂ N ₄ O ₄ .0.5H ₂ O, molecular weight 521.616 Calculated value: C; 69.08, H; 6.38, N; 10.74 Actual value: C: 69.14, H; 6.09, N; 10.54 NMR (100MHz, CDCl ₃ ) δppm: 1.36-2.52 (5H, m,), 3.00-
3.40 (3H, m, H ₆ ′, OH), 3.77 (3H, s), 4.12-4.60 (2H, m,
H ₁ ′, H ₃ ′), 4.80-5.28 (2H, br.NH ₂ ), 5.64-6.44 (2H, b
r, NH ₂ ), 6.76-6.94 (3H, m), 7.14-7.48 (12H, m) Example 6 1-[(1R, 3S, 4R) -4-hydroxymethyl-
3-hydroxyl-cyclopentan-1-yl]-(4
-Synthesis of carbamoyl-5-aminoimidazole) The compound (2.3 g, 4.4 mmol) obtained in Example 5 was dissolved in 50 ml of 80% acetic acid and stirred at 40 ° C for 7 hours. After concentration under reduced pressure,
Further, it was azeotropically distilled with toluene and then with ethanol. The residue was dissolved in 12 ml of ethanol and 130 ml of n-
The mixture was dropped into hexane-ether (1: 1, v / v) under stirring to obtain a syrup-like substance. This was purified by C ₁₈ silica gel chromatography (10 g, solvent; water and 5% acetone water), and the solvent was removed under reduced pressure to recrystallize from ethanol to obtain the target compound (0.93 g) of this example.

_{mp.162-163 ℃ λ max nm: (H} 2 O) 234 (sh), 268; (H +) 244,269; (OH -) 267.5 NMR (60MHz, DMSO-d 6 + D 2 O) δppm: 1.67- 2.67 (5H, m,),
3.43-3.60 (2H, m, H ₆ ′), 3.90-5.00 (2H, m), 7.23 (1H, s, H
₂ ); (DMSO-d ₆ ) 5.77 (2H, bs, NH ₂ ), 6.63 (2H, bs, NH ₂ ) Elemental analysis value (%) C ₁₀ H ₁₆ N ₄ O ₃ , calculated as molecular weight 240.262: C 49.99, H; 6.71, N; 23.32 Found: C; 49.32, H; 6.34, N; 22.92 Reference Example 1 1-[(1R, 3S, 4R) -4- (monomethoxytrityloxy) methyl-3- Synthesis of hydroxyl-cyclopentan-1-yl]-(4-carbamoyl-5- (N-benzoyl-S-methylisothio-carbamoyl) aminoimidazole) 25 ml of the compound obtained in Example 5 (0.88 g, 1.7 mmol) Dissolved in anhydrous acetone and heated under reflux with benzoyl isothiocyanate (260μ, 1.9mmol) in acetone (8m
l) was added dropwise over 10 minutes, followed by reflux for 50 minutes. The pale yellow glassy substance obtained by removing the solvent under reduced pressure was subjected to silica gel chromatography (15 g, solvent; CHCl ₃ / MeOH = 50/1 to 30/1).
Purification was performed to obtain a pale yellow glassy compound (0.87 g). A small amount of acetone was added to this compound (0.84 g, 1.2 mmol) to form a syrup, and then 12.5 ml of 0.2N-NaOH was added to it to obtain a uniform solution by ultrasonication. Dimethyl sulfate under stirring
(130 μ, 1.4 mmol) was added and vigorous stirring was continued for 1 hr at room temperature. Partition the reaction mixture with CHCl ₃ (15 ml × 2) and separate the organic layer.
0.1M-TEAB buffer (15ml × 3), followed by saturated saline
After washing with (20 ml), drying (anhydrous sodium sulfate) and concentration under reduced pressure, silica gel chromatography (15 g, solvent; CHCl ₃
/ MeOH = 100 / 1-60 / 1) for purification. A small amount of dichloromethane was added to the obtained glassy substance, and the precipitate formed by dropping it in hexane was spun down and dried to obtain 400 mg of the target compound powder in this Reference Example.

