JPH09143163A - Production of nitrogen-containing heteroaromatic amides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and advantageously obtain a compound useful as an intermediate for dyes, a medicine and an agrochemical, etc., in high yield by reacting a nitrogen-containing heteroaromatic ester compound with specific amines in the presence of a Lewis acid. SOLUTION: A nitrogen-containing heteroaromatic ester compound of formula I (X is an atomic group capable of forming a 5,6-membered heteroaromatic ring; R<1> is an alkyl) is reacted with amines of formula II (R<2> and R<3> are each H, an alkyl, an aryl, a heterocyclic group, etc.) in a Lewis acid to provide the objective nitrogen-containing aromatic amides of formula III. The Lewis acid is preferably used in an amount of 0.0005-0.35 equivalent based on amines of formula II. For example, ethyl picolinate, aniline and aluminum chloride are stirred under nitrogen atmosphere to provide picolinic anilide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to dye intermediates, pharmaceuticals,
Regarding a method for producing a nitrogen-containing heteroaromatic amide useful for agricultural chemicals, more specifically, a Lewis acid is used as an activator to produce a nitrogen-containing heteroaromatic amide from a nitrogen-containing heteroaromatic ester compound and amines. It relates to a method of manufacturing.

[0002]

2. Description of the Related Art Nitrogen-containing heteroaromatic amides having a carbamoyl group adjacent to a nitrogen atom are compounds useful as a skeleton for dye intermediates, pharmaceuticals, agricultural chemicals and the like.
(JP-A-51-77327, JP-A-63-139949, JP-A-6-212852, J. Med. Chem., 3
7, 2445 (1984) etc.)

Although several methods for synthesizing nitrogen-containing heteroaromatic amides have been known in the past, they are generally based on aminolysis of esters (JP-A-63-13).
9949, JP-A-6-212852, J. Med. Ch
em. , 37, 2445 (1984)). But,
When the amine is a secondary amine or aromatic amine having a reduced nucleophilicity such as morpholine or aniline, the reaction conditions of high temperature and long time are required, which is not suitable for the industrial production method.

Several methods for synthesizing nitrogen-containing heteroaromatic amides that do not rely on ester aminolysis are also known. For example, a method in which a carboxy derivative is reacted with a sulfonic acid chloride derivative, and amidation is performed via a mixed acid anhydride, etc. However, this method has the drawback of increasing costs because it requires additional multi-step processes.

The method of using a Lewis acid in the amidation reaction by aminolysis of an ester is not generally used because the Lewis acid and amines react with each other and the amines are consumed or the Lewis acidity decreases. . However, the following examples are known, albeit in small numbers. RD Gless, Jr., Synth. Comm., 16, 633 (1986) Aminolysis of 2-chloropropionate F. Porta, M. Pizzotti, C. Crotti and S. Cenini,
Gazz. Chim. Ital., 118, 475 (1988) Aminolysis with a primary amine of acetic acid or ethyl propionate JI Levin, E. Turos and SM Weinreb, Synth. Co
mm., 12, 989 (1982) Aminolysis using alkylaluminum.

However, in the case of and, since the substrates are limited to a small part of aliphatic esters and amines, it is difficult to react with aromatic amines having poor nucleophilicity such as aniline, and Although applied to esters, trimethylaluminum used as a reagent is a flammable water-prohibiting compound, which is a problematic industrial production method.

[0007]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide an industrially effective production method for synthesizing useful nitrogen-containing heteroaromatic amides in high yield.

[0008]

The present inventors have studied a method for synthesizing a nitrogen-containing heteroaromatic amide by aminolyzing the nitrogen-containing heteroaromatic ester. As a result, they have found that aminolysis of nitrogen-containing heteroaromatic ester with amines easily proceeds by using Lewis acid as an activator, and the nitrogen-containing heteroaromatic amide can be produced. Furthermore, the present inventor has found that the Lewis acid used for the above activation acts as a catalyst. This is extremely significant in industrial production from the viewpoint of post-treatment after reaction, removal of product, and environmental protection.

