JP2008266202A - Method for producing aminoimidazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an aminoimidazole derivative, by which the aminoimidazole derivative can be obtained from a diaminomaleonitrile as a starting substance. <P>SOLUTION: This method for producing the aminoimidazole derivative represented by the formula (wherein, R<SP>1</SP>and R<SP>3</SP>are each independently H, an alkyl group which may have one or more substituents, or an aryl group which may have one or more substituents; R<SP>4</SP>is -CN or -CONH<SB>2</SB>) comprises a process for reacting a diaminomaleonitrile with an ortho carboxylic acid triester in the presence of a strong acid to obtain an alkyl N-(2-amino-1,2-dicyanovinyl)formimidate derivative, a process for reacting the formimidate derivative with ammonia water, an aqueous amine solution or the like to obtain an N-(2-amino-1,2-dicyanovinyl)formamidine derivative, and a process for cyclizing the formamidine derivative in the presence of a basic aqueous solution, each in the presence of an aprotonic organic solvent. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing an aminoimidazole derivative. More specifically, the present invention relates to a production method capable of obtaining an aminoimidazole derivative represented by the formula (V) in a high yield using diaminomaleonitrile as a starting material.

（式（Ｖ）中、Ｒ¹、およびＲ³は、それぞれ独立に、水素原子、置換基を有してもよいアルキル基、または置換基を有してもよいアリール基である。Ｒ⁴は、−ＣＮ、または−ＣＯＮＨ₂である。）

(In Formula (V), R ¹ and R ³ are each independently a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent. R ⁴ is , -CN, or -CONH _2.)

  1H-4 (5) -aminoimidazole-5 (4) -carboxamides (hereinafter sometimes abbreviated as AICA), which is a kind of aminoimidazole derivatives represented by the formula (V), and 4 (5). -Amino-1H-imidazole-5 (4) -carbonitriles (hereinafter sometimes abbreviated as AICN) include anticancer drugs dacarbazine and temozoromide, and hepatoprotective drug urazamide. It is a useful intermediate material for manufacturing.

  Examples of the method for synthesizing the aminoimidazole derivative represented by the formula (V) include a method in which 4-nitroimidazole-5-carboxamide is catalytically reduced, a method in which phenylazomalonamidine is reductively closed in formic acid, α-amino-α -A method using cyanoacetamide as a raw material, a method for decomposing a compound having a purine nucleus, and the like are known. However, these have difficulty in industrial use in terms of the availability of raw materials and the ease of operation.

  4,5-Dicyanoimidazole was synthesized from diaminomaleonitrile (hereinafter sometimes abbreviated as DAMN) which is easily available as an industrial raw material (Japanese Examined Patent Publication No. Sho 46-4373) and hydrolyzed (Japanese Examined Patent Publication No. Sho 41-21026). 1H-4 (5) -Cyanoimidazole-5 (4) -carboxamide, which is further subjected to Hofmann rearrangement reaction to give 1H-4 (5) -aminoimidazole-5 (4) -carboxamide. A method is known in which 1H-4 (5) -aminoimidazole-5 (4) -carboxamide is synthesized by converting it into a nitrile (Japanese Patent Publication No. 46-10889) and then hydrolyzing it. However, this synthesis method has a low yield.

Non-Patent Document 1 reports that AICN can be synthesized by ring-closing N- (2-amino-1,2-dicyanovinyl) formamidine. In Non-Patent Document 2 and Non-Patent Document 3, N- (2-amino-1,2-dicyanovinyl) -N′-substituted-formamidine is closed to give 1-substituted-5-aminoimidazole-4- It has been reported that carbonitrile can be synthesized.
BLBooth et al. (J. Chem. Soc. Perkin Trans. I, 1990, 1705) BLBooth et al. (J. Chem. Soc. Perkin Trans. I, 1992, 2120) BLBooth et al. (J. Chem. Soc. Perkin Trans. I, 1995, 669)

  In Patent Document 1 and Patent Document 2, N- (2-amino-1,2-dicyanovinyl) form is prepared by reacting diaminomaleonitrile, hydrogen chloride, isobutyronitrile and hydrogen cyanide in an organic solvent. A method is disclosed in which an amidine derivative (hereinafter sometimes abbreviated as AMD) is obtained, and AMD is cyclized with an aqueous sodium hydroxide solution to synthesize AICN or AICA. In Patent Document 3, diaminomaleonitrile, formamide, and phosphorus oxychloride are reacted in a solvent such as tetrahydrofuran to obtain AMD, and a basic compound is added to an aqueous solution or suspension of AMD. A method of synthesizing AICN by acting is disclosed. Further, Patent Document 4 discloses a method of synthesizing AICA by cyclizing and hydrolyzing AMD in a basic aqueous solution.