Elemental analysis value (%) C ₃₉ H ₃₉ N ₅ O ₅ S ₁ , calculated with a molecular weight of 689.835: C; 67.90, H; 5.70, N; 10.15 Actual value: C; 67.45, H; 5.45, N; 9.89 NMR ( 100MHz, CDCl ₃ ) δppm: 1.34-2.60 (5H, m,), 2.52 (3
H, s, SCH ₃ ), 3.04-3.44 (2H, m, H ₆ ′), 3.79 (3H, s, OCH ₃ ),
4.08-4.44 (1H, m, H ₃ '), 4.60-5.00 (1H, m, H ₁ '), 5.64
(1H, bs, NH ₂ ), 6.72-6.94 (3H, m), 7.12-7.52 (15H, m), 7.80-
7.96 (2H, m), 11.35 (1H, bs, NH) Reference Example 2 1-[(1R, 3S, 4R) -4-hydroxymethyl-
3-hydroxyl-cyclopentan-1-yl]-[4
Synthesis of -carbamoyl-5- (N-benzoyl-S-methylisothiocarbamoyl) aminoimidazole] The compound obtained in Example 6 (815mg, 3.4mmol) was reacted with 1.1 equivalents of benzoylisothiocyanate in acetone and reduced pressure. The lower solvent was removed, and 15 ml of acetone-CHCl ₃ (2:
1, v / v) was added, and then ether was added, and the resulting precipitate was collected by filtration and dried to obtain 1.4 g of a powder. 35 ml of this powder
Dissolved in 0.2N sodium hydroxide, dimethyl sulfate 340μ
) Was added and the mixture was stirred at room temperature for 1 hr. Acetic acid was added to the reaction mixture under ice cooling (pH 4 to 5) to remove the product from the cloudy reaction mixture.
-Extract with butanol (20 ml x 3) and wash with water (10 ml x 2)
Then, the solvent was removed under reduced pressure, and C was purified by silica gel chromatography (10 g, solvent; water and 30% acetone water) to obtain a pale yellow glassy substance (920 mg). This was recrystallized from water to obtain the target compound of this Reference Example as colorless crystals (570 mg). mp.119-120 ℃ Elemental analysis value (%) C ₁₉ H ₂₃ N ₅ S ₁ O ₄・ 0.3H ₂ O ,, molecular weight 422.8
Calculated as 86: C; 53.96, H; 5.62, N; 16.56, S; 7.58 Measured value: C; 54.03, H; 5.49, N; 16.44, S; 7.53 NMR (100MHz, CMSO-d ₆ ) δppm: 2.52 (3H, s, CH ₃ ), 7.34-
7.94 (6H, m) and 11.85 (1H, bs, NH) were confirmed.

Reference Example 3 9-[(1R, 3S, 4R) -4-monomethoxytrityloxymethyl-3-hydroxyl-cyclopentane-
Synthesis of 1-yl] guanine The compound (360 mg, 0.53 mmol) obtained in Reference Example 1 was heated.
It was added to 18 ml of 6N sodium hydroxide and heated under reflux for 1 hr. The product was extracted from the reaction solution with CHCl ₃ and 0.1M-TEA
The extract was washed with B buffer (30 ml) and then saturated saline (30 ml), dried (anhydrous sodium sulfate), and purified by silica gel chromatography (8 g, solvent; CHCl ₃ / MeOH = 40/1 to 6/1). .
A small amount of acetone was added to the obtained glassy substance, and the resulting precipitate was dropped into pentane, and the precipitate was spun down and dried to obtain 210 mg of the target compound powder.

Elemental analysis value (%) C ₃₁ H ₃₁ N ₅ O ₄ · 1.0H ₂ O, calculated as molecular weight 555.633: C; 67.01, H; 5.99, N; 12.60 Actual value: C; 67.01, H; 5.69, N; 12.42 NMR (100MHz, DMSO-d ₆ ) δppm: 1.50-2.60 (5H, m,), 3.01
(2H, bs), 3.98-4.20 (1H, m), 4.70-4.96 (2H, m), 6.37 (2H, b
s, NH ₂ ), 6.82-7.46 (14H, m), 7.68 (1H, s, H ₈ ), 10.60 (1H, bs,
NH) Example 4 9-[(1R, 3S, 4R) -4-hydroxymethyl-
Synthesis of 3-hydroxyl-cyclopentan-1-yl] guanine The compound (180 mg, 0.33 mmol) obtained in Reference Example 3 was added to 10 ml of 80
% Acetic acid, and stirred at 40 ° C. for 4.5 hours. The solvent was removed under reduced pressure, and the mixture was azeotropically distilled twice with water. After adding 10 ml of water and washing with ether (10 ml × 2), water was removed under reduced pressure to obtain 41 mg of colorless crystals of the desired compound. mp24
_{6-248 ℃ λ max (nm) :(} H 2 O); 255,278 (sh) (H +); 257,282 (OH -); 256 (sh), 27
3 Elemental analysis value (%) C ₁₁ H ₁₅ N ₅ O ₃・ 0.5H ₂ O ・ 0.1C ₂ H ₅ OH, calculated as molecular weight 278.886 Calculated value: C; 48.24, H; 6.00, N; 25.11 Measured value: C; 48.61, H; 6.41, N; 25.40 Reference Example 5 9-[(1R, 3S, 4R) -4-monomethoxytrityloxymethyl-3-hydroxyl-cyclopentane-
Synthesis of 1-yl] isoguanine The compound (585 mg, 0.85 mmol) obtained in Reference Example 1 was dissolved in 10 ml of ethanol, 6 ml of 1N-NaOH and 44 ml of water were added, and the mixture was heated under reflux for 2 hr. Add 60 ml of 0.
1N-NaOH was added and heating under reflux was continued for 2 hours. After neutralizing this reaction solution with 1N-HCl, the product was extracted with CHCl ₃ , washed with saturated saline and then with water, chloroform was removed under reduced pressure, and the obtained syrup-like substance was left in a refrigerator overnight. Then, white crystals of the desired compound (200 mg, mp. 245-247 ° C) were obtained. Further, the filtrate was purified by C ₁₈ silica gel chromatography (10 g, solvent; 50-90% aqueous acetone).

