JP2012158560A - Method for producing nitrogen-containing aromatic heterocyclic carboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid by a simple means and in high selectivity in high yield.SOLUTION: The method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid is characterized in that: a nitrogen-containing aromatic heterocyclic compound where a 1C-6C alkyl group optionally having a substituent is bound to each of the carbon atoms adjacent to the nitrogen atom as a constituent of the aromatic heterocyclic ring is oxidized with an oxidizing agent in the presence of fuming nitric acid to obtain the corresponding nitrogen-containing aromatic heterocyclic carboxylic acid in which a carboxyl group is bonded to a carbon atom adjacent to the nitrogen atom; wherein, as the oxidizing agent, e.g. oxygen, or an oxidizing agent as a combination of a bromate salt and a hydrogensulfite salt, can be used.

Description

  The present invention relates to a method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid useful as a pharmaceutical, agricultural chemical, other fine chemicals or intermediates thereof, a raw material monomer for a polymer, and the like.

  As a method for producing an aromatic heterocyclic carboxylic acid in which a carboxyl group is bonded to a carbon atom adjacent to a nitrogen atom constituting an aromatic heterocyclic ring, a method obtained by oxidizing an aromatic heterocyclic compound having an alkyl group is known. It has been. For example, Japanese Patent Laid-Open No. 2001-253838 (Patent Document 1) discloses a method for producing 2-pyridinecarboxylic acid by reacting α-picoline with air (20 atm) in the presence of an imide compound catalyst. Yes. However, in this method, although the reaction proceeds relatively quickly under pressure, there is a problem that the selectivity is low (74%) because many by-products are generated.

  In Zurnal Prikladnoi Khimi (1978), 51, (11), 2553 (Non-patent Document 1), α-picoline is oxidized with oxygen in the presence of caustic soda under high pressure (80 atm) to give 2-pyridinecarboxylic acid. A method of obtaining is disclosed. However, in this method, it is necessary to perform the reaction at a high pressure, and a high-pressure facility is required.

  In Fenzi Kexue Xuebao (2007), 23 (2), 82-86 (Non-patent Document 2), α-picoline is oxidized with potassium dichromate in the presence of sulfuric acid to give 2-pyridinecarboxylic acid. A method is disclosed. However, in this method, it is necessary to use a heavy metal compound in a large amount, and post-treatment becomes complicated.

JP 2001-253838 A

Zurnal Prikladnoi Khimi (1978), 51, (11), 2553 Fenzi Kexue Xuebao (2007), 23 (2), 82-86

  Accordingly, an object of the present invention is to provide a method for industrially efficiently producing a nitrogen-containing aromatic heterocyclic carboxylic acid with a high selectivity by a simple means.

  As a result of diligent studies to achieve the above object, the present inventors have oxidized a nitrogen-containing aromatic heterocyclic compound having an alkyl group on the carbon atom adjacent to the nitrogen atom with an oxidizing agent in the presence of fuming nitric acid. It was found that the reaction proceeded smoothly and the corresponding nitrogen-containing aromatic heterocyclic carboxylic acid was obtained with high selectivity and yield, and the present invention was completed.

  That is, the present invention is a nitrogen-containing aromatic heterocycle in which an alkyl group having 1 to 6 carbon atoms which may have a substituent is bonded to a carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle. The compound is oxidized with an oxidizing agent in the presence of fuming nitric acid to obtain a corresponding nitrogen-containing aromatic heterocyclic carboxylic acid in which a carboxyl group is bonded to a carbon atom adjacent to the nitrogen atom. A method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid is provided.

  In this production method, the alkyl group may be an alkyl group having 2 to 4 carbon atoms.

  As the oxidizing agent, a reactive agent composed of oxygen or a combination of bromate and bisulfite can be used.

（式中、Ｒは水素原子又はヒドロキシル基の保護基を示す）
で表されるジカルボキシイミド骨格を有する化合物を用いることができる。 Further, as a catalyst for the oxidation reaction, the following formula (1)

(In the formula, R represents a hydrogen atom or a protecting group for a hydroxyl group)
A compound having a dicarboximide skeleton represented by the formula can be used.

  According to the production method of the present invention, a nitrogen-containing aromatic heterocyclic carboxylic acid can be obtained with high selectivity and high yield by a simple means. In particular, it is not necessary to use high-pressure equipment or a large amount of heavy metal compounds, and nitrogen-containing aromatic heterocyclic carboxylic acids can be produced industrially efficiently with simple equipment and mild conditions.

[material]
In the present invention, as a raw material, a nitrogen-containing aromatic in which an alkyl group having 1 to 6 carbon atoms which may have a substituent is bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocyclic ring A heterocyclic compound (hereinafter simply referred to as “alkyl-substituted nitrogen-containing aromatic heterocyclic compound” or “substrate”) is used. When there are multiple carbon atoms adjacent to the nitrogen atom constituting the aromatic heterocyclic ring, at least one of them (the carbon atom to which the carboxyl group is bonded in the final target compound) has a substituent. It is only necessary that an alkyl group having 1 to 6 carbon atoms which may be bonded.

  The “aromatic heterocycle” in the nitrogen-containing aromatic heterocyclic compound is not particularly limited as long as it is an aromatic ring having one or more nitrogen atoms as ring constituent atoms. For example, pyridine ring, pyrazine ring, pyrimidine Examples thereof include monocyclic aromatic heterocycles such as rings and pyridazine rings; condensed aromatic heterocycles such as quinoline rings, isoquinoline rings, 1,8-naphthyridine rings, quinoxaline rings, and quinazoline rings. Among these, a pyridine ring, a pyrazine ring, a quinoline ring, and a quinoxaline ring are preferable in terms of reactivity, usefulness of the target compound, and the like.

  In the alkyl group having 1 to 6 carbon atoms which may have the substituent, the alkyl group having 1 to 6 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t-butyl. , A linear or branched alkyl group having 1 to 6 carbon atoms such as pentyl, hexyl and isohexyl groups. Among these, from the viewpoint of the usefulness of the method of the present invention, the selectivity of the reaction, etc., in particular, a linear or branched alkyl group having 2 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl group, etc. Is preferred.

  In the alkyl group which may have the above substituent, the substituent is not particularly limited as long as it does not inhibit the oxidation reaction. For example, hydroxyl group; methoxy, ethoxy, propoxy, isopropyloxy, butoxy group, etc. An alkoxy group having 1 to 6 carbon atoms; an alkoxyalkyl group having 2 to 12 carbon atoms such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and propoxyethyl groups; 1 to 6 carbon atoms such as acetyloxy and propionyloxy groups A carboxyl group; an alkoxycarbonyl group having 2 to 6 carbon atoms such as methoxycarbonyl and ethoxycarbonyl group; an acyl group having 1 to 6 carbon atoms such as acetyl, propionyl and benzoyl group; a cyano group; a nitro group; a fluorine atom Halogen atoms such as chlorine atoms and bromine atoms And the like.

  In the aromatic heterocycle, an atom other than a carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle (a carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle and a bond of a carboxyl group) (Including carbon atoms that are not intended) may also be bonded to a substituent. Such a substituent is not particularly limited as long as it does not inhibit the oxidation reaction. For example, the alkyl group having 1 to 6 carbon atoms which may have a substituent; Good alkenyl group having 2 to 6 carbon atoms; aryl group such as phenyl and naphthyl group; aralkyl group such as benzyl and 2-phenylethyl group; hydroxyl group; carbon number 1 such as methoxy, ethoxy, propoxy, isopropyloxy and butoxy groups Alkoxy groups having 6 to 6 carbon atoms; alkoxyalkyl groups having 2 to 12 carbon atoms such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and propoxyethyl groups; acyloxy groups having 1 to 6 carbon atoms such as acetyloxy and propionyloxy groups; Carboxyl group; alkoxy having 2 to 6 carbon atoms such as methoxycarbonyl and ethoxycarbonyl groups Carbonyl group; a cyano group; a nitro group; an acetyl, propionyl, acyl group having 1 to 6 carbon atoms such as benzoyl group fluorine atom, a chlorine atom, a halogen atom such as a bromine atom. As the “optionally substituted alkyl group having 1 to 6 carbon atoms”, the “having a substituent” is bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocyclic ring. The same thing as "the C1-C6 alkyl group which you may have" is mentioned. In the above “optionally substituted alkenyl group having 2 to 6 carbon atoms”, the “alkenyl group having 2 to 6 carbon atoms” is, for example, 2 carbon atoms such as vinyl, allyl, methallyl, crotyl group and the like. To 6 linear or branched alkenyl groups, and examples of the “substituent” include those similar to the “substituent” in the alkyl group which may have the substituent.

  In the aromatic heterocycle, two or more of the substituents bonded to atoms other than the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle are bonded to each other, and the aromatic heterocycle is A 3- to 12-membered non-aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring may be formed together with the constituent atoms.

  The substituent bonded to an atom other than the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle may be converted to another substituent by oxidation or the like depending on the reaction conditions. is there.

  A typical example of the alkyl-substituted nitrogen-containing aromatic heterocyclic compound used as a raw material is a compound represented by the following formula (2).

In formula (2), X represents CR ^C (carbon atom to which R ^C is bonded) or N (nitrogen atom). R ^A represents an alkyl group having 1 to 6 carbon atoms which may have a substituent. R ^B , R ^C , R ^D , and R ^E are the same or different and are a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon number. 2-6 alkenyl groups, aryl groups, aralkyl groups, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, acyloxy groups having 1 to 6 carbon atoms, carboxyl groups, 2 carbon atoms -6 alkoxycarbonyl group, a C1-C6 acyl group, a cyano group, a nitro group, or a halogen atom is shown. Two or more groups out of R ^B , R ^C , R ^D and R ^E may be bonded to each other to form a ring together with the atoms constituting the nitrogen-containing aromatic ring in the formula.

The alkyl group having 1 to 6 carbon atoms which may have a substituent in R ^A is bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocyclic ring. It may be the same as “an alkyl group having 1 to 6 carbon atoms”. In R ^B , R ^C , R ^D , and R ^E , an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, and aryl Group, aralkyl group, alkoxy group having 1 to 6 carbon atoms, alkoxyalkyl group having 2 to 12 carbon atoms, acyloxy group having 1 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, acyl having 1 to 6 carbon atoms As the group and the halogen atom, the “optionally substituted carbon number 1 to 1” in the substituent which may be bonded to an atom other than the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocyclic ring. And the like, and the like.

Rings that two or more of R ^B , R ^C , R ^D , and R ^E may be bonded to each other to form a nitrogen-containing aromatic ring in the formula include a cyclopentane ring and a cyclopentene ring , Cyclohexane ring, cyclohexene ring, etc., 3-6 membered non-aromatic ring (carbon ring or heterocyclic ring); benzene ring, naphthalene ring, pyridine ring, pyrazine ring, etc., 5-14 member aromatic ring (carbon Ring or heterocyclic ring).

  Specific examples of the compound represented by the formula (2) include, for example, α-picoline (2-methylpyridine), 2,6-lutidine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2-ethylpyridine, 2-propylpyridine, 2-isopropylpyridine, 2-butylpyridine, 2-isobutylpyridine, 2-s-butylpyridine, 2-t-butylpyridine, 2,6-diethylpyridine, 2,3- Diethylpyridine, 2,4-diethylpyridine, 2,5-diethylpyridine, 2-methylquinoline, 2-ethylquinoline, 2-propylquinoline, 2-butylquinoline, 2,3-dimethylquinoline, 2,4-dimethylquinoline 2-methylpyrazine, 2-ethylpyrazine, 2-propylpyrazine, 2,3-dimethylpyrazine, 2,6-dimethylpyrazine Etc. are exemplified.

[Fuming nitric acid]
In the present invention, it is important to carry out the oxidation reaction in the presence of fuming nitric acid. The fuming nitric acid is not particularly limited, and fumed nitric acid prepared by blowing nitrogen dioxide into concentrated nitric acid can be used. Commercial products can also be used as fuming nitric acid. By using fuming nitric acid, not only the oxidation reaction rate is remarkably increased, but also the alkyl group bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle is highly selectively converted into a carboxyl group. The

  The amount of fuming nitric acid used is, for example, 0.01 to 1 mol, preferably 0.02 to 0.5 mol, more preferably 0.001 mol, per mol of the alkyl-substituted nitrogen-containing aromatic heterocyclic compound used as a raw material. It is 05-0.4 mol. If this amount is too small, the effect of addition is small, while if it is too large, side reactions may easily occur.

[Oxidant]
The oxidizing agent may be any oxidizing agent that can oxidize an alkyl group to a carboxyl group. For example, oxygen (molecular oxygen), a reagent comprising a combination of bromate and bisulfite, periodate A reaction agent composed of a combination of bisulphite and bisulfite, hypohalous acid or a salt thereof, and the like can be used.

  As oxygen, in addition to pure oxygen, a mixed gas of oxygen and an inert gas (nitrogen, argon, etc.), air, or the like can be used.

  In the reaction agent comprising a combination of bromate and bisulfite, examples of the bromate include sodium bromate, potassium bromate, and ammonium bromate. Examples of the bisulfite include sodium bisulfite, potassium bisulfite, and ammonium bisulfite. As the oxidizing agent comprising a combination of bromate and bisulfite, a combination of sodium bromate and sodium bisulfite is particularly preferable. Further, in the oxidizing agent consisting of a combination of periodate and bisulfite, as the periodate, for example, sodium periodate, potassium periodate and the like, and as the bisulfite, for example, The thing of the said illustration is mentioned. Examples of hypohalous acid or salts thereof include hypochlorous acid, hypobromite, hypoiodous acid, sodium salts, potassium salts, and ammonium salts thereof.

  The amount of the oxidizing agent used is usually 1 equivalent or more (eg, 1 to 10 equivalents), preferably 1.5 equivalents or more (eg, 1.5 equivalents) relative to the alkyl-substituted nitrogen-containing aromatic heterocyclic compound used as a raw material. ~ 5 equivalents). When oxygen is used as the oxidizing agent, the oxygen can be used in a large excess with respect to the raw material.

[catalyst]
A catalyst may be used in the production method of the present invention. As the catalyst, a compound having a dicarboximide skeleton represented by the formula (1) can be used. In particular, when oxygen is used as the oxidizing agent, it is preferable to use a compound having a dicarboximide skeleton represented by the formula (1). By using such a compound having a dicarboximide skeleton, the oxidation reaction proceeds more smoothly, and the target compound can be obtained with extremely high selectivity and yield.

  In the formula (1), R represents a hydrogen atom or a hydroxyl protecting group. When R is a hydroxyl-protecting group, a plurality of portions excluding R in the skeleton represented by the formula (1) may be bonded via R.

As the protecting group for the hydroxyl group represented by R, a protecting group for a hydroxyl group commonly used in the field of organic synthesis can be used. Examples of such protecting groups include alkyl groups (eg, C _1-4 alkyl groups such as methyl and t-butyl groups), alkenyl groups (eg, allyl groups), cycloalkyl groups (eg, cyclohexyl groups, etc.) ), Aryl groups (eg, 2,4-dinitrophenyl group, etc.), aralkyl groups (eg, benzyl, 2,6-dichlorobenzyl, 3-bromobenzyl, 2-nitrobenzyl, triphenylmethyl groups, etc.); substituted methyl Groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxy Methyl group), substituted ethyl group (for example, 1-ethoxyethyl, 1-methyl) -1-methoxyethyl, 1-isopropoxyethyl, 2,2,2-trichloroethyl, 2-methoxyethyl group, etc.), tetrahydropyranyl group, tetrahydrofuranyl group, 1-hydroxyalkyl group (for example, 1-hydroxyethyl group) A group capable of forming an acetal or hemiacetal group with a hydroxyl group such as 1-hydroxyhexyl, 1-hydroxydecyl, 1-hydroxyhexadecyl, 1-hydroxy-1-phenylmethyl group, etc .; an acyl group (for example, Aliphatic saturated or unsaturated such as C _1-20 aliphatic acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl groups A Acetoacetyl group; alicyclic acyl group such as cycloalkanecarbonyl group such as cyclopentanecarbonyl and cyclohexanecarbonyl group; aromatic acyl group such as benzoyl and naphthoyl group), sulfonyl group (methanesulfonyl, ethanesulfonyl, Trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl groups, etc.), alkoxycarbonyl groups (for example, C _1-4 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl groups, etc.), aralkyloxy Carbonyl group (for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, etc.), substituted or unsubstituted carbamoyl group (for example, carbamoyl, methylcarbamoyl, phenyl) Rubamoyl group), inorganic acid (sulfuric acid, nitric acid, phosphoric acid, boric acid, etc.), OH group removed, dialkylphosphinothioyl group (for example, dimethylphosphinothioyl group, etc.), diarylphosphinothioyl Group (for example, diphenylphosphinothioyl group), substituted silyl group (for example, trimethylsilyl, t-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl group, etc.) and the like.

  In addition, when a plurality of moieties other than R in the skeleton represented by the formula (1) are bonded via R, examples of R include oxalyl, malonyl, succinyl, glutaryl, adipoyl, phthaloyl, isophthaloyl, terephthaloyl A polycarboxylic acid acyl group such as a carbonyl group; a polyvalent hydrocarbon group such as a methylene, ethylidene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene group (particularly, an acetal bond is formed with two hydroxyl groups) Group).

  Preferable R includes, for example, a hydrogen atom; a group capable of forming an acetal or hemiacetal group with a hydroxyl group; an OH group is removed from an acid such as carboxylic acid, sulfonic acid, carbonic acid, carbamic acid, sulfuric acid, phosphoric acid or boric acid. Hydrolyzable protecting groups that can be removed by hydrolysis of the group (acyl group, sulfonyl group, alkoxycarbonyl group, carbamoyl group, etc.).

（式中、ｎは０又は１を示す。Ｒは前記に同じ）
で表される環状イミド骨格を有する環状イミド系化合物が含まれる。 The compound having a dicarboximide skeleton represented by the formula (1) includes the following formula (I):

(In the formula, n represents 0 or 1. R is the same as above)
The cyclic imide type compound which has the cyclic imide frame | skeleton represented by these is contained.

  The cyclic imide compound may have a plurality of cyclic imide skeletons represented by the formula (I) in the molecule. In the cyclic imide compound, a plurality of portions (N-oxy cyclic imide skeleton) excluding R in the cyclic imide skeleton may be bonded via R. In the formula (I), n represents 0 or 1. That is, Formula (I) represents a 5-membered cyclic imide skeleton when n is 0, and represents a 6-membered cyclic imide skeleton when n is 1.

［式中、ｎは０又は１を示す。Ｒは水素原子又はヒドロキシル基の保護基を示す。Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶は、同一又は異なって、水素原子、ハロゲン原子、アルキル基、アリール基、シクロアルキル基、ヒドロキシル基、アルコキシ基、カルボキシル基、置換オキシカルボニル基、アシル基又はアシルオキシ基を示し、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶のうち少なくとも２つが互いに結合して、環状イミド骨格を構成する炭素原子又は炭素−炭素結合と共に、二重結合、又は芳香族性若しくは非芳香族性の環を形成してもよい。前記Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、又はＲ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶のうち少なくとも２つが互いに結合して形成された二重結合又は芳香族性若しくは非芳香族性の環には、下記式（ａ）

（式中、ｎ、Ｒは前記に同じ）
で表される環状イミド基がさらに１又は２個以上形成されていてもよい］
で表される化合物が挙げられる。 As a typical example of the cyclic imide compound, the following formula (3)

[Wherein n represents 0 or 1; R represents a hydrogen atom or a hydroxyl-protecting group. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, halogen atom, alkyl group, aryl group, cycloalkyl group, hydroxyl group, alkoxy group, carboxyl group, substituted An oxycarbonyl group, an acyl group or an acyloxy group, wherein at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded to each other to form a cyclic imide skeleton, A double bond or an aromatic or non-aromatic ring may be formed together with the carbon bond. ^{Two of} R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , or at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded together. In the case of a heavy bond or an aromatic or non-aromatic ring, the following formula (a)

(Wherein n and R are the same as above)
1 or 2 or more cyclic imide groups represented by
The compound represented by these is mentioned.

In the imide compound represented by the formula (3), the halogen atoms among the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include iodine, bromine, chlorine and fluorine atoms. Examples of the alkyl group include about 1 to 30 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, hexyl, decyl, dodecyl, tetradecyl, and hexadecyl groups (particularly carbon number). About 1 to 20) linear or branched alkyl group.

  Aryl groups include phenyl, tolyl, xylyl, naphthyl groups, and the like, and cycloalkyl groups include cyclopentyl, cyclohexyl groups, and the like. The alkoxy group includes, for example, about 1 to 30 carbon atoms such as methoxy, ethoxy, isopropoxy, butoxy, t-butoxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, tetradecyloxy, octadecyloxy groups (particularly carbon An alkoxy group of about 1 to 20).

Examples of the substituted oxycarbonyl group include a C _1-30 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, hexyloxycarbonyl, decyloxycarbonyl, hexadecyloxycarbonyl group, etc. (Especially C _1-20 alkoxy-carbonyl group); cycloalkyloxycarbonyl group such as cyclopentyloxycarbonyl, cyclohexyloxycarbonyl group (especially 3-20 membered cycloalkyloxycarbonyl group); phenyloxycarbonyl, naphthyloxycarbonyl group aryloxycarbonyl group such as (in particular, C _6-20 aryloxy - carbonyl group); aralkyloxycarbonyl group such as benzyloxycarbonyl group (particularly, C _7-21 Ala Kiruokishi - carbonyl group).

Examples of the acyl group include C _1-30 aliphatic acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl groups (particularly, C ₁ Aliphatic saturated or unsaturated acyl groups such as _-20 aliphatic acyl groups; acetoacetyl groups; alicyclic acyl groups such as cycloalkanecarbonyl groups such as cyclopentanecarbonyl and cyclohexanecarbonyl groups; aromatics such as benzoyl and naphthoyl groups Group acyl groups and the like.

Examples of the acyloxy group include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy, octanoyloxy, decanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy Aliphatic saturated or unsaturated acyloxy groups such as C _1-30 aliphatic acyloxy groups (particularly C _1-20 aliphatic acyloxy groups); acetoacetyloxy groups; cyclopentanecarbonyloxy, cyclohexanecarbonyloxy groups, etc. Examples thereof include alicyclic acyloxy groups such as cycloalkanecarbonyloxy group; aromatic acyloxy groups such as benzoyloxy and naphthoyloxy groups.

The substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different. In the formula (1), at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded to each other to form a carbon atom or a carbon-carbon bond constituting a cyclic imide skeleton. , A double bond, or an aromatic or non-aromatic ring. A preferable aromatic or non-aromatic ring is a 5- to 12-membered ring, particularly a 6- to 10-membered ring, and may be a heterocyclic ring or a condensed heterocyclic ring, but is often a hydrocarbon ring. Such a ring includes, for example, a non-aromatic alicyclic ring (a cycloalkene ring which may have a substituent such as a cyclohexane ring and a cycloalkene ring which may have a substituent such as a cyclohexene ring). Ring), non-aromatic bridged ring (such as bridged hydrocarbon ring optionally having substituent such as 5-norbornene ring), benzene ring, naphthalene ring and the like Also included are aromatic rings (including fused rings). The ring is often composed of an aromatic ring. The ring has a substituent such as an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, a substituted oxycarbonyl group, an acyl group, an acyloxy group, a nitro group, a cyano group, an amino group, and a halogen atom. Also good.

^{Two of} R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , or at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded together. In the heavy bond or aromatic or non-aromatic ring, one or more cyclic imide groups represented by the formula (a) may be further formed. For example, when R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ is an alkyl group having 2 or more carbon atoms, the cyclic imide group containing two adjacent carbon atoms constituting the alkyl group May be formed. When at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded to each other to form a double bond together with the carbon-carbon bond constituting the cyclic imide skeleton, The cyclic imide group may be formed including a heavy bond. Furthermore, at least two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are bonded to each other, and together with the carbon atom or carbon-carbon bond constituting the cyclic imide skeleton, aromatic or non-aromatic When forming a family ring, the cyclic imide group may be formed including two adjacent carbon atoms constituting the ring.

（式中、Ｒ¹¹〜Ｒ¹⁶は、同一又は異なって、水素原子、ハロゲン原子、アルキル基、アリール基、シクロアルキル基、ヒドロキシル基、アルコキシ基、カルボキシル基、置換オキシカルボニル基、アシル基又はアシルオキシ基を示す。Ｒ¹⁷〜Ｒ²⁶は、同一又は異なって、水素原子、アルキル基、ハロアルキル基、ヒドロキシル基、アルコキシ基、カルボキシル基、置換オキシカルボニル基、アシル基、アシルオキシ基、ニトロ基、シアノ基、アミノ基、ハロゲン原子を示す。Ｒ¹⁷〜Ｒ²⁶は、隣接する基同士が結合して、式（3c）、（3d）、（3e）、（3f）、（3h）又は（3i）中に示される５員又は６員の環状イミド骨格を形成していてもよい。式（3f）中、Ａはメチレン基又は酸素原子を示す。Ｒは前記に同じ） Preferred imide compounds include compounds represented by the following formula.

(Wherein R ^{11 to} R ¹⁶ are the same or different and each represents a hydrogen atom, halogen atom, alkyl group, aryl group, cycloalkyl group, hydroxyl group, alkoxy group, carboxyl group, substituted oxycarbonyl group, acyl group or acyloxy group) R ^{17 to} R ²⁶ are the same or different and each represents a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, a substituted oxycarbonyl group, an acyl group, an acyloxy group, a nitro group, or a cyano group. In the formula (3c), (3d), (3e), (3f), (3h) or (3i), R ^{17 to} R ²⁶ are bonded to each other. And a 5-membered or 6-membered cyclic imide skeleton represented by formula (3f), wherein A represents a methylene group or an oxygen atom, R is the same as above)

Halogen atom in the substituents R ¹¹ to R ^16, an alkyl group, an aryl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, substituted oxycarbonyl group, an acyl group, the acyloxy group, in the R ¹ to R ⁶ Examples corresponding to the corresponding groups are exemplified.

In the substituents R ^{17 to} R ²⁶ , the alkyl group includes the same alkyl group as the above exemplified alkyl group, particularly an alkyl group having about 1 to 6 carbon atoms, and the haloalkyl group includes a trifluoromethyl group and the like. For haloalkyl groups and alkoxy groups having about 1 to 4 carbon atoms, the same alkoxy groups as described above, particularly for lower alkoxy groups having about 1 to 4 carbon atoms and substituted oxycarbonyl groups, the same substituted oxycarbonyl groups ( Alkoxycarbonyl group, cycloalkyloxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group and the like). Examples of the acyl group include the same acyl groups as described above (aliphatic saturated or unsaturated acyl group, acetoacetyl group, alicyclic acyl group, aromatic acyl group, etc.), and the acyloxy group is the same as described above. And an acyloxy group (aliphatic saturated or unsaturated acyloxy group, acetoacetyloxy group, alicyclic acyloxy group, aromatic acyloxy group, etc.). Examples of halogen atoms include fluorine, chlorine and bromine atoms. The substituents R ^{17 to} R ²⁶ are usually a hydrogen atom, a lower alkyl group having about 1 to 4 carbon atoms, a carboxyl group, a substituted oxycarbonyl group, a nitro group, or a halogen atom in many cases.

  Typical examples of compounds having a 5-membered N-substituted cyclic imide skeleton among preferable imide compounds include, for example, N-hydroxysuccinimide, N-hydroxy-α-methylsuccinimide, N-hydroxy-α, α. -Dimethylsuccinimide, N-hydroxy-α, β-dimethylsuccinimide, N-hydroxy-α, α, β, β-tetramethylsuccinimide, N-hydroxymaleimide, N-hydroxyhexahydrophthal Acid imide, N, N'-dihydroxycyclohexanetetracarboxylic acid diimide, N-hydroxyphthalic acid imide, N-hydroxytetrabromophthalic acid imide, N-hydroxytetrachlorophthalic acid imide, N-hydroxyhetic acid imide, N-hydroxy Highmic acid imide, N-hydroxy trimellitic acid imide N, N′-dihydroxypyromellitic acid diimide, N, N′-dihydroxynaphthalenetetracarboxylic acid diimide, α, β-diacetoxy-N-hydroxysuccinimide, N-hydroxy-α, β-bis (propionyloxy) succin Acid imide, N-hydroxy-α, β-bis (valeryloxy) succinimide, N-hydroxy-α, β-bis (lauroyloxy) succinimide, α, β-bis (benzoyloxy) -N-hydroxysuccinic acid Acid imide, N-hydroxy-4-methoxycarbonylphthalimide, 4-chloro-N-hydroxyphthalimide, 4-ethoxycarbonyl-N-hydroxyphthalimide, N-hydroxy-4-pentyloxycarbonylphthalimide 4-dodecyloxy-N-hydroxycarbonylphthalate Acid imide, N-hydroxy-4-phenoxycarbonylphthalimide, N-hydroxy-4,5-bis (methoxycarbonyl) phthalimide, 4,5-bis (ethoxycarbonyl) -N-hydroxyphthalimide, N -Hydroxy-4,5-bis (pentyloxycarbonyl) phthalic acid imide, 4,5-bis (dodecyloxycarbonyl) -N-hydroxyphthalic acid imide, N-hydroxy-4,5-bis (phenoxycarbonyl) phthalic acid Compounds in which R in formula (3) such as imide is a hydrogen atom; compounds corresponding to these compounds, wherein R is an acyl group such as an acetyl group, propionyl group, or benzoyl group; N-methoxymethyloxyphthalic acid imide, N- (2-methoxyethoxymethyloxy) phthalimide, N-tetrahydropi Compounds in which R in Formula (3) such as nyloxyphthalic imide is a group capable of forming an acetal or hemiacetal bond with a hydroxyl group; N-methanesulfonyloxyphthalimide, N- (p-toluenesulfonyloxy) phthal Compounds in which R in formula (3) such as acid imide is a sulfonyl group; R in formula (3) such as sulfate, nitrate, phosphate or borate of N-hydroxyphthalimide is converted from an inorganic acid to OH Examples thereof include a compound which is a group obtained by removing a group.

  Representative examples of compounds having a 6-membered N-substituted cyclic imide skeleton among preferable imide compounds include, for example, N-hydroxyglutarimide, N-hydroxy-α, α-dimethylglutarimide, N-hydroxy-β, β-dimethylglutarimide, N-hydroxy-1,8-decalin dicarboxylic imide, N, N′-dihydroxy-1,8; 4,5-decalin tetracarboxylic diimide, N-hydroxy-1,8-naphthalenedicarboxylic Compounds in which R is a hydrogen atom in formula (3) such as acid imide (N-hydroxynaphthalic acid imide), N, N′-dihydroxy-1,8; 4,5-naphthalenetetracarboxylic acid diimide; and the like A compound in which R is an acyl group such as an acetyl group, a propionyl group or a benzoyl group; R in formula (3) such as ruoxy-1,8-naphthalenedicarboxylic acid imide, N, N′-bis (methoxymethyloxy) -1,8; 4,5-naphthalenetetracarboxylic acid diimide is a hydroxyl group and an acetal or Compound that is a group capable of forming a hemiacetal bond; N-methanesulfonyloxy-1,8-naphthalenedicarboxylic imide, N, N′-bis (methanesulfonyloxy) -1,8; 4,5-naphthalenetetracarboxylic Compounds in which R in formula (3) is a sulfonyl group such as acid diimide; N-hydroxy-1,8-naphthalenedicarboxylic imide or N, N′-dihydroxy-1,8; 4,5-naphthalene tetracarboxylic acid diimide R in formula (3) such as sulfate ester, nitrate ester, phosphate ester or borate ester Are compounds in which OH is removed from an inorganic acid.

（式中、ｍは１又は２を示す。Ｇは炭素原子又は窒素原子を示し、ｍが２のとき、２つのＧは同一でもよく異なっていてもよい。Ｒは前記に同じ）
で表される環状アシルウレア骨格［−Ｃ（＝Ｏ）−Ｎ−Ｃ（＝Ｏ）−Ｎ−］を有する環状アシルウレア系化合物が含まれる。 The compound having a dicarboximide skeleton represented by the formula (1) includes the following formula (II) in addition to the cyclic imide compound.

(In the formula, m represents 1 or 2. G represents a carbon atom or a nitrogen atom, and when m is 2, two Gs may be the same or different. R is the same as above).
And a cyclic acylurea compound having a cyclic acylurea skeleton [—C (═O) —N—C (═O) —N—] represented by the formula:

  The cyclic acylurea compound may have a plurality of cyclic acylurea skeletons represented by the formula (II) in the molecule. In the cyclic acylurea compound, a plurality of portions (N-oxy cyclic acylurea skeleton) excluding R in the cyclic acylurea skeleton represented by the formula (II) may be bonded via R. The atom G constituting the cyclic acylurea skeleton and the nitrogen atom bonded to the G may have various substituents, and the cyclic acylurea skeleton has a non-aromatic or aromatic ring. It may be condensed. Furthermore, the cyclic acylurea skeleton may have a double bond in the ring.

（式中、Ｒは前記に同じ） The cyclic acylurea skeleton represented by the formula (II) includes a 3-hydroxy (or 3-substituted oxy) hydantoin skeleton represented by the following formula (IIa), a 4-hydroxy (or the formula (IIb) 4-substituted oxy) -1,2,4-triazolidine-3,5-dione skeleton [including 4-hydroxy (or 4-substituted oxy) -1,2,4-triazoline-3,5-dione skeleton], Hydro-3-hydroxy (or 3-substituted oxy) -1,3-diazine-2,4-dione skeleton represented by formula (IIc) [hexahydro-1-hydroxy (or 1-substituted oxy) -1,3 -Diazine-2,4,6-trione skeleton, hexahydro-1,3-dihydroxy (or 1,3-bis-substituted oxy) -1,3-diazine-2,4,6-trione skeleton, 3-hydroxy (or 3-substituted oxy) ura A hydro-4-hydroxy (or 4-substituted oxy) -1,2,4-triazine-3,5-dione skeleton represented by the formula (IId) Hydro-1-hydroxy (or 1-substituted oxy) -1,3,5-triazine-2,6-dione skeleton, and hydro-5-hydroxy (or 5-substituted oxy)-represented by formula (IIf) A 1,2,3,5-tetrazine-4,6-dione skeleton is included.

(Wherein R is the same as above)

（式中、Ｒ^a、Ｒ^dは、同一又は異なって、水素原子、アルキル基、アリール基、シクロアルキル基、保護基で保護されていてもよいヒドロキシル基、保護基で保護されていてもよいカルボキシル基、又はアシル基を示し、Ｒ^b、Ｒ^cは、同一又は異なって、水素原子、ハロゲン原子、アルキル基、アリール基、シクロアルキル基、ヒドロキシル基、アルコキシ基、カルボキシル基、置換オキシカルボニル基、アシル基又はアシルオキシ基を示す。Ｒ^a、Ｒ^b、Ｒ^c、Ｒ^dのうち少なくとも２つが互いに結合して、式中の環を構成する原子とともに二重結合、又は芳香族性若しくは非芳香族性の環を形成してもよく、Ｒ^bとＲ^cは一体となってオキソ基を形成してもよい。Ｒは前記に同じ）
で表されるヒドロ−１−ヒドロキシ（又は１−置換オキシ）−１，３，５−トリアジン−２，６−ジオン化合物が挙げられる。 As a typical example of the cyclic acylurea compound, the following formula (4)

Wherein R ^a and R ^d are the same or different and may be protected with a hydrogen atom, an alkyl group, an aryl group, a cycloalkyl group, a hydroxyl group which may be protected with a protecting group, or a protecting group. Represents a carboxyl group or an acyl group, and R ^b and R ^c are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an aryl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, or a substituted oxycarbonyl group Represents an acyl group or an acyloxy group, wherein at least two of R ^a , R ^b , R ^c and R ^d are bonded to each other to form a double bond together with the atoms constituting the ring, or aromatic or non-aromatic A ring of a family may be formed, and R ^b and R ^c may together form an oxo group (R is the same as above)
And hydro-1-hydroxy (or 1-substituted oxy) -1,3,5-triazine-2,6-dione compounds represented by:

In formula (4), examples of the alkyl group, aryl group, cycloalkyl group, and acyl group in R ^a and R ^d are the same as the alkyl group in R ^{1 to} R ⁶ described above. Examples of the protecting group for the hydroxyl group include those described above.

Examples of the protecting group for the carboxyl group include protecting groups commonly used in the field of organic synthesis, such as alkoxy groups (for example, C _1-6 alkoxy groups such as methoxy, ethoxy, butoxy, etc.), cycloalkyloxy groups, aryloxy groups ( For example, phenoxy group etc.) aralkyloxy group (eg benzyloxy group etc.), trialkylsilyloxy group (eg trimethylsilyloxy group etc.), optionally substituted amino group (eg amino group; methyl And mono- or di-C _1-6 alkylamino groups such as amino group and dimethylamino group).

As the halogen atom, alkyl group, aryl group, cycloalkyl group, hydroxyl group, alkoxy group, carboxyl group, substituted oxycarbonyl group, acyl group, and acyloxy group in R ^b and R ^c , the alkyl group in R ^{1 to} R ⁶ above. The same thing is illustrated.

In the formula (4), at least two of R ^a , R ^b , R ^c and R ^d are bonded to each other to form a double bond together with the atoms (carbon atom and / or nitrogen atom) constituting the ring shown in the formula , Or an aromatic or non-aromatic ring, and R ^b and R ^c may together form an oxo group. Examples of preferred aromatic or non-aromatic rings are the same as those described above.

［式中、Ｒ、Ｒ′、Ｒ″は、同一又は異なって、水素原子又はヒドロキシル基の保護基を示す］ Of the compounds represented by formula (4), isocyanuric acid derivatives represented by the following formula (4a) are preferred.

[Wherein, R, R ′ and R ″ are the same or different and each represents a hydrogen atom or a protecting group for a hydroxyl group]

  Representative examples of the cyclic acylurea compounds include, for example, 3-hydroxyhydantoin, 1,3-dihydroxyhydantoin, 3-hydroxy-1-methylhydantoin, 3-acetoxyhydantoin, 1,3-diacetoxyhydantoin, 3-acetoxy Compounds having a skeleton represented by the formula (IIa) such as -1-methylhydantoin; 4-hydroxy-1,2,4-triazolidine-3,5-dione, 4-hydroxy-1,2-dimethyl-1, 2,4-triazolidine-3,5-dione, 4-acetoxy-1,2,4-triazolidine-3,5-dione, 4-acetoxy-1,2-dimethyl-1,2,4-triazolidine-3, 5-dione, 4-hydroxy-1,2,4-triazoline-3,5-dione, 4-acetoxy-1,2,4-tria Compounds having a skeleton represented by formula (IIb) such as phosphorus-3,5-dione; hexahydro-3-hydroxy-1,3-diazine-2,4-dione, hexahydro-1,3-dihydroxy-1, 3-diazine-2,4-dione, hexahydro-3-hydroxy-1-methyl-1,3-diazine-2,4-dione, 3-acetoxy-hexahydro-1,3-diazine-2,4-dione, 1,3-diacetoxy-hexahydro-1,3-diazine-2,4-dione, 3-acetoxy-hexahydro-1-methyl-1,3-diazine-2,4-dione, hexahydro-1-hydroxy-1, 3-diazine-2,4,6-trione, 1-acetoxy-hexahydro-1,3-diazine-2,4,6-trione, hexahydro-1,3-dihydroxy-1, -Represented by formula (IIc) such as diazine-2,4,6-trione, 1,3-diacetoxy-hexahydro-1,3-diazine-2,4,6-trione, 3-hydroxyuracil, 3-acetoxyuracil A compound having a skeleton such as hexahydro-4-hydroxy-1,2,4-triazine-3,5-dione, hexahydro-4-hydroxy-1,2-dimethyl-1,2,4-triazine-3,5 -Dione, 4-acetoxy-hexahydro-1,2,4-triazine-3,5-dione, 4-acetoxy-hexahydro-1,2-dimethyl-1,2,4-triazine-3,5-dione, etc. Compound having a skeleton represented by formula (IId); hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (= 1,3,5-trihi Droxyisocyanuric acid), 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione, 1,3,5-tris (benzoyloxy) -hexahydro-1,3 , 5-triazine-2,4,6-trione, hexahydro-1,3,5-tris (methoxymethyloxy) -1,3,5-triazine-2,4,6-trione, hexahydro-1-hydroxy- 1,3,5-triazine-2,6-dione, hexahydro-1-hydroxy-3,5-dimethyl-1,3,5-triazine-2,6-dione, 1-acetoxy-hexahydro-1,3 It has a skeleton represented by the formula (IIe) such as 5-triazine-2,6-dione, 1-acetoxy-hexahydro-3,5-dimethyl-1,3,5-triazine-2,6-dione Compound [for example, compound represented by formula (4)]; hexahydro-5-hydroxy-1,2,3,5-tetrazine-4,6-dione, hexahydro-5-hydroxy-1,2,3-trimethyl -1,2,3,5-tetrazine-4,6-dione, 5-acetoxy-hexahydro-1,2,3,5-tetrazine-4,6-dione, 5-acetoxy-hexahydro-1,2,3 -A compound having a skeleton represented by the formula (IIf) such as trimethyl-1,2,3,5-tetrazine-4,6-dione.

  Among the compounds having the dicarboximide skeleton, a compound in which R is a hydrogen atom (N-hydroxy cyclic compound) can be produced according to a known method or by a combination of known methods. Among the compounds having the dicarboximide skeleton, a compound in which R is a hydroxyl protecting group is subjected to a conventional protecting group introduction reaction to a compound (N-hydroxy cyclic compound) in which R is a hydrogen atom. Utilizing it, it can be prepared by introducing a desired protecting group.

  Specifically, among the cyclic imide compounds, a compound in which R is a hydrogen atom (N-hydroxy cyclic imide compound) is a conventional imidization reaction, for example, by reacting a corresponding acid anhydride with hydroxylamine. It can be obtained by a method of imidization via ring opening and ring closing of an acid anhydride group. For example, N-acetoxyphthalimide can be obtained by reacting N-hydroxyphthalimide with acetic anhydride or reacting acetyl halide in the presence of a base. It is also possible to manufacture by other methods.

  Particularly preferred cyclic imide compounds as catalysts are N-hydroxyimide compounds derived from aliphatic polycarboxylic anhydrides (cyclic anhydrides) or aromatic polycarboxylic anhydrides (cyclic anhydrides) (for example, N -Hydroxysuccinimide, N-hydroxyphthalimide, N, N'-dihydroxypyromellitic diimide, N-hydroxyglutarimide, N-hydroxy-1,8-naphthalenedicarboxylic acid imide, N, N'-dihydroxy- 1,8; 4,5-naphthalenetetracarboxylic acid diimide and the like); and compounds obtained by introducing a protecting group into the hydroxyl group of the N-hydroxyimide compound.

  Among the cyclic acylurea compounds, for example, 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione (= 1,3,5-triacetoxyisocyanuric acid) is , Hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (= 1,3,5-trihydroxyisocyanuric acid) and acetic anhydride, It can be obtained by reacting acetyl halide in the presence.

  The compounds having a dicarboximide skeleton represented by the formula (1) can be used alone or in combination of two or more in the reaction. For example, a cyclic imide compound having a cyclic imide skeleton represented by formula (I) and a cyclic acylurea compound having a cyclic acylurea skeleton represented by formula (II) can be used in combination. A catalyst comprising a compound having a dicarboximide skeleton may be generated in the reaction system. A catalyst comprising a compound having a dicarboximide skeleton may be used in a form supported on a carrier. As the carrier, porous carriers such as activated carbon, zeolite, silica, silica-alumina and bentonite are often used. The amount of the compound having a dicarboximide skeleton supported on the carrier is, for example, 0.1 to 50 parts by weight, preferably 0.5 to 30 parts by weight, and more preferably 1 to 20 parts by weight with respect to 100 parts by weight of the carrier. Degree.

  The amount of the catalyst comprising the compound having a dicarboximide skeleton can be selected within a wide range. For example, 0.0000001 to 1 mol, preferably 1 mol, per mol of the raw material (alkyl-substituted nitrogen-containing aromatic heterocyclic compound) The amount is about 0.000001 to 0.5 mol, more preferably about 0.00001 to 0.4 mol.

[Cocatalyst]
In the present invention, a cocatalyst can be used together with the catalyst (for example, a catalyst comprising the compound having the dicarboximide skeleton). Examples of the cocatalyst include metal compounds. By using a metal compound as a cocatalyst, the reaction rate and the selectivity of the reaction can be improved.

  Although it does not specifically limit as a metal element which comprises a metal compound, The periodic table 1-15 group metal element is used in many cases. In this specification, boron B is also included in the metal element. Preferred metal elements include transition metal elements (periodic group 3-12 elements). Of these, Mn, Co, Zr, Ce, Fe, V, Mo and the like are preferable, and Mn and Co are particularly preferable. Moreover, activity may be improved by using a transition metal element in combination with a periodic table group 1 or group 2 element. The valence of the metal element is not particularly limited, and is about 0 to 6, for example.

Examples of the metal compound include simple substances, hydroxides, oxides (including composite oxides), halides (fluorides, chlorides, bromides, iodides), oxo acid salts (eg, nitrates, sulfates) of the above metal elements. , Phosphates, borates, carbonates, etc.), inorganic compounds such as isopolyacid salts, heteropolyacid salts; organic acid salts (eg acetate, propionate, cyanate, naphthenate, stearic acid) Salt) and organic compounds such as complexes. The ligands constituting the complex include OH (hydroxo), alkoxy (methoxy, ethoxy, propoxy, butoxy, etc.), acyl (acetyl, propionyl, etc.), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, etc.), acetylacetonato , Cyclopentadienyl group, halogen atom (chlorine, bromine, etc.), CO, CN, oxygen atom, H ₂ O (aquo), phosphine (triarylphosphine such as triphenylphosphine), phosphorus compound, NH ₃ (ammine) ), NO, NO ₂ (nitro), NO ₃ (nitrato), nitrogen-containing compounds such as ethylenediamine, diethylenetriamine, pyridine and phenanthroline.

  Specific examples of the metal compound include, for example, a cobalt compound, an inorganic compound such as cobalt hydroxide, cobalt oxide, cobalt chloride, cobalt bromide, cobalt nitrate, cobalt sulfate, and cobalt phosphate; cobalt acetate, naphthene Examples include organic acid salts such as cobalt acid and cobalt stearate; divalent or trivalent cobalt compounds such as complexes such as cobalt acetylacetonate. Examples of vanadium compounds include inorganic compounds such as vanadium hydroxide, vanadium oxide, vanadium chloride, vanadyl chloride, vanadium sulfate, vanadyl sulfate, sodium vanadate; complexes such as vanadium acetylacetonate and vanadyl acetylacetonate Examples thereof include divalent to pentavalent vanadium compounds. Furthermore, examples of sodium compounds that are Group 1 element compounds of the periodic table include inorganic compounds (including simple metals) such as sodium, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium chloride, sodium sulfate; sodium methoxide, Organic compounds such as sodium ethoxide, sodium acetate, sodium benzoate, sodium p-toluenesulfonate, and the like can be mentioned. Examples of other metal element compounds include compounds corresponding to the cobalt compounds, vanadium compounds, and sodium compounds. A metal compound can be used individually or in combination of 2 or more types. In particular, when a cobalt compound, a manganese compound, and optionally a zirconium compound are combined, the reaction rate is often significantly improved. It is also preferable to use a combination of a plurality of metal compounds having different valences (for example, a divalent metal compound and a trivalent metal compound, more specifically, a divalent manganese compound and a trivalent cobalt compound). . Further, when a catalyst in which X is an —OR group and R is a protecting group for a hydroxyl group in the formula (I) or (II) is used, a transition metal element compound such as a cobalt compound and a periodic table are used as the metal compound. When used in combination with a Group 1 element or Group 2 element compound, a high catalytic activity can be obtained even in a reaction in a non-acidic solvent or an aprotic solvent, and the reaction between the substrate and the catalyst can be suppressed. .

  The usage-amount of the said metal compound is 0.0001-10 mol with respect to 1 mol of catalysts which consist of a compound which has the said dicarboximide frame | skeleton, for example, Preferably it is about 0.005-3 mol. Moreover, the usage-amount of a metal compound is 0.00001 mol%-10 mol% with respect to 1 mol of raw materials (alkyl substituted nitrogen-containing aromatic heterocyclic compound), Preferably it is about 0.1 mol%-5 mol%. It is.

[reaction]
The reaction is carried out in the presence or absence of a solvent. The solvent can be appropriately selected depending on the type of oxidizing agent, etc., for example, organic acids such as acetic acid and propionic acid; nitriles such as acetonitrile, propionitrile and benzonitrile; formamide, acetamide, dimethylformamide (DMF), dimethyl Amides such as acetamide; alcohols such as t-butanol and t-amyl alcohol; aliphatic hydrocarbons such as hexane and octane; aromatic hydrocarbons such as benzene and toluene; chloroform, dichloromethane, dichloroethane, carbon tetrachloride, chlorobenzene Halogenated hydrocarbons such as trifluoromethylbenzene; nitro compounds such as nitrobenzene, nitromethane and nitroethane; esters such as ethyl acetate and butyl acetate; esters such as diethyl ether and diisopropyl ether Ethers; and the like mixed solvents thereof. As the solvent, organic acids such as acetic acid, nitriles such as benzonitrile, halogenated hydrocarbons such as trifluoromethylbenzene are often used.

  The reaction temperature can be appropriately selected according to the type of substrate, the type of oxidizing agent, and the like, and is, for example, −10 ° C. to 250 ° C., preferably 0 to 200 ° C. When the oxidizing agent is oxygen, a range of 50 to 200 ° C. is particularly preferable, and when the oxidizing agent is a reagent composed of a combination of bromate and bisulfite, a range of 0 to 100 ° C. is particularly preferable. The reaction can be carried out at normal pressure or under pressure. When the reaction is carried out under pressure (for example, when oxygen is used as the oxidizing agent), usually 0.1 to 10 MPa (for example, 0.15 to 5 MPa). It is preferably about 0.2 to 2 MPa. The reaction time can be appropriately selected from the range of about 30 minutes to 48 hours, for example, depending on the reaction temperature and pressure.

  The reaction can be carried out by a conventional method such as a batch system, a semi-batch system, or a continuous system in the presence of an oxidant or when the oxidant is a gas such as oxygen, under the flow of the oxidant. After completion of the reaction, the reaction product can be separated and purified by a conventional method, for example, separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, or a combination means combining these.

  According to the method of the present invention, an alkyl group having 1 to 6 carbon atoms which may have a substituent bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocycle of the substrate is smoothly formed. Oxidized and converted to a carboxyl group, the corresponding nitrogen-containing aromatic heterocyclic carboxylic acid is produced. In the present invention, since oxidation is performed in the presence of fuming nitric acid, conversion of an alkyl group to a carboxyl group is performed quickly and selectively, so that the target nitrogen-containing aromatic heterocyclic carboxylic acid is obtained with high yield and selectivity. Is industrially extremely useful.

When the compound represented by the formula (2) is used as the substrate, a compound represented by the following formula (5) is generated.

Wherein (5), X represents a CR ^C or N. R ^B , R ^C , R ^D and R ^E are the same as described above. However, in the reaction process, R ^B , R ^C , R ^D , and R ^E change, and may differ from R ^B , R ^C , R ^D , and R ^E in the formula (2) that is the raw material compound.

Note that since R ^E and R ^B and R ^D when X is N (nitrogen atom) are bonded to the carbon atom adjacent to the nitrogen atom, they may have a substituent. In the case of an alkyl group having 1 to 6 carbon atoms, it can be converted to a carboxyl group in the same manner as R ^A. Therefore, by selecting these substituents, it is possible to obtain dicarboxylic acid, tricarboxylic acid, and tetracarboxylic acid in addition to monocarboxylic acid.

  According to the present invention, for example, α-picoline, 2-ethylpyridine, 2-propylpyridine, 2-butylpyridine, etc., 2-pyridinecarboxylic acid is converted from 2,6-lutidine, 2,6-diethylpyridine, etc. 2,2-pyridinedicarboxylic acid, 2-quinolinecarboxylic acid from 2-methylquinoline, 2-ethylquinoline, etc., 2-pyrazinecarboxylic acid from 2-methylpyrazine, 2-ethylpyrazine, etc. 2,6-pyrazinedicarboxylic acid is obtained from 6-dimethylpyrazine, 2,6-diethylpyrazine, etc., and 2,6-pyrazinedicarboxylic acid is obtained from 2,3,5,6-tetramethylpyrazine, 2,3,5,6-tetraethylpyrazine, etc. 3,5,6-pyrazinetetracarboxylic acid can be obtained with high selectivity and high yield.

  The nitrogen-containing aromatic heterocyclic carboxylic acid thus obtained is useful as a fine chemical such as pharmaceuticals and agricultural chemicals, or an intermediate thereof, and a monomer component of a polymer.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited by these Examples.

Example 1
In a glass flask, 1.0 g of 2-ethylpyridine, 0.15 g of N-hydroxyphthalimide (10 mol% with respect to 2-ethylpyridine), 17 mg of Co (acac) ₃ [cobalt (III) acetylacetonate] (2- 0.5 mol% with respect to ethylpyridine), Mn (OAc) ₂ [manganese acetate (II)] (0.5 mol% with respect to 2-ethylpyridine), fuming nitric acid (20 mol% with respect to 2-ethylpyridine) Was dissolved in 10 mL of acetic acid. A condenser and an oxygen balloon were attached to this glass flask and sealed, and the inside of the system was replaced with oxygen, followed by heating and stirring at 100 ° C. for 10 hours. The reaction solution was cooled to room temperature, and a part of the reaction solution was sampled and analyzed by gas chromatography. As a result, 2-pyridinecarboxylic acid (= α-picolinic acid) was found to have a yield of 20% and a selectivity> 99%. It was generated with.

Comparative Example 1
The same operation as in Example 1 was performed except that fuming nitric acid was not used. When the obtained reaction liquid was analyzed by gas chromatography, 2-pyridinecarboxylic acid was produced at a yield of 4.1% and a selectivity> 99%.

Example 2
The same operation as in Example 1 was performed except that Co (acac) ₂ [cobalt (II) acetylacetonato] (0.5 mol% with respect to 2-ethylpyridine) was used instead of Co (acac) _3. went. When the obtained reaction liquid was analyzed by gas chromatography, 2-pyridinecarboxylic acid was produced in a yield of 40% and a selectivity> 99%.

Example 3
Instead of using an oxygen balloon, the same operation as in Example 2 was performed except that the reaction was performed under pressure of 0.4 MPa under pressure with oxygen. When the obtained reaction liquid was analyzed by gas chromatography, 2-pyridinecarboxylic acid was produced in a yield of 80% and a selectivity> 99%.

Example 4
The same operation as in Example 1 was performed except that 2-ethylquinoline was used instead of 2-ethylpyridine as a raw material. When the obtained reaction liquid was analyzed by gas chromatography, 2-quinolinecarboxylic acid was produced in a yield of 25% and a selectivity> 99%.

Example 5
After the inside of the system was replaced with nitrogen in a glass flask, 1.0 g of 2-ethylpyridine, sodium bromate (NaBrO ₃ ) (3 equivalents relative to 2-ethylpyridine), sodium bisulfite (NaHSO ₃ ) (2- 3 equivalents with respect to ethylpyridine), Mn (OAc) ₂ [manganese acetate (II)] (0.5 mol% with respect to 2-ethylpyridine), dissolved in 10 mL of acetic acid, and then at room temperature (25 ° C.) Stir for 4 hours. When a part of the reaction solution was sampled and analyzed by gas chromatography, 2-pyridinecarboxylic acid (= α-picolinic acid) was produced at a yield of 90% and a selectivity> 99%.

Example 6
The same operation as in Example 5 was performed except that 2-propylpyridine was used instead of 2-ethylpyridine as a raw material. When a part of the reaction solution was sampled and analyzed by gas chromatography, 2-pyridinecarboxylic acid (= α-picolinic acid) was produced in a yield of 96% and a selectivity> 99%.

Claims (4)

  A nitrogen-containing aromatic heterocyclic compound in which an alkyl group having 1 to 6 carbon atoms, which may have a substituent, is bonded to the carbon atom adjacent to the nitrogen atom constituting the aromatic heterocyclic ring, Nitrogen-containing aromatic heterocyclic ring, characterized by being oxidized with an oxidizing agent in the presence to obtain a corresponding nitrogen-containing aromatic heterocyclic carboxylic acid having a carboxyl group bonded to a carbon atom adjacent to the nitrogen atom A method for producing carboxylic acid.   The method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid according to claim 1, wherein the alkyl group is an alkyl group having 2 to 4 carbon atoms.   The method for producing a nitrogen-containing aromatic heterocyclic carboxylic acid according to claim 1 or 2, wherein a reactive agent comprising oxygen or a combination of bromate and bisulfite is used as the oxidizing agent. As a catalyst for the oxidation reaction, the following formula (1)

(In the formula, R represents a hydrogen atom or a protecting group for a hydroxyl group)
The manufacturing method of the nitrogen-containing aromatic heterocyclic carboxylic acid of any one of Claims 1-3 using the compound which has the dicarboximide frame | skeleton represented by these.