JPH11199584A - Cyclopropane ring-containing purine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound capable of being produced into a cyclopropane ring-opened purine derivative of a production intermediate for an antivirus preparation, and useful as an intermediate for the production intermediate for the antivirus preparation. SOLUTION: This new compound is the compound of formula I [X<1> is H, a halogen, OH or a 1-10C alkoxy; X<2> and X<3> are each a halogen; X<4> is H or X<2> ; R<1> and R<2> are each H, a (substituted) 1-7C alkyl or a (substituted) 7-11C aralkyl; R<3> is H, a halogen or a (protected) amino], e.g. 2 amino 6-chloro-9-(3,3- dicarbomethoxy-2,2-dichlorocyclopropyl)purine. The compound of formula I is obtained by reacting a compound of formula II (X<5> is X<2> ) with a compound of formula III, for example, in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a cyclopropane ring-containing purine derivative, a method for producing the same, and a method for producing a cyclopropane ring-cleaved purine derivative using the cyclopropane ring-containing purine derivative.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a cyclopropane ring-cleaved purine derivative useful as an intermediate for producing an antiviral agent, for example, a production method described in JP-A-3-120279 can be mentioned. However, when a cyclopropane ring-cleaved purine derivative is produced using a production intermediate in such a production method, the yield is about 20 to 40%.
In addition, the production of such a production intermediate requires a very complicated operation, and as a result, there is a disadvantage that a cyclopropane ring-cleaved purine derivative cannot be easily obtained.

[0003] Therefore, in recent years, there has been a demand for the development of a production intermediate used for a method capable of easily producing a cyclopropane ring-cleaved purine derivative in high yield.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above prior art, and is a method for easily producing a cyclopropane ring-cleaved purine derivative in high yield, and preferably used for the production method. It is an object of the present invention to provide a cyclopropane ring-containing purine derivative which can be obtained and a method for producing the same.

[0005]

The gist of the present invention is to provide (1)
Formula (I):

[0006]

Embedded image

(Wherein X ¹ is a hydrogen atom, a halogen atom,
X ² and X ³ are each independently a halogen atom, X ⁴ is a hydrogen atom or a halogen atom, R ¹ and R ² are each independently a hydrogen atom or a substituent, 1 to 1 carbon atom (s)
7 alkyl groups or aralkyl groups having 7 to 11 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom, a halogen atom or an amino group which may have a protecting group). Cyclopropane ring-containing purine derivatives, (2)
Formula (II):

[0008]

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(Where X is^Two, X^ThreeAnd X^FiveAre each
Independently a halogen atom, R¹And R ^TwoAre independent
To form a hydrogen atom, an optionally substituted
7 alkyl groups or carbon atoms which may have a substituent
Represents an aralkyl group of 7 to 11).
Conductor and formula (III):

[0010]

Embedded image

(Wherein X ¹ is a hydrogen atom, a halogen atom,
An alkoxy group or a hydroxyl group having 1 to 10 carbon atoms, X ⁴ represents a hydrogen atom or a halogen atom, and R ³ represents a hydrogen atom, a halogen atom or an amino group which may have a protecting group)
Reacting with a purine compound represented by formula (I):

[0012]

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Wherein X ¹ , X ² , X ³ , X ⁴ , R ¹ ,
R ² and R ³ are the same as described above), and a method for producing a cyclopropane ring-containing purine derivative represented by the formula (I):

[0014]

Embedded image

(Wherein X ¹ is a hydrogen atom, a halogen atom,
X ² and X ³ are each independently a halogen atom, X ⁴ is a hydrogen atom or a halogen atom, R ¹ and R ² are each independently a hydrogen atom or a substituent, 1 to 1 carbon atom (s)
7 alkyl groups or aralkyl groups having 7 to 11 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom, a halogen atom or an amino group which may have a protecting group). Formula (IV), characterized by hydrogenating a purine derivative having a cyclopropane ring:

[0016]

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(Wherein X ⁶ is a hydrogen atom, having 1 to 10 carbon atoms)
R ⁴ represents a hydrogen atom or an amino group which may have a protecting group, and R ¹ and R
² is the same as described above).