That is, the object of the present invention is to formula (A)
The compound represented by the following general formula (B) in the presence of a Lewis acid
It was achieved by a method for producing a nitrogen-containing heteroaromatic amide represented by the following general formula (C), which comprises reacting with an amine represented by

[0010]

Embedded image

(In the formula, X represents an atomic group capable of forming a 5- or 6-membered heteroaromatic ring, R ¹ represents an alkyl group,
R ² and R ³ each represent a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic group, and may combine with each other to form a ring. )

Next, the general formula (A) will be described in detail. X is an atomic group capable of forming a 5- or 6-membered heteroaromatic ring composed of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom, and these atomic groups are a carbon atom, an oxygen atom, a nitrogen atom, or It may have an organic substituent linked by a sulfur atom or a substituent such as a hydroxyl group, a halogen atom or a sulfonic acid group. These organic substituents include, for example, alkyl groups, aryl groups, heterocyclic groups, cyano groups, acyl groups, carboxyl groups, aryloxy groups, alkoxy groups, heterocyclic oxy groups, amino groups, sulfamoylamino groups, sulfones. Amide group, alkylthio group, arylthio group, heterocyclic thio group, sulfamoyl group, sulfonyl group,
It is a sulfinyl group.

The 5- or 6-membered heteroaromatic ring formed by X may have its substituents bonded to each other to be further condensed. explain. The 5- or 6-membered heteroaromatic ring formed by X is, for example, pyridine, pyrimidine, pyrazine, pyridazine, triazines, imidazole, triazoles, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, quinoline,
Examples include benzopyrimidine, benzimidazole, benzoxazole and purine.

The 5- or 6-membered heteroaromatic ring formed by X is a 5- or 6-membered heteroaromatic ring formed by only carbon and nitrogen atoms.
A membered heteroaromatic ring, or a 5-membered heteroaromatic ring formed only from a carbon atom, a nitrogen atom and a sulfur atom, or benzoxazole is preferable, and pyridine, pyrimidine, pyrazine, pyrazole, imidazole, quinoline, thiazole, isothiazole, 1,3,4-thiadiazole is more preferable, and pyridine and imidazole are the most preferable.

R ¹ represents an alkyl group, but it may be substituted, and more specifically, it is a linear or branched alkyl group having 1 to 12 carbon atoms, specifically, methyl, ethyl, propyl, Isopropyl, n-butyl, s-butyl, 1- (2-ethylhexyl), decyl, dodecyl,
Examples include cyclopentyl and cyclohexyl groups.

R ¹ is preferably an alkyl group having 1 to 6 carbon atoms, more preferably a linear alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group or an ethyl group.

Next, specific examples of the 5- or 6-membered heterocyclic aromatic ester represented by the general formula (A) are shown, but of course, the present invention is not limited thereto.

[0018]

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Next, the general formula (B) will be described in detail. The amines represented by the general formula (B) used in the present invention are the groups represented by R ² and R ³ of the 5- or 6-membered nitrogen-containing heteroaromatic amides represented by the general formula (C). Is ammonia or a primary or secondary amine.

R ² and R ³ will be described in detail. R ² , R ³
Represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic group, and any of them may be substituted. More specifically, the alkyl group is a straight chain or branched chain alkyl group having 1 to 12 carbon atoms. The alkyl groups of R ² and R ³ may be linked to each other to form a ring. The aryl group represents a phenyl group having 6 to 10 carbon atoms or a naphthyl group, and the heterocyclic group represents a saturated or unsaturated heterocyclic group having a 5- to 7-membered ring. These groups may have a substituent such as an organic substituent linked by a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom, a hydroxyl group, a halogen atom, and a sulfonic acid group. These organic substituents include, for example, alkyl groups, aryl groups, heterocyclic groups, cyano groups, acyl groups, carboxyl groups, aryloxy groups, alkoxy groups, heterocyclic oxy groups, amino groups, sulfamoylamino groups, sulfones. An amide group, an alkylthio group, an arylthio group, a heterocyclic thio group, a sulfamoyl group, a sulfonyl group, and a sulfinyl group.

