JP2003113181A - Method for producing 6-halopurine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing a 6-halopurine useful for an intermediate in producing a medicinal compound. SOLUTION: This method for producing the 6-halopurine is characterized by comprizing a process of reacting a 2-amino-6-halopurine derivative expressed by the following formula (wherein, R is H, a 1-8C acyl, carbamoyl or an aralkyl which may have a substituent; and X is a halogen atom) with a diazotizing agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 6-halopurine. More specifically, it relates to a method for producing 6-halopurine represented by 6-chloropurine which is useful as a raw material for nucleoside compounds useful as pharmaceuticals.

[0002]

2. Description of the Related Art 6-Halopurine is a nucleoside drug such as CTV-510, or Leteprinim p.
It is an important intermediate in the production of nucleobase pharmaceuticals such as Otassium.

6-Halopurine is obtained, for example, by reacting an alkali metal of 6-hydroxypurine with phosgene in an inert medium (Japanese Patent Laid-Open No. 58-35188), a tertiary amine (for example, dimethyl- or diethyl). Aniline) in the presence of purin-6-ol and phosphorus oxychloride (JACS, 1954, 607)
3-6077), hypoxanthine (Hypoxanth
ine) with phosphorus oxychloride
8-41880), a method of reacting hypoxanthine with a liquid chlorinating agent in a solvent-free system in the presence of a phase transfer catalyst (JP-A-5-170766), the following formula

[0004]

[Chemical 2]

(In the formula, R ¹ represents a halogen atom or the like,
R ² represents a hydrogen atom or the like, and R ³ represents a hydrogen atom or the like. It is known that it can be produced by a method of iodizing the aminopurine derivative of 1) in the presence of cesium iodide (JP-A-2001-72680).

[0006]

The object of the present invention is to provide 6-
It is intended to provide a novel method for producing halopurine.

[0007]

As a result of studying the production of 6-halopurine by a method different from the conventional method, the present inventors have found that the following formula, which has not been used as a raw material for producing 6-halopurine so far, The present invention has been completed by discovering a novel method for producing 6-halopurine using a 2-amino-6-halopurine derivative as a raw material.

That is, the present invention is as follows. 1. formula

[0009]

[Chemical 3]

(In the formula, R represents a hydrogen atom, an acyl group having 1 to 8 carbon atoms, a carbamoyl group or an aralkyl group which may have a substituent, and X represents a halogen atom).
The method for producing 6-halopurine, comprising the step of reacting the 2-amino-6-halopurine derivative represented by and a diazotizing agent. 2. 1. The diazotizing agent is a nitrite. Manufacturing method. 3. The 2-amino-6-halopurine derivative is 7-acetyl-2-amino-6-chloropurine or 9-acetyl-2-amino-6-chloropurine, and the 6-halopurine is 6-chloropurine. ． Or 2. Manufacturing method. 4. 2-Amino-6-halopurine produced by acylating the nitrogen atom at the 7-position or 9-position and then produced 2-amino-6-
The halopurine derivative (wherein R is an acyl group having 1 to 8 carbon atoms) is reacted with a diazotizing agent without isolation, and the above 1. Manufacturing method. 5. 3. The nitrogen atom at the 7-position or 9-position of 2-amino-6-halopurine is acetylated. Manufacturing method.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The “acyl group having 1 to 8 carbon atoms” in R is
An acyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms,
Examples thereof include an alkylcarbonyl group such as a formyl group, an acetyl group, a propanoyl group and a butanoyl group, and an arylcarbonyl group such as a benzoyl group, and the acetyl group is preferable in terms of reactivity and yield.

