JPH06184185A - Production of 3-deazapurine nucleosides and 3-halogeno-3-deazapurine nucleoside - Google Patents

Abstract

PURPOSE:To extremely readily obtain the subject compounds having physiological activity such as antiviral action in high purity without a mixed state of isomers, etc., by carrying out a new method using a specific imidazole nucleoside compound as a starting raw material. CONSTITUTION:A compound of formula I [Z is carbamoyl or cyano; Y1 is H or (hydroxy)lower alkyl; R is H or protecting group of hydroxyl group] is made to react with ammonia or amines (preferably a secondary amine such as dimethylamine) to afford the objective compound of formula II (X is OH or amino). This reaction is preferably carried out at 70-150 deg.C for 2-3hr in a sealed tube by using an alcoholic solvent such as methanol. Furthermore, e.g. 5-ethyl-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide can be used as the raw material compound of formula I. In this case, 4-hydroxy-1-beta-D-ribofuranosyl-1H- imidazo[4,5-c]pyridine is obtained as the objective compounds of formula II.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel process for producing 3-deazapurine nucleosides and a novel 3-halogeno-3-
It concerns deazapurine nucleosides.

[0002]

2. Description of the Related Art A conventional method for synthesizing 3-deazapurine nucleosides is to condense a deazapurine derivative with a sugar moiety (see, for example, Heterocycles, 17 , 615 (1982)).
Is the mainstream, and there are very few reports on the synthesis of 3-deazapurine nucleosides from nucleosides.
According to the condensation method, the target compound to be synthesized is usually obtained in a mixed state of both α-isomer and β-isomer, and therefore it is necessary to separate them from each other, and the method is usually extremely complicated. Therefore, this method was not always a satisfactory method for synthesizing 3-deazapurine nucleosides.

[0003]

The 3-deazapurine nucleoside is a compound which has been attracting attention from the viewpoint of physiological activity such as antiviral activity. Therefore, the establishment of a simple synthetic method for this compound is earnestly desired by many researchers involved in the research of nucleoside science. From the viewpoint of physiological activity such as antiviral action, it is desired to develop a novel derivative of 3-deazapurine nucleoside, for example, a 3-substituted-3-deazapurine nucleoside derivative having a carbon functional group introduced at the 3-position. At present, it is the current situation that the acquisition of useful intermediates that can be used in the development of such new compounds is desired. Therefore, the first object of the present invention is to establish a convenient method for producing 3-deazapurine nucleoside. A second object of the present invention is to develop a compound which is considered to be useful for synthesizing a 3-substituted-3-deazapurine nucleoside having a carbon functional group introduced at the 3-position, and a method for producing the same. To provide.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted various studies in order to achieve the above object, and as a result, used a specific imidazole nucleoside compound as a starting compound and functionalized the alkynyl group at the 5-position of the imidazole. It was found that 3-deazapurine nucleosides can be synthesized by an extremely simple method by group conversion. Also,
The present inventors have found that a compound obtained by reacting a 3-deazapurine nucleoside with a halogenating agent is a novel compound that can achieve the second object. The present inventors have conducted further research based on such findings and completed the present invention.

The present invention uses the formula (1)

[Chemical 10] (In the formula, X is a hydroxyl group or an amino group, Y ₁ is a hydrogen atom,
A lower alkyl group or a hydroxy lower alkyl group, R represents a hydrogen atom or a hydroxyl group-protecting group) 3
-A process for the production of deazapurine nucleosides, comprising the formula (2)

[Chemical 11] (Wherein Z represents a carbamoyl group or a cyano group, Y ₁ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, and R represents a hydrogen atom or a hydroxyl-protecting group), and ammonia or amines. The present invention provides a method for producing a 3-deazapurine nucleoside, which comprises reacting to obtain a compound represented by the above formula (1).

The present invention also provides the equation (3)

[Chemical 12] (Wherein R represents a hydrogen atom or a hydroxyl-protecting group), and a method for producing 3-deazaguanosine represented by the formula (4)

[Chemical 13] A compound represented by the formula (5)

[Chemical 14] A compound of the formula (6) is obtained by reacting this compound with isocyanic acid.

[Chemical 15] (Wherein R has the above meaning), and then subjecting this compound to alkali treatment to obtain the compound represented by the above formula (3)
A method for producing deazaguanosine is provided.

Further, the present invention provides the formula (7)

[Chemical 16] (In the formula, X is a hydroxyl group or an amino group, Y ₂ is a hydrogen atom or an amino group, Hal is a halogen atom, and R is a hydrogen atom or a hydroxyl-protecting group), and is a 3-halogeno-3-deazapurine nucleoside. Of the formula (8)

[Chemical 17] (Wherein X, Y ₂ and R have the above meanings) and a halogenating agent are reacted to obtain the compound represented by the above formula (7).
The present invention provides a method for producing a halogeno-3-deazapurine nucleoside.

Furthermore, the present invention provides the formula (7)

[Chemical 18] (In the formula, X is a hydroxyl group or an amino group, Y ₂ is a hydrogen atom or an amino group, Hal is a halogen atom, and R is a hydrogen atom or a hydroxyl-protecting group), and is a 3-halogeno-3-deazapurine nucleoside. Is provided.

The present invention will be described in detail below. I. Method of Synthesizing Compound of Formula (1) In the compound of formula (1), the groups represented by X, Y ₁ and R are as defined above, and the lower alkyl group represented by Y ₁ has 1 to 6 carbon atoms. Alkyl groups to a degree, specifically methyl, ethyl, n-propyl, i-propyl,
Examples thereof include n-butyl, t-butyl, n-pentyl, n-hexyl and the like. Examples of the hydroxy lower alkyl group represented by Y ₁ include those having 1 to 3 hydroxyl groups at any position of the above lower alkyl group. The protective group for the hydroxyl group represented by R is not particularly limited as long as it is commonly used as a protective group for the hydroxyl group of nucleoside, and specifically, acetyl,
Chloroacetyl, dichloroacetyl, trifluoroacetyl, methoxyacetyl, propionyl, n-butyryl, (E) -2-methylbutenoyl, isobutyryl, pentanoyl, benzoyl, o- (dibromomethyl) benzoyl, o- (methoxycarbonyl) benzoyl, p -
Acyl groups such as phenylbenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, p-chlorobenzoyl, p-nitrobenzoyl, α-naphthoyl; benzyl, phenethyl, 3-phenylpropyl, p-methoxy Benzyl, p-nitrobenzyl, o-
Aralkyl groups such as nitrobenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl (trityl), α or β-naphthylmethyl, α-naphthyldiphenylmethyl; trimethylsilyl, triethylsilyl, dimethylisopropylsilyl,
Silyl groups such as isopropyldimethylsilyl, methyldi-t-butylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, tetraisopropyldisiloxanyl; alkoxymethyl groups such as methoxymethyl, ethoxymethyl; isopropylidene, Examples thereof include acetal-type or ketal-type protecting groups such as ethylidene, propylidene, benzylidene, and methoxymethylidene. In addition, such a protective group may be introduced according to a conventional method.

