JPH10120682A - Production of purine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and selectively obtain the subject compound which has a substituent in the 9-position and shows antiviral activity and anticancer activ ity by reaction a specific 7-benzylpurine derivative with a cyclopropane carboxylic acid type compound. SOLUTION: The reaction of 7-benzylpurine derivative of formula I[R<1> and R<2> are each H, OH, a 1-8C (un)saturated lower alkoxy, a 1-8C (un)saturated acyloxy, siloxy, a halogen, a 1-8C lower alkyl; R<3> is H, a 1-6C lower alkyl, a 1-6C lower alkoxy, OH, nitro, amino, sulfonic acid, carboxyl, a halogen] with a cyclopropanecarboxylic acid type compound of formula II [R<4> and R<5> are each H, a 1-20C (un)saturated alkyl, a 1-20C alkoxy, a 1-10C acyl, a 1-10C acyloxy] affords the objective purine derivative without complicated operation which has a substituent on 9-position and manifests antiviral and anticancer actions in high selectivity.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a useful purine derivative having an antiviral action and an anticancer action. More specifically, the present invention relates to a method for producing a regioselective purine derivative by selective addition of a 7-benzylpurine derivative to the 9-position.

[0002]

2. Description of the Related Art Purine derivatives having a substituent at the 9-position of purine nucleic acid bases include penciclovir, famciclovir, herpes virus, shingles, AIDS, hepatitis,
Many compounds useful as therapeutic agents for viral infectious diseases such as cytomegalovirus are known. As a method for producing these purine derivatives, a method in which a substituent called a side chain is usually added to a purine base has been adopted. At that time, it is very difficult to introduce a substituent only at the target 9-position of the purine base, and a substituent is introduced at the 7-position other than the target position, and it is difficult to perform isomerization after the addition reaction. Needed or steps had to be introduced to remove by-products.

For example, in the synthesis of penciclovir, guanine or N-acetylguanine is used as a starting material (C
hinese J. of Chem., 9, 536, 1991), 2-amino-6
-React chloropurine with brominated side chains (TET
RAHEDRON LETT. 26 (35) 4265, 1985), 2-amino-6
-An example of reacting benzyloxypurine with a side chain tosylate is known (J. HETEROCYCLIC CHEM. 26 (5),
1261, 1989), all of which require complicated purification steps.

In the synthesis of famciclovir, 2-
There have been examples of reacting amino-6-chloropurine with an iodinated side chain (TETRAHEDRON LETT. 46 (19), 6903, 1990) and performing Michael-type addition with a side chain precursor. (TETRAHEDRON LETT. 33 (32) 4609, 1992), but also in these cases, there was a problem that a complicated processing step was required.

[0005] In the literature described above, the side chain moiety introduced into the purine base is mainly of the alkyl halide type, but other than that, a compound of the cyclopropane dicanorubonic acid type and 2-amino-6-chloropurine Is subjected to an addition reaction using potassium carbonate as a base to obtain the desired compound (Nucleosides & Nucleotides, 15 (5), 98
1,1996). However, even in this method, the yield of the target 9-position adduct is only 60%, and the 7-position adduct is produced in a large amount as a by-product, requiring a treatment step (34).
%). In any case, these reactions are based on the 9th position of purines.
A base is added to the amino proton of the primary amine to remove it,
An anion is generated at the amino group, and a reaction with the side chain is performed there.

As a method of solving this problem, the present inventors selectively react the 7-benzylpurine derivative with an alkyl halide type side chain under neutral conditions by heating, if necessary, to selectively react at the 9-position. It was found that the addition reaction proceeded. Further, they have found that purine derivatives having a desired substituent introduced only at the ninth position can be synthesized by subjecting the obtained compound to a debenzylation reaction (Japanese Patent Application No. 8-10).
710).

On the other hand, the above-mentioned compound of the cyclopropanedicanulbonic acid type is aniline (J. Am. Chem. Soc., 97 (11), 3239,
1975) and primary amines such as lysine derivatives (J. Org. Chem., 50, 3631, 1985) and hydrazine derivatives (Heterocycles, 36 (2), 219, 1993). further,
The reaction with secondary amines such as piperidine to form twitter ions, and the reaction with weakly nucleophilic tertiary amines such as pyridine to produce similar ionic compounds. Known (J. Am. Chem. Soc., 97 (11), 3
239, 1975). As an example of the reaction between an amine having a structure closer to 7-benzylguanine (purine) and a compound of the cyclopropanedican rubonic acid type, the reaction of an imidazole derivative, a pyrrole derivative, or a purine derivative is known. Needed a base (J. Or
g. Chem., 47, 1682, 1982, Hisamitsu Pharmaceuticals: J
P87-227702).

As described above, in the reaction of a cyclopropanedicarboxylic acid type compound, for example, a compound having two or more nitrogen atoms in a ring, such as a purine base derivative, is treated under basic conditions. Only addition reaction is known, and no reaction example under neutral conditions was known. Further, no addition reaction of a purine base derivative to a tertiary nitrogen atom has been known at all.

[0009]

An object of the present invention is to develop a method for selectively producing a compound having a side chain at the 9-position of purine.

[0010]

The inventors of the present invention have conducted detailed studies on the reactivity of 7-benzylpurine derivatives with various types of side chains other than alkyl halides, and surprisingly found that the use of a base was not possible. Under neutral conditions without addition of any catalyst or other reagents, in a solvent or without a solvent, a compound of the cyclopropane dicanorubonic acid type reacts well with the 7-benzylpurine derivative, The present inventors have found that the adduct can be obtained in a high yield, and have completed the present invention.

That is, the present invention relates to a 7-benzylpurine derivative represented by the following general formula (I):

[0012]

Embedded image

(Wherein R ¹ is hydrogen, a hydroxyl group, C ¹ -C 8
A saturated or unsaturated lower alkoxy group, C1 to C8
A saturated or unsaturated lower acyloxy group, siloxy group, fluoro group, chloro group, bromo group, iodo group, amino group, mono- or di-C1 to C8 acylamino group,
Represents a C1 to C8 alkoxycarbonylamino group, an allyloxycarbonylamino group, or a C1 to C8 saturated or unsaturated lower alkyl group, and R ² represents hydrogen, a hydroxyl group, a C1 to C8 saturated or unsaturated Lower alkoxy group, C1-C8 saturated or unsaturated lower acyloxy group, siloxy group, fluoro group, chloro group, bromo group, iodo group, amino group, mono- or di-C1-C
8 acylamino groups, C1 to C8 alkoxycarbonylamino groups, allyloxycarbonylamino groups, or C
Represents any of 1 to C8 saturated or unsaturated lower alkyl groups, and R ³ represents hydrogen, a C1 to C6 lower alkyl group, a C1 to C6 lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a sulfonic acid group. , Carboxyl group, C1
Represents any of C6 alkoxycarbonyl group, fluoro group, chloro group, bromo group, and iodo group. )

Reacting with a cyclopropanecarboxylic acid type compound represented by the following general formula (II):

[0015]

Embedded image

(Wherein R ⁴ and R ⁵ may be the same or different and each may be hydrogen, C1-C20 linear or branched, saturated or unsaturated alkyl, C1-C5
20 alkoxy groups, C1-C10 acyl groups, C1-C1
C10 acyloxy group, carboxyl group, C1 to C10
It represents alkoxycarbonyl group, also 3 between R ⁴ to R ⁵
It may form a ring of up to eight members. This is a method for producing a compound represented by the following general formula (III).

[0017]

Embedded image

(In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as those described above.)

The present invention further provides a method for producing a 9-substituted purine derivative represented by the following general formula (IV), wherein the compound represented by the above general formula (III) obtained above is subjected to a debenzylation reaction. It is.

[0020]

Embedded image

(The definitions of R ¹ , R ² and R ^{4 in} the formula are the same as those described above.)

In the above reaction, the compound represented by the general formula (III) is subjected to the following debenzylation reaction without isolation to give a 9-substituted purine derivative represented by the general formula (IV). It is also possible to lead.

In the present invention, in the general formula (I), R ¹ is a hydroxyl group, R ² is an amino group, a mono- or di-C1 to C8 acylamino group, a C1 to C8 alkoxycarbonylamino group, or an allyloxy group. Any of the carbonylamino groups, and the compound represented by the general formula (I
When R ⁴ and R ⁵ of the compound represented by I) are methyl groups, a compound represented by the following general formula (V) can be obtained by an addition reaction and a reduction reaction.

[0024]

Embedded image

This compound is described, for example, in Graham R. G
een et al.'s method (Nucleosides & Nucleotides, 15 (5), 98
1, 1996), the following general formula (VI)
This is particularly useful as a method for synthesizing a pencyclovir derivative represented by the following formula or a famciclovir derivative represented by the formula (VII).

[0026]

Embedded image

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the above general formula (I) used as a raw material of the present invention can be synthesized from a purine nucleoside having a sugar chain substituted at the 9-position or a derivative thereof. Specifically, guanosine, inosine, adenosine, 9- (β-D-ribofuranosyl) -2-aminopurine and the like are used as raw materials to react with benzyl halides such as benzyl bromide, benzyl chloride and para-nitrobenzyl bromide, and By hydrolyzing the sugar chain with an acid such as hydrochloric acid or sulfuric acid, 7-benzylguanine,
-Benzyladenine, 7-benzylhypoxanthine, 7
-Benzyl-2-aminopurine, 7-benzylxanthine and modified products other than the 7-position thereof can be synthesized.

The benzyl group introduced at the 7-position may have a substituent at any of the ortho, meta and para positions on the benzene ring of the benzyl group. Examples of the substituent include a methyl group and a nitro group. Methoxy group, fluoro group, chloro group, bromo group, iodo group and the like, and the number of substituents may be one or more. Specific examples include a benzyl group, a paranitrobenzyl group, and a paramethoxybenzyl group.

The compound represented by the general formula (II) can be obtained from Org.
It can be synthesized by the methods described in Synth. 60, 66, 1981 and J. Org. Chem., 40 (20), 2969, 1975. Usually, 1,1-cyclopropanedicarboxylic acid is synthesized by reacting dibromoethane with a malonic acid derivative, and then the carboxylic acid is cyclized to carry out a protection reaction to synthesize.

The target compound of the present invention is represented by the general formula (II)
The compound represented by I) is obtained by reacting the compound represented by the general formula (I) with the compound represented by the general formula (II). The compound represented by the general formula (I) can be used as a free form or as a salt such as hydrochloride or sulfate. In some cases, an amino group to be substituted with a purine base can be used in ordinary nucleic acid synthesis such as an acyl group. The amino group may be used after being protected with a protecting group for the amino group.

The reaction is carried out in a solvent or without a solvent. Examples of the solvent include dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, aromatic hydrocarbons (eg, toluene, xylene, etc.), ethers (eg, diethyl ether, diisopropyl ether, dioxane) ), Alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), esters (eg, ethyl acetate, methyl acetate, isobutyl acetate, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, methyl ethyl ketone) , Methyl isobutyl ketone, etc.) and one of organic solvents such as a halogen-based solvent (eg, chloroform, dichloromethane, etc.) or a mixed solvent thereof. From the solubility of the purine base, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide,
When N-methylpyrrolidinone is used, the reaction often proceeds favorably. There is no problem even if the reaction is performed without solvent.

The reaction is preferably carried out usually at a temperature of 0 to 200 ° C., and in the range of 10 to 100 ° C. in view of the working efficiency. The reaction is usually completed in 0.5 to 48 hours. The reaction is usually carried out at a concentration of 0.1 g / dL or more or in the absence of a solvent, but preferably at a concentration of about 1 g / dL. As for the equivalence ratio, (I) and (II) are usually reacted at a molar ratio of 1: 1. However, in order to increase the yield to either one, the other may be used in excess.

In the present invention, since the 7-benzylpurine derivative is used as a raw material, only the 9-position adduct is obtained in a high yield exceeding 90%, and no 7-position adduct is produced.

The compound represented by the general formula (III) obtained by this reaction is a novel compound and an important intermediate in the production of the useful compound of the present invention having a substituent at the 9-position of purine. . Further, it is a compound that can be easily synthesized for the first time by the method of the present invention.

The compound represented by the general formula (III) is a compound forming a zwitter ion in the molecule.
It is generally considered to have the structure of (III), but may have the structure of the following general formula (III ′).

[0036]

Embedded image

Since (III) has a very low solubility in a solvent, it can be easily isolated usually by filtering a product which crystallizes out of the reaction system as the reaction proceeds. A solvent such as ethyl acetate or chloroform may be added to obtain a slurry property of the liquid.

By subjecting (III) to a debenzylation reaction, a benzyl group or a substituted benzyl group is eliminated to obtain a target compound represented by the general formula (IV). The reaction may be carried out in a solvent using (III) isolated above. However, the reaction solution obtained by synthesizing (III) may be subjected to a debenzylation reaction as it is or by adding a necessary solvent. You can also.

In the compound of the general formula (III), a benzyl group is substituted at the 7-position or a benzyl group is substituted at the para-position with a substituted benzyl group such as a nitro group. General methods for de-N-benzyl groups, such as reduction with a palladium catalyst in an atmosphere, reduction with a palladium catalyst in the presence of formic acid or formate, and reduction with sodium and ammonia, can be used.

Examples of the palladium catalyst include palladium supported on carbon, palladium hydroxide, palladium black, Lindlar catalyst, Pd—CaCO ₃ , and Pd—BaC.
O ₃ or the like is used. The amount of the catalyst is usually 1 to 1 based on the substrate.
0 mol% is used. The hydrogen used can be reacted at normal pressure, but the pressure can increase the reaction rate. Usually, it is performed under a pressure of about 1 to 5 atm. In addition, 3, 4
In the case of a substituted benzyl group which can be eliminated under acidic conditions, light or the like, such as -dimethoxybenzyl group, orthonitrobenzyl group, di (p-methoxyphenyl) methyl group, elimination is carried out by a corresponding method.

Examples of the solvent include water, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, aromatic hydrocarbons (eg, toluene, xylene, etc.), ethers (eg, diethyl ether, diisopropyl ether) , Dioxane, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), carboxylic acids (eg, acetic acid, propionic acid, etc.), esters (eg, ethyl acetate, methyl acetate,
One of solvents such as isobutyl acetate and the like, nitriles (for example, acetonitrile and the like), ketones (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like) or a mixed solvent thereof is used. From the solubility, N, N-dimethylformamide, N, N-dimethylacetamide,
N-methylpyrrolidinone, carboxylic acids (eg, acetic acid,
The use of alcohols (eg, propionic acid, etc.) and alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.) often favors the reaction.

The reaction is usually carried out at a temperature of 0 to 150 ° C., preferably from 10 to 80 ° C. in view of the working efficiency. The reaction is usually completed in 0.5 to 48 hours. The reaction is generally performed at a concentration of 1 to 10 g / dL. After the reaction, the catalyst is removed by filtration, the solvent is concentrated if necessary, and a poor solvent is added or an extraction operation is performed to isolate the desired product.

As described above, the present invention has made it possible to selectively synthesize a 9-substituted purine derivative which is extremely useful as a medicine.
Hereinafter, an embodiment will be described in detail.

[0044]

【Example】

(Synthesis Example 1) Guanosine 20.1 g (water 11.5%,
62.7 mmol) was dissolved in 100 ml of dimethyl sulfoxide, and 20 ml (166 mmol) of benzyl bromide was added thereto.
Was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, 50 ml of concentrated hydrochloric acid was added, the solution was poured into 600 ml of methanol, and 25 ml of concentrated hydrochloric acid was further added.
Heated at 50 ° C. for 1 hour. Thereafter, the heating was stopped, the mixture was stirred for 3 hours, and the precipitated crystals were filtered, sufficiently washed with methanol, and dried at 50 ° C. under reduced pressure to obtain 17.4 g of 7-benzylguanine dihydrochloride as a white solid ( 55.
5 mmol, 88.5%).

¹ H NMR (DMSO-d ⁶ ): 8.90
(S, 1H, H-8), 7.45-7.29 (m, 5
H, Ph), 5.52 (s , 2H, Ph CH 2) MS (ESI, MH +): 242

Example 1 4.44 ml (45.1 mmol) of acetic anhydride and paratoluenesulfonic acid monohydrate in a solution of 4.37 g (13.9 mmol) of 7-benzylguanine dihydrochloride in acetic acid (9 ml) 132.8 mg (0.698 mmo
l) was added and the mixture was reacted at 105 ° C. for 3 hours, and then allowed to cool. 180 ml of water is added to the reaction solution, 150 ml of 5% aqueous sodium bicarbonate and 100 ml of 1N aqueous sodium hydroxide are added to adjust the pH to 5.3, the crystals are filtered, and 50 ml of water are added.
The crystals were dried under reduced pressure at 55 ° C. for 5 hours to give 3.77 g (13.3 mmol, 95.7 g) of N ² -acetyl-7-benzylguanine as a white solid.
%).

¹ H NMR (DMSO-d ⁶ ): 12.10
(Brs, 1H), 11.57 (s, 1H), 8.35
(S, 1H, H-8), 7.41-7.25 (m, 5
H, Ph), 5.51 (s , 2H, Ph CH 2), 2.
16 (s, 3H, NHCO CH ₃ )

[0048]

Example 1 N ² -acetyl-7-benzylguanine 4
73.3 mg (1.42 mmol, purity 91.2 wt)
%) In DMF (2.2 ml) was heated to 60 ° C,
Here, 483.0 mg of 2,2-dimethyl-1,3-dioxaspiro [5.2] octane-4,6-dione
(2.84 mmol) was added dropwise over 12 hours, and an additional 6
The mixture was heated and stirred at 0 ° C. for 12 hours. A solid precipitated from the homogeneous reaction solution immediately after the start of the reaction as the reaction progressed. After allowing to cool to room temperature, 9.0 ml of ethyl acetate was added to the reaction solution, and the precipitated solid was suspended and collected by filtration. The solid is 5
After drying under reduced pressure at 0 ° C. for 2 hours, 5- (2- (2-acetylamino-7-benzylguanio-9-yl) ethyl)-
2,2-dimethyl-1,3-dioxacyclohexane-
562 mg (90% yield) of 4,6-dionide was obtained as a pale yellow solid. ^{1 HNMR (DMSO-d 6)} : 9.62 (s, 1H),
7.51-7.32 (m, 5H), 5.64 (s, 2
H), 4.20 (t, J = 6.0 Hz, 2H), 2.6.
4 (t, J = 6.0 Hz, 2H), 2.21 (s, 3
H), 1.35 (s, 6H) MASS (ESI MH +): 454

[0049]

