JPH0578358A - New method for preparing and purififying compound - Google Patents

Abstract

PURPOSE:To obtain 6-chloropurine in high yield and in high purity. CONSTITUTION:Hypoxanthine of formula I is subjected to a chlorinating agent such as phosphorus oxychloride in an organic solvent such as acetonitrile in the presence of a phase-transfer catalyst such as tetraethylammonium chloride to obtain the objective 6-chloropurine of formula II. The crude 6-chloropurine thus obtained is dissolved in an alkaline solution such as of sodium hydroxide, and insolubles are removed by active carbon treatmenr and filtration, and the filtrate is neutralized with an acid. Taking advantage of the salting-out effect with the neutral salt thus formed, the other objective high-purity 6-chloropurine can be obtained.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing and purifying a compound used as a useful intermediate in producing a drug and its raw material.

[0002]

PRIOR ART AND PROBLEM TO BE SOLVED BY THE INVENTION Formula [I] 6-chloropurine, which is a compound represented by, is a useful intermediate for the production of purine nucleoside analogues, as described in, for example, JP-A No. 2-308797.

Formula [II] There are several known methods for directly chlorinating the 6-position of purine represented by. (Aaron Bendich et al. J. Org. Chem., 19
6073 (1954), and R. Marumoto et al. Chem. Pharm. Bul.
l., 24 2624 (1976))

However, all of the previous methods have problems in the reaction itself and in the purification process after the reaction, so that the yield is low.

For example, according to the method of Bendich et al., A compound represented by the formula [II] is added to DMF in chloroform.
Although (dimethylformamide) -SOCl ₂ (thionyl chloride) is reacted as a chlorinating agent, unreacted thionyl chloride and dimethylformamide must be distilled off under reduced pressure after the reaction is completed. For this reason,
A powerful heating and depressurizing device is required, and the experimental operation is complicated. Further, the compound of the formula [I] (ie 6-
Chloropurine) tends to cause a side reaction such as decomposition, resulting in a decrease in yield.

In the method of Marumoto et al., Phosphorus oxychloride is used as the chlorinating agent.
In this method as well, N, N-dimethylaniline used as a solvent had to be distilled off under reduced pressure, which was a cause of complexity and a decrease in yield.

As a conventional example of a reaction using a phase transfer catalyst such as tetra-substituted ammonium chloride, 6-chloroguanine is synthesized from guanine as a raw material, MLHer
There is a report from nden et al. (JP-A-61-227583). However, their purpose was to synthesize 6-chloroguanine, which is disclosed by the present invention.
It is not a synthetic method of chloropurine. Further, 6-chloropurine of the present invention and 6-chloroguanine of Hernden et al. Mean that the generation state of reaction by-products or the compound itself (that is, 6-chloropurine or 6-chloroguanine) is Solubility in various organic solvents is remarkably different. Therefore, from the report of Hernden et al., The novel method for synthesizing 6-chloropurine disclosed in the present invention cannot be easily inferred. In fact, even if the method of Hernden et al. Is directly applied to 6-chloropurine, the desired product cannot be obtained easily.

[0008]

Means and Actions for Solving the Problems We have found a simple method with a high yield of the compound of the formula [I], in a single step, and without the need to distill off excess chlorinating agent under reduced pressure. It has become possible to avoid complicated distillation operations such as reaction solvents.

That is, according to the present invention, the above-mentioned formula [II]
By reacting the compound of formula (I) with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ion, there is provided a method for easily producing the compound of formula (I) in high yield.

The reaction is preferably a polar inert organic solvent,
For example, in acetonitrile, tetrahydrofuran, dioxane, nitromethane, diglyme, or dimethoxyethane. Of these, acetonitrile is particularly preferable.

