JP2022163759A - Manufacturing method of 3-hydroxy-2-pyrazinecarboxamide and composition suitable therefor, as well as manufacturing method of 2-aminomalonamide - Google Patents

Abstract

To provide a manufacturing method of 3-hydroxy-2-pyrazinecarboxamide, which is suitable for industrial application such that 2-aminomalonamide is manufactured by simplified operation and a shortened process to cyclize this.SOLUTION: A method for manufacturing 3-hydroxy-2-pyrazinecarboxamide sequentially performs the following steps (a) to (c). Step (a): a malonate compound is reacted with a chlorinating agent to generate a chloromalonate compound, step (b): ammonia is reacted with the chloromalonate compound for amination and amidation to generate 2-aminomalonamide, and step (c): glyoxal is reacted with the 2-aminomalonamide for cyclization to generate 3-hydroxy-2-pyrazinecarboxamide.SELECTED DRAWING: None

Description

The present invention relates to a method for producing 3-hydroxy-2-pyrazinecarboxamide and a composition suitable therefor, and a method for producing 2-aminomalonamide.

3-Hydroxy-2-pyrazinecarboxamide is a compound useful as an intermediate for pharmaceuticals and agricultural chemicals, and various production methods have been investigated so far.

As a method for synthesizing 3-hydroxy-2-pyrazinecarboxamide, for example, Patent Document 1 discloses a cyclization method in which glyoxal and a base are simultaneously added dropwise to a phosphate buffer containing 2-aminomalonamide. is proposed. 2-Aminomalonamide, which is the raw material, is converted to diethyl nitrosomalonate by combining the contents described in Patent Documents 2 and 3, for example, by allowing sodium nitrite to act on industrially inexpensively available diethyl malonate. Thereafter, this diethyl nitrosomalonate is hydrogenated and reduced to be converted to diethyl aminomalonate, which is then amidated with ammonia. As an aid to understanding, this reaction scheme is shown below.

However, in this method, 2-aminomalonamide is obtained from diethyl malonate through three steps of nitrosation, hydrogenation reduction and amidation, and finally cyclization is performed to obtain the desired product, 3-hydroxy-2-pyrazinecarboxamide. A total of 4 steps are required to obtain , and purification operations are required by extraction after nitrosation, removal of the catalyst after hydrogenation reduction, filtration after amidation, and filtration after cyclization. and requires complicated operations until the desired product is obtained.

On the other hand, as another method for synthesizing 2-aminomalonamide, for example, Patent Document 4 discloses a method in which a chloromalonic acid ester compound is reacted with ammonia to effect amination and amidation at the same time. However, when trying to synthesize a chloromalonic ester compound, which is a raw material for this reaction, from an industrially inexpensive malonic ester compound, as described in Patent Document 5, sulfuryl chloride is added to the malonic ester compound. However, according to this reaction, the target chloromalonic acid ester compound is obtained as a mixture with the by-product dichloromalonic acid ester compound ( See Example 1 of Patent Document 4). As an aid to understanding, this reaction scheme is shown below.

As a method for removing the dichloromalonic acid ester compound by-produced together with the chloromalonic acid ester compound, for example, as described in Non-Patent Document 1, this mixture is reacted with isopropylmagnesium chloride and then hydrolyzed with an aqueous hydrochloric acid solution. method. However, this operation is not only complicated, but also requires an expensive organometallic compound. A method of fractionating the chloromalonic acid ester compound and the dichloromalonic acid ester compound by precision distillation using the difference in boiling point between them is also conceivable, but it takes a long time using a distillation column with a high number of plates. Since fractional distillation is required, it is difficult to say that this is a highly productive method.

JP 2010-241806 A JP 2011-26309 A JP 2010-241805 A JP-A-59-227844 WO2016/193822

Journal of Organometallic Chemistry, 1972, 34, 209-219.

The present invention has been made in view of the above circumstances, and is suitable for industrial practice of producing 2-aminomalonamide with a simpler operation and a shorter number of steps than before, and further cyclizing it. An object of the present invention is to provide a method for producing 3-hydroxy-2-pyrazinecarboxamide.

As a result of intensive studies to solve the above problems, the present inventors have found that even if a malonic acid diester compound is chlorinated to obtain a chloromalonic acid ester compound as a mixture with a dichloromalonic acid ester compound, If these are not separated but amination and amidation with ammonia followed by a cyclization reaction, the desired 3-hydroxy-2-pyrazinecarboxamide can be obtained with high purity only by a simple operation of filtration. I found According to this method, the target 3-hydroxy-2-pyrazinecarboxamide can be obtained from the malonic acid ester compound in three steps, one step less than the four-step process combined described in Patent Documents 1 to 3. can. Moreover, according to this method, it is not necessary to separate the chloromalonate compound and the dichloromalonate compound as described above. Since 3-hydroxy-2-pyrazinecarboxamide can be obtained, it is even possible to obtain 3-hydroxy-2-pyrazinecarboxamide, which is the final product, from the malonic acid ester compound, which is the starting material, by one-pot synthesis. The inventor has found The present invention has been made based on the above findings, and provides the following.

