JP2001226378A - Halogenopurine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new halogenopurine compound useful as a raw material for economically advantageously synthesizing, in a good yield by using an inexpensive auxiliary material, a 2-formylamino-6-halogenopurine or a salt thereof, which is useful for producing a 2-amino-6-halogenopurine useful as a synthesis intermediate product for producing a compound useful as an antiviral agent. SOLUTION: This new halogenopurine compound is represented by general formula (1) (wherein R1 and R2 are each H, methyl group, ethyl group or an aromatic group; R3 is a single bond or a 1-5C alkylene group; R1 is H, a 1-5C alkyl group or an aromatic group; and X is chlorine atom, bromine atom, iodine atom or fluorine atom).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a halogenopurine compound. More specifically, the present invention relates to a halogenopurine compound useful for producing 2-amino-6-halogenopurine, which is useful as a synthetic intermediate for producing a compound useful as an antiviral agent.

[0002]

BACKGROUND OF THE INVENTION 2-Amino-6-halogenopurines are disclosed, for example, in JP-B-56-333.
No. 96, JP-A-60-58982, JP-A-60-20
8954, JP-A-2-59583, JP-A-4-10
It is known as an intermediate useful for producing a guanine nucleoside analog, as described in each of JP-A-8788.

[0003] As a method of synthesizing 2-amino-6-halogenopurine, several methods have been conventionally developed. As a method of forming a 6-chloro form, for example, a guanine is reacted with phosphorus pentasulfide to form a 6-chloro form.
Introduced a mercapto group at
Method for forming chloro form (British Patent 767,216,
J. Am. Chem. Soc. 77, 1676). But,
In this method, the decomposed product of phosphorus pentasulfide used has a strong odor, which may cause pollution. In addition, the yield was not satisfactory, and the resulting thioguanine was dangerous because it was mutagenic.
Also, a method of reacting 2-amino-6-mercaptopurine with methyl iodide to form a 6-methylthio form and then blowing chlorine to form a 6-chloro form (J. Am.
Chem. Soc. 79, 2185-8, J. Am. Chem. Soc. 82, 2633
-40) is also known, but also from thioguanine as a raw material, there is a concern about the same dangers as in the above method.

Further, as another method, there has been reported a method in which phosphorus oxychloride is allowed to act on guanine in the presence of a quaternary ammonium salt to directly synthesize a 6-chloro compound (Japanese Patent Application Laid-Open No. 61-227583). However, in this method, the quaternary ammonium salt is expensive, and the solubility of guanine is low, so that the yield is as low as 30 to 42%, which is not economically advantageous.

As a method of forming a 6-bromo compound, for example, a method of forming bromide on thioguanine to form a 6-bromo compound (J. Org. Chem., 2)
7,986,1962), as a method of forming a 6-iodo form, a method of obtaining an iodine form by reacting thioguanine with chlorine to form a 6-chloro form, followed by hydrogen iodide (J. Pharm). Sci., 57, 205.
6,1968) and the like. However, also in these methods, since thioguanine as a starting material is produced by reacting guanine with phosphorus pentasulfide in the same manner as described above, the decomposition product of phosphorus pentasulfide has a strong odor, and there is a risk of generating pollution. Is not satisfactory because the overall yield of 2-amino-6-halogenopurine is low, the operation is complicated, and the like.

An object of the present invention is to provide a halogenopurine compound which is a synthetic intermediate of 2-amino-6-halogenopurine.

[0007]

Means for Solving the Problems The present inventors have sought a completely different production method that does not include the above-mentioned problems, and have found a novel halogenopurine compound and obtained the desired compound 2 in good yield from this intermediate. The inventors have found that -amino-6-halogenopurine can be synthesized, and have completed the present invention.