The substituents represented by R ² and R ³ will be specifically described in more detail. The alkyl group represented by R ² and R ³ is
For example, methyl, ethyl, propyl, isopropyl, n
-Butyl, s-butyl, cyclopentyl, cyclohexyl, methoxyethyl, 2-hydroxyethyl, carboxymethyl, phenoxyethyl, methanesulfonylethyl, (3-pentadecylphenoxy) propyl, 3-
(2,4-diamylphenoxy) propyl, 2-sulfoethyl, 4-sulfobutyl, 2'-sulfobenzyl group and the like.

The ring formed by connecting the alkyl groups represented by R ² and R ³ to each other is a 5- or 6-membered ring, and more specifically, for example, pyrrolidine, piperidine, 4-
Examples include methylpiperazine, 4-ethylpiperazine, morpholine and the like. The aryl group represented by R ² and R ³ includes, for example, phenyl, 4-tolyl, 4-methoxyphenyl,
2,4-xylyl, 2-chlorophenyl, 4-carboxyphenyl, 4-sulfophenyl, 2,5-disulfophenyl, 1-naphthyl, 1- (3,5-disulfonaphthyl) groups and the like.

The heterocyclic group represented by R ² and R ³ is, for example,
2-tetrahydrofuranyl, 2-tetrahydrothienyl, 1-piperidino, 2-pyridyl, 1-pyrazolyl,
2-thienyl, 2-pyrimidinyl, 2-benzothiazolyl, 3- (1,1-dioxotetrahydrothienyl) group and the like.

The alkyl group of R ² and R ³ is preferably an alkyl group having 1 to 7 carbon atoms, and more preferably
It is a C1-C7 alkyl group substituted with a carboxyl group, a sulfo group, an alkoxy group, or a hydroxyl group, or an unsubstituted methyl group. The ring formed by connecting the alkyl groups represented by R ² and R ³ to each other is preferably pyrrolidine, piperidine, 4-methylpiperazine or morpholine, and more preferably morpholine.

The aryl group represented by R ² and R ³ is preferably a phenyl group, and more preferably a phenyl group substituted with a carboxyl group or a sulfo group.

R ² and R ³ are each a hydrogen atom, a methyl group, a carboxyethyl group, a linear alkyl group having 2 to 4 carbon atoms substituted with a sulfo group, a 4-sulfophenyl group, or a 2,5-disulfophenyl group. A group or a morpholino group formed by connecting R ² and R ³ to each other is particularly preferable, and a morpholino group is most preferable.

Next, the amines used in the present invention will be described. The amines used in the present invention are ammonia, amines having a substituted or unsubstituted primary or secondary alkyl, aryl, or heterocyclic group, and these alkyl, aryl, or heterocyclic groups are compounds. It is a substituent represented by R ² and R ³ of (B).

The amines used in the present invention will be described in more detail with reference to specific examples. For example, ammonia, methylamine, ethylamine, propylamine, isopropylamine, n-butylamine, s-butylamine, cyclopentylamine, cyclohexylamine, methoxy. Ethylamine, 2-hydroxyethylamine, glycine, phenoxyethylamine, methanesulfonylethylamine,
(3-pentadecylphenoxy) propylamine, 3-
(2,4-Diamylphenoxy) propylamine, 2-
Sulfoethylamine, 4-sulfobutylamine, 2'-
Sulfobenzylamine, dimethylamine, diethylamine, dipropylamine, di-n-butylamine, di (methoxyethyl) amine, di (2-hydroxyethyl) amine, glycine, pyrrolidine, piperidine, 4-methylpiperazine, 4-ethylpiperazine, Alkylamines such as morpholine, aniline, 4-toluidine, 4-anisidine, 2,4-dimethylaniline, 2-chloroaniline, 4-nitroaniline, 4-aminobenzoic acid, 4-aminobenzenesulfonic acid, 2-aminobenzene -1,4
Arylamines such as disulfonic acid, 1-naphthylamine, 1-amino-naphthalene-3,5-disulfonic acid, 2-tetrahydrofuranylamine, 2-tetrahydrothienylamine, 2-pyridylamine, pyrazole,
Heterocyclic amines such as 2-thienylamine, 2-pyrimidinylamine, 2-benzothiazolylamine, and 3- (1,1-dioxotetrahydrothienyl) amine.