Z, Y ₁ and R in the compound of the formula (2) which is a starting material are as defined above, and a lower alkyl group and a hydroxy lower alkyl group represented by Y ₁
Examples of the protective group for the hydroxyl group represented by R are the same as those of the compound of formula (1). Further, it Y ₁ in the compound of formula (2) is the same as Y ₁ in the compound of formula (1) of synthetic purposes is of course, equation (1)
When Y ₁ of the compound of formula (1) is a hydroxy lower alkyl group, the hydroxy lower alkyl group of Y ₁ of the compound of formula (2) has a hydroxyl group in the unprotected state, or an acyl group or a silyl group. Any of those protected with a hydroxyl-protecting group such as Such raw material compounds are
It is a known compound and can be prepared according to a known method (JP-A-1-221388, JP-A1-2).
No. 54697, Japanese Patent Laid-Open No. 1-254698, Ch
See em, Pharm.Bull., 36 (7), 2730 (1988) etc.).

The amines to be reacted with the raw material compounds may be primary amines, secondary amines or tertiary amines, but secondary amines are particularly preferable. Specific examples of the secondary amine include aliphatic amines having an alkyl group having about 1 to 4 carbon atoms, such as dimethylamine, diethylamine, and dipropylamine.

The reaction of the compound of the formula (2) with ammonia or amines is carried out by using an excess amount of ammonia or amines in a reaction solvent (alcohols such as methanol and ethanol) at 70 to 150 ° C. for 2 to 30. It can be carried out by reacting for about time. The reaction is preferably carried out in a sealed tube to prevent evaporation of ammonia or amines. When it is necessary to remove the hydroxyl-protecting group of R and Y ₁ of the compound of formula (1) thus obtained, the hydroxyl-protecting group may be removed by a method commonly used for the protecting group used. . The compound of formula (1) can be isolated and purified by a nucleoside isolation and purification method (eg, adsorption chromatography, recrystallization method, etc.).

II. Method for Synthesizing Compound of Formula (3) The method for synthesizing 3-deazaguanosine represented by Formula (3) is as described above. The compound of formula (4), which is a starting material compound, is a known compound (Japanese Patent Laid-Open No. 221388/1989) and can be prepared by a conventional method. As the amines to be reacted with the raw material compound, hydroxyamines can be used in addition to the amines that can be used when synthesizing the compound of the formula (1). In the present invention, it is preferable that after reacting the aliphatic amine, further reacting with the hydroxyamine. The reaction between the raw material compound and amines can be carried out by using an excess amount of amines in a reaction solvent (alcohols such as methanol and ethanol) and reacting at 40 to 60 ° C. for about 1 to 20 hours. it can.

Next, the compound of formula (5) thus obtained is reacted with isocyanic acid to prepare a compound of formula (6). Isocyanic acids used in the reaction,
The oxime form (-CH = NOH) is converted to the acetonitrile form (-
It is not particularly limited as long as it can be converted into CH ₂ CN). Specifically, isocyanic acid, or methyl isocyanate, ethyl isocyanate, phenyl isocyanate,
Illustrative examples include isocyanates such as naphthyl isocyanate. The reaction between the compound of formula (5) and the isocyanic acid is carried out by adding 1 part of isocyanic acid to the compound of the formula (5).
It can be carried out by using about 3 equivalents and reacting in a reaction solvent (benzene, toluene, pyridine, etc.) at 10 to 40 ° C. for about 0.1 to 10 hours. After the above reaction, the residue obtained by concentration may be subjected to a heat treatment in pyridine (for example, at room temperature to 60 ° C. for about 0.1 to 1 hour), if necessary.

Finally, the equation (6) thus obtained is obtained.
The compound of (3) is subjected to an alkali treatment to obtain 3-deazaguanosine represented by the above formula (3). The alkali treatment is preferably performed by using a carbonate, for example, by refluxing the compound of the formula (6) in a mixed solution of an aqueous solution of sodium carbonate, potassium carbonate, sodium potassium carbonate and the like and alcohols such as methanol and ethanol. The desired compound of formula (3) can be obtained. When it is necessary to remove the protective group for the hydroxyl group of R of the compound of formula (3) thus obtained, the protective group for the hydroxyl group may be removed by a method commonly used for the protective group used. The compounds of formula (3), formula (5) and formula (6) can be isolated and purified by a nucleoside isolation and purification method (for example, adsorption chromatography, recrystallization method, etc.).

III. Compound of Formula (7) and Method for Synthesizing It Not only is itself useful as a physiologically active substance such as antiviral action, but also as described above, for example, at the 3-position. It is expected as a synthetic intermediate that can be used in the development of a novel 3-substituted-3-deazapurine nucleoside having a functional group introduced therein. For example, it is believed that various carbon functional groups can be introduced at the 3-position using a palladium catalyst in the compound of formula (7). In the formula, X, Y ₂ , Hal and R are as defined above, and examples of the halogen atom represented by Hal include fluorine, bromine, chlorine and iodine. Further, as the protective group for the hydroxyl group represented by R, the same ones as R in the compound of formula (1) can be exemplified.

The compound of formula (7) can be prepared by reacting the compound of formula (8) with a halogenating agent. The compound of formula (8) is a known compound and can be prepared according to a known method, or can be prepared as a starting compound using the imidazole nucleoside compound according to the method of the present invention as described above. When an amino group is present in the compound of formula (8), the amino group may be protected with an acyl group such as acetyl, propyl or benzoyl in order to improve the yield. As the halogenating agent used in the reaction, N-
Examples thereof include halogenosuccinimide and molecular halogen, and N-halogenosuccinimide is particularly preferable. The reaction is carried out using 1-1.5 equivalents of N-halogenosuccinimide in a reaction solvent (dichloromethane, dimethylformamide, etc.) at -90 to 50 ° C for 1 minute to 1 minute.
It can be carried out by reacting for about time.
After the reaction, the protective group for the hydroxyl group represented by R is removed by a conventional method if necessary, and the compound of formula (7) is prepared by a usual isolation and purification method of nucleoside (eg, adsorption chromatography method, recrystallization method, etc.). Can be isolated and purified.

[0018]

INDUSTRIAL APPLICABILITY According to the method of the present invention, 3-deazapurine nucleosides, which have been attracting attention for their physiological activities such as antiviral activity, have not been in a mixed state of isomers, but only the desired compound can be very easily prepared. It can be manufactured. Further, according to the present invention, 3-halogeno-3-deazapurine nucleoside and its production method, which may be advantageously used as synthetic intermediates in the development of novel derivatives of 3-deazapurine nucleoside in the future, Will be provided.