Suitable phase transfer catalysts include tetra-substituted ammonium chloride. Examples of ammonium substituents are C _2-12
It contains alkyl, usually C _2-4 alkyl, or an aromatic functional group such as phenyl or benzyl. Alternatively, a phase transfer catalyst such as tetra-substituted phosphonium chloride can also be used. Most suitable is the method using tetraethylammonium chloride as the phase transfer catalyst. The phase transfer catalyst is preferably present in an amount of 1 to 6 molar equivalents relative to the compound of formula [I], particularly preferably 1
~ 1.5 equivalents.

The preferred chlorinating agent is an oxychlorinating agent. The preferred amount of the chlorinating agent is 2 to 10 molar equivalents of the compound represented by the formula [II], and preferably 3 to 6 molar equivalents is present.

The reaction can be carried out in the presence of a weakly basic organic compound. As the weakly basic organic compound, tertiary amino and the like are preferable, and for example, the reaction can be carried out in the presence of N, N-dimethylaniline. The base is usually present in an amount of 1 to 6 molar equivalents relative to the compound of formula [II], and most preferably 1.0 to 1.2 equivalents.

However, when acetonitrile is used as the reaction solvent, the addition of the weakly basic organic compound may sometimes be effective in shortening the reaction time, but it is not always necessary.

The reaction can be catalyzed by adding a small amount of water.

The reaction temperature is preferably in the range of 30 to 120 ° C. More preferably,
It is recommended to be done at 60-100 ° C. As the most suitable condition, the reaction can be carried out under mild reflux conditions. Furthermore, if ultrasonic treatment is performed in the temperature range of 60 to 70 ° C,
The reaction proceeds well.

The reaction time is preferably 0.5 to 30 hours. Particularly preferably, it is 1.0 to 6.0 hours,
When a base such as dimethylaniline is added to the reaction system, the reaction may be completed within 0.5 hours.

The reaction described above is particularly advantageous because it is suitable for the large scale production of compounds of formula [I].

[0019]

The following examples serve to illustrate the invention in more detail, without restricting it.

Example 1 Synthesis Method of 6-Chloropurine (Method A) Hypoxanthine 204 g (1.5 mol) and tetraethylammonium chloride 373 g (2.25 mol) were placed in a 5 L three-necked flask equipped with a reflux device (Dimroth, etc.). , Add 3.0 L of acetonitrile and stir. While stirring slowly, 875 ml of phosphorus oxychloride was carefully added thereto. The internal temperature is raised to reflux and the reaction is allowed to stir for 2 hours. After 2 hours, after returning to room temperature, the solid content (cake) is collected by suction filtration. The solid content thus obtained is added to and dissolved in an aqueous sodium hydroxide (300 g) solution (2 L). 100 ml of activated charcoal is added to this, and the mixture is treated, filtered, and the filtrate is directly neutralized with concentrated hydrochloric acid. When the pH of the reaction solution was around 8, 6-chloropurine dissolved in the reaction solution was precipitated.

The solid content was collected by filtration, washed with cold water, and the cake obtained was dried by blast (60 ° C., 1 day).
To do. Yield 213.2g (1.38mol) 92%

The 6-chloropurine thus obtained has a color (pure white) and a high purity that cannot be obtained by the conventional method. (99% or more, HPLC)

(Example 2) Method for synthesizing 6-chloropurine (method B) In Example 1, the reaction was carried out under reflux for 2 hours.
Instead, ultrasonic treatment was performed at 60 ° C. for 4 hours. Other than that, the same method as shown in the example was carried out. Yield 150.6g (0.974mol) 65%

(Example 3) Method for synthesizing 6-chloropurine (Method C) In the method shown in Example 1, the reaction was carried out under reflux for 2 hours. Instead, N, N
-1.5 mol of dimethylaniline was added, and the mixture was reacted under reflux for 30 minutes. Other than that, the same method as shown in the example was carried out. Yield 139.0g (0.899mol) 60%

Example 4 Synthesis of Antiviral Agent Using 6-Chloropurine Synthesized by the method shown in Example 1 and having high purity
Using 6-chloropurine (7.0 mmol) and 2 ', 3'-dideoxyuridine (7.0 mmol) as raw materials, E. coli (Eecherichi
6-chloropurine-9-BD-2 ', 3'-dideoxyribofuranoside, which is an antiretroviral agent, was synthesized by a base exchange reaction using a. Yield 56% For details, follow the method disclosed in JP-A-2-308797.