[0018]

DETAILED DESCRIPTION OF THE INVENTION As described above, the cyclopropane ring-containing purine derivative of the present invention has the formula (I):

[0019]

Embedded image

(Wherein X ¹ is a hydrogen atom, a halogen atom,
X ² and X ³ are each independently a halogen atom, X ⁴ is a hydrogen atom or a halogen atom, R ¹ and R ² are each independently a hydrogen atom or a substituent, 1 to 1 carbon atom (s)
7 alkyl groups or aralkyl groups having 7 to 11 carbon atoms which may have a substituent, and R ³ represents a hydrogen atom, a halogen atom or an amino group which may have a protecting group). Compound.

In the formula (I), X ¹ represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms or a hydroxyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among these, a chlorine atom, a bromine atom and an iodine atom are preferable.

The alkoxy group having 1 to 10 carbon atoms includes, for example, methoxy group, ethoxy group, propoxy group,
Examples include a benzyloxy group, a 2-methyl-2-propoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

X ² and X ³ each independently represent a halogen atom, and X ⁴ represents a hydrogen atom or a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among these, a chlorine atom, a bromine atom and an iodine atom are preferable.

R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 7 carbon atoms which may have a substituent or a C 7 to 11 carbon atom which may have a substituent. Represents an aralkyl group.

The alkyl group having 1 to 7 carbon atoms includes:
For example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-methylpropyl group and the like can be mentioned.

The aralkyl group having 7 to 11 carbon atoms includes, for example, a benzyl group.

Examples of the substituent which the alkyl group and the aralkyl group may have include, for example, an alkoxy group having 1 to 6 carbon atoms such as a methoxy group and a phenoxy group, a hydroxyl group, a nitro group, an amino group and a chlorine atom. And a cyano group.

R ³ represents a hydrogen atom, a halogen atom or an amino group which may have a protecting group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the present invention, when R ³ has a protecting group, the protecting group may be, for example, one having 1 to 7 carbon atoms.
And a group represented by CH ₃ —N (CH ₃ ) —CH ＝. Examples of the acyl group having 1 to 7 carbon atoms include a formyl group, an acetyl group, a pivaloyl group,
And a benzoyl group.

In the formula (I), X ¹ , X ² and X ³
Represents a chlorine atom, a bromine atom or an iodine atom, X
⁴ is a hydrogen atom, R ¹ and R ² each have 1 to 1 carbon atoms
The alkyl group or hydrogen atom 5 and R ³ are each preferably an amino group optionally having a protective group. As the alkyl group having 1 to 5 carbon atoms, for example,
Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a pentyl group.

The cyclopropane ring-containing purine derivative represented by the formula (I) is represented by the formula (II):

[0032]

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(Wherein X ⁵ represents a halogen atom;
X ² , X ³ , R ¹ and R ² are the same as defined above) and a malonic acid derivative represented by the formula (III):

[0034]

Embedded image

(Wherein X ¹ , X ⁴ and R ³ are the same as described above).

In the above X ⁵ , examples of the halogen atom include the same groups as X ² and X ³ in the formula (I).

In the present invention, the reaction between the malonic acid derivative represented by the formula (II) and the purine compound represented by the formula (III) is carried out, for example, by reacting the purine compound represented by the formula (III)
It can be carried out by adding it in a solvent in advance, stirring, and then adding a malonic acid derivative represented by the formula (II).

In the formula (II), X ² , X ³ and X ⁵
Is a chlorine atom, a bromine atom or an iodine atom,
Each of ¹ and R ² is preferably an alkyl group having 1 to 5 carbon atoms or a hydrogen atom, respectively.

In the formula (III), X ¹ is a chlorine atom, bromine atom or iodine atom, X ⁴ is a hydrogen atom, R ³
Is preferably an amino group which may have a protecting group.

Examples of the solvent include N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and the like. Among them, N, N-dimethylformamide is preferred from the viewpoint of reactivity and economy. And dimethyl sulfoxide are preferably used.

The amount of the solvent to be used is generally 500 to 1 with respect to 100 parts by weight of the purine compound represented by the formula (III).
It is preferably about 0000 parts by weight.

In the present invention, the reaction between the malonic acid derivative represented by the formula (II) and the purine compound represented by the formula (III) can be carried out in the presence of a base having low nucleophilicity. preferable. Representative examples of such bases having low nucleophilicity include, for example, alkali metal carbonates.

Examples of the alkali metal carbonate include potassium carbonate, sodium carbonate, rubidium carbonate,
Cesium carbonate and the like, among these, among these,
From the viewpoint of reactivity, potassium carbonate is preferably used.