[0019]

EXAMPLES The present invention will be described more specifically below with reference to examples. Example 1 4-Hydroxy-1-β-D-ribofuranosyl-1H-
Imidazo [4,5-c] pyridine [Formula (1): X = hydroxyl group, Y ₁ = hydrogen atom, R = hydrogen atom] 5-ethynyl-1- (β-D-ribofuranosyl) imidazole-4-carboxamide 400 mg ( 1.5 mmol) was suspended in 40 ml of ethanol, 15 ml of 50% dimethylamine aqueous solution was added, and the mixture was heated in a steel sealed tube at 80 ° C. for 5.5 hours. After confirming the disappearance of the raw materials, the solvent was distilled off, and a mixed solvent of etal-50% acetic acid aqueous solution (15 ml / 15 ml) was added to the residue, and the mixture was reacted with stirring at room temperature overnight. Evaporate the solvent,
After azeotropic distillation with ethanol, the obtained yellow crystals were recrystallized from etal-water to give 257 mg of the title compound (yield 64.3%).
Got ^{FAB-MS: 268 (M +} +1) 1 H-NMR (DMSO-d 6): 1.18 (brs,
1H, NH), 8.22 (s, 1H, H-2), 7.1
4 (brt, 1H, H-6), 6.69 (d, 1H, H
-7, J _7,6 = 7.1 Hz), 5.71 (d, 1H, H
-1 ', J1 _{', 2 '} = 6.6 Hz), 5.47 (d, 1
H, 2'-OH, _{J2'-OH, 2 '} = 6.6 Hz), 5.19
(D, 1H, 3'-OH, J3' _{-OH, 3 '} = 4.9Hz),
5.08 (dd, 1H, 5'-OH, _{J5'-OH, 5 '} = 4.
9 Hz, J _{5'-OH, 5 "} = 5.5 Hz), 4.23 (dt,
1H, H-2 ', J2 _{', 1 '} = J2 _{', 2'-OH} = 6.6Hz,
J _{2 ', 3'} = 6.0 Hz), 4.06 (ddd, 1H, H
-3 ', J3 _{', 2 '} = 6.0Hz, J3 _{', 3'-OH} = 4.9H
z, J _{3 ', 4'} = 3.3 Hz), 3.94 (m, 1H, H
-4 '), 3.60 (m, 2H, H-5', 5 ")

Example 2 4-amino-1-β-D-ribofuranosyl-1H-imidazo [4,5-c] pyridine [Formula (1): X = amino group, Y ₁ = hydrogen atom, R = hydrogen atom ] 5-Ethynyl-1- (β-D-ribofuranosyl) imidazole-4-carbonitrile 797 mg (3.2 mmol) was dissolved in 20 ml of distilled dimethylformamide to give t-butyldimethylchlorosilane 1.92 g (4 equivalents) and imidazole. 1.74 g (8 equivalents) was added, and the mixture was reacted at room temperature for 2 nights. After adding ethanol to stop the reaction and distilling off the solvent,
The residue was partitioned twice with ethyl acetate-water (200 ml-50 ml) and once with saturated brine (50 ml), and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by filtering sodium sulfate and then concentrating it was purified on a silica gel column (eluent: ethyl acetate / hexane) to give 5-ethynyl-1- (2,3,5-tri-Ot-butyldimethyl). 1477 mg (yield 78.1%) of yellow crystals of silyl-β-D-ribofuranosyl) imidazole-4-carbonitrile.
Got 867 mg (1.47 mmol) of the above compound was dissolved in 10 ml of methanol, transferred to a steel sealed tube, ammonia / methanol (20 ml) was added, and the mixture was heated at 120 ° C. for 4 hours. After distilling off the solvent, the residue was purified by a silica gel column (eluent: hexane / ethyl acetate), and 4-amino-1
-(2,3,5-Tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) -1H-imidazo [4,5
-C] pyridine yellow crystals 640 mg (yield 71.8%)
Got 274 mg (0.45 mmol) of this compound was dissolved in 10 ml of distilled tetrahydrofuran, 1.8 ml (4 equivalents) of 1N t-butylammonium fluoride was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off,
The residue was dissolved in a small amount of water and purified using a column (eluent: 0-60% methanol) packed with an adsorption resin (polystyrene) to quantitatively obtain pale yellow crystals of the title compound. MS: 266 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ ): 8.29 (s, 1
H, H-2), 7.66 (d, 1H, H-6, J = 5.
9 Hz), 6.91 (d, 1H, H-7, J = 5.9H)
_{z), 6.15 (brs, 2H} , NH 2), 5.75
(D, 1H, H-1 ', J1 _{', 2 '} = 6.2 Hz), 5.
45 (d, 1H, 2'-OH, J2' _{-OH, 2 '} = 6.2H
z), 5.19 (d, 1H, 3'-OH, _{J3'-OH, 3 '} =
4.4 Hz), 5.08 (dd, 1H, 5'-OH, J
_{5'-OH, 5 '} = 5.1 Hz, J _{5'-OH, 5 "} = 5.5 Hz),
4.31 (dt, 1H, H-2 ', J2 _{', 1 '} = J
_{2 ', 2'-OH} = 6.2 Hz, J2 _{', 3 '} = 5.1 Hz), 4.
09 (ddd, 1H, H-3 ', J3 _{', 2 '} = 5.1H
z, J _{3 ', 3'-OH} = 4.4 Hz, J _{3', 4 '} = 3.3H
z), 3.95 (dt, 1H, H-4 ', J4 _{', 3 '} =
3.3 Hz, J _{4 ', 5'} = J _{4 ', 5 "} = 3.6 Hz), 3.
66 (ddd, 1H, H-5 ', J5 _{', 4 '} = 3.6H
z, J _{5 ', 5 "} = 12.1 Hz, J _{5', 5'-OH} = 5.1H
z), 3.59 (ddd, 1H, H-5 ", J5 _{", 4 '} =
3.6 Hz, J _{5 ", 5 '} = 12.1 Hz, J _{5', 5'-OH} =
5.5 Hz)

Example 3 4-hydroxy-6-hydroxymethyl-1-β-D-
Ribofuranosyl -1H- imidazo [4,5-c] pyridine [Formula (1): X = hydroxyl, _{Y 1} = hydroxymethyl
Group, R = hydrogen atom] 5- (3-hydroxy-1-propyn-1-yl) -1
157 mg (0.53 mmol) of-(β-D-ribofuranosyl) imidazole-4-carboxamide was dissolved in 5 ml of distilled dimethylformamide, and 398 mg of t-butyldimethylchlorosilane (5 equivalents) and 360 mg of imidazole.
(10 equivalents) was added, and the mixture was reacted at room temperature for 17 hours. After the reaction, 199 mg of t-butyldimethylchlorosilane
(2.2 eq) and 180 mg (5 eq) of imidazole were added and reacted for 22 hours. The reaction was stopped by adding an appropriate amount of ethanol, the solvent was distilled off, and the obtained residue was distributed twice with ethyl acetate-water (3: 1) and once with saturated saline,
The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain a residue, which was purified with a silica gel column (eluent: hexane / ethyl acetate), and 5- (3-t-butyldimethylsilyl-
1-propyn-1-yl) -1- (2,3,5-tri-
Ot-butyldimethylsilyl-β-D-ribofuranosyl) imidazole-4-carboxamide (173 g, yield 43.5%) was obtained. 160 mg (0.21 mm) of this compound
ol) was dissolved in 5 ml of ethanol, 1 ml of 50% dimethylamine aqueous solution was added, and the mixture was heated in a steel sealed tube at 80 ° C. for 9 hours. After the reaction, the solvent was distilled off and the obtained residue was purified with a silica gel column (eluent: ethanol / chloroform).
6-t-Butyldimethylsilyloxymethyl-4-hydroxy-1- (2,3,5-tri-O-t-butyldimethylsilyl-β-D-ribofuranosyl) -1H-imidazo [4,5-c] Pyridine and 4-hydroxy-6-
Hydroxymethyl-1- (2,3,5-tri-Ot-
Butyldimethylsilyl-β-D-ribofuranosyl) -1
49 mg each of H-imidazo [4,5-c] pyridine
(Yield 30.6%) and 61 mg (Yield 44.9%) were obtained. 47 mg (0.06 mmol) and 59 of the above two compounds
mg (0.09 mmol) was added to distilled tetrahydrofuran (2 ml), and 1N t-butylammonium fluoride was added under ice cooling to 0.3 ml (5 equivalents) and 0.36 ml, respectively.
(4 equivalents) was added and reacted at room temperature for 30 minutes. The reaction solutions were combined, the solvent was distilled off, and the resulting residue was packed with an adsorption resin (polystyrene) on a column (eluent: 0 to 60).
% Methanol) to give 40 mg of the title compound (yield 8
7.0%) was obtained. ^{FAB-MS: 298 (M +} +1) 1 H-NMR (DMSO-d 6): 11.00 (br
s, 1H, NH), 8.21 (s, 1H, H-2),
7.37 (s, 1H, H-7), 5.70 (d, 1H,
H-1 ', J _{1', 2 '} = 6.0 Hz), 5.50 (d, 1
H, 2'-OH, _{J2'-OH, 2 '} = 6.6 Hz), 5.41
_{(T, 1H, CH 2 O} H, J = 6.0Hz), 5.22
(D, 1H, 3'-OH, J3' _{-OH, 5 '} = 4.9 Hz),
5.08 (dd, 1H, 5'-OH, _{J5'-OH, 5 '} = 5.
4 Hz, J _{5'-OH, 5 "} = 4.9 Hz), 4.35 (d, 2
H, C H ₂ OH, J = 6.0 Hz), 4.27 (dd
d, 1H, H-2 ', J2 _{', 1 '} = 6.0Hz, J
_{2 ', 2'-OH} = 6.6 Hz, J2 _{', 3 '} = 5.5 Hz), 4.
08 (ddd, 1H, H-3 ', J3 _{', 2 '} = 5.5H
z, J _{3 ', 4'} = 4.9 Hz, J _{3 ', 4 "} = 3.3 Hz),
3.96 (m, 1H, H-4 '), 3.61 (m, 2
H, H-5 ', 5 ")