The "aralkyl group" for R includes an aralkyl group having a preferred carbon number of 4 to 15, more preferably 5 to 10, and the aralkyl group may have a substituent. Examples of the substituent here include a halogen atom (which has the same meaning as the “halogen atom” in X), a nitro group, an alkoxy group (which may be linear or branched, and is preferably a methoxy group). . Examples of the "aralkyl group which may have a substituent (s)" include, for example, benzyl group, 4-halobenzyl group (4-chlorobenzyl group, 4-bromobenzyl group, 4-fluorobenzyl group, 4-iodobenzyl group). , 4-nitrobenzyl group, 4-methoxybenzyl group, 9-anthrylmethyl group, 2,4-dichlorobenzyl group and the like, and preferably benzyl group, 4-halobenzyl group and 4-methoxybenzyl group.

The "halogen atom" in X is a chlorine atom, a fluorine atom, a bromine atom or an iodine atom, preferably a chlorine atom, a fluorine atom or a bromine atom, and particularly preferably a chlorine atom.

The 2-amino-6-halopurine derivative in the present invention is preferably one in which R is an acyl group having 1 to 8 carbon atoms, and among them, 7-acetyl-2-amino-6.
-Chloropurine and 9-acetyl-2-amino-6-chloropurine are particularly preferred.

6-Halopurine can be produced by a method including a step of reacting a 2-amino-6-halopurine derivative with a diazotizing agent. Specifically, the reaction between the 2-amino-6-halopurine derivative and the diazotizing agent is carried out, for example, by adding the 2-amino-6-halopurine derivative in the reaction solvent and then adding the diazotizing agent thereto. It can be performed by stirring.

Examples of the diazotizing agent in the present invention include nitrite, nitric oxide, nitrogen dioxide, sodium nitrite, nitrosylsulfuric acid, etc. Among them, nitrite is easily dissolved in the solvent used in the present invention. Moreover, it is preferable because it is easy to operate.

As the nitrite ester in the present invention,
Examples thereof include nitrites having 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, and specifically, propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite, sec nitrite. -Butyl, nitrite tert
-Butyl, pentyl nitrite, isoamyl nitrite, 1-methylbutyl nitrite, 2-methylbutyl nitrite, t nitrite
Examples thereof include ert-pentyl and the like, and isoamyl nitrite is particularly preferable.

The amount of the diazotizing agent used is 2-amino-6-
The amount is usually 1 to 8 times, and preferably 4 to 6 times the molar amount of the halopurine derivative.

The reaction solvent of the present invention is not particularly limited as long as it is an organic solvent that can serve as a hydrogen source, and examples thereof include aprotic polar solvents (eg, N, N-dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide). (DMSO) etc., ethers (eg tetrahydrofuran (THF) etc.), fatty acids (eg
Acetic acid, etc.), lower alcohols having 1 to 4 carbon atoms (eg, methanol, ethanol, propanol, butanol, etc.), fatty acid esters having 2 to 6 carbon atoms (eg,
Ethyl acetate, etc.) and mixed solvents thereof. A mixed solvent of THF and DMF is preferable,
The case where the mixing ratio (THF: DMF (volume)) is 5: 1 to 5: 2 is more preferable. If the amount of THF is too much over this range, the reaction will be slow, and conversely, if the amount of DMF is too much, impurities will be easily produced.

The reaction solvent is usually 5 to 50 ml, preferably 15 to 30 ml per 1 g of the 2-amino-6-halopurine derivative. THF and D as reaction solvents
When a mixed solvent with MF is used, 2-amino-6-
1-10 ml of DMF for 1 g of halopurine derivative
(More preferably 5 ml or less) and THF is 1
A mixed solvent of 2.5 to 25 ml is preferable.

The reaction between the 2-amino-6-halopurine derivative and the diazotizing agent is usually carried out at room temperature to about 80 ° C., preferably 40 to 70 ° C., usually 10 depending on the charged amount.
It is completed in minutes to 6 hours, preferably 1 hour to 3 hours.

For example, when R is a hydrogen atom, 6-halopurine is obtained by the above reaction, but when R is other than a hydrogen atom, the substituent R at the 7-position or 9-position is eliminated by a conventional method. As a result, 6-halopurine can be obtained. The elimination of the substituent R will be described below by taking the case where R is an acyl group having 1 to 8 carbon atoms as an example.