The amount of the alkali metal carbonate used is usually based on 1 mol of the purine compound represented by the formula (III).
In order to allow the reaction to proceed promptly, the amount is preferably 0.5 mol or more, preferably 1 mol or more, and from the viewpoint of economy, it is desirably 20 mol or less, preferably 5 mol or less.

The alkali metal carbonate can be used by adding it to a solvent together with the purine compound represented by the formula (III).

Usually, the amount of the malonic acid derivative represented by the formula (II) is theoretically required to be 1 mol per 1 mol of the purine compound represented by the formula (III). ,
It is preferably at least 1.1 mol, and from the viewpoint of economy, it is preferably at most 50 mol, more preferably at most 5 mol.

The malonic acid derivative represented by the formula (II) can be easily produced, for example, by the method described in US Pat. No. 3,495,012.

The malonic acid derivative represented by the formula (II) and the formula (I)
The atmosphere for the reaction with the purine compound represented by II) is not particularly limited, and may be air or an inert gas atmosphere such as a nitrogen gas or an argon gas. The reaction temperature is usually desirably about -10 to 100C, preferably about 0 to 60C.

The reaction time varies depending on conditions such as the reaction temperature and cannot be unconditionally determined. However, the reaction time may be such that the reaction is completed, and is usually about 0.5 to 5 hours.

The completion of the reaction can be confirmed by, for example, high performance liquid chromatography.

After the completion of the reaction, the obtained cyclopropane ring-containing purine derivative represented by the formula (I) can be isolated by, for example, filtration, crystallization, washing, concentration and the like.

Thus, the cyclopropane ring-containing purine derivative represented by the formula (I) can be easily obtained.

The above-described cyclopropane ring-containing purine derivative represented by the formula (I) is a novel compound, for example, a nucleoside nucleotide (Nucleoside).
Nucleotide), 15 [5] (1996), p. 981-994, Tokuhei 5
Formula (IV), which is an intermediate for producing an antiviral agent described in JP-86792-A and the like:

[0054]

Embedded image

(Wherein X ⁶ is a hydrogen atom and has 1 to 10 carbon atoms)
R ⁴ is a hydrogen atom or an amino group which may have a protecting group, R ¹ and R ² are the same as described above), and as a production intermediate of a cyclopropane ring-cleaved purine derivative represented by the following formula: It is a compound that can be suitably used.

In X ⁶ , examples of the alkoxy group having 1 to 10 carbon atoms include the same groups as the alkoxy groups having 1 to 10 carbon atoms described for X ¹ in the formula (I).

In R ⁴ , examples of the amino group optionally having a protecting group include the same groups as the amino group optionally having a protecting group described for R ³ in the formula (I). it can.

In the present invention, a cyclopropane ring-cleaved purine derivative represented by the formula (IV) can be produced by hydrogenating the cyclopropane ring-containing purine derivative represented by the formula (I). .

As a method for hydrogenating the cyclopropane ring-containing purine derivative represented by the formula (I), for example, a method by catalytic reduction of a cyclopropane ring-containing purine derivative represented by the formula (I) (hereinafter referred to as the method (A)) and a method of reacting the cyclopropane ring-containing purine derivative represented by the formula (I) with formic acid or formate (hereinafter, referred to as method (B)). Among these methods, the method (B) is preferable from the viewpoint of reactivity and operability.

In the above method (A), the catalytic reduction of the cyclopropane ring-containing purine derivative represented by the formula (I)
For example, a cyclopropane ring-containing purine derivative represented by the formula (I) and a catalyst are suspended in a solvent to form a suspension,
It can be carried out by shaking or stirring such a suspension under a hydrogen atmosphere, or by blowing hydrogen gas into the suspension.

Examples of the catalyst include palladium, platinum, nickel, and compounds thereof. Examples of the compound include hydroxides such as palladium hydroxide, oxides such as platinum oxide, Raney nickel, Raney cobalt,
Metallic catalysts such as palladium black and platinum black are exemplified. The catalyst may be used as it is, or may be used as a supported catalyst supported on carbon or the like, such as palladium carbon or platinum carbon. Among these, palladium carbon, platinum carbon, palladium black, palladium hydroxide and Raney nickel are preferred from the viewpoint of versatility and reactivity.