JP 2001-158776 A WO04 / 035529 JP 2002-155059 A JP 2001-151760 A

An object of the present invention is to provide a production method capable of obtaining an aminoimidazole derivative represented by the formula (V) in a high yield by cyclizing the compound represented by the formula (IV) and / or a salt thereof. There is to do.
Another object of the present invention is to provide a production method capable of obtaining an aminoimidazole derivative represented by the formula (V) in a high yield using diaminomaleonitrile as a starting material.

As a result of intensive studies to achieve the above object, the present inventor, in the step (C) of cyclizing the compound represented by the formula (IV) and / or a salt thereof in the presence of a basic aqueous solution, alcohol and the like When a large amount of the protic organic solvent is used, a by-product is easily generated, and it has been found that there is a limit to increasing the yield. Accordingly, the present inventor used an aprotic organic solvent in the step (C) of cyclizing the compound represented by the formula (IV) and / or a salt thereof in the presence of a basic aqueous solution to produce a by-product. It was found that the product was greatly reduced and the aminoimidazole derivative represented by the formula (V) was obtained in high yield.
In addition, a process represented by formula (II) in which the compound represented by formula (II) is obtained by reacting diaminomaleonitrile with a compound represented by formula (I) in the presence of a strong acid. The compound represented by formula (III) and the compound represented by formula (IV) and / or a salt thereof are reacted with the compound represented by formula (III), and the formula (IV) In any of the steps (C) in which the compound and / or the salt thereof are cyclized in the presence of a basic aqueous solution, an amino compound represented by the formula (V) is obtained from diaminomaleonitrile by using an aprotic organic solvent. It was found that imidazole derivatives can be synthesized in a single pot in a short time with a high yield. The present invention has been completed as a result of further studies based on these findings.

That is, the present invention includes the following aspects.
(1) The step (C) of cyclizing the compound represented by the formula (IV) and / or a salt thereof in the presence of a basic aqueous solution is performed in the presence of an aprotic organic solvent. A process for producing an aminoimidazole derivative represented by V).

（式（ＩＶ）中、Ｒ¹およびＲ³は、それぞれ独立に、水素原子、置換基を有してもよいアルキル基、または置換基を有してもよいアリール基である。）

(In Formula (IV), R ¹ and R ³ are each independently a hydrogen atom, an alkyl group that may have a substituent, or an aryl group that may have a substituent.)

（式（Ｖ）中、Ｒ¹およびＲ³は、式（ＩＶ）中のものと同じものを表す。Ｒ⁴は、−ＣＮ、または−ＣＯＮＨ₂である。）

(In formula (V), R ¹ and R ³ represent the same as those in formula (IV). R ⁴ is —CN or —CONH _2. )

(2) Step (A) of obtaining a compound represented by the formula (II) by reacting a diaminomaleonitrile with a compound represented by the formula (I) in the presence of a strong acid.
CR ¹ (OR ² ) ₃ (I)
(In Formula (I), R ¹ is a hydrogen atom, and each R ² is independently an alkyl group that may have a substituent, or an aryl group that may have a substituent.)

（式（ＩＩ）中、Ｒ¹およびＲ²は、式（Ｉ）中のものと同じものを表す。）

式（ＩＩ）で表される化合物と、式（ＩＩＩ）で表される化合物とを、反応させて、式（ＩＶ）で表される化合物及び／又はその塩を得る工程（Ｂ）、
ＮＨ₂Ｒ³ （ＩＩＩ）
（式（ＩＩＩ）中、Ｒ³は、水素原子、置換基を有してもよいアルキル基、または置換基を有してもよいアリール基である。）

(In formula (II), R ¹ and R ² represent the same as those in formula (I).)

A step (B) of obtaining a compound represented by formula (IV) and / or a salt thereof by reacting a compound represented by formula (II) with a compound represented by formula (III);
NH ₂ R ³ (III)
(In Formula (III), R ³ is a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent.)