[0026]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, it becomes a useful intermediate for drug synthesis such as antiviral agents, anticancer agents, antibiotics, and immunosuppressants.
Chloropurine can be obtained in a single step with high purity and high yield, which is extremely useful.

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[Procedure amendment]

[Submission date] November 19, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0013

[Correction method] Change

[Correction content]

The reaction can be carried out in the presence of a weakly basic organic compound. The weakly basic organic compound is preferably a tertiary amine, and the reaction can be carried out in the presence of N, N-dimethylaniline, for example. The base is usually present in an amount of 1 to 6 molar equivalents relative to the compound of formula [11], and most preferably 1.0 to 1.2 equivalents.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0025

[Correction method] Change

[Correction content]

(Example 4) Synthesis of antiviral agent using 6-chloropurine High-purity 6-chloropurine (7.0 mmol) synthesized by the method shown in Example 1 and 2 ', 3' −
Using dideoxyuridine (7.0 mmol) as a starting material and using Escherichia coli, a base exchange reaction was performed to induce 6-chloropurine-9-β-D-2 ', 3'-di- Deoxyribofuranoside was synthesized. Yield 56% For details, follow the method disclosed in JP-A-2-308797.

Claims (17)

[Claims] 1. The formula [II] A method for producing a compound represented by the formula [I] by reacting a compound represented by the formula (1) with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions. 2. The method of claim 1, wherein the chlorinating agent is phosphorus oxychloride. 3. The chlorinating agent is 1-10 of the compound of formula [II].
3. A method according to claim 1 or 2 which is present in a molar equivalent amount. 4. The method according to claim 1, wherein the phase transfer catalyst is tetra-substituted ammonium. 5. The tetra-substituted ammonium is tetra-C
The method according to claim 4, which is _2-4 alkyl ammonium chloride. 6. The method according to claim 5, wherein the tetra C _2-4 alkylammonium chloride is tetraethylammonium chloride. 7. The method according to claim 1, wherein the phase transfer catalyst is present in an amount of 1 to 6 equivalents. 8. The method according to claim 1, wherein the reaction of the compound of formula [II] is carried out in an acetonitrile solvent. 9. Mainly described with reference to the embodiments,
A method for producing the compound of formula [I] according to claim 1. 10. A compound represented by the formula [I] containing impurities is dissolved in an alkali, insoluble matter is removed by a filtration operation, and then neutralized with an acid to precipitate a compound represented by the formula [I]. A process for producing compound [I], which comprises: 11. The method according to claim 10, characterized in that activated carbon treatment is carried out before the filtration operation. 12. The method according to claim 10, wherein the alkali is an aqueous sodium hydroxide solution. 13. The method according to claim 10, wherein the acid is concentrated hydrochloric acid or an aqueous hydrochloric acid solution. 14. A compound represented by the formula [I] is obtained by a salting-out effect of concentrated sodium chloride produced by dissolving a compound of the formula [I] containing impurities in a concentrated aqueous sodium hydroxide solution and neutralizing the solution with concentrated hydrochloric acid. 11. The method according to claim 10, characterized in that the compound obtained is precipitated and purified. 15. The method of claim 10 described with respect to an embodiment.
The method described. 16. A method for producing or purifying a compound represented by the formula [I] according to claim 1, which is produced by the method according to any one of claims 1 to 15. 17. A purine nucleoside analog antiviral agent produced from the compound of formula [I] according to claim 1, which is produced or purified by the method according to any one of claims 1 to 15.