（上記一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に、置換基を有してもよい炭素数１～６のアルキル基又はシクロアルキル基である。）

（上記一般式（２）中、Ｒ^１及びＲ^２は、それぞれ独立に、置換基を有してもよい炭素数１～６のアルキル基又はシクロアルキル基である。）
（ｂ）：一般式（２）で表すクロロマロン酸エステル化合物にアンモニアを作用させてアミノ化及びアミド化を行い、下記化学式（３）で表す２－アミノマロンアミドを生成させる工程、

（ｃ）：化学式（３）で表す２－アミノマロンアミドにグリオキサールを作用させて環化させることで、下記化学式（４）で表す３－ヒドロキシ－２－ピラジンカルボキサミドを生成させる工程、

(1) The present invention provides a method for producing 3-hydroxy-2-pyrazinecarboxamide, characterized by sequentially performing the following steps.
(a): a step of reacting a malonic acid ester compound represented by the following general formula (1) with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2);

(In general formula (1) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)

(In general formula (2) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)
(b): A step of aminating and amidating a chloromalonic acid ester compound represented by the general formula (2) with ammonia to produce a 2-aminomalonamide represented by the following chemical formula (3);

(c): a step of cyclizing 2-aminomalonamide represented by chemical formula (3) with glyoxal to produce 3-hydroxy-2-pyrazinecarboxamide represented by chemical formula (4) below;

(2) Further, in the present invention, in the step (a), the step (b), which is the next step, is performed without separating the dichloromalonic acid ester compound by-produced when reacted with the chlorinating agent. The manufacturing method according to item (1), characterized by:

（上記一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に、置換基を有してもよい炭素数１～６のアルキル基又はシクロアルキル基である。）

（上記一般式（２）中、Ｒ^１及びＲ^２は、それぞれ独立に、置換基を有してもよい炭素数１～６のアルキル基又はシクロアルキル基である。）
（ｂ）：一般式（２）で表すクロロマロン酸エステル化合物にアンモニアを作用させてアミノ化及びアミド化を行い、下記化学式（３）で表す２－アミノマロンアミドを生成させる工程、

(3) The present invention also provides a method for producing 2-aminomalonamide, characterized by sequentially performing the following steps.
(a): a step of reacting a malonic acid ester compound represented by the following general formula (1) with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2);

(In general formula (1) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)

(In general formula (2) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)
(b): A step of aminating and amidating a chloromalonic acid ester compound represented by the general formula (2) with ammonia to produce a 2-aminomalonamide represented by the following chemical formula (3);

(4) Further, in the present invention, in the step (a), the step (b), which is the next step, is performed without separating the dichloromalonic acid ester compound by-produced when reacted with the chlorinating agent. The manufacturing method according to item (3), characterized by:

(5) Further, the present invention is the production method according to any one of (1) to (4), characterized in that the next step is performed without isolating the intermediate product of each step. .

(6) Further, according to the present invention, a one-pot synthesis is carried out from the malonic acid ester compound as a starting material until the final target product is obtained. is a manufacturing method.

(7) The present invention provides a composition containing a chloromalonate compound and a dichloromalonate ester, wherein the content of the dichloromalonate compound is lower than the content of the chloromalonate compound on a mass basis. is 0.01 times or more and 0.15 times or less.

(8) In the present invention, the composition described in item (7) is subjected to amination and amidation by reacting ammonia (this is referred to as step (b)), and then glyoxal is reacted (this is referred to as step ( It is also a method for producing 3-hydroxy-2-pyrazinecarboxamide characterized by c).).

(9) Further, in the present invention, the production method according to (1), (2) or (8), wherein the solvent in the step (c) is an aqueous solution of phosphoric acid or an aqueous solution of citric acid. be.

According to the present invention, the production of 3-hydroxy-2-pyrazinecarboxamide, which is suitable for industrial implementation, involves producing 2-aminomalonamide with a simpler operation and a shorter number of steps than before, and further cyclizing it. A method is provided.