Example 4 4-Hydroxy-6-propyl-1- (2,3,5-tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridine [formula (1): X = hydroxyl, _{Y 1} = propyl, R = t-butyl dimethyl silyl group] 5- (1-pentyne-1-yl) -1- (beta-D-ribofuranosyl) imidazole - 4-carboxamide 200
5- (1-Pentyn-1-yl) -1- (2,3,5) was reacted in the same manner as in Example 3 using mg (0.65 mmol).
-Tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) imidazole-4-carboxamide 323
mg (yield 76.6%) was obtained. 310 mg of this compound
Dissolve (0.48 mmol) in 15 ml of ethanol, 50%
Add 5 ml of dimethylamine aqueous solution and add 1 in a steel sealed tube.
Heated at 20 ° C. for 24 hours. The solvent was evaporated and the obtained residue was purified by a silica gel column (eluent: hexane / ethyl acetate) to obtain 44 mg (yield 14.1%) of the title compound. MS: 651 (M ⁺ ) ¹ H-NMR (CDCl ₃ ): 10.88 (brs, 1
H, NH), 8.03 (s, 1H, H-2), 6.26
(S, 1H, H-7), 5.70 (d, 1H, H-
1 ', J _{1', 2 '} = 7.1 Hz), 4.30 (dd, 1
H, H-2 ', J2 _{', 1 '} = 7.1 Hz, J2 _{', 3 '} = 4.
9 Hz), 4.20 (m, 1H, H-3 '), 4.12
(Brs, 1H, H-4 '), 3.92 to 3.79.
(M, 2H, H-5 ', 5 "), 2.65 (t, 2H,
CH ₂ CH ₂ CH ₃ , J = 7.7 Hz), 1.74
(M, 2H, CH ₂ CH ₂ CH ₃ ), 0.99, 0.9
5, 0.77 (each s, each 9H, t-butyl x 3),
_{0.82 (m, 3H, CH 2} CH 2 CH 3), 0.1
6, 0.15, 0.13, 0.12 (each s, each 3
H, methyl x 4), 0.09 (s, 6H, methyl x 2)

Example 5 4-Amino-6-hydroxymethyl-1-β-D-ribofuranosyl-1H-imidazo [4,5-c] pyridine [Formula (1): X = amino group, Y ₁ = hydroxyme Chill
Group, R = hydrogen atom] 5- (3-hydroxy-1-propyn-1-yl) -1
Example 2 using 188 mg (0.67 mmol) of-(β-D-ribofuranosyl) imidazole-4-carbonitrile
The same reaction was carried out as in the above to give 108 mg of the title compound. FAB-MS: 297 (M ⁺⁺ 1), 598 (2M ⁺⁺ )
1) ¹ H-NMR (DMSO-d ₆ ): 8.33 (s, 1
H, H-2), 6.99 (s, 1H, H-7), 6.5
3 (brs, 2H, NH ₂ ), 5.76 (d, 1H, H
-1 ', J _{1', 2 '} = 6.1 Hz), 5.48 (d, 1
H, 2'-OH, J2' _{-OH, 2 '} = 6.1 Hz), 5.30
_{(Brs, 1H, CH 2 O} H), 5.21 (d, 1H,
3'-OH, J3' _{-OH, 3 '} = 4.4 Hz), 5.06 (b
rt, 1H, 5'-OH) , 4.45 (s, 2H, C H
₂ OH), 4.31 (dt, 1H, H-2 ', J
_{2 ', 1'} = J _{2 ', 2'-OH} = 6.1 Hz, J _{2', 3 '} = 5.5H
z), 4.09 (brd, 1H, H-3 '), 3.96
(M, 1H, H-4 '), 3.62 (m, 2H, H-
5 ', 5 ")

Example 6 4-Amino-6-propyl-1- (2,3,5-tri-
O-t-butyldimethylsilyl-β-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridine [Formula (1): X = amino group, Y ₁ = propyl group, R = t-butyldimethylsilyl Group] 5- (1-Pentyn-1-yl) -1- (β-D-ribofuranosyl) imidazole-4-carbonitrile 320
Using mg (1.1 mmol) and reacting in the same manner as in Example 2, 100 mg of the title compound was obtained. ^{MS: 650 (M +) 1} H-NMR (CDCl 3): 8.02 (s, 1H, H
-2), 6.65 (s, 1H, H-7), 5.77.
(D, 1H, H-1 ', J1 _{', 2 '} = 7.0Hz), 5.
10 (brs, 2H, NH ₂ ), 4.34 (dd, 1
H, H-2 ', J2 _{', 1 '} = 7.0 Hz, J2 _{', 3 '} = 4.
4Hz), 4.22 (dd, 1H, H-3 ', J3 _{', 2 '}
= 4.4 Hz, J _{3 ', 4'} = 1.5 Hz), 4.12 (d
dd, 1H, H-4 ', J4 _{', 3 '} = 1.5Hz, J
_{4 ', 5'} = 2.9 Hz, J _{4 ', 5 "} = 2.6 Hz), 3.9
2 (dd, 1H, H-5 ', J5 _{', 4 '} = 2.9Hz, J
_{5 ', 5 "} = 11.4 Hz, 3.82 (dd, 1H, H-
5 ", J _{5 ', 4'} = 2.6Hz, J _{5 ', 5"} = 11.4H
z), 2.65 (dd, 2H, CH ₂ CH ₂ CH ₃ , J
= 7.0 Hz, 8.4 Hz), 1.73 (m, 2H,
CH ₂ CH ₂ CH ₃ ), 0.97, 0.96, 0.76
(Each s, each 9H, t-butyl x 3), 0.94
_{(M, 3H, CH 2 CH} 2 CH 3), 0.17,0.1
6, 0.13, 0.12, -0.11, -0.47 (each s, each 3H, methyl x 6)