Next, the Lewis acid used in the present invention will be described. The central element of the Lewis acid that acts as an electron acceptor is a typical element such as boron, aluminum, silicon, tin or the like, or a transition metal element of the fourth period such as titanium, iron, nickel, copper and zinc.

The Lewis acid ligand is a halide ion such as chloride ion and fluoride ion, and an alkoxy ion such as ethoxide, propoxide and butoxide, and these ligands are used for the central element of the Lewis acid. May be one kind, or may be a combination of two or more kinds. When the Lewis acid has two or more kinds of ligands, such Lewis acid may be prepared in advance, but by a well-known method,
It may be synthesized by in-situ ligand exchange reaction (Fuji Kaoru, Node Manabu, Synthetic Organic Chemistry, 42, 194 (1
984)).

The Lewis acid used in the present invention is specifically boron trihalide such as boron trifluoride, boron trichloride or boron tribromide, aluminum trihalide such as aluminum chloride or aluminum bromide, Tin tetrahalides such as tin tetrachloride, tin dihalides such as tin dichloride, titanium tetrahalides such as titanium tetrachloride, titanium trihalides such as titanium trichloride, titanium alkoxides such as titanium isopropoxide, Examples include iron dihalides such as iron chloride, iron trihalides such as iron trichloride, nickel dihalides such as nickel dichloride, and zinc halides such as zinc chloride and zinc bromide.

The Lewis acid is more preferably boron trihalide, aluminum trihalide, tin tetrahalide, titanium tetrahalide, titanium alkoxide, iron trihalide or zinc halide, and more preferably trichloride. Iron, aluminum chloride, titanium isopropoxide, titanium tetrachloride, zinc chloride, most preferably aluminum chloride.

The Lewis acid used in the present invention can be used in any amount, but the range is based on amines.
From 0.0005 equivalent to 1 equivalent. Further, it is preferably used as a catalyst, and in this case, 0.0005 equivalent to 0.35 equivalent is preferable, and 0.005 equivalent to 0.
Two equivalents are particularly preferred. In the reaction of the present invention, a non-nucleophilic amine may be added for the purpose of adjusting the reactivity of the Lewis acid. Such amines include tertiary amines such as triethylamine, tertiary anilines such as diethylaniline,
Pyridines such as pyridine and collidine, DBU and the like.

Among the non-nucleophilic amines, pyridines are preferable, 2-methylpyridine, 2,6-lutidine and γ-collidine are more preferable, and 2,6-lutidine and γ-collidine are most preferable.

Various solvents can be used in the reaction of the present invention. Examples thereof include aromatic hydrocarbon solvents such as toluene and xylene, halogenated hydrocarbon solvents such as chloroform, chlorobenzene and o-dichlorobenzene, ether solvents such as tetrahydrofuran and dimethoxyethane, dimethyl sulfoxide and sulfolane. Further, amines may be used in excess and used as a solvent itself.

Of the solvents, preferred are toluene, xylene, cumene, chlorobenzene, o-dichlorobenzene, dimethoxyethane, sulfolane, and excess amine itself, and more preferred are toluene, xylene, and
Chlorobenzene or excess amine itself, with the excess amine being most preferred.

The reaction temperature is 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C, and more preferably 80 ° C to 130 ° C in the case of reacting with morpholine.
The reaction is preferably carried out under a nitrogen atmosphere to prevent the product from being oxidized. Next, specific examples of the heteroaromatic amides synthesized in the present invention are shown, but of course, the present invention is not limited to these.