Hereinafter, the first embodiment and second embodiment of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention, one embodiment of the method for producing 2-aminomalonamide, and one embodiment of the composition of the present invention are described below. It should be noted that the present invention is not limited to the following modes and embodiments, and can be implemented with appropriate modifications within the scope of the present invention. In addition, the term "step" as used herein refers not only to an independent step, but also to the term even if the intended effect of the step is achieved even if it cannot be clearly distinguished from other steps. shall be

<First embodiment of the method for producing 3-hydroxy-2-pyrazinecarboxamide>
First, the first embodiment of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention will be explained. In the production method of the present embodiment, the target 3-hydroxy-2-pyrazinecarboxamide is obtained from the malonic acid ester compound as a raw material through three steps of chemical reactions, and the following steps (a) to ( c) is performed sequentially. Step (a) is a step of reacting a malonic acid ester compound represented by the following general formula (1) with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2), and step (b). is a step of reacting the chloromalonic acid ester compound obtained in step (a) with ammonia to effect amination and amidation to produce 2-aminomalonamide represented by the following chemical formula (3); ) is a step of cyclizing the 2-aminomalonamide obtained in step (b) with glyoxal to produce 3-hydroxy-2-pyrazinecarboxamide represented by the following chemical formula (4). A reaction scheme for these steps is shown below.

As already mentioned, the step (a) is to obtain the chloromalonic acid ester compound (2) by reacting the malonic acid ester compound (1) with a chlorinating agent. Synthesized as a product. In the present invention, the chloromalonic acid ester compound (2) obtained in this step is not separated and purified, that is, the mixture of the chloromalonic acid ester compound (2) and the dichloromalonic acid ester compound is used in the next step. (b) and step (c) may be performed. According to the production method of the present invention, even if step (b) and step (c) are performed without such separation and purification, 3-hydroxy-2-pyrazinecarboxamide (4), which is the final product, can be obtained. It was made based on the knowledge that it can be obtained with high purity by a simple purification operation. The reason why such an effect is obtained is not necessarily clear, but is presumed to be as follows. The by-product dichloromalonate ester compound will have two reaction sites (i.e., two chlorine atoms) when undergoing amination in step (b), but if both of these are aminated, it will be unusable. A stable aminal structure is formed, and this site is converted to a ketone or imine structure and no amino group is introduced. Also, when an amino group is introduced into only one of the two reaction sites, the chlorine atom in the vicinity becomes susceptible to amination due to the effect of the introduction of the amino group, and is also converted to a ketone or imine structure to form an amino group. It is believed that no groups are introduced. As a result, the dichloromalonamide compound, which is a by-product, will not have an amino group introduced even after the step (b), and will not undergo the cyclization reaction in the step (c). Since the cyclized 3-hydroxy-2-pyrazinecarboxamide (4) and the uncyclized by-product differ greatly in solvent solubility, the final product, 3-hydroxy-2-pyrazinecarboxamide (4 ) can be obtained with high purity by a simple refining operation called filtration.

In the present invention, it is not necessary to separate and purify the chloromalonic acid ester compound that has undergone the step (a), and 2-aminomalonamide that has undergone the subsequent step (b) can also c) can be performed. Therefore, according to the production method of the present invention, steps (a) to (c) from the raw material malonic acid ester compound (1) to the final target 3-hydroxy-2-pyrazinecarboxamide (4) are carried out in one pot. Synthesis is also possible. Thus, the production method of the present invention can be said to be superior in that it requires fewer steps than the four-step synthetic route combining Patent Documents 1 to 3 and does not require separation and purification in the intermediate steps. Of course, at the end of step (a) and/or step (b), the target product of each step may be separated and purified before proceeding to the next step.

Each step of step (a), step (b) and step (c) will be described below.

[Step (a)]
In step (a), a malonic acid ester compound represented by the following general formula (1) is reacted with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2). That is, this step is to chlorinate the carbon atom at the 2-position of the malonic acid ester compound.

In general formula (1) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group. Examples of such alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, t-butyl group, n-pentyl group and n-hexyl group. is mentioned. Moreover, such a cycloalkyl group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. R ¹ and R ² may be the same or different from each other.

Examples of substituents that these alkyl groups or cycloalkyl groups may have include linear or branched alkyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 1 to 6 carbon atoms, and linear groups having 1 to 6 carbon atoms. or a branched alkoxy group, a haloalkyl group having 1 to 6 carbon atoms, a carboxyl group or a metal salt thereof, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, an amino group, a linear or branched chain having 1 to 6 carbon atoms alkylamino group, linear or branched alkylcarbonylamino group having 1 to 6 carbon atoms, nitro group, hydroxyl group, aryl group, aryloxy group, heteroaryl group and the like. Examples of linear or branched alkyl groups having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, t-butyl group, n- pentyl group, n-hexyl group and the like. The cycloalkyl group having 1 to 6 carbon atoms includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Linear or branched alkoxy groups having 1 to 6 carbon atoms include methoxy, ethoxy, n-propoxy and isopropoxy groups. The haloalkyl group having 1 to 6 carbon atoms includes fluoromethyl group, difluoromethyl group, trifluoromethyl group and the like. A phenyl group etc. are mentioned as an aryl group. Heteroaryl groups include pyridyl, thienyl, and furanyl groups.