Elemental analysis value (%) Calculated as C ₃₁ H ₃₁ N ₅ O ₄ molecular weight 537.618 Calculated value: C; 69.26, H; 5.81, N; 13.03 Measured value: C; 68.80, H; 5.86, N; 12.60 NMR (100 MHz, DMSO-d ₆ ) δppm: 1.46-2.46 (5H, m, 2
H ₂ ′, 2H ₅ ′, H ₄ ′), 3.00-3.38 (4H, m), 3.75 (3H, s, C
H ₃ ), 3.96-4.16 (1H, m, H ₃ ′), 4.68-4.94 (2H, m), 6.38 (1
H, bs, NH), 6.80-7.50 (14H, m), 7.77 (1H, s, H 8) Reference Example 6 9 - [(1R, 3S , 4R) -4- hydroxymethyl -
Synthesis of 3-hydroxyl-cyclopentan-1-yl] isoguanine The compound (148 mg, 0.27 mmol) obtained in Reference Example 5 was dissolved in 11 ml of 80% acetic acid, and the mixture was stirred at 45 ° C for 6 hr. Remove the solvent under reduced pressure,
After azeotropic distillation with water, ether (1
It was washed with 0 ml × 2). The glassy substance obtained by removing water under reduced pressure is suspended in ethanol to give the desired compound (69 m
g, mp162-165 (decomposition) was obtained.

Elemental analysis value (%) C ₁₁ H ₁₅ N ₅ O ₃・ 0.5H ₂ O ・ 0.1EtOH, molecular weight 2
Calculated as 78.887: C; 48.24, H; 6.00, N; 25.11 Measured value: C; 47.92, H; 6.05, N; 24.89 λ _max (nm): (H ₂ O); 249,253 (sh), 294 (H ⁺ ); 236,242 (sh),
283 (OH ⁻ ); 250,285 NMR (100MHz, DMSO-d ₆ + D ₂ O) δppm: 1.10-2.60 (5H, m, 2H
₂ ', 2H ₅ ', H ₄ '), 3.40-3.60 (2H, m, 2H ₆ '), 4.00-
4.20 (1H, m, H ₃ ′), 4.60-5.10 (1H, m, H ₁ ′), 7.90 (1H,
s, H ₈ ) Reference Example 7 Synthesis of Compound of Reference Example 4 (Alternative Method) The compound of Reference Example 2 (420 mg) was dissolved in 10 m of 6N sodium hydroxide, and rapidly heated and refluxed for 1 hr. After being brought to room temperature, it was neutralized with 1N hydrochloric acid, and the reaction solution was purified by chromatography on HP-20 (190 m, solvent; water and 10% ethanol water) and concentrated to obtain colorless crystals (174 mg). .

As a result, the C-analog of AICA-riboside represented by the general formula [I] of the present invention is useful as an intermediate in the production of the compound of the general formula [III]. The compound represented by the general formula [III] has antiviral activity and can be used equivalently to a nucleoside having guanine, isoguanine or hypoxanthine as a base in the field of genetic engineering or biochemistry. For example, in the general formula [III], a compound in which Y is guanine-9-yl has a strong growth inhibitory action against herpesvirus (type I, HF strain), and instead of GTP which is a substrate for DNA polymerase. A DN which can be used and contains the carbocyclic analog of guanosine obtained
A is useful in various recombinant DNA techniques.

Claims (2)

[Claims] 1. A general formula (Wherein R ₁ and R ₂ represent a hydroxyl group which may be protected). 2. General formula (In the formula, R ₁ and R ₂ represent an optionally protected hydroxyl group, and R ₃ represents hydrogen or an alkoxymethyl group)
A general formula characterized by treating the compound represented by (Wherein R ₁ and R ₂ have the same meanings as described above).