That is, the gist of the present invention is represented by the general formula (1):

[0009]

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(Wherein R ¹ and R ² are each a hydrogen atom, a methyl group, an ethyl group or an aromatic group, R ³ is a single bond or an alkylene group having 1 to 5 carbon atoms, R ⁴ is a hydrogen atom,
X represents an alkyl group or an aromatic group having 1 to 5 carbon atoms, X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom).

The synthetic intermediate used in the method for producing 2-amino-6-halogenopurine is (1) a halogenopurine compound represented by the general formula (1).

First, a halogenopurine compound represented by the general formula (1), which is a novel synthetic intermediate, will be described below.

In the halogenopurine compound represented by the general formula (1), the groups represented by R ¹ and R ² are a hydrogen atom, a methyl group, an ethyl group or an aromatic group. Examples of the aromatic group include a phenyl group.

R ³ represents a single bond or a linear alkylene group having 1 to 5 carbon atoms such as a methylene group, an ethylene group and a propylene group. The group represented by R ⁴ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an aromatic group, and examples of the alkyl group or the aromatic group are the same as those described above. Preferred examples of the halogenopurine compound represented by the general formula (1) represented by such a substituent include, for example, both R ¹ and R ² are methyl groups, or one is a phenyl group and the other is a methyl group. And R ³ are single bonds, and R ⁴ is a hydrogen atom compound.

X represents a chlorine, bromine, iodine or fluorine atom. Preferred are a chlorine atom and a bromine atom.

The halogenopurine compound represented by the general formula (1) in the present invention is a novel synthetic intermediate, and guanine, a salt thereof or a hydrate thereof is converted to a compound of the general formula (3) in the presence of a halogenating agent. :

[0017]

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(Wherein R ¹ and R ² are each a hydrogen atom, a methyl group, an ethyl group or an aromatic group, R ³ is a single bond or an alkylene group having 1 to 5 carbon atoms, R ⁴ is a hydrogen atom,
Which represents an alkyl group or an aromatic group having 1 to 5 carbon atoms).

In the present invention, guanine is usually used as a raw material, but may be a salt or hydrate thereof. The guanine salt is not particularly limited, and includes, for example, hydrochloride, sulfate, acetate, hydrobromide, sodium salt and the like. The hydrate of guanine is not particularly limited. For example, guanine hydrochloride monohydrate, guanine hydrochloride dihydrate, guanine phosphate hydrate, guanine sodium salt monohydrate Objects and the like.

Examples of the halogenating agent used here include known chlorinating agents such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene; phosphorus oxybromide, thionyl bromide; Phosphorus tribromide,
Known brominating agents such as phosphorus pentabromide; known iodizing agents such as phosphorus triiodide; known fluorinating agents such as phosphorus trifluoride and phosphorus oxyfluoride are exemplified. As the chlorinating agent, phosphorus oxychloride is preferable in consideration of the reaction rate.

In the compound represented by the general formula (3), the groups represented by R ¹ , R ² , R ³ and R ⁴ are the same as those of the halogenopurine compound represented by the general formula (1). And the same. Such a general formula (3)
Specific examples of the compound represented by
-Dimethylformamide, N, N-diethylformamide, N-methylformanilide, N, N-dimethylacetamide, N-formylpyrrolidine, N-formylpiperidine, N-formylpiperazine, N-formylmorpholine, N-formylthiomorpholine, etc. And N, N-dimethylformamide and N-methylformanilide are preferred.

The compound represented by the general formula (3) reacts with guanine, a salt thereof or a hydrate thereof in the presence of a halogenating agent as described above. In the present invention, a solvent is not particularly required, but an inert solvent is preferably used from the viewpoint of improvement in operability, and examples thereof include dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, and chloroform.

In the reaction in the step of producing the halogenopurine compound represented by the general formula (1), a halogenating agent is generally used in an amount of 2 to 1 mol of guanine, a salt thereof or a hydrate thereof.
It is used in an amount of 10 mol, preferably 2 to 5 mol, more preferably 2.5 to 3.5 mol. When a solvent is used, the amount of the compound represented by the general formula (3) is usually 1 to 1 mol per 1 mol of guanine, a salt thereof or a hydrate thereof.
It is 20 mol, preferably 3 to 10 mol, more preferably 4 to 6 mol. When a solvent is not used, usually 5 to 3 mol per 1 mol of guanine, a salt thereof or a hydrate thereof is used.
0 mol, preferably 10 to 20 mol, more preferably 10 to 15 mol. If it is less than this, the yield decreases, and if it is more, the yield does not increase correspondingly and it is not economical.

When no solvent is used, the reaction temperature varies depending on the type of the compound represented by the general formula (3), but is usually from 20 to 150 ° C. For example, when N, N-dimethylformamide is used, usually 80 to 12
The temperature is 0 ° C, and when N-methylformanilide is used, the range is usually preferably from 40 to 60 ° C. When a solvent is used, it is carried out at a temperature near the normal boiling point of the solvent used, and it is preferable that the temperature does not exceed 120 ° C. from the viewpoint of the thermal stability of the halogenopurine compound represented by the general formula (1). For example, as a compound represented by the general formula (3), N,
When N-dimethylformamide or N-methylformanilide is used and 1,2-dichloroethane is used as a solvent, the temperature is usually preferably in the range of 70 to 85 ° C. The reaction time is generally 1 to 15 hours, preferably 3 hours.
The reaction is completed for 10 to 10 hours, more preferably 4 to 8 hours.

The thus obtained halogenopurine compound represented by the general formula (1) may be separated and purified and used in the next step, or the reaction mixture is directly used in the next step without separation and purification. May be used.

When the next step is carried out without separation and purification, water is added to the reaction mixture to hydrolyze the remaining reaction reagents and, at the same time, hydrolyze the halogenopurine compound represented by the general formula (1). The target compound 2
-Amino-6-halogenopurine can be obtained. In this case, a strongly acidic substance is by-produced by adding water to the reaction mixture, so that hydrolysis can be performed without adding a strongly acidic substance or the like as shown in the example of hydrolysis described below.

When separating and purifying the halogenopurine compound represented by the general formula (1), the reaction mixture is cooled, and an aqueous solution of sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like is cooled. Obtained by treating The halogenopurine compound represented by the general formula (1) can be obtained as it is in the next step because it can be obtained in a yield close to the theoretical value, but if there is any concern about the presence of some by-products, It can be isolated by appropriately using known means such as filtration, recrystallization and the like.

Next, a method for producing the target compound 2-amino-6-halogenopurine using the thus obtained halogenopurine compound of the general formula (1) will be described below.

That is, the following two methods are used for producing the target compound, 2-amino-6-halogenopurine, by hydrolyzing the halogenopurine compound of the general formula (1).

(1) Method a: A method in which a halogenopurine compound represented by the general formula (1) which has been separated or purified is immediately hydrolyzed. (2) Method b: 2-formylamino-6-halogenopurine (a compound of the general formula (2), which is obtained by hydrolyzing a separated and purified halogenopurine compound of the general formula (1) under weakly acidic conditions in advance. A novel synthetic intermediate) or an acetate thereof, followed by hydrolysis.

In the method a, when the reaction is carried out at a very low temperature, hydrolysis is difficult, and when the temperature exceeds 20 ° C., guanine by-products increase. Therefore, usually at a temperature of 0 to 100 ° C., 1 to 24
The reaction is completed by reacting at a temperature of preferably 10 to 20 ° C. for 10 to 20 hours. In this case, in order to hydrolyze the separated and purified halogenopurine compound of the general formula (1), it is preferable to hydrolyze in the presence of a strongly acidic substance, a neutral substance, an alkaline substance or the like. Examples include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, sodium hydroxide, potassium hydroxide and the like. When a reaction mixture having a halogenopurine compound of the general formula (1) that has not been separated and purified is used, addition of a strongly acidic substance or the like is not necessary as described above.

In the method (b), hydrolysis is first carried out under weakly acidic conditions to obtain a compound of the general formula (2):

[0033]

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(Wherein, X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom), thereby obtaining 2-formylamino-6-halogenopurine or a salt thereof.
2-Formylamino-6-halogenopurine or a salt thereof is a novel compound discovered for the first time in the present invention. Usually at a temperature of 20-100 ° C. for 1-10 hours, preferably 5
The reaction is completed by reacting at a temperature of 0 to 70 ° C. for 3 to 5 hours. Here, the adjustment to a weakly acidic condition is carried out by adding an acidic substance, for example, acetic acid, propionic acid, hydrochloric acid, etc., although not particularly limited.

Next, the desired compound 2-amino-6-halogenopurine can be obtained by further hydrolysis. The reaction is usually completed at a temperature of 0 to 50 ° C for 1 to 24 hours, preferably at a temperature of 5 to 30 ° C for 2 to 20 hours. Also in this case, it is preferable to carry out the hydrolysis in the presence of a strongly acidic substance, a neutral substance, an alkaline substance, or the like as in the case of the above-mentioned method a.

Of these methods, method b is better than method a.
It has been found that guanine is less produced than by-products. The reaction product obtained by hydrolysis may contain the target compound, 2-amino-6-halogenopurine in most cases, or may contain a small amount of guanine. When a small amount of guanine is contained, hot ammonia water is added to the mixture, and guanine, which is an insoluble matter, is filtered to obtain 2-amino-6.
-Separation and purification of halogenopurine.

In one embodiment of the present invention, R ¹ and R ² are both methyl groups, R ³ is a single bond, R ⁴ is a hydrogen atom, X
Is a chlorine atom, the synthesis route of 2-amino-6-chloropurine is as follows.

[0038]

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In this way, the compound can be produced using the halogenopurine compound represented by the general formula (1).
As described above, amino-6-halogenopurine is disclosed in, for example, JP-B-56-33396 and JP-A-60-58982.
JP-A-60-208954, JP-A-2-5958
No. 3, JP-A-4-108788, it can be used as a synthetic intermediate of a guanine nucleoside analog useful as an antiviral agent.

[0040]

The present invention will be described in more detail with reference to the following examples and comparative examples, but the present invention is not limited to these examples.

Example 1 46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N, N-dimethylformamide.
Next, guanine (manufactured by Sumika Finechem Co., Ltd.) 15.1
g (0.1 mol) was added and the mixture was stirred at 100 ° C. for 4 hours.
After cooling, 100 ml of water was carefully added at 20 ° C. After stirring at room temperature for 24 hours, the precipitated crystals were collected by filtration. The obtained crystals were dissolved by heating in 100 ml of 25% aqueous ammonia, and insolubles were filtered. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. White crystals of 2-amino-6-chloropurine 9.3
g (0.055 mol) was obtained (yield 55%).

Example 2 115.0 g (0.75 mol) of phosphorus oxychloride was added to N, N
-Dimethylformamide (263.1 g, 3.6 mol), followed by guanine (manufactured by Sumika Finechem KK) 4
5.3 g (0.3 mol) was added, and the mixture was stirred at 100 ° C. for 5 hours. After cooling, 315.0 g of sodium hydrogen carbonate (3.
(75 mol) in 1500 ml of water. The precipitated crystals are collected by filtration, washed with 500 ml of water,
Crystals of 2-dimethylaminomethyleneamino-6-chloropurine were obtained. Its physical properties are as follows.

Melting point 300 ° C. (decomposition) Elemental analysis Actual value C: 42.85% H: 4.18% N: 37.05% Cl: 15.93% Calculated value C: 42.77% H: 4.04 % N: 37.41% Cl: 15.78% MS 224 (M ⁺ ), 209, 189, 168.

The obtained crystals of 2-dimethylaminomethyleneamino-6-chloropurine were subjected to 250.0 g of 35% hydrochloric acid.
(2.40 mol) and stirred at 15 ° C. for 20 hours.
The crystals were collected by filtration and washed with 50 ml of methanol. The obtained crystals were dissolved by heating in 300 ml of 25% aqueous ammonia and treated with 5.0 g of activated carbon. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 30.5 g (0.18 mol) of white crystals of 2-amino-6-chloropurine (yield: 60).
%).

Example 3 A crystal of 2-dimethylaminomethyleneamino-6-chloropurine obtained in the same manner as in Example 2 was treated with 78.1 g of acetic acid.
(1.3 mol) and stirred at 60 ° C. for 4 hours. A part of the reaction solution was taken and its physical properties were examined. As a result, it was confirmed that the product was 2-formylamino-6-chloropurine.
Its physical properties are as follows.

Melting point: 300 ° C. or more (decomposition) Elemental analysis Actual value: C: 36.45% H: 2.10% N: 35.40% Cl: 18.15% Calculated value C: 36.47% H: 2. 04% N: 35.45% Cl: 17.94% MS 197 (M ⁺ ), 168, 153, 119

Then, the reaction mixture was cooled to 5 ° C.
218.8 g (2.1 mol) of hydrochloric acid was added, and
Stirred for hours. The crystals were collected by filtration and washed with 50 ml of methanol. The obtained crystals are 300 ml of 25% aqueous ammonia.
And treated with 5.0 g of activated carbon. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 33.0 g (0.195 mol) of 2-amino-6-chloropurine as white crystals (yield: 65%).

Example 4 Crystals of 2-dimethylaminomethyleneamino-6-chloropurine obtained in the same manner as in Example 2 were added to 650 ml of a 12% aqueous acetic acid solution and stirred at 70 ° C. for 3 hours. The precipitated crystals were collected by filtration and washed with water to obtain 2-formylamino-6-chloropurine acetate. Next, the crystals were dissolved in a 10% aqueous sodium hydroxide solution and stirred at room temperature for 2 hours.
Thereafter, the mixture was neutralized with 35% hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and white crystals of 2-amino-6-chloropurine.
6 g (0.21 mol) was obtained (yield 70%).

Example 5 45.3 g of guanine (manufactured by Sumika Finechem Co., Ltd.)
(0.3 mol) was added to N-methylformanilide 490.5
g (3.6 mol), and then phosphorus oxychloride 13
8.0 g (0.9 mol) was added dropwise, and the mixture was stirred at 50 ° C. for 5 hours. After cooling, the reaction solution was neutralized with 217.5 g (2.05 mol) of sodium carbonate while dropping the reaction solution in 1500 ml of water. The precipitated crystals were collected by filtration and washed with water to obtain crystals of 2-phenylmethylaminomethyleneamino-6-chloropurine. Its physical properties are as follows.

Melting point: 223 ° C. (decomposition) Elemental analysis Actual value: C: 54.54% H: 3.90% N: 29.31% Cl: 12.25% Calculated value C: 54.46% H: 3.87 % N: 29.30% Cl: 12.36% MS 269 (M ⁺ ), 243, 209, 168

Next, the crystals of 2-phenylmethylaminomethyleneamino-6-chloropurine were treated in the same manner as in Example 4 to give white crystals of 2-amino-6-chloropurine.
8.2 g (0.225 mol) were obtained (75% yield).

Example 6 131.6 g (1.8 mol) of N, N-dimethylformamide and 138.0 g (0.9 mol) of phosphorus oxychloride were added to 500 ml of 1,2-dichloroethane, and then guanine (Suika Finechem). 45.3 g (0.3
Mol) was added and the mixture was stirred at 80 ° C for 8 hours. After cooling, water 1
The reaction solution was injected into 200 ml. Then, 175.6 g (1.65 mol) of sodium carbonate was added, and p of the aqueous layer was added.
H was adjusted to 4. After stirring for 30 minutes, the mixture was allowed to stand, and the aqueous layer was separated. 25.2 g (0.63 mol) of sodium hydroxide
Was added slowly. The precipitated crystals are collected by filtration and washed with water 20
After washing with 0 ml, 2-dimethylaminomethyleneamino-
60.7 g (0.27 mol) of crystals of 6-chloropurine were obtained. Next, the same treatment as in Example 4 was carried out to obtain 35.6 g (0.21 mol) of white crystals of 2-amino-6-chloropurine (yield: 70%).

Example 7 The procedure of Example 1 was repeated, except that 187.4 g (0.9 mol) of phosphorus pentachloride was used instead of phosphorus oxychloride as the chlorinating agent. White crystals of -amino-6-chloropurine can be obtained.

Example 8 An intermediate was prepared in the same manner as in Example 2 except that N, N-diethylformamide or N-formylpiperidine was used instead of N, N-dimethylformamide. 2-diethylaminomethyleneamino-6-chloropurine or 2-
Crystals of piperidinomethyleneamino-6-chloropurine can be obtained. Further, these crystals are treated in the same manner as in Example 2 to obtain white crystals of 2-amino-6-chloropurine.

Example 9 A white crystal of 2-amino-6-chloropurine was obtained by performing the reaction in the same manner as in Example 6 except that chlorobenzene was used instead of 1,2-dichloroethane. be able to.

Example 10 86.0 g (0.3 mol) of phosphorus oxybromide was added to 73.1 g (1.0 mol) of N, N-dimethylformamide.
Next, guanine (manufactured by Sumika Finechem Co., Ltd.) 15.1
g (0.1 mol) was added and the mixture was stirred at 100 ° C. for 4 hours.
After cooling, 200 ml of water were carefully added at 20 ° C. After stirring at room temperature for 24 hours, the precipitated crystals were collected by filtration. The obtained crystals were dissolved by heating in 200 ml of 25% aqueous ammonia, and insolubles were filtered. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 2-amino-6-bromopurine pale yellow crystals 1
1.1 g (0.052 mol) were obtained (52% yield).

Obtained value C: 28.06% H: 1.88% N: 32.72% Br: 37.33% Calculated value C: 27.89% H: 1.75% N: 32.95% Br : 37.42%

Example 11 203.0 g (0.75 mol) of phosphorus tribromide was added to 263.1 g (3.6 mol) of N, N-dimethylformamide, and then guanine (manufactured by Sumika Finechem Co., Ltd.) 4
5.3 g (0.3 mol) was added, and the mixture was stirred at 100 ° C. for 8 hours. After cooling, 315.0 g of sodium hydrogen carbonate (3.
(75 mol) was added to 2000 ml of water. The precipitated crystals are collected by filtration, washed with 500 ml of water,
Crystals of 2-dimethylaminomethyleneamino-6-bromopurine were obtained. Its physical properties are as follows.

Elemental analysis Actual value C: 35.71% H: 3.37% N: 31.23% Br: 29.69% Calculated value C: 35.90% H: 3.27% N: 31.40 % Br: 29.45%

The obtained crystals of 2-dimethylaminomethyleneamino-6-bromopurine were treated with 30% hydrobromic acid 64
The mixture was added to 7.3 g (2.40 mol) and stirred at 15 ° C. for 20 hours. The crystals were collected by filtration and washed with 50 ml of methanol.

The obtained crystals were subjected to 25% aqueous ammonia 500
The mixture was heated and dissolved in ml, and treated with 5.0 g of activated carbon. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 2-amino-6.
37.2 g (0.17 mol) of pale yellow crystals of -bromopurine were obtained (58% yield). The result is shown in Example 10.
LC and UV coincided with those synthesized in the above.