Preferred examples of the malonic acid ester compound represented by the general formula (1) include dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, and di-malonate. sec-butyl, diisobutyl malonate, di-t-butyl malonate, di-n-pentyl malonate, di-n-hexyl malonate, dicyclopropyl malonate, dicyclobutyl malonate, dicyclopentyl malonate, dicyclohexyl malonate , dibenzyl malonate, and the like. Among these, diethyl malonate is more preferable.

R ¹ and R ² in general formula (2) above are the same as R ¹ and R ² described in general formula (1) above.

The chlorinating agent is not particularly limited as long as it can introduce a chlorine atom at the 2-position of the malonic acid ester compound, but chlorine; sulfur oxychlorides such as sulfuryl chloride and thionyl chloride; sulfur dichloride and disulfur dichloride. sulfur chlorides such as; chlorine oxoacid salts such as sodium hypochlorite, sodium chlorite, sodium chlorate and sodium perchlorate; phosphorus chlorides such as phosphorus oxychloride, phosphorus pentachloride and phosphorus trichloride; Examples include metal chlorides such as aluminum chloride and zinc chloride. Among these, sulfur oxychlorides such as sulfuryl chloride and chlorine are preferred, and sulfur oxychlorides such as sulfuryl chloride are more preferred, from the viewpoints of availability, ease of handling, solubility, reactivity, and the like. . These chlorinating agents may be used alone or in combination of two or more at any ratio.

A method for supplying the chlorinating agent may be dripping using a head or a pump, but is not particularly limited as long as the supply speed, that is, the dripping speed can be adjusted. The dropping time during dropping is such that the chloromalonic acid ester compound (general formula (2) above) produced by reacting the malonic acid ester compound represented by the above general formula (1) with the chlorinating agent undergoes further chlorination. is sufficient as long as the concentration of the chlorinating agent in the reaction system is kept low so that the side reaction of is sufficiently suppressed and the monochlorination reaction proceeds preferentially. Such dropping time is preferably about 1 hour to 30 hours.

The molar ratio of the chlorinating agent to the malonic ester compound represented by the above general formula (1) is not particularly limited, but the molar ratio of the chlorinating agent to the malonic ester compound is 0.3 to 1. About 0.5 is preferable, about 0.7 to 1.3 is more preferable, and about 0.9 to 1.2 is even more preferable. When the molar ratio of the chlorinating agent is 0.3 or more when the malonic acid ester compound is 1, the conversion rate of the chlorination reaction is improved and the yield is improved, which is preferable. When the molar ratio of the chlorinating agent is 1.5 or less with respect to the ester compound being 1, it is possible to suppress the formation ratio of dichloromalonic acid esters as by-products, which is preferable.

Although this step may be carried out without a solvent, it is preferable to use a solvent in order to facilitate the reaction. Any solvent that does not interfere with the reaction and has a boiling point lower than that of the chloromalonic esters that are the products can be used. Halogen solvents; aliphatic hydrocarbons such as n-hexane, cyclohexane, n-decane, and the like. Among these, halogen-containing solvents such as chlorobenzene are preferred from the viewpoint that the reaction mixture can be made homogeneous.

The amount of the solvent may be any amount that can sufficiently stir the reaction system, but as an example, it is preferably about 0 to 1 L with respect to 1 mol of the malonic acid ester compound represented by the general formula (1). and more preferably about 0.05 to 0.5L.

The reaction temperature in this step may be in the range from 0° C. to the reflux temperature of the solvent used, and preferably about 40 to 100° C. from the viewpoint of improving reactivity. Depending on the reaction rate and reaction equipment, the reaction may be carried out under pressurized or reduced pressure conditions in order to change the reflux temperature of the solvent.

After the completion of the reaction, the excess chlorinating agent and gaseous by-products such as hydrogen chloride are removed under reduced pressure, so that the product can be used in the next step without complicated operations such as liquid separation. It can be used in step (b). When a solvent is used in this step, the excess chlorinating agent and gaseous by-products such as hydrogen chloride can be removed at the same time by recovering the used solvent.

The product of this step is obtained as a mixture of the chloromalonic acid ester compound represented by the general formula (2) and the by-product dichloromalonic acid ester compound. As for the product of this step, the chloromalonic acid ester compound represented by the above general formula (2) may be isolated by a separation operation such as precision distillation, but as already mentioned, it can be transferred to the next step without performing a separation operation. may be used.

The product of this step is subjected to the next step (b).

[Step (b)]
In the step (b), the chloromalonic acid ester compound represented by the general formula (2) is reacted with ammonia to effect amination and amidation to produce 2-aminomalonamide represented by the following chemical formula (3). That is, in this step, the chlorine atom introduced into the carbon atom at the 2-position of the chloromalonic acid ester compound is converted to an amino group, and the ester is converted to an amide.

Ammonia used in this step can be ammonia water or ammonia gas. These may be used singly or by mixing at any ratio.

The molar ratio of ammonia to the chloromalonic acid ester compound represented by the general formula (2) is not particularly limited. One is preferred, about 1 to 20 is more preferred, and about 3 to 10 is even more preferred.

In this step, it is preferable to use a solvent in order to facilitate the reaction. Ammonia water or water is preferably mentioned as such a solvent. It is more preferable to use aqueous ammonia as the solvent because it also serves as a reactant.

The amount of the solvent may be any amount as long as it can sufficiently stir the reaction system. It is preferably mentioned, and more preferably about 0.02 to 1 L.

The reaction temperature in this step may be in the range from 0° C. to the reflux temperature of the solvent used, preferably about 30 to 60° C. from the viewpoint of improving reactivity. Depending on the reaction speed and reaction facilities, the reaction may be carried out under pressurized or sealed conditions in order to suppress the scattering of ammonia.

The reaction time in this step is preferably about 1 to 24 hours, more preferably about 5 to 12 hours.

After completion of this step, the aminomalonamide represented by the above chemical formula (3) may be isolated by a separation operation such as filtration and used in the next step, or ammonia may be deaerated from the reaction solution under reduced pressure. This may be used in the next step.

The product of this step is subjected to the next step, step (c).

[Step (c)]
In step (c), 3-hydroxy-2-pyrazinecarboxamide represented by the following chemical formula (4) is produced by reacting 2-aminomalonamide represented by the above chemical formula (3) with glyoxal to cyclize it. That is, in this step, 2-aminomalonamide is reacted with glyoxal to cyclize it.

More specifically, in this step, 2-aminomalonamide represented by the chemical formula (3) and glyoxal are reacted in the presence of a base. At this time, glyoxal may be added to 2-aminomalonamide before the base is supplied, or glyoxal and the base may be simultaneously supplied to 2-aminomalonamide. As a supply method, dropping using a drop or a pump is common, but there is no particular limitation as long as the supply speed, that is, the dropping speed can be adjusted. The drop time during dropwise addition was such that 2-aminomalonamide reacted with glyoxal to sufficiently suppress side reactions, and the concentration of glyoxal in the reaction system was kept low in order to preferentially proceed with the cyclization reaction. Anything that can be done is acceptable. Such dropping time is preferably about 1 to 30 hours.

Glyoxal may be used alone or in an aqueous solution. The molar ratio of glyoxal to 2-aminomalonamide to be used is not particularly limited, but the molar ratio of 2-aminomalonamide to 1 is preferably about 0.1 to 10, and 0.5. About 5 is more preferable, and about 1 to 1.5 is more preferable.

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; organic bases such as triethylamine and pyridine. Among these, inorganic bases such as sodium hydroxide and potassium hydroxide are preferred, and sodium hydroxide is more preferred.

The molar ratio of the base to 2-aminomalonamide used is not particularly limited, but the molar ratio of 2-aminomalonamide to 1 is preferably about 0.1 to 10, and 0.5. About 5 is more preferable, and about 1 to 3 is more preferable.

In this step, it is preferable to use a solvent in order to facilitate the reaction. As such a solvent, water, an aqueous solution of phosphoric acid or an aqueous solution of citric acid is preferably mentioned. When an aqueous phosphoric acid solution or an aqueous citric acid solution is used as the solvent, the concentration thereof is preferably about 1 to 10% by mass.

The amount of the solvent may be any amount that can sufficiently stir the reaction system, but as an example, it is about 0 to 10 L with respect to 1 mol of 2-aminomalonamide, and 0.02 to 0.02 More preferably, it is about 1 L.

The reaction temperature in this step may be in the range of 0°C to the reflux temperature of the solvent used, and preferably about 0 to 40°C from the viewpoint of improving reactivity.

The reaction time in this step is preferably about 1 to 24 hours, more preferably about 1 to 15 hours.

After this step is completed, the reaction solution is neutralized with an acid and then filtered to easily isolate the desired product, 3-hydroxy-2-pyrazinecarboxamide. Acids used for this neutralization include inorganic acids such as hydrochloric acid and sulfuric acid; carboxylic acids such as acetic acid and citric acid; phosphoric acid and the like; be done. These acids may be used alone or in combination of two or more at any ratio.

According to this embodiment, the malonic acid ester compound represented by the above general formula (1) is used as a raw material, and a special reaction apparatus is used through the three steps of steps (a), (b), and (c). Under mild conditions, the target 3-hydroxy-2-pyrazinecarboxamide can be produced with high selectivity, efficiency, and simple operation at low cost. In this case, it is not always necessary to isolate each intermediate, and all steps can be performed as one-pot synthesis. The resulting 3-hydroxy-2-pyrazinecarboxamide is a compound useful as an intermediate for pharmaceuticals and agricultural chemicals.

<Second embodiment of method for producing 3-hydroxy-2-pyrazinecarboxamide>
Next, the second embodiment of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention will be explained. The production method of the present embodiment is a composition containing a chloromalonate ester compound and a dichloromalonate ester, wherein the content of the dichloromalonate compound is a mass relative to the content of the chloromalonate compound. A composition having a ratio of 0.01 to 0.15 times the standard is used, and this composition is subjected to the action of ammonia for amination and amidation, followed by the action of glyoxal. That is, by successively performing the steps (b) and (c) in the first embodiment on this composition, the target product, 3-hydroxy-2-pyrazinecarboxamide, is produced. Steps (b) and (c) are the same as those described in the first embodiment, so descriptions thereof will be omitted here.

The intermediate 2-aminomalonamide obtained through the step (b) can be subjected to the next step (c) without separation and purification. This is also as already described in the explanation of the first embodiment. Therefore, the production method of this embodiment can also obtain 3-hydroxy-2-pyrazinecarboxamide, which is the final target product, by one-pot synthesis as in the first embodiment.

The composition used as a raw material in this embodiment contains a chloromalonic acid ester compound and a dichloromalonic acid ester, and the content of the dichloromalonic acid ester compound is lower than the content of the chloromalonic acid ester compound on a mass basis. is 0.01 times or more and 0.15 times or less. This composition can be prepared by using the malonic acid ester compound represented by the general formula (1) as a starting material and carrying out the step (a) in the first embodiment. Step (a) is the same as described in the first embodiment above, so the description is omitted here. This composition may be prepared by a method different from the above step (a).

<Method for producing 2-aminomalonamide>
Next, one embodiment of the method for producing 2-aminomalonamide of the present invention will be described. The production method of this embodiment is to obtain the desired product, 2-aminomalonamide, through a two-step chemical reaction from a malonate ester compound as a raw material. Step (a) and step (b) in the first embodiment of the production method are performed in sequence. Since these steps (a) and (b) have already been explained, their explanation is omitted here.

As already described, when the malonic acid ester compound represented by the general formula (1) is used as a raw material and chlorinated in step (a), the chloromalonic acid ester compound represented by the general formula (2) and a by-product yields dichloromalonic acid. Therefore, the product obtained in step (a) is a mixture of the chloromalonic acid ester compound and the dichloromalonic acid ester compound, and the next step (b) is carried out as is without any particular separation and purification of this mixture. 2-aminomalonamide, which is the target product, can be obtained. That is, according to the production method of the present embodiment, it is possible to obtain the desired product, 2-aminomalonamide, from the raw malonate ester compound by one-pot synthesis.

<Composition>
Next, one embodiment of the composition of the present invention will be described. The composition of the present invention contains a chloromalonic acid ester compound and a dichloromalonic acid ester, and the content of the dichloromalonic acid ester compound is 0.01 times the content of the chloromalonic acid ester compound on a mass basis. It is characterized by being 0.15 times or less. This is obtained by performing step (a) in the first embodiment of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention, and as already explained, 2-aminomalonamide and It can be used as a raw material for producing 3-hydroxy-2-pyrazinecarboxamide. That is, 2-aminomalonamide is obtained by performing the step (b) using this composition as a raw material, and 3-hydroxymalonamide is obtained by sequentially performing the steps (b) and (c) using this composition as a raw material. -2-pyrazinecarboxamide is obtained. Since these matters have already been described, descriptions thereof are omitted here.

EXAMPLES Hereinafter, the present invention will be described in more detail by showing examples, but the present invention is not limited to the following examples.

[Preparation of diethyl chloromalonate (Example 1)]
A chlorobenzene solution (100 mL) of 80 g (0.5 mol) of diethyl malonate was added to a 200 mL flask equipped with a magnetic stirrer, a dropping funnel, a reflux tube and a caustic trap, heated to 60°C, and 74.2 g of sulfuryl chloride was added over 1 hour. (0.55 mol) was added dropwise. After aging for 1 hour, chlorobenzene was distilled off under reduced pressure to obtain 95.4 g of oil. The composition of this oil was 1% diethyl malonate, 88% diethyl chloromalonate, and 10% diethyl dichloromalonate as determined by gas chromatography area value. This Example 1 corresponds to step (a) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention.