[0038]

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[0039]

The present invention will be described in more detail with reference to the following examples. Example 1 [Synthesis of anilide picolinate C-1] 3.02 g (20 mmol) of ethyl picolinate, 14.6 g (160 mmol) of aniline, and 0.27 g (2 mmol) of aluminum chloride were placed in a nitrogen atmosphere at 110 ° C for 3 hours 20. Stir for minutes. After cooling, 100 ml of ethyl acetate
The mixture was diluted with, washed with 2N hydrochloric acid, and further washed with aqueous sodium hydrogen carbonate and brine. Ethyl acetate was evaporated to obtain the desired anilide picolinate. 3.74 g (94%), melting point (isopropanol) 76-77 ° C.

Comparative Example 1 The reaction was carried out under the same conditions as in Example except that aluminum chloride was not added. The desired formation of anilide picolinate was not observed at all.

Example 2 [Synthesis of anilide picolinic acid C-1] 0.76 g (5 mmol) of ethyl picolinate, 0.51 g (5.5 mmol) of aniline and aluminum chloride 67
mg (0.5 mmol) and 0.27 g of 2,6-lutidine
(2.5 mmol) and 9 ml of chlorobenzene were stirred at 100 ° C. for 7 hours under a nitrogen atmosphere. After cooling, it was diluted with 15 ml of ethyl acetate, washed with 0.5N hydrochloric acid, and further washed with aqueous sodium hydrogen carbonate and brine. Ethyl acetate was evaporated to obtain the desired anilide picolinate. 0.93 g (9
3%).

Example 3 [Synthesis of 4-nitroanilide C-2 picolinate] 0.76 g (5 mmol) of ethyl picolinate, 0.76 g (5.5 mmol) of p-nitroaniline and 67 mg (0.5 mmol) of aluminum chloride. And 2,6-lutidine 0.27 g (2.5 mmol) and chlorobenzene 9 ml
Was stirred at 120 ° C. for 8 hours under a nitrogen atmosphere. After cooling,
The mixture was diluted with 800 ml of ethyl acetate, washed with 2N hydrochloric acid, and further washed with aqueous sodium hydrogen carbonate and brine. To 0.98 g of a viscous oil obtained by evaporating ethyl acetate, 5 ml of ethanol was added to crystallize the desired picolinic acid 4-
Nitroanilide was obtained. 0.71 g (58%). Melting point 236-237 [deg.] C.

Example 4 [Synthesis of 4-methyl-5-imidazolecarboxoanilide C-7] Ethyl 4-methyl-5-imidazolecarboxylate 3.0
8 g (20 mmol) and aniline 14.6 g (160 m
mol) and aluminum chloride 0.27 g (2 mmol)
Was stirred at 110 ° C. for 1.5 hours under a nitrogen atmosphere. After cooling, it was diluted with ethanol and the precipitate was collected by filtration to obtain the desired anilide. 4.1 g (quantitative), melting point 258-2
59 ° C.

[0044]

The method for producing nitrogen-containing heteroaromatic amides of the present invention, which comprises reacting a nitrogen-containing heteroaromatic ester compound with amines in the presence of a Lewis acid, can set a low reaction temperature, and Also, the reaction time can be shortened and it can be widely used for the synthesis of nitrogen-containing heteroaromatic amides.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 277/68 C07D 239/55 285/12 285/12 B

Claims (2)

[Claims] 1. A nitrogen-containing heteroaromatic ester compound represented by the following general formula (A) is reacted with an amine represented by the following general formula (B) in the presence of a Lewis acid. A method for producing a nitrogen-containing heteroaromatic amide represented by the formula (C). Embedded image (In the formula, X represents an atomic group capable of forming a 5- or 6-membered heteroaromatic ring, R ¹ represents an alkyl group, R ² and R
Each ³ represents a hydrogen atom, an alkyl group, an aryl group, or a heterocyclic group, which may be bonded to each other to form a ring. ) 2. The Lewis acid relative to amines is 0.00
The method for producing a heteroaromatic amide according to claim 1, which is used in an amount of from 05 equivalent to 0.35 equivalent.