The amount of the catalyst used is based on 100 parts by weight of the cyclopropane ring-containing purine derivative represented by the formula (I).
In order to allow the reaction to proceed rapidly, it is desirable that the amount be 1 part by weight or more, preferably 20 parts by weight or more, more preferably 30 parts by weight or more, and from the viewpoint of economy, 200 parts by weight or less, preferably 100 parts by weight or less. , More preferably 5
It is desirable that the content be 0 parts by weight or less.

Examples of the solvent include alcohols such as methanol, ethanol and 2-propanol, ethers such as tetrahydrofuran, organic acids such as acetic acid, esters such as ethyl acetate, and polar solvents such as N, N-dimethylformamide. , Water, etc., of which methanol is preferred. The solvents can be used alone or in combination of two or more.

The amount of the solvent used is usually 1 to 100 parts by weight, preferably 1 to 50 parts by weight, of the cyclopropane ring-containing purine derivative represented by the formula (I) per 100 parts by weight of the solvent.
It is preferable that the amount is adjusted to be about 5 parts by weight, more preferably about 5 to 30 parts by weight, particularly preferably about 2 to 10 parts by weight.

The reaction temperature for the catalytic reduction of the cyclopropane ring-containing purine derivative represented by the formula (I) is usually
About 0 to 200 ° C, preferably about 0 to 130 ° C, more preferably about 50 to 90 ° C, particularly preferably 70 to 9 ° C.
It is desirable that the temperature is about 0 ° C. When the suspension of the cyclopropane ring-containing purine derivative represented by the formula (I) is shaken or stirred under a hydrogen atmosphere, the pressure of the hydrogen gas is usually about 0 to ²⁰ kgf / cm ^2. , Preferably about 0 to 10 kgf / cm ² , more preferably about 1 to 10 kgf / cm ^2.
７7 kgf / cm ² , particularly preferably 3-7 kgf / c
m ² is desirable.

The reaction time cannot be determined unequivocally because it varies depending on the reaction conditions such as the reaction temperature. However, the reaction time may be such that the reaction is completed.
It is preferably about 8 hours, preferably about 4 to 7 hours. The completion of the reaction can be confirmed using, for example, high performance liquid chromatography.

After completion of the reaction, for example, the compound of the formula (I) obtained by ordinary separation operations such as filtration, concentration, extraction and purification is used.
The cyclopropane ring-cleaved purine derivative represented by V) can be recovered.

On the other hand, in the above method (B), the formula (I)
The reaction of the cyclopropane ring-containing purine derivative represented by the formula (I) with formic acid or formate is carried out, for example, by adding a cyclopropane ring-containing purine derivative represented by the formula (I) and a catalyst to a solvent, followed by formic acid or formic acid It can be carried out by adding a salt.

As the catalyst, in the above method (A),
The same catalyst as that used in the catalytic reduction can be used. The amount of such a catalyst to be used is usually 0.1 part by weight or more, preferably 10 parts by weight, with respect to 100 parts by weight of the cyclopropane ring-containing purine derivative represented by the formula (I), in order to allow the reaction to proceed rapidly. The amount is preferably at least 100 parts by weight, more preferably at most 50 parts by weight, from the viewpoint of economy.

The solvent is not particularly restricted but includes, for example, water, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, esters such as ethyl acetate, polar solvents such as N, N-dimethylformamide and the like. These can be used alone or in combination of two or more. The solvent is used in an amount of the formula (I) per 100 parts by weight of the solvent.
Wherein the cyclopropane ring-containing purine derivative represented by
It is preferable to adjust so as to be about 0 parts by weight.

Examples of the formate include alkali metal formate such as sodium formate and potassium formate, ammonium formate,
And triethylammonium formate. Of these, alkali metal formate such as sodium formate and potassium formate are preferred from the viewpoints of economy, workability and reduction of reaction time.

The amount of formic acid or formate used is not less than 1 mol, preferably not less than 1.5 mol, per mol of the cyclopropane ring-containing purine derivative represented by the formula (I) in order to complete the reaction. Desirably, from the viewpoint of economy, it is desirably 20 mol or less, preferably 10 mol or less.

The reaction temperature of the reaction between the cyclopropane ring-containing purine derivative represented by the formula (I) and formic acid or formate is usually 0 to 150 ° C., preferably 20 to 150 ° C.
Desirably, the temperature is 80 ° C. The atmosphere during the reaction is not particularly limited, but is preferably under an inert gas atmosphere or a hydrogen gas atmosphere. The reaction does not need to be particularly pressurized in the reaction system, and may be performed under normal pressure.