Example 7 3-Deazaguanosine [6-amino-1-β-D - ribofuranosylimidazo [4,5-c] pyridine-4 (5
H) -one] [formula (3): R = hydrogen atom] 5-ethynyl-1- (β-D-ribofuranosyl) imidazole-4-carboxamide was reacted in the same manner as in Example 3 using 534 mg (2 mmol). 5-ethynyl-1-
(2,3,5-tri-Ot-butyldimethylsilyl-
1.12 g (yield 92%) of β-D-ribofuranosyl) imidazole-4-carboxamide was obtained. This compound 4
10 mg (0.67 mmol) was dissolved in 12 ml of ethanol,
3 ml of 50% dimethylamine aqueous solution was added, and the mixture was heated in a steel sealed tube at 50 ° C. for 8 hours. After the reaction, the reaction solution was transferred to an eggplant-type Kolben, and hydroxyamine hydrochloride (NH ₂
OH-HCl) (94 mg, 2 equivalents) and acetic acid (2 ml) were added, and the mixture was reacted at room temperature for 7.5 hours. The reaction was stopped by adding an appropriate amount of acetone, the solvent was distilled off, and the residue was washed twice with ethyl acetate-water (60 ml-20 ml), once with saturated aqueous sodium hydrogen carbonate solution (20 ml), and saturated saline (20 ml). And the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate, the residue obtained by concentrating was purified with a silica gel column (eluent: hexane / ethyl acetate) to obtain 5
-White crystals of 3-hydroxyiminoethylidene-1- (2,3,5-tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) imidazole-4-carboxamide (391 mg, yield 90.5%) were obtained. . This compound 110
mg (0.17 mmol) was suspended in 10 ml of distilled benzene, 28 μl (1.5 equivalents) of phenyl isocyanate was added under ice cooling, and the mixture was stirred at room temperature under an argon stream for about 1 hour. After the reaction, ice was added to stop the reaction, 30 ml of ethyl acetate was added to the reaction solution, the organic layer was partitioned twice with water (10 ml) and once with saturated saline solution (10 ml), and the organic layer was dried over anhydrous sodium sulfate. Dried in. After removing sodium sulfate, the residue was dissolved in 10 ml of distilled pyridine and heated at 50 ° C. for 20 minutes. After distilling off the solvent, the residue was azeotropically distilled with toluene three times,
Purify with silica gel column (eluent: ethyl acetate / hexane) to prepare 5-cyanomethyl-1- (2,3,5-tri-
O-t-butyldimethylsilyl-β-D-ribofuranosyl) imidazole-4-carboxamide 70 mg (yield 6
5.5%) was obtained. 392 mg of this compound (0.63 mmo
l) was dissolved in a mixed solution of 5% sodium carbonate aqueous solution and ethanol (5 ml / 15 ml) and refluxed at 100 ° C. for 40 minutes. After distilling off the solvent, the residue was purified by a silica gel column, and 6-amino-1- (2,3,5-tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) imidazo [4,5-c ] Pyridin-4 (5H) -one 319 mg
(Yield 81.3%) was obtained. This compound was reacted in the same manner as in Example 2 to remove the silyl protecting group to obtain the title compound quantitatively. ^{FAB-MS: 283 (M +} +1) 1 H-NMR (DMSO-d 6): 10.32 (br
s, 1H, NH), 7.89 (s, 1H, H-2),
_{5.58 (brs, 2H, NH 2} ), 5.46 (d, 1
H, H-1 ', J1 _{', 2 '} = 6.1 Hz), 5.45 (b
rs, 1H, 2'-OH), 5.44 (s, 1H, H-
7), 5.21 (brs, 1H, 3'-OH), 5.0
2 (brt, 1H, 5'-OH), 4.25-3.87
(M, 3H, H-2 ', 3', 4 '), 3.64-3.
57 (m, 2H, H-5 ', 5 ")

Example 8 7-Chloro-4-hydroxy-1-β-D-ribofuranosyl-1H-imidazo [4,5-c] pyridine [Formula (7): X = hydroxyl group, Y ₂ = hydrogen atom, Hal = salt MotoHara
Child, R = hydrogen atom] 5-ethynyl-1- (β-D-ribofuranosyl) imidazole-4-carboxamide 777 mg (2.91 mmol)
Was suspended in 30 ml of ethanol, 15 ml of 50% dimethylamine aqueous solution was added, and the mixture was heated in a steel sealed tube at 80 ° C. for 5 hours. After the solvent was distilled off, a mixed solvent of ethanol and a 50% aqueous acetic acid solution (10 ml-10 ml) was added to the residue, and the mixture was reacted overnight at room temperature. The solvent was distilled off, and the residue was azeotropically distilled with benzene and ethanol three times each and dried overnight in a desiccator. 30 ml of distilled pyridine from the residue obtained
Then, 1.1 ml (4 equivalents) of acetic anhydride was added, and the mixture was reacted overnight at room temperature. An appropriate amount of ethanol was added to the reaction solution to stop the reaction, the solvent was distilled off, and the resulting residue was chloroform / saturated sodium hydrogen carbonate aqueous solution (200 ml / 50 ml).
Distribute twice with mixed solution and once with saturated saline solution (50 ml),
The organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate, the residue obtained by concentration was azeotropically distilled three times with toluene to completely remove pyridine, and purified by silica gel column (eluent: ethanol / chloroform) to prepare 4-hydroxy-1- ( 2,3,5-tri-O-acetyl-β-
D-ribofuranosyl) -1H-imidazo [4,5-c]
1.023 g (yield 89.4%) of pyridine was obtained. Dichloromethane 1 obtained by distilling 393 mg (1 mmol) of this compound.
Dissolved in 0 ml, N-chlorosuccinimide 200 mg
(1.5 eq.) Was added and reacted at room temperature, and after 5 hours, 20
0 mg and 400 mg were added after 18 hours and the reaction was carried out for 24 hours. After adding 0.5 ml of cyclohexene to the reaction solution and stirring for 1 hour, the solvent was distilled off and the obtained residue was purified by a silica gel column (eluent: ethanol / chloroform) to obtain 7-chloro-4-hydroxy-1- ( 2,3,5-
Tri-O-acetyl-β-D-ribofuranosyl) -1H
-Imidazo [4,5-c] pyridine 302 mg (yield 7
0.7%) was obtained. 300 mg (0.7 mmol) of this compound
Was dissolved in 10 ml of an ammonia / methanol mixed solvent, reacted overnight at room temperature, the solvent was distilled off, and the resulting residue was purified by a silica gel column (eluent: ethanol / chloroform) to obtain 115 mg of the title compound (yield: 54.8%) was obtained as white crystals. FAB-MS: 304 (M ⁺ +1) Elemental analysis: as C ₁₁ H ₁₂ N ₃ O ₅ Cl · 1/3 MeOH ¹ H-NMR (DMSO-d ₆ ): 11.58 (brs, 1H, H-5), 8.51 (s,
1H, H-2), 7.36 (s, 1H, H-6), 6.
34 (d, 1H, H-1 ', J1 _{', 2 '} = 4.4 Hz),
5.54 (d, 1H, 2'-OH, _{J2'-OH, 2 '} = 6.0
Hz), 5.19 (d, 1H, 3'-OH, _{J3'-OH, 3 '}
= 4.9 Hz), 5.13 (dd, 1H, 5'-OH,
J _{5'-OH, 5 '} = 5.5 Hz, J _{5'-OH, 5 "} = 4.9 Hz),
4.33 (ddd, 1H, H-2 ', J2 _{', 1 '} = 4.4
Hz, J _{2 ', 2'-OH} = 6.0 Hz, J _{2 ', 3 '} = 4.9H
z), 4.08 (q, 1H, H-3 ', J3 _{', 2 '} = J
_{3 ', 3'-OH} = J _{3', 4 '} = 4.9 Hz) + (q, 1 / 3H,
MeO H, J = 5.5Hz), 3.93 (dt, 1H,
H-4 ', J _{4', 3 '} = 4.9 Hz, J _{4', 5 '} = J _{4', 5 "}
= 3.3 Hz), 3.68 (ddd, 1H, H-5 ',
J _{5 ', 4'} = 3.3 Hz, J _{5 ', 5'-OH} = 5.5 Hz, J
_{5 ', 5 "} = 12.1 Hz, 3.57 (ddd, 1H, H
-5 ", J _{5", 4 '} = 3.3Hz, J _{5 ", 5'-OH} = 4.9H
z, J _{5 ', 5 "} = 12.1 Hz), 3.15 (d, 1H,
_{C H 3 OH, J = 5.5Hz} )