The reaction of a 2-amino-6-halopurine derivative with a diazotizing agent gives a compound of the formula

[0024]

[Chemical 4]

It is considered that 7- or 9-acyl-6-halopurine (wherein R is an acyl group having 1 to 8 carbon atoms) can be obtained, and this is subjected to elimination reaction of the acyl group (for example, acid or A 6-halopurine derivative can be obtained by subjecting to an alkali treatment or reduction reaction. 7- or 9-
It is preferable that the acyl-6-halopurine is directly subjected to the acyl group elimination reaction (for example, acid or alkali treatment or reduction reaction) without isolation. The elimination of the acyl group here can be carried out in the same manner as the deprotection of the amino group protected by the acyl group, and the elimination method is appropriately selected depending on the kind of the acyl group.

For example, when R is an acetyl group,
For example, the acetyl group can be eliminated by reaction with an aqueous alkali solution (preferably an aqueous sodium hydroxide solution). Preferably, for example, 6-halopurine is obtained by reacting the 2-amino-6-halopurine derivative with the diazotizing agent, and then adding an alkaline aqueous solution (preferably sodium hydroxide aqueous solution) to the residue and stirring.

Isolation and purification of the obtained 6-halopurine can be carried out by a conventional method. For example, a reaction solution (when R is a hydrogen atom, a 2-amino-6-halopurine derivative and a diazotizing agent are used). The reaction solution after the reaction with, or the reaction solution after the elimination reaction of R when R is other than a hydrogen atom) is filtered, and the filtrate is concentrated and subjected to crystallization to isolate the isolated product. It can be purified by subjecting it to recrystallization.

As the starting material, a 2-amino-6-halopurine derivative may be a commercially available product.

As the 2-amino-6-halopurine derivative in which R is an acyl group having 1 to 8 carbon atoms, for example, commercially available 2-amino-6-halopurine is obtained, and the nitrogen at the 7-position or 9-position thereof is obtained. Atoms can be acylated (preferably acetylated) and used as a starting material. In this case, after the acylation, the generated 2-amino-6-halopurine derivative (wherein R is an acyl group having 1 to 8 carbon atoms) is reacted with a diazotizing agent without isolation, which is a simple operation. It is preferable from the viewpoints of properties and yield of the final product.

The acylation can be carried out by a conventional method,
For example, in a reaction solvent, 2-amino-6-halopurine and a carboxylic acid compound (R'-OH (in the formula, R'is one to 1 carbon atoms.
It is an acyl group having 8 carbon atoms, which has 1 to 8 carbon atoms in R.
Synonymous with “acyl group”)) or a reactive derivative thereof (eg, ester, acid halide, acid anhydride, etc.). Specifically, for example, a carboxylic acid compound or its reactive derivative is added to a mixture of 2-amino-6-halopurine and a reaction solvent, and the mixture is stirred (heating). If necessary, a reagent such as a base and a catalyst for promoting the reaction can be further added.

The reaction solvent used for acylation includes, for example, DMF, DMSO, N, N-dimethylacetamide, THF, acetic acid ester, etc., preferably DMF, DMSO, N, N-dimethylacetamide. The amount of the solvent used is usually 2 ml to 20 ml, preferably 2 m with respect to 1 g of 2-amino-6-halopurine.
1 to 5 ml.

The amount of the carboxylic acid compound or its reactive derivative used is preferably 1 mol to 2 mol, more preferably 1.1 mol, relative to 1 mol of 2-amino-6-halopurine.
It is from mol to 1.3 mol.

The acylation varies depending on the reagents used and the like, but is usually 10 ° C to 80 ° C, preferably 50 ° C to 6 ° C.
At 0 ° C., usually 2 hours to 10 hours, preferably 2 hours to 5
Finish in time. Acylation can be confirmed by, for example, liquid chromatography.