The reaction time varies depending on the reaction conditions such as the reaction temperature and the like, and cannot be unconditionally determined. However, the reaction time may be such that the reaction is completed.
It is desirably about an hour, preferably about 1 to 10 hours. The completion of the reaction can be confirmed, for example, by confirming the disappearance of the raw material using high performance liquid chromatography.

After completion of the reaction, for example, the compound of the formula (I) obtained by ordinary separation operations such as filtration, concentration, extraction and purification is obtained.
The cyclopropane ring-cleaved purine derivative represented by V) can be recovered.

The thus obtained cyclopropane ring-cleaved purine derivative represented by the formula (IV) can be further recrystallized as needed using, for example, 2-propanol.

The cyclopropane ring-cleaved purine derivatives represented by the formula (IV) obtained according to the present invention include, for example, Fanciclovir, Pencyclovia (Pe
nciclovir) is a very useful compound as an intermediate for the production of antiviral agents.

[0078]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.

Example 1 7.06 g of 2-amino-6-chloropurine (manufactured by Sumika Finechem Co., Ltd.) was added to 188 ml of N, N-dimethylformamide in a 0.3-liter four-necked flask.
6 mmol) and 12.4 g (89.7 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 30 minutes. Next, 16.0 g (61.2 mmol) of dimethyl 2,2,2-trichloroethylidenemalonate prepared by the method described in U.S. Pat. No. 3,495,012 was added to the obtained mixture.
After stirring for 4 hours at room temperature, the reaction mixture was filtered and the filtrate was poured into water. At this time, the crystallized crystals were collected by filtration, washed with 100 ml of water, dried under reduced pressure, and dried under a reduced pressure to give 2-amino-6-chloro-9- (3,3-dicarbomethoxy-2,2-dichloromethane. 12.14 g (34.7 mmol) of white crystals of (cyclopropyl) purine were obtained (yield: 83.4%).

The obtained 2-amino-6-chloro-
Physical properties of 9- (3,3-dicarbomethoxy-2,2-dichlorocyclopropyl) purine are as follows. (1) EI-MS: 393 (M ⁺ ) (2) ¹ H-NMR (300 MHz, DMSO-d ₆ )
δ (ppm): 3.72 (s, 3H), 3.89 (s,
3H), 4.95 (s, 1H), 6.90-7.10.
(Br, 2H), 8.16 (s, 1H) (3) ¹³ C-NMR (75 MHz, DMSO-d ₆ ) δ
(Ppm): 163.2, 161.6, 160.1, 1
54.9, 149.9, 142.2, 122.4, 6
0.4, 54.0, 46.2

Example 2 2-amino-6-chloro-9- (3,3-dicarbomethoxy-2,2-dichlorocyclopropyl) purine obtained in Example 1 in a 0.25 liter autoclave 4.0 g (10.1 mmol) and 2.0 g of 5% palladium carbon were added to methanol (75 ml), and 90 ° C.
The reaction was carried out for 5 hours while stirring under a hydrogen gas pressurizing condition of about 5 kgf / cm ² . Filtering the reaction mixture,
After the filtrate was concentrated under reduced pressure, 10 ml of water and 75 ml of ethyl acetate were added to the concentrate, stirred for 30 minutes, allowed to stand, and then the ethyl acetate layer was separated. After purification by column chromatography, 2- (2- (2-aminopurine-9-
1.78 g of white crystals of yl) ethyl) dimethyl malonate
(6.07 mmol) was obtained (yield: 60.0%).

The physical properties of the obtained dimethyl 2- (2- (2-aminopurin-9-yl) ethyl) malonate are as follows:
It is as follows. (1) Melting point: 106.5 ° C. (2) EI-MS: 293 (M ⁺ ) (3) ¹ H-NMR (300 MHz, CDCl ₃ ) δ
(Ppm): 2.45-2.52 (m, 2H), 3.4
1 (t, 1H), 3.73 (s, 6H), 4.19-
4.23 (m, 2H), 5.20-5.30 (br, 2
H), 7.76 (s, 1H), 8.69 (s, 1H) (4) ¹³ C-NMR (300 MHz, CDCl ₃ ) δ
(Ppm): 168.9, 160.1, 153.3, 1
49.9, 142.5, 128.1, 52.9, 48.
8, 40.9, 28.7