Example 9 7-Bromo-4-hydroxy-1-β-D-ribofuranosyl-1H-imidazo [4,5-c] pyridine [Formula (7): X = hydroxyl group, Y ₂ = hydrogen atom, Hal = smell MotoHara
Child, R = hydrogen atom] 4-hydroxy-1- (2,3,5 ) prepared in Example 8
-Tri-O-acetyl-β-D-ribofuranosyl) -1
H-imidazo [4,5-c] pyridine 393mg (1mmo
l) was dissolved in 10 ml of distilled dichloromethane, 267 mg (1.5 equivalents) of N-bromosuccinimide was added, and the mixture was reacted at room temperature for 3 hours. Cyclohexene 0.1 ml in the reaction solution
Was added and stirred for 30 minutes, the solvent was distilled off, and the resulting residue was purified by a silica gel column (eluent: ethanol / chloroform) to obtain 7-bromo-4-hydroxy-1-
(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridine 36
6 mg (yield 77.7%) was obtained. 294 mg of this compound
The acetyl group was removed in the same manner as in Example 8 using (0.62 mmol) to give 150 mg of the title compound as white crystals (yield 6
9.7%). FAB-MS: 348 (M ⁺ +1) Elemental analysis: as C ₁₁ H ₁₂ N ₃ O ₅ Br · 3/4 MeOH ¹ H-NMR (DMSO-d ₆ ): 11.60 (br
s, 1H, NH), 8.50 (s, 1H, H-2),
7.41 (s, 1H, H-6), 6.47 (d, 1H,
H-1 ', J _{1', 2 '} = 5.0 Hz, 5.52 (d, 1
H, 2'-OH, J2' _{-OH, 2 '} = 6.0 Hz), 5.19
(D, 1H, 3'-OH, J3' _{-OH, 3 '} = 4.9Hz),
5.12 (dd, 1H, 5'-OH, _{J5'-OH, 5 '} = 5.
5 Hz, J _{5'-OH, 5 "} = 4.9 Hz), 4.38 (dd
d, 1H, H-2 ', J2 _{', 1 '} = 5.0Hz, J
_{2 ', 2'-OH} = 6.0 Hz, J2 _{', 3 '} = 4.4 Hz), 4.
08 (ddd, 1H, H-3 ', J3 _{', 2 '} = 4.4H
z, J _{3 ', 3'-OH} = 4.9 Hz, J _{3', 4 '} = 3.8 Hz)
+ (Q, 3 / 4H, MeO H, J = 5.5Hz), 3.
93 (dt, 1H, H-4 ', J4 _{', 3 '} = 3.8Hz,
J _{4 ', 5'} = J = _{4 ', 5 "} = 3.3 Hz), 3.65 (dd
d, 1H, H-5 ', J5 _{', 4 '} = 3.3Hz, J
_{5 ', 5'-OH} = 5.5 Hz, J _{5', 5 "} = 12.1 Hz),
3.54 (ddd, 1H, H-5 ", J5 _{", 4 '} = 3.3
Hz, J _{5 ", 5'-OH} = 4.9 Hz, J _{5 ", 5 '} = 12.1H
z), 3.15 (d, 9 / 4H, C H 3 OH, J = 5.
5Hz)

Example 10 4-Hydroxy-7-iodo-1-β-D-ribofuranosyl-1H-imidazo [4,5-c] pyridine [Formula (7): X = hydroxyl group, Y ₂ = hydrogen atom, Hal = iodine
Atom, R = hydrogen atom] 4-hydroxy-1- (2,3,5 ) prepared in Example 8
-Tri-O-acetyl-β-D-ribofuranosyl) -1
H-imidazo [4,5-c] pyridine 393mg (1mmo
l) was dissolved in 10 ml of distilled dimethylformamide,
Add 450 mg (2 equivalents) of N-iodosuccinimide,
The reaction was carried out at room temperature under light shielding for 9.5 hours. Cyclohexene (0.1 ml) was added to the reaction mixture, the mixture was stirred for 30 minutes, the solvent was evaporated, and the obtained residue was partitioned twice with chloroform-water (100 ml-30 ml) and once with saturated brine (30 ml) to obtain an organic layer. Was dried over anhydrous sodium sulfate. The residue obtained by concentrating after removing sodium sulfate was purified by a silica gel column (eluent: ethanol / chloroform), and 4-hydroxy-7-iodo-1- (2,3,5-tri-O-acetyl) was purified. 391 mg (yield 75.3%) of -β-D-ribofuracinol) -1H-imidazo [4,5-c] pyridine was obtained. 391 mg (0.66 mmol) of this compound was used in Example 8.
White crystals of the title compound by removing the acetyl group as in 2
39 mg (yield 91.9%) were obtained. FAB-MS: 394 (M ⁺ +1) Elemental analysis: as C ₁₁ H ₁₂ N ₃ O ₅ I.3 / ₅ MeOH ¹ H-NMR (DMSO-d ₆ ): 11.49 (br
s, 1H, NH), 8.44 (s, 1H, H-2),
7.44 (s, 1H, H-6), 6.61 (d, 1H,
H-1 ', J1 _{', 2 '} = 5.5 Hz), 5.48 (d, 1
H, 2'-OH, J2' _{-OH, 2 '} = 6.0 Hz), 5.22
(D, 1H, 3'-OH, J _{3'-OH, 3 '} = 4.4 Hz),
5.07 (dd, 1H, 5'-OH, _{J5'-OH, 5 '} = 5.
5Hz, J _{5'-OH, 5 "} = 5.0Hz), 4.44 (dd
d, 1H, H-2 ', J2 _{', 1 '} = 5.5Hz, J
_{2 ′, 2′-OH} = 6.0 Hz, J _{2 ′, 3 ′} = 5.0 Hz), 4.
10 (ddd, 1H, H-3 ', J3 _{', 2 '} = 5.0H
z, J _{3 ', 3'-OH} = 4.4 Hz, J _{3', 4 '} = 3.3H
z), 3.92 (dt, 1H, H-4 ', J4 _{', 3 '} =
3.3 Hz, J _{4 ', 5'} = J _{4 ', 5 "} = 3.9 Hz), 3.
59 (ddd, 1H, H-5 ', J5 _{', 4 '} = 3.9H
z, J _{5 ', 5'-OH} = 5.5 Hz, J _{5', 5 "} = 12.1H
z), 3.55 (ddd, 1H, H-5 ", J5 _{", 4 '} =
3.9 Hz, J _{5 ", 5'-OH} = 5.0 Hz, J _{5", 5 '} = 1
2.1 Hz)