Example 2 100 mg of 5- (2- (2-acetylamino-7-benzylguanio-9-yl) ethyl) -2,2-dimethyl-1,3-dioxacyclohexane-4,6-dionide (0. 22 mmol) was suspended in 4.0 ml of a mixed solution of methanol / water (mixing ratio: 4/1 (v / v)), and 50.0 mg of 5% Pd-C catalyst (water 5%) was added thereto.
(3.5%, 0.011 mmol), and the mixture was heated and stirred at 60 ° C. overnight under a normal atmosphere of hydrogen using a rubber balloon. After allowing to cool to room temperature, the catalyst was filtered through celite, and methanol /
Washed with a mixture of water. The filtrate was concentrated, and the white crystals obtained were dissolved in 1.0 ml of a 2N aqueous sodium hydroxide solution and stirred at 40 ° C. for 1.5 hours. After returning to room temperature, 2
When the solution was neutralized with N hydrochloric acid to around pH 4, crystals precipitated, and were collected by filtration (primary crystals). To the residue obtained by concentrating the filtrate, a 2N aqueous sodium hydroxide solution and 1N hydrochloric acid were further added to adjust the pH to around 4, and the precipitated crystals were collected by filtration (secondary crystals). These crystals were dried under reduced pressure at 50 ° C. overnight, and the white crystals of 9- (3,3-dicarboxyprop-1-yl) guanine were combined in a primary crystal and a secondary crystal in an amount of 56.9 mg.
(92% yield). ^{1 HNMR (DMSO-d 6)} : 10.51 (br s,
1H), 7.63 (s, 1H), 6.44 (br s,
2H), 4.00 (t, J = 7.6 Hz, 2H), 3.
07-2.96 (m, 1H), 2.24-2.11
^{(M, 2H) 13 CNMR (} DMSO-d 6): 170.26,15
6.76,153.48,151.14,137.3
1,116.54,49.04,40.94,28.5
5 MASS (ESI MH +): 282

[0050]

Example 3 N ² -acetyl-7-benzylguanine 7
10.0 mg (2.13 mmol, purity 91.2 wt
%) In DMF (10 ml) was heated to 60 ° C., where 2,2-dimethyl-1,3-dioxaspiro [5.
2] Octane-4,6-dione 724.5 mg (4.2
6 mmol) was added dropwise over 12 hours, and the mixture was further heated and stirred at 60 ° C for 12 hours. A solid precipitated from the homogeneous reaction solution immediately after the start of the reaction as the reaction progressed. After cooling to room temperature, a mixed solution of methanol / water (mixing ratio 4/1)
(V / v)) 50 ml was added, and to this was added 75.0 mg of 5% Pd-C catalyst (water content 53.5%, 0.017 mmol).
And heated and stirred at 60 ° C. overnight under a hydrogen atmosphere at normal pressure using a rubber balloon. After allowing to cool to room temperature, the catalyst was filtered through celite and washed with a mixed solution of methanol / water. The white crystals obtained by concentrating the filtrate were dissolved in a 2N aqueous solution of sodium hydroxide and stirred at 50 ° C. for 2 hours. After returning to room temperature, the mixture was neutralized to pH around 4 with 2N hydrochloric acid, and the precipitated crystals were collected by filtration, dried under reduced pressure at 50 ° C. overnight, and dried to give 9- (3,3-dicarboxyprop-1-yl) guanine as white crystals. 500m
g (86% yield). ^{1 HNMR (DMSO-d 6)} : 10.51 (br s,
1H), 7.63 (s, 1H), 6.44 (br s,
2H), 4.00 (t, J = 7.6 Hz, 2H), 3.
07-2.96 (m, 1H), 2.24-2.11
^{(M, 2H) 13 CNMR (} DMSO-d 6): 170.26,15
6.76,153.48,151.14,137.3
1,116.54,49.04,40.94,28.5
5 MASS (ESI MH +): 282

As described above, it is possible to selectively synthesize a purine derivative having a substituent at the 9-position which is extremely useful as a medicine.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Kunisuke Izawa, 1-1 Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc.

Claims (3)

[Claims] 1. A 7-benzylpurine derivative represented by the following general formula (I): (Wherein, R ¹ is hydrogen, a hydroxyl group, a C1-C8 saturated or unsaturated lower alkoxy group, a C1-C8 saturated or unsaturated lower acyloxy group, a siloxy group, a fluoro group, a chloro group, a bromo group, an iodo group. A group, an amino group, a mono- or di-C1 to C8 acylamino group, a C1 to C8 alkoxycarbonylamino group, an allyloxycarbonylamino group, or a C1 to C8 saturated or unsaturated lower alkyl group, R ² is hydrogen, a hydroxyl group,
A C1-C8 saturated or unsaturated lower alkoxy group,
C1-C8 saturated or unsaturated lower acyloxy groups,
A siloxy group, a fluoro group, a chloro group, a bromo group, an iodo group, an amino group, a mono- or di-C1 to C8 acylamino group, a C1 to C8 alkoxycarbonylamino group,
Represents an allyloxycarbonylamino group, or a C1-C8 saturated or unsaturated lower alkyl group,
R ³ is hydrogen, C1-C6 lower alkyl, C1-C6
Represents a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a sulfonic acid group, a carboxyl group, a C1 to C6 alkoxycarbonyl group, a fluoro group, a chloro group, a bromo group, or an iodo group. Reacting with a cyclopropanecarboxylic acid type compound represented by the following general formula (II): (In the formula, R ⁴ and R ⁵ may be the same or different from each other, and may be hydrogen, C1-C20 linear or branched,
Saturated or unsaturated alkyl group, alkoxy group C1 to C20, acyl groups of C1 -C10, acyloxy C1 -C10, carboxyl group, alkoxycarbonyl groups C1 -C10, also among R ⁴ to R ⁵ A 3- to 8-membered ring may be formed. ) A method for producing a compound represented by the following general formula (III). Embedded image (R ¹ , R ² , R ³ , R ⁴ and R ⁵ in the formula are the same as defined above.) 2. The compound represented by the following general formula (III) obtained by the production method according to claim 1 is subjected to a debenzylation reaction. (In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as defined above.) A method for producing a 9-substituted purine derivative represented by the following general formula (IV). Embedded image (R ¹ , R ² and R ⁴ in the formula are the same as those described above.) 3. A compound represented by the following general formula (III). Embedded image (Wherein R ¹ is hydrogen, a hydroxyl group, a C1-C8 saturated or unsaturated lower alkoxy group, a C1-C8 saturated or unsaturated lower acyloxy group, a siloxy group, a fluoro group,
Chloro group, bromo group, iodo group, amino group, mono- or di-C1 to C8 acylamino group, C1 to C8 alkoxycarbonylamino group, allyloxycarbonylamino group, or C1 to C8 saturated or unsaturated lower alkyl R ² represents hydrogen, a hydroxyl group, C1
-C8 saturated or unsaturated lower alkoxy group, C1
To C8 saturated or unsaturated lower acyloxy, siloxy, fluoro, chloro, bromo, iodo,
Represents an amino group, a mono- or C1 to C8 acylamino group having di, C1 to C8 alkoxycarbonylamino group, allyloxycarbonyl amino group or any lower alkyl group, saturated or unsaturated C1 to C8,, R ³
Is hydrogen, C1-C6 lower alkyl group, C1-C6 lower alkoxy group, hydroxyl group, nitro group, amino group, sulfonic acid group, carboxyl group, C1-C6 alkoxycarbonyl group, fluoro group, chloro group, bromo group Or iodine; R ⁴ and R ⁵ may be the same or different and each may be hydrogen, C1-C20 linear or branched, saturated or unsaturated alkyl, C1
To C20 alkoxy group, C1 to C10 acyl group, C
1-C10 acyloxy group, carboxyl group, C1-C
10 represents an alkoxycarbonyl group, and may form a 3- to 8-membered ring between R ^{4 and} R ⁵ )