Example 3 50.0 g (294.9 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Finechem KK) and potassium carbonate 88 were added to 650 ml of dimethyl sulfoxide in a 1-liter four-necked flask. 0.2 g (648.0 mmol)
Was added, and 26.1 g (1449.9 mmol) of water was introduced, followed by stirring at room temperature. Next, 127.4 g (440.0 mmol) of diethyl 2,2,2-trichloroethylidenemalonate prepared by the method described in U.S. Pat. After stirring at room temperature, the reaction mixture was filtered and the filtrate was poured into water. At this time, the crystallized crystals are collected by filtration, and water 1
After washing with 00 ml, it was dried under reduced pressure to give 2-
101.5 g (240.1 mmol) of white crystals of amino-6-chloro-9- (3,3-dicarbethoxy-2,2-dichlorocyclopropyl) purine were obtained (yield: 8).
2.8%).

The obtained 2-amino-6-chloro-
The physical properties of 9- (3,3-dicarbethoxy-2,2-dichlorocyclopropyl) purine are as follows.

(1) ¹ H-NMR (400 MHz, CD
Cl ₃ ) δ (ppm): 1.25 (t, 3H), 1.3
9 (t, 3H), 4.24 (m, 2H), 4.41
(M, 2H), 4.76 (s, 1H), 5.29 (s,
1H), 8.03 (s, 1H) (2) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ
(Ppm): 162.5, 161.0, 159.2, 1
54.8, 151.6, 140.7, 124.2, 6
3.9, 63.3, 60.1, 47.2, 46.6, 1
4.1, 13.8

Example 4 2-amino-6-chloro-9- (3,3-dicarboethoxy-2,2-dichlorocyclopropyl) purine
0 g (23.7 mmol) and 10% palladium on carbon (5
0% wet product, Kawaken Fine Chemical Co., Ltd.) 1
0.0 g to 100 ml of ethyl acetate, followed by
To this was added 8.04 g (118.2 mmol) of sodium formate. After reacting at 55-61 ° C. for 16 hours, the reaction mixture was filtered. 25 ml of water was poured into the filtrate, neutralized with hydrochloric acid, separated, and the organic layer was concentrated. The concentrated residue was dissolved in ethyl acetate, n-heptane was added dropwise, and the crystallized crystals were collected by filtration, dried under reduced pressure, and dried under reduced pressure to give 2- (2- (2
This yielded 4.14 g (12.9 mmol) of white crystals of diethyl -aminopurin-9-yl) ethyl) malonate (yield: 54.5%).

The physical properties of the obtained diethyl 2- (2- (2-aminopurin-9-yl) ethyl) malonate are as follows:
It is as follows. (1) ¹ H-NMR (400 MHz, CDCl ₃ ) δ
(Ppm): 1.25 (t, 6H), 2.47 (q, 2
H), 3.35 (t, 1H), 4.19 (m, 6H),
5.14 (s, 2H), 7.77 (s, 1H), 8.6
9 (s, 1H) (2) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ
(Ppm): 168.3, 159.6, 153.1, 1
49.5, 142.4, 128.1, 61.9, 49.
1, 40.9, 28.6, 14.1

Example 5 15.0 g (88.5 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Finechem KK) and carbonic acid were added to 195 ml of dimethyl sulfoxide in a 0.3 liter four-neck flask. 26.9 g (194.6 mmol) of potassium
Was added, and 8.0 g (442.5 mmol) of water was introduced, followed by stirring at room temperature. Next, 42.2 g (132.9 mmol) of diisopropyl 2,2,2-trichloroethylidenemalonate prepared by the method described in U.S. Pat. After stirring at room temperature, the reaction mixture was filtered and the filtrate was poured into water. At this time, the crystallized crystals are
After washing with 1 l, the crystals were collected by filtration and recrystallized from isopropanol to give pale yellow crystals of 2-amino-6-chloro-9- (3,3-dicarboisopropoxy-2,2-dichlorocyclopropyl) purine. 1 g (60.1 mmol) was obtained (yield: 67.9%).

The obtained 2-amino-6-chloro-
Physical properties of 9- (3,3-dicarboisopropoxy-2,2-dichlorocyclopropyl) purine are as follows. (1) ¹ H-NMR (400 MHz, CDCl ₃ ) δ
(Ppm): 1.23 (d, 3H), 1.26 (d, 3
H), 1.36 (d, 3H), 1.38 (d, 3H),
4.74 (s, 1H), 5.08 (m, 1H), 5.2
3 (m, 1H), 5.34 (s, 2H), 8.04
(S, 1H) (2) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ
(Ppm): 162.0, 160.4, 159.2, 1
54.9, 151.5, 140.7, 124.2, 7
2.3, 71.7, 60.1, 47.3, 46.4, 2
1.8, 21.6, 21.4

Example 6 5.0 g (11.1 mmol) of 2-amino-6-chloro-9- (3,3-dicarboisopropoxy-2,2-dichlorocyclopropyl) purine and 10% palladium on carbon ( 50% wet product, manufactured by Kawaken Fine Chemical Co., Ltd.)
5.0 g were added to 100 ml of isopropanol, followed by 3.8 g (55.5 mmol) of sodium formate. After reacting at 55-61 ° C. for 16 hours, the reaction mixture was filtered. 25 ml of water was poured into the filtrate, neutralized with hydrochloric acid, separated, and the organic layer was concentrated. The concentrated residue was dissolved in ethyl acetate, n-heptane was added dropwise, and the crystallized crystals were collected by filtration, dried under reduced pressure, and dried under reduced pressure to give 2- (2- (2
2.4 g (6.9 mmol) of white crystals of (-aminopurin-9-yl) ethyl) diisopropylmalonate were obtained (yield: 62.4%).

The physical properties of the obtained diisopropyl 2- (2- (2-aminopurin-9-yl) ethyl) malonate are as follows. (1) ¹ H-NMR (400 MHz, CDCl ₃ ) δ
(Ppm): 1.24 (d, 6H), 1.25 (d, 6
H), 2.44 (q, 2H), 3.28 (t, 1H),
4.21 (t, 2H), 5.05 (m, 2H), 5.0
9 (s, 2H), 7.76 (s, 1H), 8.69
(S, 1H) (2) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ
(Ppm): 167.9, 159.7, 153.0, 1
49.7, 142.3, 128.2, 69.5, 49.
4, 40.9, 28.5, 21.7, 21.6

Example 7 4.13 g of 2-amino-6-methoxypurine (manufactured by Sumika Finechem Co., Ltd.) was added to 110 ml of N, N-dimethylformamide in a 0.3-liter four-necked flask.
5.0 mmol) and 7.6 g (55.0 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature. Next, 9.8 g (37.5 mmol) of dimethyl 2,2,2-trichloroethylidenemalonate prepared by the method described in U.S. Pat. No. 3,495,012 was added to the obtained mixture,
After stirring at room temperature for 2.5 hours, the reaction mixture was filtered, and the filtrate was poured into water. At this time, the crystallized crystals were collected by filtration, washed with 165 ml of water, dried under reduced pressure, and dried under a reduced pressure to give 2-amino-9- (3,3-dicarbomethoxy-).
8.81 g (22.6 mmol) of white crystals of 2,2-dichlorocyclopropyl) -6-methoxypurine were obtained (yield: 90.3%).

The obtained 2-amino-9- (3,3
The physical properties of -dicarbomethoxy-2,2-dichlorocyclopropyl) -6-methoxypurine are as follows. (1) ¹ H-NMR (400 MHz, DMSO-d ₆ )
δ (ppm): 3.72 (s, 3H), 3.88 (s, 3H)
3H), 3.97 (s, 3H), 4.94 (s, 1
H), 6.54 (s, 2H), 7.86 (s, 1H) (2) ¹³ C-NMR (100 MHz, DMSO-d ₆ )
δ (ppm): 163.0, 161.2, 160.6,
159.8, 154.7, 138.0, 112.6, 6
0.3, 54.2, 53.8, 53.3, 46.1, 4
6.0

Example 8 6.03 g of 2-amino-6-benzyloxypurine (manufactured by Sumika Finechem Co., Ltd.) was added to 160 ml of N, N-dimethylformamide in a 0.3-liter four-necked flask.
(25.0 mmol) and 7.6 g of potassium carbonate (55.
0 mmol) and stirred at room temperature. Next, 9.8 g (37.5 mmol) of dimethyl 2,2,2-trichloroethylidenemalonate prepared by the method described in U.S. Pat. No. 3,495,012 was added to the obtained mixture, and the mixture was added for 2.5 hours. After stirring at room temperature, the reaction mixture was filtered and the filtrate was poured into water. At this time, the crystallized crystals were collected by filtration, washed with 240 ml of water, dried under reduced pressure, and dried under a reduced pressure to give 2-amino-6-benzyloxy-9- (3,3
11.0 g (23.6 mmol) of white crystals of -dicarbomethoxy-2,2-dichlorocyclopropyl) purine
Was obtained (yield: 94.5%).