[Preparation of 2-aminomalonamide (Example 2)]
34 g (0.5 mol) of 25% aqueous ammonia and 19.4 g (approximately 0.09 mol as diethyl chloromalonate) of the oil obtained in Example 1 were added to a 100 ml flask equipped with a magnetic stirrer and a balloon, and stirred at room temperature for 1 hour. After that, the mixture was stirred at 50° C. for 4 hours, and the contents were cooled and filtered. The filtered product was dried to obtain 7.5 g of milky white crystals. The purity of 2-aminomalonamide in this crystal was 98.8% in terms of mass. The two-step yield from diethyl malonate was 63%. Example 2 corresponds to step (b) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention.

[Preparation 1 of 3-hydroxy-2-pyrazinecarboxamide (Example 3)]
6 g of water and 1.17 g (10 mmol) of 2-aminomalonamide obtained in Example 2 were added to a 100 ml flask equipped with a magnetic stirrer to suspend them, and then a 40% glyoxal aqueous solution was added at 5°C or lower in an ice bath. 1.74 g (12 mmol) was added, then 2.86 g (20 mmol) of 28% aqueous sodium hydroxide solution was added, and the mixture was stirred at 20° C. for 4 hours. The reaction liquid became homogeneous immediately after the addition of the aqueous sodium hydroxide solution, and then gradually slurried again. After that, when hydrochloric acid and sodium bicarbonate were added to neutralize, the contents became a thick slurry, to which water was added and filtered to separate a solid. The obtained solid was washed with water, then with acetone, and dried to obtain 1.04 g of pale yellow crystals. And the purity of 3-hydroxy-2-pyrazinecarboxamide in this crystal was 99%. The yield of this reaction was 75%. When the obtained solid was measured by LCMS, a peak was observed at m/z 138 [M-1]. Note that Example 3 corresponds to the step (c) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention, and uses water as the reaction solvent.

As shown in Examples 1 to 3 above, according to the present invention, 3-hydroxy-2-pyrazinecarboxamide with good purity can be obtained by a simple procedure.

[Preparation 2 of 3-hydroxy-2-pyrazinecarboxamide (Example 4)]
6 g of water and 0.18 g (1.6 mmol) of phosphoric acid were added and dissolved in a 100 ml flask equipped with a magnetic stirrer, and 1.17 g (10 mmol) of the aminomalonamide obtained in Example 2 was added to suspend them. After making the mixture cloudy, 1.74 g (12 mmol) of 40% aqueous glyoxal solution was added at 5°C or lower in an ice bath, followed by 2.86 g (20 mmol) of 28% aqueous sodium hydroxide solution, followed by stirring at 20°C for 4 hours. The reaction liquid became homogeneous immediately after the addition of the aqueous sodium hydroxide solution, and then gradually slurried again. Thereafter, hydrochloric acid was added for neutralization, and the solid was separated by filtration. The obtained solid was washed with water, then with acetone, and dried to obtain 1.10 g of pale yellow crystals. rice field. The purity of 3-hydroxy-2-pyrazinecarboxamide in this crystal was 98%. And the yield of this reaction was 79%. Note that Example 4 corresponds to the step (c) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention, and the reaction solution is an aqueous solution of phosphoric acid.

[Preparation 3 of 3-hydroxy-2-pyrazinecarboxamide (Example 5)]
6 g of water and 0.31 g (1.5 mmol) of citric acid monohydrate were added and dissolved in a 100 ml flask equipped with a magnetic stirrer, and 1.17 g (10 mmol) of aminomalonamide obtained in Example 2 was added thereto. After suspending them with an ice bath, 1.74 g (12 mmol) of 40% glyoxal aqueous solution was added at 5°C or lower in an ice bath, followed by adding 2.86 g (20 mmol) of 28% aqueous sodium hydroxide solution, and the mixture was stirred at 20°C for 4 hours. Stirred. The reaction liquid became homogeneous immediately after the addition of the aqueous sodium hydroxide solution, and then gradually slurried again. Thereafter, hydrochloric acid was added for neutralization, and the solid was separated by filtration. The obtained solid was washed with water, then with acetone, and dried to obtain 1.07 g of pale yellow crystals. rice field. The purity of 3-hydroxy-2-pyrazinecarboxamide in this crystal was 99%. And the yield of this reaction was 77%. Note that Example 5 corresponds to the step (c) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention, and the reaction solution is an aqueous citric acid solution.

[Preparation 4 of 3-hydroxy-2-pyrazinecarboxamide (Example 6)]
17 g (250 mmol) of 25% aqueous ammonia and 9.75 g (approximately 45 mmol as diethyl chloromalonate) of the oil obtained in Example 1 were added to a 100 ml flask equipped with a magnetic stirrer and stirred for 1 hour in an ice bath to give crystals. After confirming the precipitation of , the mixture was stirred at 40 to 50° C. for 6 hours. About 7 mL of water was recovered from the resulting aqueous solution under reduced pressure. Next, add 25 mL of water, add 8.7 g (60 mmol) of 40% aqueous glyoxal solution at 5°C or lower in an ice bath, then add 25 g (150 mmol) of 24% aqueous sodium hydroxide solution, and stir for 15 hours while gradually returning to room temperature. did. The reaction liquid became homogeneous immediately after the addition of the aqueous sodium hydroxide solution, and then gradually slurried again. Thereafter, hydrochloric acid and sodium bicarbonate were added for neutralization, and the solid was separated by filtration. The obtained solid was washed with water, then with acetone, and dried to give 3.9 g of pale yellow crystals. got The purity of 3-hydroxy-2-pyrazinecarboxamide in this crystal was 97%. And the yield over the three steps from diethyl malonate was 55%. In Example 6, step (b) and step (c) of the method for producing 3-hydroxy-2-pyrazinecarboxamide of the present invention were continuously performed without separating and purifying the intermediate product. . In addition, in Example 6, the oil obtained in Example 1 was used as the raw material, and considering that this oil was unrefined, in Examples 1 and 6, the raw material, diethyl malonate, was used as the starting material for intermediate production. The target product, 3-hydroxy-2-pyrazinecarboxamide, was obtained without separating and purifying the product, and the purity of the 3-hydroxy-2-pyrazinecarboxamide obtained by such a simple procedure was as high as 97%. It turns out that it was a thing.

Further, considering the operations in Examples 1 and 6, according to the production method of the present invention, from the starting material diethyl malonate to the target product 3-hydroxy-2-pyrazinecarboxamide can be prepared by one-pot synthesis. understood.

As shown in the above examples, according to the present invention, the malonic acid ester compound represented by general formula (1), which is easily available as a raw material, undergoes chlorination reaction, amination and amidation reaction, and cyclization reaction. , without the use of special reactors and tedious purification operations, under mild conditions, the desired 3-hydroxy-2-pyrazinecarboxamides can be obtained in highly selective and practical yields with simple operations. In addition to being able to be manufactured, it is possible to manufacture without discharging harmful wastes derived from catalysts or transition metals. Thus, it can be said that the present invention facilitates waste disposal, is environmentally friendly, and has high industrial utility value.

Claims (9)

A method for producing 3-hydroxy-2-pyrazinecarboxamide, characterized in that the following steps are performed in sequence.
(a): a step of reacting a malonic acid ester compound represented by the following general formula (1) with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2);

(In general formula (1) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)

(In general formula (2) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)
(b): A step of aminating and amidating a chloromalonic acid ester compound represented by the general formula (2) with ammonia to produce a 2-aminomalonamide represented by the following chemical formula (3);

(c): a step of cyclizing 2-aminomalonamide represented by chemical formula (3) with glyoxal to produce 3-hydroxy-2-pyrazinecarboxamide represented by chemical formula (4) below;

2. The method according to claim 1, wherein in the step (a), the step (b), which is the next step, is carried out without separating the dichloromalonic acid ester compound by-produced when reacted with the chlorinating agent. manufacturing method. A method for producing 2-aminomalonamide, characterized in that the following steps are performed in sequence.
(a): a step of reacting a malonic acid ester compound represented by the following general formula (1) with a chlorinating agent to produce a chloromalonic acid ester compound represented by the following general formula (2);

(In general formula (1) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)

(In general formula (2) above, R ¹ and R ² are each independently an optionally substituted alkyl group having 1 to 6 carbon atoms or a cycloalkyl group.)
(b): A step of aminating and amidating a chloromalonic acid ester compound represented by the general formula (2) with ammonia to produce a 2-aminomalonamide represented by the following chemical formula (3);

4. The method according to claim 3, wherein in the step (a), the step (b), which is the next step, is carried out without separating the dichloromalonic acid ester compound by-produced when reacted with the chlorinating agent. manufacturing method. 5. The production method according to any one of claims 1 to 4, wherein the next step is carried out without isolating the intermediate product of each step. 6. The production method according to any one of claims 1 to 5, wherein one-pot synthesis is performed from the malonic acid ester compound as a raw material until the final target product is obtained. A composition containing a chloromalonic acid ester compound and a dichloromalonic acid ester, wherein the content of the dichloromalonic acid ester compound is at least 0.01 times the content of the chloromalonic acid ester compound on a mass basis. .15 times or less. Amination and amidation by acting ammonia on the composition according to claim 7 (this is referred to as step (b)), followed by the action of glyoxal (this is referred to as step (c)). A process for the preparation of 3-hydroxy-2-pyrazinecarboxamides characterized. 9. The production method according to claim 1, 2 or 8, wherein the solvent in step (c) is an aqueous phosphoric acid solution or an aqueous citric acid solution.