The 2-amino-6 produced after the above acylation
When a halopurine derivative (wherein R is an acyl group having 1 to 8 carbon atoms) is reacted with a diazotizing agent without isolation, a reagent defined based on the 2-amino-6-halopurine derivative is used. The amount is calculated on the assumption that the 2-amino-6-halopurine derivative was quantitatively obtained from 2-amino-6-halopurine.

The 6-halopurine obtained by the method of the present invention can be obtained, for example, from Tetrahedron, 53, 1997, 2291-2302, J.
It can be converted into a pharmaceutical compound according to the method described in Med. Chem., 2000, 43, 1817-1825 and the like.

[0036]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited thereto. Example 1 9-acetyl-2-amino-6-chloropurine (1.0
0 g, 4.7 mmol) was added to a THF-DMF mixed solution (volume ratio 5: 1, 25 ml), and isoamyl nitrite (3.00 g, 2.56 mol) was added thereto. The resulting mixture was stirred at 50-55 ° C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, 1% NaOH aqueous solution (25 g) was added at room temperature, and the mixture was stirred. It was extracted with acetonitrile (7 × 50 ml) and the extracts were combined.

The extract was dried over anhydrous sodium sulfate and then filtered, and the obtained filtrate was concentrated under reduced pressure. Toluene (100
(ml) with the concentrated residue flowing in and the solid obtained was filtered off. The solid collected by filtration was recrystallized from ethanol to give 6-chloropurine pale yellow crystals (0.30 g, 1.
9 mmol, yield 41%) was obtained.

Physical properties: melting point 164-165 ° C. (reference value 1
64-165 ° C.) ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (p
pm) = 8.71 (s, 1H), 8.76 (s, 1H)

Example 2 2-Amino-6-chloropurine (3.00 g, 17.7)
Mmol) was added to DMF (7 ml), and acetic anhydride (2.16 g, 21.2 mmol) was added thereto. The resulting mixture was stirred at 50-55 ° C for 4 hours. After confirming acetylation by liquid chromatography, DMF (8 ml) and T
HF (75 ml) was added. Isoamyl nitrite (10.00 g, 85.3 mmol) was added to the resulting mixture,
The mixture was stirred at 50 to 55 ° C for 2 hours. The obtained mixture was concentrated under reduced pressure, 1% NaOH aqueous solution (25 g) was added at room temperature,
It was stirred. Extract with acetonitrile (7 x 50 ml),
The extracts were combined. The extract was dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure. The concentrated residue was poured into toluene (100 ml), and the obtained solid was collected by filtration. The solid collected by filtration was recrystallized from water to give 6-chloropurine pale yellow crystals (1.04 g, 6.
73 mmol, yield 38%) was obtained.

[0040]

INDUSTRIAL APPLICABILITY According to the present invention, 6-halopurine, which is a compound useful as an intermediate in the production of pharmaceutical compounds,
It can be produced from a 2-amino-6-halopurine derivative which has not been used as a raw material for producing 6-halopurine until now, and this will expand the choice of 6-halopurine manufacturers.

Claims (5)

[Claims] 1. The formula: (In the formula, R represents a hydrogen atom, an acyl group having 1 to 8 carbon atoms, a carbamoyl group or an aralkyl group which may have a substituent, and X represents a halogen atom).
A method for producing 6-halopurine, comprising the step of reacting an -amino-6-halopurine derivative with a diazotizing agent. 2. The method according to claim 1, wherein the diazotizing agent is a nitrite. 3. A 2-amino-6-halopurine derivative is 7
-Acetyl-2-amino-6-chloropurine or 9-
The production method according to claim 1, which is acetyl-2-amino-6-chloropurine, and 6-halopurine is 6-chloropurine. 4. A 2-amino-6-halopurine derivative produced by acylating the 7- or 9-position nitrogen atom of 2-amino-6-halopurine (wherein R is an acyl group having 1 to 8 carbon atoms). Is reacted with the diazotizing agent without isolation. 5. The production method according to claim 4, wherein the nitrogen atom at the 7-position or 9-position of 2-amino-6-halopurine is acetylated.