The physical properties of the obtained 2-amino-6-benzyloxy-9- (3,3-dicarbomethoxy-2,2-dichlorocyclopropyl) purine are as follows. (1) ¹ H-NMR (400 MHz, DMSO-d ₆ )
δ (ppm): 3.72 (t, 3H), 3.88 (t,
3H), 4.94 (s, 1H), 5.50 (dd, 2
H), 6.59 (s, 2H), 7.35-7.52
(M, 5H), 7.87 (s, 1H) (2) ¹³ C-NMR (100 MHz, DMSO-d ₆ )
δ (ppm): 163.0, 161.2, 160.0,
159.7, 154.9, 138.2, 136.4, 1
28.4, 128.3, 128.0, 112.6, 6
7.0, 60.3, 54.2, 53.9, 46.1, 4
6.0

From the above results, it can be seen that the methods of Examples 1, 3, 5, 7, and 8 can easily obtain purine derivatives containing a cyclopropane ring. Further, according to the methods of Examples 2, 4 and 6, using such a cyclopropane ring-containing purine derivative, a cyclopropane ring-cleaved purine derivative useful as an intermediate for producing an antiviral agent was obtained.
It can be seen that it can be obtained easily and efficiently with high yield.

[0097]

According to the present invention, a cyclopropane ring-containing purine derivative can be easily produced. Further, according to the present invention, a cyclopropane ring-cleaved purine derivative can be efficiently produced with high yield using the cyclopropane ring-containing purine derivative.

Claims (3)

[Claims] 1. A compound of formula (I): (In the formula, X ¹ is a hydrogen atom, a halogen atom, and has 1 to 1 carbon atoms.
X ² and X ³ are each independently a halogen atom, X ⁴ is a hydrogen atom or a halogen atom, R ¹ and R ² are each independently a hydrogen atom or a substituent. A C 1-7 alkyl group or a C 7-11 aralkyl group which may have a substituent; R ³ represents a hydrogen atom, a halogen atom or an amino group optionally having a protecting group; A) a cyclopropane ring-containing purine derivative represented by the following formula: 2. A compound of formula (II):(Where X^Two, X^ThreeAnd X^FiveAre independently halo
Gen atom, R¹And R ^TwoAre each independently a hydrogen source
And alkyl having 1 to 7 carbon atoms which may have a substituent
A group having 7 to 11 carbon atoms which may have a group or a substituent;
A malonic acid derivative represented by the formula (I)
II):(Where X¹Represents a hydrogen atom, a halogen atom, and a carbon number of 1 to 1.
0 alkoxy or hydroxyl group, X^FourIs a hydrogen atom or
Halogen atom, R^ThreeIs a hydrogen atom, halogen atom or
Represents an amino group which may have a protecting group)
Formula (I) characterized by reacting with a phosphorus compound:(Where X¹, X^Two, X^Three, X^Four, R¹, R^TwoAnd R
^ThreeIs the same as described above).
A method for producing a derivative. 3. Formula (I): (In the formula, X ¹ is a hydrogen atom, a halogen atom, and has 1 to 1 carbon atoms.
X ² and X ³ are each independently a halogen atom, X ⁴ is a hydrogen atom or a halogen atom, R ¹ and R ² are each independently a hydrogen atom or a substituent. A C 1-7 alkyl group or a C 7-11 aralkyl group which may have a substituent; R ³ represents a hydrogen atom, a halogen atom or an amino group optionally having a protecting group; Hydrogenation to a cyclopropane ring-containing purine derivative represented by the following formula (IV): (In the formula, X ⁶ represents a hydrogen atom, an alkoxy group or a hydroxyl group having 1 to 10 carbon atoms, R ⁴ represents a hydrogen atom or an amino group which may have a protecting group, and R ¹ and R ² are the same as those described above. A method for producing a cyclopropane ring-cleaved purine derivative represented by the formula: