JP3198276B2 - 2-Formylamino-6-halogenopurine or a salt thereof, a method for producing the same, and a synthetic intermediate thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 2-formylamino-
The present invention relates to 6-halogenopurine or a salt thereof, a production method thereof, and a synthetic intermediate thereof. More specifically, 2-formylamino-6-halogenopurine or a salt thereof useful for producing 2-amino-6-halogenopurine useful as a synthetic intermediate for producing a compound useful as an antiviral agent, and production thereof The present invention relates to a method and a synthetic intermediate thereof.

[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 for forming a 6-chloro form, for example, a method of reacting guanine with phosphorus pentasulfide to introduce a mercapto group at the 6-position of a purine ring, and then blowing chlorine to form a 6-chloro form (British Patent 767, 216) , J. A
m. Chem. Soc. 77, 1676). However, in this method, the decomposition 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. C
hem. Soc. 79, 2185-8, J. Am. Chem. Soc. 82, 2633-4
0) is also known, but since it also uses thioguanine as a raw material, the same dangers as in the above-mentioned method are feared.

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, in these methods, thioguanine, which is a starting material, is produced by reacting guanine with phosphorus pentasulfide in the same manner as described above. Is not satisfactory because the overall yield up to 2-amino-6-halogenopurine is low and the operation is complicated.

An object of the present invention is to provide an intermediate for the synthesis of 2-amino-6-halogenopurine, 2-formylamino-6-.
It is an object of the present invention to provide halogenopurine or a salt thereof, a production method thereof, and a synthetic intermediate thereof.

[0007]

Means for Solving the Problems The present inventors have sought a completely different production method which does not include the above-mentioned problems, and have found a novel synthetic intermediate, and obtained the desired compound from the intermediate in good yield. 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 as follows: [1] General formula (2):

[0009]

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Wherein X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom, and 2-formylamino-6-halogenopurine or a salt thereof, [2] a general formula (1):

[0011]

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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,
Generally, characterized alkyl group or an aromatic group having 1 to 5 carbon atoms, X is a chlorine atom, a bromine atom, hydrolyzing under the conditions of weakly acidic compound represented by showing a iodine atom or a fluorine atom) Equation (2):

[0013]

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(Wherein X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom), a method for producing 2-formylamino-6-halogenopurine or a salt thereof,
And [3] general formula (1):

[0015]

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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,
An alkyl group or an aromatic group having 1 to 5 carbon atoms, and 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 compound represented by the general formula (1) and (2) a compound represented by the general formula (1) 2 represented by the general formula (2) obtained in the process of synthesizing 2-amino-6-halogenopurine using a compound
-Formylamino-6-halogenopurine or a salt thereof.

First, a compound represented by the general formula (1), which is a novel synthetic intermediate, and a method for producing the compound,
This will be described below.

In the compound represented by the general formula (1),
The groups represented by R ¹ and R ² are a hydrogen atom, a methyl group,
It is 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 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; ³ is a single bond and R ⁴ is a hydrogen atom compound.

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

The 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.
By reacting with a compound represented by the formula:

In the present invention, guanine is usually used as a raw material, but may be a salt or a 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 herein include known chlorinating agents such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene and diphosgene; phosphorus oxybromide, thionyl bromide, and the like. 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 compound represented by the general formula (1). One. As the compound represented by the general formula (3), specifically, for example, N, N-dimethylformamide, N, N-diethylformamide, N-methylformanilide, N, N-dimethylacetamide, N −
Formylpyrrolidine, N-formylpiperidine, N-formylpiperazine, N-formylmorpholine, N-formylthiomorpholine, and the like are preferable.
-Dimethylformamide, N-methylformanilide.

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 compound represented by the general formula (1), the halogenating agent is usually used in an amount of 2 to 10 moles, preferably 2 to 10 moles, per mole of guanine, a salt thereof or a hydrate thereof. 5 mol, more preferably 2.5 to 3.5 mol is used. When a solvent is used, the amount of the compound represented by the general formula (3) is usually 1 to 20 mol, preferably 3 to 10 mol, per 1 mol of guanine, a salt thereof or a hydrate thereof. And more preferably 4 to 6 mol. When no solvent is used, it is usually 5 to 30 mol, preferably 10 to 20 mol, more preferably 10 to 15 mol, per 1 mol of guanine, a salt thereof or a hydrate thereof. 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 to be used, and preferably does not exceed 120 ° C. from the viewpoint of the thermal stability of the compound represented by the general formula (1). For example, as a compound represented by the general formula (3), N, N-dimethylformamide or N-methylformanilide is used,
When 1,2-dichloroethane is used as the solvent, the temperature is usually preferably in the range of 70 to 85C. The reaction time is usually 1 to 15 hours, preferably 3 to 10 hours, and more preferably 4 to 8 hours.