（式（ＩＶ）中、Ｒ¹は、式（Ｉ）中のものと同じものを表す。Ｒ³は式（ＩＩＩ）中のものと同じものを表す。）
および
式（ＩＶ）で表される化合物及び／又はその塩を塩基性水溶液の存在下に環化させる工程（Ｃ）を、いずれも、
非プロトン性有機溶媒の存在下で行うことを含む、式（Ｖ）で表されるアミノイミダゾール誘導体の製造方法。

(In formula (IV), R ¹ represents the same as in formula (I). R ³ represents the same as in formula (III).)
And the step (C) of cyclizing the compound represented by the formula (IV) and / or a salt thereof in the presence of a basic aqueous solution,
The manufacturing method of the aminoimidazole derivative represented by Formula (V) including performing in presence of an aprotic organic solvent.

（式（Ｖ）中、Ｒ¹は式（Ｉ）中のものと同じものを表す。Ｒ³は式（ＩＩＩ）中のものと同じものを表す。Ｒ⁴は、−ＣＮ、または−ＣＯＮＨ₂である。）

(In formula (V), R ¹ represents the same as in formula (I). R ³ represents the same as in formula (III). R ⁴ represents —CN or —CONH _2. .)

(3) The method for producing the aminoimidazole derivative, wherein the strong acid is trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or concentrated sulfuric acid.
(4) The step (B) is performed by mixing an aprotic organic solvent solution or suspension of the compound represented by the formula (II) with an aqueous solution of the compound represented by the formula (III). , A method for producing the aminoimidazole derivative.
(5) The said aminoimidazole derivative manufacturing method whose aprotic organic solvent is tetrahydrofuran.

  By the production method of the present invention, by-products are greatly reduced, and an aminoimidazole derivative represented by the formula (V) is obtained in high yield. In the production method of the present invention, the solvent used in each step until the aminoimidazole derivative represented by the formula (V) is obtained from the starting material diaminomaleonitrile can be unified with the aprotic organic solvent. The aminoimidazole derivative represented by the formula (V) can be synthesized from maleonitrile in a short time with a high yield in one pot.

  Diaminomaleonitrile (DAMN), which is a starting material of the production method of the present invention, can be easily synthesized from a tetramerization reaction of cyanic acid, and is an industrially available compound.

  The compound represented by the formula (I) is orthocarboxylic acid triester known as orthoformate triester, orthoacetate triester and the like. These are industrially available compounds.

R ¹ in formula (I) is a hydrogen atom, an alkyl group that may have a substituent, or an aryl group that may have a substituent.
Examples of the alkyl group that may have a substituent include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group, and an n-decyl group. , Methoxymethyl group, methylthiomethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 4-acetoxy-3-acetoxymethyl-butyl group, 4-hydroxy-3-hydroxymethyl-butyl group, 2-hydroxyethoxymethyl Group, 2-hydroxy-1-hydroxymethyl-ethoxymethyl group, 4-hydroxy-2-hydroxymethyl-butyl group, 5- (N-methylcarbamoyloxy) butyl group, hydroxycarbonylmethyl group, 2-chloroethyl group, 2 -Dimethylaminoethyl group, N-substituted-2-asparagyl group and the like.

As the aryl group which may have a substituent, a phenyl group, 4-methylphenyl group, 4-chlorophenyl group, 2,3-dimethylphenyl group, 3,5-dimethylphenyl group, 2,6-dimethylphenyl group 4-methoxyphenyl group, 3-phenoxyphenyl group, 4-phenylphenyl group, 4- (2-chlorophenyl) phenyl group, 4- (3-isoxazolylphenyl) phenyl group, 3-benzylphenyl group, 2 -A pyridylmethylphenyl group etc. are mentioned. Among these, R ¹ is preferably a hydrogen atom in consideration of the efficiency of the amidine reaction in the step (B). When R ¹ is a methyl group or a phenyl group, formation of a dicyanoimidazole derivative is preferential during the cyclization reaction in step (C).

R ² in the formula (I) is each independently an alkyl group which may have a substituent or an aryl group which may have a substituent. Specific examples of the alkyl group which may have a substituent or the aryl group which may have a substituent in R ² include the same as those exemplified for R ¹ above. R ² in formula (I) may all be the same or different. According to the production method of the present invention, alcohol (R ² OH) derived from R ² in formula (I) is by-produced. R ² is preferably a C1-C5 alkyl group, and most preferably a methyl group or an ethyl group, from the viewpoint that it is easy to efficiently remove and recover by-produced alcohol.

In step (A), diaminomaleonitrile and a compound represented by formula (I) are reacted in the presence of a strong acid to obtain a compound represented by formula (II).
The compound represented by the formula (I) is reacted with 1 to 2 equivalents, preferably 1.05 to 1.3 equivalents, with respect to DAMN.

  The strong acid used in the step (A) is an acid that is almost completely ionized in an aqueous solution. Specific examples include sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, hydrochloric acid, perchloric acid; methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like. Weak acids such as carbonic acid, acetic acid, boric acid and hydrogen sulfide are not suitable for the production method of the present invention. The amount of strong acid used is preferably 0.2 to 0.5 mol% with respect to DAMN. If the amount of strong acid is too large, the amount of by-products tends to increase.

  The step (A) is preferably performed in the presence of an aprotic organic solvent. An aprotic organic solvent is a solvent that does not have proton donating properties. The amount of the aprotic organic solvent used in the step (A) is usually 0.1 to 1 L, preferably 0.1 to 0.3 L, with respect to 1 mol of DAMN. Examples of the aprotic organic solvent include ethers such as tetrahydrofuran, dioxane, diethyl ether and diethylene glycol dimethyl ether; ketones such as acetone. Of these, tetrahydrofuran is preferred.

  In the step (A), it is sufficient that a strong acid is present in the reaction between DAMN and the compound represented by the formula (I), and there are no particular limitations on the order of addition and the addition rate of the synthetic raw materials. In step (A), usually the solvent is first charged to the reactor, to which a predetermined amount of DAMN and the compound of formula (I) are added together or separately, and then the strong acid is added. After adding the strong acid, the reaction is maintained at a predetermined temperature.

  The reaction temperature in step (A) is not particularly limited, but if the temperature is too low, the reaction is slow and requires a long time for production. If the temperature is too high, byproducts such as 4,5-dicyanoimidazole increase and the purity decreases. Become a trend. Therefore, the reaction temperature is usually from room temperature (around 20 ° C.) to the solvent reflux temperature, preferably 30 to 50 ° C. The reaction time is preferably within 1 hour. If the reaction time is too long, by-products increase and the purity tends to decrease. The reaction liquid containing the compound represented by the formula (II) obtained in the step (A) can be directly used for the step (B).

In step (B), a compound represented by formula (II) and a compound represented by formula (III) are reacted to obtain a compound represented by formula (IV) and / or a salt thereof. The step (B) is preferably performed in the presence of an aprotic organic solvent as in the step (A).
NH ₂ R ³ (III)
In Formula (III), R ³ is a hydrogen atom, an alkyl group that may have a substituent, or an aryl group that may have a substituent. Specific examples of the alkyl group which may have a substituent or the aryl group which may have a substituent in R ³ include the same as those exemplified for R ¹ above.

In the step (B), an aprotic organic solvent solution or suspension of the compound represented by the formula (II) is mixed with an aqueous solution of the compound represented by the formula (III), and then the mixture is brought to a predetermined temperature. It is preferable to carry out while maintaining.
One-pot synthesis can be carried out by using the reaction solution obtained in step (A) as it is as an aprotic organic solvent solution or suspension of the compound represented by formula (II).

In the aqueous solution of the compound represented by the formula (III), the compound represented by the formula (III) is preferably 1 to 10 equivalents, more preferably 3 to 6 equivalents with respect to the compound represented by the formula (II). Add to be.
Specific examples of the compound represented by the formula (III) include ammonia; amines such as methylamine and ethylamine; alkanolamines such as methanolamine, ethanolamine, propanolamine and isopropanolamine.

  The reaction temperature in the step (B) is not particularly limited, but if the temperature is too low, the reaction is slow and requires a long time for production. If the temperature is too high, by-products increase and the purity tends to decrease. Therefore, reaction temperature is 0-50 degreeC normally, Preferably it is 10-30 degreeC. The reaction time is preferably within 1 hour. If the reaction time is too long, by-products increase and the purity tends to decrease. The reaction liquid containing the compound represented by the formula (IV) and / or a salt thereof obtained in the step (B) can be directly used for the step (C).

In step (C), the compound represented by formula (IV) and / or a salt thereof is cyclized in the presence of a basic aqueous solution. Step (C) is performed in the presence of an aprotic organic solvent. By this cyclization reaction, a compound represented by the formula (V) is obtained.
A basic aqueous solution is obtained by dissolving a basic compound in water. Examples of the basic compound include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; ammonia and amines. Of these, alkali metal hydroxides are preferred.

The basic aqueous solution is preferably 1 to 3 equivalents, more preferably 1.5 to 2.5 equivalents, relative to the compound represented by formula (IV) and / or a salt thereof. When the reaction temperature in step (C) is preferably 0 to 50 ° C., more preferably 0 to 30 ° C., the cyclization reaction proceeds and a derivative (AICN) in which R ⁴ is —CN is obtained.
The basic aqueous solution is added so that the basic compound is preferably 3 to 5 equivalents with respect to the compound represented by the formula (IV) and / or a salt thereof, and the reaction temperature in the step (C) is set as the solvent. When the reflux temperature is reached, a cyclization hydrolysis reaction proceeds, and a derivative (AICA) in which R ⁴ is —CONH ₂ is obtained.

  After completion of step (C), the compound represented by formula (V) can be purified. Examples of the purification method include a method in which an acid such as hydrochloric acid is added to the reaction solution obtained in the step (C) to extract or concentrate to a hydrochloride or the like. Further, as described in JP-A No. 2004-75610, there is a method of adding a decoloring agent such as activated carbon to the extract and performing a decoloring treatment.

  The compound represented by the formula (V) obtained by the production method of the present invention, particularly 1H-4 (5) -aminoimidazole-5 (4) -carboxamide and 4 (5) -amino-1H-imidazole-5 (4) -Carbonitrile can be used as a useful intermediate material for producing the anticancer agents dacarbazine and temozoromide, and the hepatoprotectant urazamide.

Next, the present invention will be described in more detail with reference to examples and comparative examples. The present invention is not limited to these examples.
Example 1 (DAMN->MMD->AMD-> AICN)
Tetrahydrofuran (THF) (400 mL) was charged into a 3 L capacity four-necked flask, and 219.1 g of DAMN (purity 98.7%, 2.00 mol) and 254.7 g (2.40 mol) of trimethyl orthoformate were added. To this mixture, 480 mg of methanesulfonic acid was added, and the mixture was stirred at 1 hour while maintaining at 40 ° C. to obtain a slurry of MMD.
To the MMD slurry, 200 mL of THF was added, 545.0 g (8.0 mol) of 25% aqueous ammonia was added, and the mixture was maintained at 30 ° C. and stirred for 1 hour.
Next, 640.0 g (4.0 mol) of a 25% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour while maintaining the temperature at 30 to 40 ° C. to obtain an AICN reaction solution.
The ammonia content was distilled off under reduced pressure from the resulting reaction solution, and 560 g (5.4 mol) of 35% hydrochloric acid was added to adjust the pH to 6. The precipitated black insoluble material was removed by filtration.
Subsequently, the extraction operation of AICN was repeated 3 times by adding 1.2 L of THF. When AICN in the THF extract was quantitatively analyzed, the AICN content was 169 g (1.56 mol).
The THF extract was concentrated, then water was added and the THF was distilled off to obtain an AICN aqueous solution. Activated carbon 40g was added to this aqueous solution, and it stirred at 50 degreeC for 30 minutes. Activated carbon was separated by filtration, and water was added so that the weight of the obtained filtrate became 1000 g. The liquid was gradually cooled, maintained at a temperature of 0 to 5 ° C. and stirred for 30 minutes to precipitate crystals, and the crystals were filtered. The crystals were washed with 300 mL of cold water and dried under reduced pressure at 40 to 50 ° C. to obtain 146.2 g of AICN crystals (purity 98.1%, yield 66.4%).

Example 2
20 mL of THF was charged into a 200 mL four-necked flask, and 10.95 g of DAMN (purity 98.7%, 0.100 mol) and 12.73 g (0.120 mol) of trimethyl orthoformate were added. 27 mg of methanesulfonic acid was added to this mixture, and the mixture was stirred for 1 hour while maintaining at 40 ° C. to obtain an MMD slurry.
15 mL of THF was added to the MMD slurry, 27.25 g (0.400 mol) of 25% aqueous ammonia was added, and the mixture was maintained at 30 ° C. and stirred for 1 hour.
Next, 32.00 g (0.200 mol) of 25% aqueous sodium hydroxide solution was added and stirred at a temperature of 30 to 40 ° C. for 1 hour to obtain an AICN reaction solution.
To the obtained reaction solution, 20.8 g (0.20 mol) of 35% hydrochloric acid was added. As a result of quantitative analysis of AICN in the solution, 9.43 g (0.0872 mol) of AICN was contained.

Comparative Example MMD 3.00 g (20 mmol) and methanol 10 mL were added to a four-necked flask with a capacity of 100 mL to obtain an MMD slurry.
To the MMD slurry, 10 mL of a methanol solution of 1.77 g (100 mmol) of ammonia was added and stirred at room temperature for 3 hours to obtain an AMD slurry.
Next, 3.20 g (20 mmol) of 25% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 20 hours. When the reaction solution was analyzed by HPLC, the area ratio was 46% AICN, 4% DCI, and 35% AIC-imidate represented by the formula (VI).

Example 3
An MMD slurry was obtained in the same manner as in Example 1. To the MMD slurry (MMD 9.0 g (0.06 mol), THF 60 mL), isopropanolamine (R) 4.89 g (0.066 mol) was added at 5 ° C., and the mixture was stirred at 5 to 10 ° C. for 4 hours. A liquid of the compound represented was obtained.
Next, 14.4 g (90 mmol) of 25% aqueous sodium hydroxide solution was added dropwise at 10 ° C. over 10 minutes. After completion of the addition, the mixture was stirred at 10 ° C. for 18 hours. To the obtained reaction solution, 11.8 g (0.11 mol) of 35% hydrochloric acid was added and stirred for 30 minutes. When the reaction solution was analyzed by HPLC, 82.0% of AICN- (R) HP represented by the formula (Va) in terms of area ratio was contained.

実施例４
イソプロパノールアミン（Ｒ）をイソプロパノールアミン（Ｓ）に替えた他は実施例３と同様にして、式（ＩＶｂ）で表される化合物および式（Ｖｂ）で表されるＡＩＣＮ−（Ｓ）ＨＰを得た。ＨＰＬＣで分析したところ、面積比で式（Ｖｂ）で表されるＡＩＣＮ−（Ｓ）ＨＰが９０．２％含まれていた。

Example 4
A compound represented by the formula (IVb) and an AICN- (S) HP represented by the formula (Vb) were obtained in the same manner as in Example 3 except that the isopropanolamine (R) was replaced with the isopropanolamine (S). It was. When analyzed by HPLC, 90.2% of AICN- (S) HP represented by the formula (Vb) in terms of area ratio was contained.

  From the above results, when a protic organic solvent such as methanol is used, many side reactions occur and the yield of the aminoimidazole derivative does not increase. On the other hand, when an aprotic solvent such as tetrahydrofuran is used according to the present invention, it can be seen that the aminoimidazole derivative represented by the formula (V) can be obtained in high yield from diaminomaleonitrile.

Claims (5)

The step (C) of cyclizing the compound represented by formula (IV) and / or a salt thereof in the presence of a basic aqueous solution, in the presence of an aprotic organic solvent; The manufacturing method of the aminoimidazole derivative represented.

(In Formula (IV), R ¹ and R ³ are each independently a hydrogen atom, an alkyl group that may have a substituent, or an aryl group that may have a substituent.)

(In formula (V), R ¹ and R ³ represent the same as those in formula (IV). R ⁴ is —CN or —CONH _2. ) A step of reacting diaminomaleonitrile with a compound represented by the formula (I) in the presence of a strong acid to obtain a compound represented by the formula (II), (A),
CR ¹ (OR ² ) ₃ (I)
(In Formula (I), R ¹ is a hydrogen atom, and each R ² is independently an alkyl group that may have a substituent, or an aryl group that may have a substituent.)

(In formula (II), R ¹ and R ² represent the same as those in formula (I).)

A step (B) of obtaining a compound represented by formula (IV) and / or a salt thereof by reacting a compound represented by formula (II) with a compound represented by formula (III);
NH ₂ R ³ (III)
(In Formula (III), R ³ is a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent.)

(In formula (IV), R ¹ represents the same as in formula (I). R ³ represents the same as in formula (III).)
And the step (C) of cyclizing the compound represented by formula (IV) and / or a salt thereof in the presence of a basic aqueous solution, each in the presence of an aprotic organic solvent, A process for producing an aminoimidazole derivative represented by V).

(In formula (V), R ¹ represents the same as in formula (I). R ³ represents the same as in formula (III). R ⁴ represents —CN or —CONH _2. .)   The method for producing an aminoimidazole derivative according to claim 2, wherein the strong acid is trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or concentrated sulfuric acid.   The step (B) is performed by mixing an aprotic organic solvent solution or suspension of the compound represented by the formula (II) with an aqueous solution of the compound represented by the formula (III). A process for producing the aminoimidazole derivative according to 2 or 3.   The manufacturing method of the aminoimidazole derivative in any one of Claims 1-4 whose aprotic organic solvent is tetrahydrofuran.