[0029]Example 11 4-amino-7-bromo-1-β-D-ribofuranosyl
-1H-imidazo [4,5-c] pyridine [formula (7):
X = amino group, Y_Two= Hydrogen atom, Hal = bromine sourceChild, R
= Hydrogen atom)  4-amino-1- (2,3,5-tri-Ot-butyl
Dimethylsilyl-β-D-ribofuranosyl) -1H-I
122 mg (0.2 mmol) of midazo [4,5-c] pyridine
Was dissolved in 5 ml of distilled dichloromethane and cooled to -15 ° C.
After rejection, 53 mg of N-bromosuccinimide (1.5 equivalents)
2 ml of a dichloromethane suspension of was added and allowed to stir for 30 minutes.
It was Add 20 μl of cyclohexene to the reaction mixture and continue for 30 minutes.
The residue obtained by stirring and evaporating the solvent was removed with ethyl acetate-
2 times with a mixed solution of water (60 ml-10 ml), saturated saline solution
(10 ml) was distributed once, and the organic layer was dried over anhydrous sodium sulfate.
Dried in. After removing sodium sulfate, the solvent was distilled off.
The resulting residue is a silica gel column (eluent: hexane /
Ethyl acetate), 4-amino-7-bromo-1-
(2,3,5-tri-Ot-butyldimethylsilyl-
β-D-ribofuranosyl) -1H-imidazo [4,5-
c] 102 mg of pyridine (yield 74.1%) was obtained. this
Tetrahydr obtained by distilling 540 mg (0.79 mmol) of the compound
Dissolve in 10 ml of lofuran, 1N t-butylan under ice cooling
Add 3.1 ml (4 equivalents) of monium fluoride solution at room temperature
Let stir for 1 hour. The residue obtained by distilling off the solvent
With a kagel column (eluent: ethanol / chloroform)
Purify to give 250 mg of yellow crystals of the title compound (yield 92.1
%) Was obtained. FAB-MS: 347 (M⁺+1) Elemental analysis: C₁₁H₁₃N_FourO_FourAs Br ¹1 H-NMR (DMSO-d₆): 8.54 (s, 1
H, H-2), 7.73 (s, 1H, H-6), 6.4
8 (d, 1H, H-1 ', J_{1 ', 2'}= 5.5 Hz),
6.46 (brs, 1H, NH_Two), 5.51 (d, 1
H, 2'-OH, J_{2'-OH, 2 '}= 6.0 Hz), 5.20
(D, 1H, 3'-OH, J_{3'-OH, 3 '}= 5.0 Hz),
5.10 (dd, 1H, 5'-OH, J_{5'-OH, 5 '}= 5.
5Hz, J_{5'-OH, 5 "}= 5.0 Hz), 4.40 (dd
d, 1H, H-2 ', J_{2 ', 1'}= 5.5 Hz, J
_{2 ', 2'-OH}= 6.0 Hz, J_{2 ', 3'}= 5.1 Hz), 4.
10 (ddd, 1H, H-3 ', J_{3 ', 2'}= 5.1H
z, J_{3 ', 3'-OH}= 5.0 Hz, J_{3 ', 4'}= 4.4H
z), 3.92 (ddd, 1H, H-4 ', J_{4 ', 3'}=
4.4Hz, J_{4 ', 5'}= 3.3 Hz, J_{4 ', 5 "}= 3.7
Hz), 3.64 (ddd, 1H, H-5 ', J_{5 ', 4'}
= 3.3 Hz, J_{5 ', 5 "}= 12.1 Hz, J_{5 ', 5'-OH}=
5.5 Hz), 3.54 (ddd, 1H, H-5 ", J
_{5 ", 4 '}= 3.7 Hz, J_{5 ", 5 '}= 12.1 Hz, J
_{5 ", 5'-OH}= 5.0 Hz)

[0030]Example 12 4-amino-7-iodo-1-β-D-ribofuranosyl
-1H-imidazo [4,5-c] pyridine [formula (7):
X = amino group, Y_Two= Hydrogen atom, Hal = iodineatom,
R = hydrogen atom]  4-amino-1- (2,3,5-tri-Ot-butyl
Dimethylsilyl-β-D-ribofuranosyl) -1H-I
Steaming 608 mg (1 mmol) of midazo [4,5-c] pyridine
Dissolve in 10 ml of distilled dimethylformamide,
450 mg (2 equivalents) of dosuccinimide was added,
Stir at temperature for 11 hours. Cyclohexene 0.1 in the reaction solution
ml was added and stirred for 30 minutes, and the residue obtained by distilling off the solvent was
2 times with ethyl acetate-water (120ml-40ml), saturated sodium chloride
Partition once with water (40 ml) and the organic layer is dried over anhydrous sodium sulfate.
Dried. Obtained by removing sodium sulfate and then concentrating
The residue was applied to a silica gel column (eluent: hexane / ethyl acetate
4-amino-7-iodo-1- (2,
3,5-Tri-Ot-butyldimethylsilyl-β-D
-Ribofuranosyl) -1H-imidazo [4,5-c] pi
524 mg of lysine (71.4% yield) was obtained. This compound
Using 524 mg (0.71 mmol) as in Example 11.
The silyl group was removed to give 228 mg of the title compound (yield 81.5
%) Was obtained. FAB-MS: 393 (M⁺+1) Elemental analysis: C₁₁H₁₃N_FourO_FourAs I ¹H-NMR (DMSO): 8.49 (s, 1H, H-
2), 7.88 (s, 1H, H-6), 6.62 (d,
1H, H-1 ', J_{1 ', 2'}= 5.5 Hz), 6.40
(Brs, 2H, NH_Two), 5.46 (d, 1H, 2 '
-OH, J_{2'-OH, 2 '}= 6.1 Hz), 5.20 (d, 1
H, 3'-OH, J_{3'-OH, 3 '}= 5.0 Hz), 5.05
(Dd, 1H, 5'-OH, J_{5'-OH, 5 '}= 5.5 Hz,
J_{5'-OH, 5 "}= 5.0 Hz), 4.46 (ddd, 1H,
H-2 ', J_{2 ', 1'}= 5.5 Hz, J_{2 ', 2'-OH}= 6.1
Hz, J_{2 ', 3'}= 4.9 Hz), 4.10 (ddd, 1
H, H-3 ', J_{3 ', 2'}= 4.9 Hz, J_{3 ', 3'-OH}=
5.0Hz, J_{3 ', 4'}= 4.4 Hz), 3.92 (d
t, 1H, H-4 ', J_{4 ', 3'}= 4.4 Hz, J_{4 ', 5'}
= J_{4 ', 5 "}= 3.7 Hz), 3.60 (ddd, 1H,
H-5 ', J_{5 ', 4'}= 3.7 Hz, J_{5 ', 5 "}= 12.1
Hz, J_{5 ', 5'-OH}= 5.5 Hz), 3.55 (ddd,
1H, H-5 ", J_{5 ", 4 '}= 3.7 Hz, J_{5 ", 5 '}= 1
2.1 Hz, J_{5 ", 5'-OH}= 5.0 Hz)

[0031]Example 13 4-amino-7-chloro-1-β-D-ribofuranosyl
-1H-imidazo [4,5-c] pyridine [formula (7):
X = amino group, Y_Two= Hydrogen atom, Hal = chlorine sourceChild, R
= Hydrogen atom)  4-amino-1- (2,3,5-tri-Ot-butyl
Dimethylsilyl-β-D-ribofuranosyl) -1H-I
Midazo [4,5-c] pyridine 500mg (0.82mmo
l) is dissolved in 10 ml of acetonitrile and acetic anhydride 0.3 m
l (4 equivalents), triethylamine 0.45 ml (4 equivalents)
And dimethylaminopyridine (10 mg) were added at room temperature for 20
Reacted for hours. Add ethanol to the reaction mixture to stop the reaction.
The residue obtained by evaporating the solvent and distilling off the solvent was removed.
After adding 10 ml of a mixed solvent of tanol and leaving it for 20 minutes at room temperature,
The residue obtained by distilling off the solvent is passed through a silica gel column (eluting
Agent: ethanol / chloroform), 4-aceto
Amido-1- (2,3,5-tri-Ot-butyl dime
Cylsilyl-β-D-ribofuranosyl) -1H-imida
501 mg of zo [4,5-c] pyridine (yield 93.7%)
Got 314 mg (0.48 mmol) of this compound was distilled
Dissolved in 15 ml of dichloromethane, N-chlorosuccin
Add 321 mg (5 equivalents) of imide and stir at room temperature for 27:00
321 mg was added after a while, and the reaction was further performed for 18 hours. Anti
Add 0.5 ml of cyclohexene to the reaction solution and stir for 1 hour to dissolve.
Ether was added to the residue obtained by distilling off the medium, and the insoluble matter was filtered off.
did. The residue obtained by concentrating the filtrate is ethyl acetate-5%
2 with a mixed solution of aqueous sodium carbonate solution (50 ml-10 ml)
Once with water (10 ml), once with saturated saline solution (10 ml)
It was partitioned and the organic layer was dried over anhydrous sodium sulfate. Sulfuric acid
After removing sodium, the residue obtained by concentration is subjected to silica gel extraction.
Column (eluent: hexane / ethyl acetate)
4-acetamido-7-chloro-1- (2,3,5-to
Li-Ot-butyldimethylsilyl-β-D-ribofla
Nosyl) -1H-imidazo [4,5-c] pyridine 24
8 mg (yield 75.1%) was obtained. FAB-MS: 687 (M⁺+1)¹ H-NMR (CDCl_Three): 8.55 (brs, 1
H, NH), 8.43 (s, 1H, H-2), 8.11
(S, 1H, H-6), 6.75 (d, 1H, H-
1 ', J_{1 ', 2'}= 7.1 Hz), 4.34 (dd, 1
H, H-2 ', J_{2 ', 1'}= 7.1 Hz, J_{2 ', 3'}= 4.
4 Hz), 4.19 (brd, 1H, H-3 '), 4.
12 (brs, 1H, H-4 '), 3.93 (dd, 1
H, H-5 ', J_{5 ', 4'}= 2.8 Hz, J_{5 ', 5 "}= 1
1.5Hz), 3.80 (dd, 1H, H-5 ", J
_{5 ", 4 '}= 1.7 Hz, J_{5 ", 5 '}= 11.5 Hz), 2.
52 (s, 3H, acetyl), 0.99, 0.95
0.73 (each s, each 9H, t-butyl x 3), 0.
18, 0.17, 0.13, 0.11, -0.11,-
0.49 (each s, each 3H, methyl x 6) Then, the acetyl group and silyl group of this compound were converted into a conventional method.
Therefore, the title compound is synthesized by deprotection.

Examples 14 to 16 6-Amino-7-halogeno-1- (2,3,5-tri-
O-t-butyldimethylsilyl-β-D-ribofuranosyl) imidazo [4,5-c] pyridin-4 (5H) -one [Formula (7): X = hydroxyl group, Y ₂ = amino group, Hal =
Halogen atom, R = t-butyldimethylsilyl group] 6-amino-1- (2,3,5-tri-Ot-butyldimethylsilyl-β-D-ribofuranosyl) imidazo [4,5-c] pyridine -4 (5H) -one was reacted with N-halogenosuccinimide (1 to 10 equivalents) under the following conditions to give the title compound having a halogen atom introduced at the 7-position. _{Title compound Reaction temperature Reaction yield} (7th halogen) Solvent time _{I Dimethylpho-15 ° C 5 minutes 46%} Lumamide Br Dichlorome -70 ° C 15 minutes 38% Tan _{Cl Dichlorome -85 ° C 5 minutes 57%} Tan

Claims (4)

[Claims] 1. A formula (1): (In the formula, X is a hydroxyl group or an amino group, Y ₁ is a hydrogen atom,
A lower alkyl group or a hydroxy lower alkyl group, R represents a hydrogen atom or a hydroxyl group-protecting group) 3
-A process for the production of deazapurine nucleosides, comprising the formula (2): (Wherein Z represents a carbamoyl group or a cyano group, Y ₁ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, and R represents a hydrogen atom or a hydroxyl-protecting group), and ammonia or amines. A method for producing a 3-deazapurine nucleoside, which comprises reacting to obtain a compound represented by the above formula (1). 2. A formula (3): A method for producing 3-deazaguanosine represented by the formula (wherein R represents a hydrogen atom or a hydroxyl-protecting group), which is represented by the formula (4): (Wherein R has the above meaning) and an amine are reacted to form a compound of the formula (5) A compound of the formula (6) is obtained by reacting this compound with isocyanic acid. (Wherein R has the above meaning), and then subjecting this compound to alkali treatment to obtain the compound represented by the above formula (3)
Method for producing deazaguanosine. 3. A formula (7): (In the formula, X is a hydroxyl group or an amino group, Y ₂ is a hydrogen atom or an amino group, Hal is a halogen atom, and R is a hydrogen atom or a hydroxyl-protecting group), and is a 3-halogeno-3-deazapurine nucleoside. A method of producing a compound of formula (8): (Wherein X, Y ₂ and R have the above meanings) and a halogenating agent are reacted to obtain the compound represented by the above formula (7).
Method for producing halogeno-3-deazapurine nucleoside. 4. Formula (7): (In the formula, X is a hydroxyl group or an amino group, Y ₂ is a hydrogen atom or an amino group, Hal is a halogen atom, and R is a hydrogen atom or a hydroxyl-protecting group), and is a 3-halogeno-3-deazapurine nucleoside. .