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

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 to hydrolyze the compound represented by the general formula (1). 2-amino-6 which is a compound
A 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 the compound represented by the general formula (1) is separated and purified, the reaction mixture is cooled and treated with an aqueous solution of sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like. It is obtained by doing. The 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. However, if there is concern about the presence of some by-products, , For example, by appropriately using means such as filtration and recrystallization.

Next, using the thus obtained compound of the general formula (1), the desired compound 2-amino-
A method for producing 6-halogenopurine will be described below. That is, the following two methods are used as a method of producing the target compound, 2-amino-6-halogenopurine, by hydrolyzing the compound of the general formula (1).

(1) Method a: A method of immediately hydrolyzing a compound represented by the general formula (1) which has been separated or purified.

(2) Method b: General formula (1) separated and purified
Is hydrolyzed in advance under mildly acidic conditions to give 2-formylamino-6-halogenopurine (compound of general formula (2), a novel synthetic intermediate of the present invention) or an acetate thereof, and further hydrolyzes how to.

In the method a, when the reaction is carried out at an extremely 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 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. For example, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, sodium hydroxide, potassium hydroxide and the like can be mentioned. When a reaction mixture containing the 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 unnecessary as described above.

In the method (b), 2-formylamino-6-halogenopurine represented by the general formula (2) or a salt thereof is obtained by first hydrolyzing under slightly acidic conditions. 2-Formylamino-6-halogenopurine or a salt thereof is a novel compound discovered for the first time in the present invention. The reaction is usually completed at a temperature of 20 to 100 ° C for 1 to 10 hours, preferably at a temperature of 50 to 70 ° C for 3 to 5 hours. To adjust to weakly acidic conditions here,
Although not particularly limited, the reaction is performed by adding an acidic substance such as acetic acid, propionic acid, or hydrochloric acid.

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.

[0040]

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As described above, 2-amino-6-halogenopurine which can be produced by using the compound represented by the general formula (1), as described above, is described in, for example, JP-B-56-3.
3396, JP-A-60-58982, JP-A-60-589
208954, JP-A-2-59583, JP-A-4-
As described in each of JP-A-108788, it can be used as a synthetic intermediate of a guanine nucleoside analog useful as an antiviral agent.

[0042]

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 subjected to 25% ammonia water 300
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.
-30.5 g (0.18 mol) of white crystals of chloropurine
Was obtained (60% yield).

Example 3 Crystals of 2-dimethylaminomethyleneamino-6-chloropurine obtained in the same manner as in Example 2 were 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 solution 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 were subjected to 25% aqueous ammonia 300
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.
33.0 g (0.195 mol) of white crystals of -chloropurine were obtained (65% yield).

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 Found: C: 54.54% H: 3.90% N: 29.31% Cl: 12.25% Calculated 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 A reaction was carried out in the same manner as in Example 1 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 reacting 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).

Measured 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 KK) 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 The 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 Obtained 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, and then guanine hydrochloride (suminum) was added. 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%).

[0074]

The general formula (1) found by the present invention
When the synthetic intermediate represented by is used as a raw material, 2-formylamino-6-halogenopurine or a salt thereof useful for the intended 2-amino-6-halogenopurine can be synthesized in high yield. In addition, the auxiliary material is inexpensive and economically advantageous.

────────────────────────────────────────────────── (5) References European Patent Application Publication 433845 (EP, A1) European Patent Application Publication 433846 (EP, A1) Org. Chem. Vol. 56, No. 4 (February 15, 1991) p. 1553-1564 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 473/40 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (2): (In the formula, X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom).
Halogenopurine or a salt thereof. 2. 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 alkyl group or an aromatic group, X is a chlorine atom, a bromine atom, formula, which comprises hydrolyzing under the conditions of a compound weak acidic represented by showing a iodine atom or a fluorine atom) (2) : (In the formula, X represents a chlorine atom, a bromine atom, an iodine atom or a fluorine atom).
A method for producing halogenopurine or a salt thereof. 3. A compound of the general formula (3): wherein guanine, a salt thereof or a hydrate thereof is prepared in the presence of a halogenating agent. (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,
The compound represented by formula (1) is produced by reacting a compound represented by formula (1):