Example 12 Crystals of 2-dimethylaminomethyleneamino-6-bromopurine obtained in the same manner as in Example 11 were treated with 78.1 acetic acid.
g (1.3 mol) and stirred at 60 ° C. for 4 hours. A part of the reaction solution was taken, and the physical properties thereof were examined. As a result, it was confirmed that it was 2-formylamino-6-bromopurine. Its physical properties are as follows.

Elemental analysis Actual value C: 31.88% H: 1.78% N: 30.98% Br: 35.35% Calculated value C: 31.82% H: 1.70% N: 31.00 % Br: 35.58%

Next, the reaction solution was cooled to 5 ° C.
Add 566.4 g (2.1 mol) of hydrobromic acid and add 10 ° C
For 12 hours. The crystals were collected by filtration and methanol 50m
l.

The obtained crystals were subjected to 25% aqueous ammonia 500
The mixture was dissolved by heating in 5.0 ml and treated with 5.0 g of activated carbon. The mother liquor was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 2-amino-6.
40.5 g (0.19 mol) of pale yellow crystals of -bromopurine were obtained (63% yield). The result is shown in Example 10.
LC and UV coincided with those synthesized in the above.

Example 13 The procedure of Example 12 was repeated, except that phosphorus tribromide was replaced by phosphorus triiodide, to give 2-amino-6.
-Light yellow crystals of iodopurine were obtained in a yield of 47%.

Obtained value C: 23.00% H: 1.54% N: 26.83% I: 48.62% Calculated value C: 22.85% H: 1.63% N: 26.61% I : 48.88%

Example 14 76.7 g (1.05 mol) of N, N-dimethylformamide and 138.0 g (0.9 mol) of phosphorus oxychloride were added to 500 ml of 1,2-dichloroethane. 56.3 g)
(0.3 mol), and the mixture was stirred at 80 ° C. for 8 hours. After cooling, the reaction solution was poured into 600 ml of water. Then, 21
760 g (1.5 mol) of a 10% aqueous sodium carbonate solution was added, and the pH of the aqueous layer was adjusted to 4. After stirring for 30 minutes, the mixture was allowed to stand, and the aqueous layer was separated. 30% sodium hydroxide aqueous solution 1
00 g (0.75 mol) were added dropwise. The precipitated crystals were collected by filtration, washed with 200 ml of water, and 60.7 g of 2-dimethylaminomethyleneamino-6-chloropurine crystals (0.
27 mol) (yield 90%).

Comparative Example (method disclosed in JP-A-61-227583) 4.5 g of guanine (manufactured by Sumika Finechem Co., Ltd.)
03 mol), tetraethylammonium chloride 7.5
g (0.045 mol), phosphorus oxychloride 27.1 g
(0.177 mol) was added to 60 ml of acetonitrile,
The mixture was stirred for 70 minutes under reflux. After cooling, the crystals were collected by filtration and suspended in 50 ml of water. Further make alkaline with a 30% aqueous sodium hydroxide solution, and then pH with 1N hydrochloric acid.
Was adjusted to 7. The crystals were collected by filtration, and 25% aqueous ammonia 5
The mixture was dissolved by heating in 0 ml, and the insoluble matter was removed by filtration. The mother liquor was concentrated under reduced pressure to obtain 2.0 g (0.012 mol) of precipitated 2-amino-6-chloropurine crystals (yield 39%).

[0070]

The general formula (1) found by the present invention
When the halogenopurine compound represented by the following formula is used as a raw material, the useful 2-amino-6-halogenopurine can be obtained in good yield.
-Formylamino-6-halogenopurine or a salt thereof can be synthesized. In addition, the auxiliary material is inexpensive and economically advantageous.

Claims (1)

[Claims] 1. General formula (1): (Wherein, R ¹ and R ² are each a hydrogen atom, a methyl group, an ethyl group or an aromatic group, R ³ is a single bond or an alkylene group having 1 to 5 carbon atoms, R ⁴ is a hydrogen atom,
5 is an alkyl group or an aromatic group, and X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom).