JP2015172008A - Method of producing nitrogen-containing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a chemical compound production method realizing easy and high-yield production of a nitrogen-containing heterocyclic compound useful as a synthetic intermediate and the like in many fields such as medicine, agriculture and synthetic resin additives.SOLUTION: In the production method, an ortho-substituted benzene azide derivative represented by formula (1) is reacted with carbon dioxide in the presence of a reductant to obtain a compound represented by formula (2). [R is H and/or a substituent; A is an intramolecular cyclizable group; and B is a divalent linking group of C, N and O.

Description

  The present invention relates to a novel method for producing a nitrogen-containing heterocyclic compound in which an ortho-substituted azide benzene derivative and carbon dioxide are reacted to synthesize a nitrogen-containing heterocyclic compound.

  Nitrogen-containing heterocyclic compounds composed of two or more elements including nitrogen element are known to have various structures, and are used for various applications in various fields. For example, isatoic anhydride having a ring structure composed of carbon, nitrogen and oxygen is known as a raw material for producing sivelestat (human neutrophil elastase inhibitor), which is a therapeutic agent for acute pneumonia (Patent Document 1). It is also used as a raw material for producing herbicides and ultraviolet absorbers, and is an important compound as a raw material for producing pharmaceuticals, agricultural chemicals, additives for synthetic resins and the like.

Various methods for producing such nitrogen-containing heterocyclic compounds have been proposed. For example, regarding the method for producing isatoic anhydride, the corresponding anthranilic acids or salts thereof and phosgene are mixed with water and organic. A method of reacting in a mixed solvent with a solvent (Patent Document 2), anthranilic acid and triphosgene [(Cl ₃ CO) ₂ C═O] are reacted in an appropriate organic solvent such as tetrahydrofuran, or anthranil A method in which acids are refluxed in ethyl chloroformate in the presence of a catalytic amount of triethylamine is known (Patent Document 3).

However, the method using phosgene as a reactant that reacts with anthranilic acids is irritating and suffocating because phosgene is inhaled.
1394521428601_0
In the method using triphosgene, triphosgene is easier to handle than phosgene, but in the reaction system, it is decomposed into 3 equivalents of phosgene and involved in the reaction. Furthermore, the method using ethyl chloroformate is a liquid that is strongly corrosive and irritating to eyes, mucous membranes, skin, etc., where ethyl chloroformate is made from phosgene and ethanol. It is a substance that has a problem of corrosion with respect to and its handling problem, and also increases the manufacturing cost.

  By the way, in recent years, awareness of the environment has increased due to issues such as global warming, and the use of renewable resources is indispensable for a sustainable society. Have been proposed (for example, Non-Patent Document 1 and Non-Patent Document 2). However, using carbon dioxide as a carbon source is attractive, but because it is in the most oxidized and stable state of carbon, to convert this carbon dioxide to another substance It has also been pointed out that a large amount of energy is required and is not easy (see Non-Patent Document 2).

JP 2011-051,974 Japanese Patent Laid-Open No. 10-204,067 Japanese Patent Laid-Open No. 08-119,952

Koji Nemoto, Satoru Onozawa, Naoki Egusa, Naoya Morohashi, Tetsutaro Hattori, Tetrahedron Letters, Vol.50 (2009) pp.4512-4514 Chem. Rev. 2007, 107, 2365-2387

  Therefore, the present inventors effectively use carbon dioxide as a reactant in the production of nitrogen-containing heterocyclic compounds, and are used for various applications in many fields such as pharmaceuticals, agricultural chemicals, and synthetic resin additives. As a result of intensive studies on a method that can produce a nitrogen-containing heterocyclic compound industrially advantageously, reduction of azide benzene derivative having a substituent having a π bond in the ortho position and carbon dioxide in a reaction solvent It has been found that by reacting in the presence of an agent, nitrogen-containing heterocyclic compounds such as isatoic anhydride can be easily synthesized with good yield, and the present invention has been completed.

  Accordingly, an object of the present invention is to include useful compounds as synthetic intermediates in many fields such as isatoic anhydride and other pharmaceuticals, agricultural chemicals, synthetic resin additives, etc. from ortho-substituted azide benzene derivatives and carbon dioxide. It is an object of the present invention to provide a novel method for producing a nitrogen-containing heterocyclic compound, which can easily produce a nitrogen heterocyclic compound with good yield.

〔但し、一般式（１）において、Ｒはベンゼン核の３〜６位のいずれかの位置に結合した１〜４個の水素及び／又は水素以外の置換基であって、互いに同じでも異なっていてもよく、また、Ａは反応系内で生成したイソシアネートとの間で分子内環化反応が可能なオルト置換基である。〕
で表されるオルト置換アジ化ベンゼン誘導体を、反応溶媒中で還元剤の存在下に二酸化炭素と反応させ、下記一般式（２）

〔但し、一般式（２）において、Ｒは前記一般式（１）の場合と同じであり、また、Ｂは下記式（Ｂ）から選ばれたいずれかの結合基であって、Ｃは下記式（Ｃ）から選ばれたいずれかの結合基である。

（但し、前記結合基Ｂの式（Ｂ）及び結合基Ｃの式（Ｃ）において、Ｒ¹、Ｒ²、Ｒ³は水素、−ＯＨ、炭素数１〜４の低級アルキル基、炭素数７〜１０のアリールアルキル基、炭素数２〜５のアルキルカルボニル基、炭素数２〜５のアルコキシカルボニル基、アルコキシ基、及びシリル基から選ばれたいずれかの置換基である。）〕
で表される含窒素複素環化合物を合成することを特徴とする含窒素複素環化合物の製造方法。 That is, the present invention is as follows.
(1) The following general formula (1)

[In the general formula (1), R is 1-4 hydrogens and / or substituents other than hydrogen bonded to any of the 3-6 positions of the benzene nucleus, and they are the same or different from each other. In addition, A is an ortho substituent capable of undergoing an intramolecular cyclization reaction with an isocyanate formed in the reaction system. ]
Is substituted with carbon dioxide in the presence of a reducing agent in a reaction solvent, and the following general formula (2):

[In the general formula (2), R is the same as in the general formula (1), and B is any linking group selected from the following formula (B); Any linking group selected from the formula (C).

(However, in the formula (B) of the linking group B and the formula (C) of the linking group C, R ¹ , R ² , and R ³ are hydrogen, —OH, a lower alkyl group having 1 to 4 carbon atoms, and 7 carbon atoms. -10 arylalkyl group, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxy group, and a silyl group.
A method for producing a nitrogen-containing heterocyclic compound, comprising synthesizing a nitrogen-containing heterocyclic compound represented by the formula:

〔但し、前記オルト置換基Ａの式（Ａ）において、Ｒ⁴、Ｒ⁵、及びＲ⁶は水素、炭素数１〜４の低級アルキル基、炭素数７〜１０のアリールアルキル基、アルコキシ基、及びシリル基から選ばれたいずれかの置換基である。〕
から選ばれた置換基であることを特徴とする前記(1)に記載の含窒素複素環化合物の製造方法。 (2) The ortho substituent A is represented by the following formula (A)

[However, in the formula (A) of the ortho substituent A, R ⁴ , R ⁵ , and R ⁶ are hydrogen, a lower alkyl group having 1 to 4 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, an alkoxy group, And any substituent selected from silyl groups. ]
The method for producing a nitrogen-containing heterocyclic compound according to (1), wherein the substituent is selected from the group consisting of:

(3) The linking group B is a linking group selected from —CO—, —CH═, and —C (OH) ═, and the linking group C is —O—, ═CH—, ═ The nitrogen-containing complex according to (1) or (2) above, which is a linking group selected from C (COOC ₂ H ₅ ) —, —N (Bn) —, and —N (Ac) —. A method for producing a ring compound.

(4) The nitrogen-containing heterocyclic compound according to any one of (1) to (3), wherein the reducing agent is phosphine (PR ₃ ) or phosphite [P (OR) ₃ ]. Production method.
(5) The reaction system according to any one of (1) to (4), wherein the reaction system is a reaction system in which a reducing agent and a base are present in an organic solvent, and the reaction temperature is 40 to 100 ° C. The manufacturing method of the nitrogen-containing heterocyclic compound of description.

(6) The production of the nitrogen-containing heterocyclic compound according to any one of (1) to (4), wherein the reaction system is a reaction system in which a reducing agent and a surfactant are present in an aqueous solvent. Method.
(7) The method for producing a nitrogen-containing heterocyclic compound according to (6), wherein the surfactant is a cationic surfactant.

  According to the method for producing a nitrogen-containing heterocyclic compound of the present invention, it is synthesized from an ortho-substituted azide benzene derivative and carbon dioxide in many fields such as pharmaceuticals, agricultural chemicals, synthetic resin additives including isatoic anhydride. Nitrogen-containing heterocyclic compounds useful as intermediates and the like can be easily produced with good yield.

〔但し、一般式（１）において、Ｒはベンゼン核の３〜６位のいずれかの位置に結合した１〜４個の水素及び／又は水素以外の置換基であって、互いに同じでも異なっていてもよく、また、Ａは反応系内で生成したイソシアネートとの間で分子内環化反応が可能なオルト置換基である。〕で表される化学構造を有するものである。 Hereafter, the manufacturing method of the nitrogen-containing heterocyclic compound of this invention is demonstrated in detail.
In the present invention, an ortho-substituted azide benzene derivative used as a production raw material has the following general formula (1):

[In the general formula (1), R is 1-4 hydrogens and / or substituents other than hydrogen bonded to any of the 3-6 positions of the benzene nucleus, and they are the same or different from each other. In addition, A is an ortho substituent capable of undergoing an intramolecular cyclization reaction with an isocyanate formed in the reaction system. It has a chemical structure represented by

Here, in the ortho-substituted azide benzene derivative as the raw material for production, examples of the substituent R other than hydrogen substituted at the 3-6 position of the benzene nucleus include alkyl groups such as a hydroxyl group and a methyl group (—CH ₃ ), a methoxy group, and the like. Electron-donating substituents such as alkoxy groups such as (-OCH ₃ ), alkoxycarbonyloxy groups (-OCOR), aryl groups, amino groups, alkyl-substituted amino groups, alkylcarbonyl-substituted amino groups (-NHCOR), Carboxyl group (-COOH), nitro group (-NO ₂ ), cyano group, aldehyde group, alkylcarbonyl group (-COR), alkoxycarbonyl group (-COOR), sulfonic acid group (-SO ₃ H), sulfone group ( -SO ₂ R), halogen such as chlorine, electron-withdrawing substituents such as monochloromethyl group, trichloromethyl group, trifluoromethyl group and the like. Also, among these substituents, selected from various substituents such as substituents further substituted with other substituents, carboxylic acid and derivatives thereof, sulfonic acid and derivatives thereof, phosphoric acid and derivatives thereof, and the like. The substituted groups may be present in the range of 1 to 5 and form a condensed ring with or without a heteroatom between the substituted positions of the 4 to 7 positions. It may be a polycyclic compound. In the present invention, an ortho-substituted azide benzene derivative in which a wide range of substituents are substituted can be used as a raw material for production as the substituent R substituted at the 3-6 position of the benzene nucleus.

〔但し、前記オルト置換基Ａの式（Ａ）において、Ｒ⁴、Ｒ⁵、及びＲ⁶は水素、炭素数１〜４の低級アルキル基、炭素数７〜１０のアリールアルキル基、アルコキシ基、及びシリル基から選ばれたいずれかの置換基である。〕
で表される置換基であるのがよい。 Further, in the ortho-substituted azide benzene derivative as a raw material for production, the ortho substituent A is a substituent substituted at the ortho position of benzene azide, which is the basic structure, and is in the α position adjacent to the benzene nucleus of azide benzene. When the ortho-substituted azide benzene derivative and carbon dioxide are reacted in the reaction solvent in the presence of a reducing agent, the isocyanate produced in the reaction system The substituent may be any substituent capable of undergoing an intramolecular cyclization reaction, but preferably the following formula (A)

[However, in the formula (A) of the ortho substituent A, R ⁴ , R ⁵ , and R ⁶ are hydrogen, a lower alkyl group having 1 to 4 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, an alkoxy group, And any substituent selected from silyl groups. ]
It is good that it is a substituent represented by these.

Regarding this ortho substituent A, preferred specific examples of the ortho substituent A ¹ include, for example, —CH═CH ₂ , —C (CH ₃ ) ═CH ₂ , —C (OCH ₃ ) ═CH ₂ , —C (OSi (CH ₃ ) ₃ ) ═CH _{2 and the} like can be exemplified. Further, preferred specific examples of the ortho substituent A ² include, for example, —CONHBn (Bn: benzyl group), —CONHAc (Ac: acetyl group) and the like. Furthermore, preferred specific examples of the ortho substituent A ³ include, for example, —C (═O) —CH ₂ —CO ₂ Et, —C (═O) —CH ₂ —C (= O) —CH _{3 and the} like can be exemplified.

In the present invention, the ortho-substituted azide benzene derivative is reacted with carbon dioxide in the presence of a reducing agent in a reaction solvent. Examples of the reducing agent used here include phosphine (PR ₃ ), Phosphite [P (OR) ₃ ], carbene and the like are mentioned, and from the viewpoint of handling, preferably triphenylphosphine (PPh ₃ ), tris (2-tolyl) phosphine, tris (2-MeO-phenyl) phosphine Phosphine ligands (PR ₃ ) such as tris (2,4-di-tert-butylphenyl) phosphine, tris (2-tolyl) phosphite, tris (2-MeO-phenyl) phosphite, tris (2,4 A phosphite ligand [P (OR) ₃ ] such as -di-tert-butylphenyl) phosphite.

  The amount of the reducing agent used is usually 1 mol or more and 2 mol or less, preferably 1 mol or more and 1.1 mol or less with respect to 1 mol of the ortho-substituted azide benzene derivative, and the amount used is less than 1 mol. If it is, there is a problem that unreacted raw material remains, and if it exceeds 2 mol, there is a problem that unreacted reducing agent remains.

  In the present invention, for a reaction system in which an ortho-substituted azide benzene derivative and carbon dioxide are reacted in a reaction solvent in the presence of the reducing agent, an organic solvent is used as the reaction solvent, and the reducing agent and the base are contained in the organic solvent. There are a reaction system in which the reaction is carried out at a reaction temperature of 40 to 100 ° C. and a reaction system in which an aqueous solvent is used as the reaction solvent and the reaction is carried out in the presence of a reducing agent and a surfactant in the aqueous solvent.

  Here, as the organic solvent used in the reaction system of the above organic solvent, the ortho-substituted azide benzene derivative can be dissolved and used without reacting with the ortho-substituted azide benzene derivative as a raw material for production. It does not react with a reducing agent and a base and only needs to achieve a reaction temperature of 40 to 100 ° C., for example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, trichloromethane, dichloromethane, dichloroethane (DCE), halogenated alkyl solvents, acetonitrile, ethyl cyanide alkyl halide solvents, 1,4-dioxane and other cyclic ether solvents, N, N-dimethylformamide (DMF), etc. Protic polar solvents, aliphatic hydrocarbon solvents such as hexane, cyclohexane, pentane, methanol, ethanol, isopropanol And alcohol solvents such as propanol, acetone, and ketone solvents such as methyl ethyl ketone, diisopropyl ether, can be exemplified an ether-based solvent such as phenyl ether.

In addition, the base used in the reaction system of the organic solvent acts as a reaction aid for increasing the carbon dioxide activity in the liquid phase in the reaction system, and at the same time increases the reactivity by deprotonation of the reaction raw material. As the base, inorganic bases such as sodium carbonate (Na ₂ CO ₃ ) and potassium carbonate (K ₂ CO ₃ ), potassium t-butoxide (KOtBu), sodium ethoxide ( Alkoxides such as NaOC ₂ H ₅ ), 1,8-diazabicyclo [5,4,0] undecene (DBU), triethylamine (TEA), 1,5-diazabicyclo [4,3,0] nonene (DBN), Examples include organic alkalis such as 1,1,3,3-tetramethylguanidine, amides such as potassium hexamethyldisilazide (KHMDS), and the like.

  Regarding the reaction conditions for carrying out the reaction in the above organic solvent, the reaction temperature is usually from 40 ° C. to 100 ° C., preferably from 50 ° C. to 90 ° C., and the reaction time is usually from 6 hours to 72 hours. Preferably, it is 12 hours or more and 30 hours or less. Further, the supply of carbon dioxide into the reaction system can be performed by making the inside of the reaction system an atmosphere of carbon dioxide, or an atmosphere of a mixed gas with another gas such as an inert gas, The pressure of carbon dioxide at the time of the reaction (the pressure of the mixed gas when used as a mixed gas with another gas such as an inert gas) is not particularly limited, but is an industrial reaction. Considering equipment, manufacturing process, etc., the lower limit is preferably 0.05 MPa or more and the upper limit is about 1 MPa or less, more preferably about atmospheric pressure (1 atm; 0.1 MPa). The production method of the present invention is also advantageous in that the pressure of carbon dioxide during the reaction can be greatly reduced.

  As the aqueous solvent used in the above aqueous solvent reaction system, water, a mixed solvent of water and an organic solvent, a mixed solvent of a buffer solution and an organic solvent, or the like can be used. Here, as the buffer, one having a pH value of usually 5.0 to 10.0, preferably 6.0 to 8.0 is used, and specifically, for example, phosphate, bicarbonate, etc. Examples include buffers using bases such as acids, metal alcosides, and carbonates. The organic solvent constituting the mixed solvent is added for the purpose of solubility of the substrate and the reducing agent, and forms a micelle in the water mixed system to provide a reaction field, so that it is relatively hydrophobic. Well, for example, aliphatic hydrocarbon solvents such as hexane, cyclohexane and pentane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, ethyl ether, cyclopentyl methyl ether (CPME), t-butyl methyl ether ( MTBE), ether solvents such as diisopropyl ether (DIPE), cyclic ether solvents such as 1,4-dioxane and tetrahydrofuran (THF), aprotic polar solvents such as N, N-dimethylformamide (DMF) , Alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol; ester solvents such as ethyl acetate (EtOAc); It can be exemplified glycol solvents such glycol (Ethyleneglycol).

  Further, the cationic surfactant used in the reaction system of this aqueous solvent acts as a substance that forms a micelle in the reaction system and provides a hydrophobic reaction field.For example, cetyltrimethylammonium bromide: And alkyltrimethylammonium salts such as CTMABr), dialkyldimethylammonium salts such as didecyldimethylammonium salt, and tetraalkylammonium salts such as alkylbenzyldimethylammonium salt.

  In addition, the reaction conditions for the reaction in this aqueous solvent reaction system are sufficiently limited at room temperature (20 ° C), so the reaction temperature is not particularly limited, and it is particularly necessary to cool or heat. However, depending on the type of ortho-substituted azide benzene derivative used, it may be heated to a temperature of up to 100 ° C. if necessary, and the reaction time is usually from 6 hours to 72 hours, preferably It is good that it is 12 hours or more and 30 hours or less. Moreover, about the supply of the carbon dioxide in a reaction system, it can implement similarly to the case where said reaction is performed in the reaction system of an organic solvent.

〔但し、一般式（２）において、Ｒは前記一般式（１）の場合と同じであり、また、Ｂは下記式（Ｂ）から選ばれたいずれかの結合基であって、Ｃは下記式（Ｃ）から選ばれたいずれかの結合基である。

（但し、前記結合基Ｂの式（Ｂ）及び結合基Ｃの式（Ｃ）において、Ｒ¹、Ｒ²、Ｒ³は水素、−ＯＨ、炭素数１〜４の低級アルキル基、炭素数７〜１０のアリールアルキル基、炭素数２〜５のアルキルカルボニル基、炭素数２〜５のアルコキシカルボニル基、アルコキシル基、及びシリル基から選ばれたいずれかの置換基である。）〕
で表される各種の含窒素複素環化合物を挙げることができる。 In the method of the present invention, the nitrogen-containing heterocyclic compound obtained by reacting an ortho-substituted azide benzene derivative with carbon dioxide has a different ring structure formed by intramolecular cyclization depending on the type of ortho substituent A. The following general formula (2)

[In the general formula (2), R is the same as in the general formula (1), and B is any linking group selected from the following formula (B); Any linking group selected from the formula (C).

(However, in the formula (B) of the linking group B and the formula (C) of the linking group C, R ¹ , R ² , and R ³ are hydrogen, —OH, a lower alkyl group having 1 to 4 carbon atoms, and 7 carbon atoms. -10 arylalkyl group, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyl group, and a silyl group.
And various nitrogen-containing heterocyclic compounds represented by the formula:

Specific examples of the nitrogen-containing heterocyclic compound obtained by the method of the present invention include, for example, isatoic anhydride having the following basic structure (a) and derivatives thereof, and 2 (1H) having the following basic structure (b). -Quinolinone and derivatives thereof, 2,4-quinazolinedione and derivatives thereof having the following basic structure (c) can be exemplified.

In the present invention, the inventors consider that the reaction mechanism in which an ortho-substituted azide benzene derivative and carbon dioxide react to form a nitrogen-containing heterocyclic compound is as follows.
For example, ortho-azide benzoic acid in which the substituent R is hydrogen (—H) and the ortho substituent A is carboxyl group (—COOH) is used as the ortho-substituted azide benzene derivative, and triphenylphosphine (PPh ₃ ) is used as the reducing agent. In the case of isatoic anhydride in which the linking group B is —C (═O) — and the linking group C is —O— as an example of the nitrogen-containing heterocyclic compound produced, the reaction mechanism is as follows: It can be shown as reaction formula (1).

That is, at the beginning of the reaction, the azide group of orthoazide benzoic acid reacts with triphenylphosphine to form azaphosphatran, which then reacts with carbon dioxide (CO ₂ ) to form a 4-membered ring. It is converted to isocyanate through a transition state, and the produced isocyanate undergoes an intramolecular cyclization reaction with an ortho-position carboxyl group (—COOH) to produce the desired isatoic anhydride.

  Hereinafter, based on an Example, the manufacturing method of the nitrogen-containing heterocyclic compound of this invention is demonstrated more concretely.

[Example 1: Examination by reaction system of organic solvent]
In the examination of the reaction system of the organic solvent, orthoazide benzoic acid is used as the ortho-substituted azide benzene derivative, triphenylphosphine (PPh ₃ ) is used as the reducing agent, and the organic solvents shown in Table 1 and Table 1 are used. The indicated proportion of base was used.
First, 2.5 mL of the organic solvent shown in Table 1 in the reaction vessel, orthoazide benzoic acid (81.6 mg: 0.0005 mol) used in the reaction, and the base shown in Table 1 in an equivalent amount (0.0005 mol) to this orthoazide benzoic acid. Then, the inside of the reaction vessel is degassed, and the atmosphere in the reaction vessel is changed to a carbon dioxide atmosphere using a balloon inflated with carbon dioxide, and carbon dioxide is bubbled for 30 minutes with stirring to make the solution carbon dioxide. Saturated with

Next, orthoazidobenzoic acid (81.6 mg: 0.0005 mol) and triphenylphosphine (131.2 mg: 0.0005 mol) are added to the reaction vessel, and the reaction is carried out under the conditions of reaction temperature and reaction time shown in Table 1. At the end of the reaction, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction solution to terminate the reaction. After completion of the reaction, the target product was extracted three times with 5 mL of methylene chloride, and the total extract obtained was dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure to obtain a crude product. Obtained.
The crude product was purified by neutral silica gel column chromatography to obtain the desired isatoic anhydride in the yield shown in Table 1.

The reaction formula (2) in Example 1 is shown below, and the results of Test Nos. (Ex.No.) 1 to 17 performed in Example 1 are shown in Table 1.

[Example 2: Examination by reaction system of aqueous solvent]
In the investigation of the reaction system of the aqueous solvent, orthoazide benzoic acid was used as the ortho-substituted azide benzene derivative, triphenylphosphine (PPh ₃ ) was used as the reducing agent, and cetyltrimethyl bromide was used as the cationic surfactant. Ammonium (CTMABr) was used, and water or a 9: 1 mixed solvent of water and an organic solvent shown in Table 2 was used as an aqueous solvent. In addition, “pH7.6Buffer” shown in Table 2 is a pH 7.6 potassium dihydrogen phosphate (KH ₂ P0 ₄ ) / sodium hydroxide (NaOH) buffer solution.

First, 0.5 mL of water (in the case of Ex. No. 1) or an organic solvent (in the case of Ex. Nos. 2 to 17) is charged into a reaction vessel, and orthoazide benzoic acid (81.6) used for the reaction in this solvent. mg: 0.0005 mol), an equivalent amount (0.0005 mol) of triphenylphosphine (131.2 mg: 0.0005 mol) to this orthoazidobenzoic acid, and 1.5 times equivalent (0.00075 mol) of CTMABr of orthoazidebenzoic acid, and 20 Stir at 5 ° C. for 5 minutes. Thereafter, 4.5 mL of water or potassium dihydrogen phosphate (KH ₂ P0 ₄ ) / sodium hydroxide (NaOH) buffer at pH 7.6 is added to make the reaction system an aqueous solvent, and the reaction container is degassed. The inside of the reaction vessel was filled with a carbon dioxide atmosphere using a balloon inflated with carbon dioxide, and then reacted under stirring at 20 ° C. for 18 hours.

At the end of the reaction, 5 mL of saturated aqueous ammonium chloride solution is added to the reaction solution to terminate the reaction, and then the target product is extracted three times with 5 mL of methylene chloride, and the total extract obtained is anhydrous. After drying with sodium sulfate, methylene chloride was distilled off under reduced pressure to obtain a crude product.
The crude product was purified by neutral silica gel column chromatography to obtain the desired isatoic anhydride in the yield shown in Table 1.

The reaction formula (3) in Example 2 is shown below, and the results of Test Nos. (Ex.No.) 1 to 17 performed in Example 2 are shown in Table 2.

[Examples 3 to 13]
The corresponding general formula (2) according to Ex. No. 17 of Example 2, except that the ortho-substituted azide benzene derivative of the general formula (1) is the one of the substituent R and the ortho substituent A shown in Table 3 A nitrogen-containing heterocyclic compound was synthesized.
The yield of the obtained nitrogen-containing heterocyclic compound of the general formula (2) is shown in Table 3 together with the result of Ex. No. 17 in Example 2 above.

In addition, the nitrogen-containing heterocyclic compound of Examples 3-13 represented by General formula (2) is as follows.
Example 3: 8-methyl isatoic anhydride, Example 4: 7-methyl isatoic anhydride, Example 5: 6-methoxy isatoic anhydride, Example 6: 6-hydroxy isatoic anhydride, Example 7: 7-nitroisatoic anhydride, Example 8: 7-chloroisatoic anhydride, Example 9: 2 (1H) -quinolinone, Example 10: 6-carboxy isatoic anhydride, Example 11: ), 3-benzyl-2,4-quinazolinedione, Example 12: 3-acetyl-2,4-quinazolinedione represented by the following compound (2), and Example 13: the following compound (3) 3-Ethoxycarbonyl-4-hydroxy-2 (1H) -quinolinone represented by

Claims (7)

The following general formula (1)

[In the general formula (1), R is 1-4 hydrogens and / or substituents other than hydrogen bonded to any of the 3-6 positions of the benzene nucleus, and they are the same or different from each other. In addition, A is an ortho substituent capable of undergoing an intramolecular cyclization reaction with an isocyanate formed in the reaction system. ]
Is reacted with carbon dioxide in the presence of a reducing agent in a reaction solvent to give the following general formula (2):

[In the general formula (2), R is the same as in the general formula (1), and B is any linking group selected from the following formula (B); Any linking group selected from the formula (C).

(However, in the formula (B) of the linking group B and the formula (C) of the linking group C, R ¹ , R ² , and R ³ are hydrogen, —OH, a lower alkyl group having 1 to 4 carbon atoms, and a carbon number. It is a substituent selected from an arylalkyl group having 7 to 10 carbon atoms, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxy group, and a silyl group.
A method for producing a nitrogen-containing heterocyclic compound, comprising synthesizing a nitrogen-containing heterocyclic compound represented by the formula: The ortho substituent A is represented by the following formula (A)

[However, in the formula (A) of the ortho substituent A, R ⁴ , R ⁵ , and R ⁶ are hydrogen, a lower alkyl group having 1 to 4 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, an alkoxy group, And any substituent selected from silyl groups. ]
The method for producing a nitrogen-containing heterocyclic compound according to claim 1, wherein the substituent is selected from the group consisting of: The linking group B is a linking group selected from —CO—, —CH═, and —C (OH) ═, and the linking group C is —O—, ═CH—, ═C (COOC ₂ H ₅ ) The method for producing a nitrogen-containing heterocyclic compound according to claim 1 or 2, which is a linking group selected from-, -N (Bn)-, and -N (Ac)-. The method for producing a nitrogen-containing heterocyclic compound according to any one of claims 1 to ₃ , wherein the reducing agent is phosphine (PR ₃ ) or phosphite [P (OR) ₃ ].   The nitrogen-containing complex according to any one of claims 1 to 4, wherein the reaction system is a reaction system in which a reducing agent and a base are present in an organic solvent, and the reaction temperature is 40 to 100 ° C. A method for producing a ring compound.   The method for producing a nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, wherein the reaction system is a reaction system in which a reducing agent and a cationic surfactant are present in an aqueous solvent.   The method for producing a nitrogen-containing heterocyclic compound according to claim 6, wherein the surfactant is a tetraalkylammonium salt.