JP2002187948A - Production method for amide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially easily producing an amide compound. SOLUTION: An amide compound is produced by reacting a compound having amino group(s) with an anhydride of a polyaminopolycarboxylic acid in the presence of the polyaminopolycarboxylic acid. Examples of the compound having the amino group(s) are a protein, a peptide, an amino acid, an amino sugar, or an amine. Examples of an amino sugar are an aminooligosaccharide and an aminooligosaccharide having its reducing terminal reduced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an amide compound.

[0002]

2. Description of the Related Art An amide compound of polyaminopolycarboxylic acid is useful as an intermediate for medical and agricultural chemicals. For example, the following equation (1) Can be used as an imaging agent by complexing it with a radioactive or paramagnetic metal element.

Conventionally, as a method for producing an amide compound of a compound having an amino group and a polyaminopolycarboxylic acid, a method using human serum albumin as a compound having an amino group (Int. J. Appl. Rad. Iso)
t. , 33 , 327 (1982)). In this method, human serum albumin and an anhydride of polyaminopolycarboxylic acid are reacted. Solid human serum albumin and an anhydride of solid polyaminopolycarboxylic acid are mixed, and the mixture is mixed in Hepes buffer. To dissolve quickly in Hep and Hep
Because a special buffer called es buffer is used,
It was not an industrially feasible method.

[0004]

SUMMARY OF THE INVENTION Under such circumstances,
The present inventors have studied a method for producing an amide compound which can be easily carried out industrially and does not use a special buffer, and found that a compound having an amino group and an anhydride of a polyaminopolycarboxylic acid are converted into the polyaminopolycarboxylic acid. The present inventors have found that by reacting in the presence of a carboxylic acid, the desired amide compound can be produced by an operation which can be carried out industrially, and have led to the present invention.

[0005]

That is, the present invention provides a method for producing an amide compound, comprising reacting a compound having an amino group with an anhydride of a polyaminopolycarboxylic acid in the presence of the polyaminopolycarboxylic acid. Is provided.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The compound having an amino group used in the present invention is not particularly limited as long as it is an organic compound having one or more amino groups in the molecule, and examples thereof include proteins, peptides, amino acids, amino sugars, and amines. Is mentioned.

[0007] Examples of proteins include blood proteins such as serum albumin and fibrinogen, modified proteins such as galactosyl serum albumin, enzymes such as amylase and pepsin, eg IgG, and fragments F thereof.
Abs, Fab 'and other immune antibodies, for example, thyroid stimulating hormone, growth hormone, and other hormones, for example, prolamin, glutelin, and other simple proteins.

[0008] Peptides include, for example, Pyr-Lys
-Arg-Pro-Ser-Gln-Arg-Ser-
Lys-Tyr-Leu, D-Phe-octreot
synthetic peptides such as ide and polylysine; hormones such as ochitocin and bradykinin; and antibiotics such as valinomycin and colistin.

Examples of the amino acid include α-amino acids such as alanine, leucine and lysine, such as β-alanine,
Β-amino acids such as isoserine, for example, γ-aminobutyric acid,
Γ-amino acids such as 4-amino-3-hydroxybutyric acid, for example, δ-aminovaleric acid and δ-amino acids such as δ-aminolevulinic acid
Amino acids and the like.

Examples of amino sugars include glucosamine,
Monosaccharides such as galactosamine, for example, these glucosamines,
Examples include amino oligosaccharides that are polymers such as galactosamine, and reduced terminal reduced products in which the reducing ends of the sugar chains of these amino oligosaccharides are reduced.

Examples of amino oligosaccharides include those having a molecular weight of 500 to 2,000. Examples of amino oligosaccharides having a molecular weight of 500 to 2,000 include chitosan 3 having a repeating unit of a constituent monosaccharide of 3 to 10. ~
Chitosan oligosaccharides such as decasaccharides, for example, galactosamine oligosaccharides such as galactosamine 3-10 sugars in which the repeating unit of the constituent monosaccharide is 3-10, and the like. Examples of the amino oligosaccharide in which the reducing end of the sugar chain of the amino oligosaccharide is reduced include, for example, the following formula (2) A reducing terminal reduced form of chitosan trisaccharide represented by the following formula (3): And the reducing terminal reduced form of galactosamine trisaccharide represented by

As amines, for example, aniline, 4-amine
Methylaniline, 4-octylaniline, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, isobutylamine, tert-butylamine, n-octylamine, n
-Decylamine, (1-naphthylmethyl) amine, N-
Methylaniline, N-methyl-4-ethylaniline, N
-Methyl-4-octylaniline, diethylamine, N
Monoamines such as -ethyl-N-propylamine, for example, diamines such as ethylenediamine, dansylethylenediamine, dansylhexamethylenediamine, N- (1-naphthyl) ethylenediamine, 1-naphthalenesulfonylethylenediamine, hexamethylenediamine, phenylenediamine, diethylenetriamine And the like.

The compound having an amino group may be used as it is, or may be used as a solution or suspension, for example, by dissolving or suspending in a solvent described below.
Further, as the compound having an amino group, a salt of the compound having the amino group with a mineral acid such as hydrochloric acid and sulfuric acid can be used. When the salt is used, it is preferable to convert the salt to a free amino group by, for example, mixing the salt and an alkali in advance and converting the salt to a free amino group, or adding an alkali to the reaction system.

Examples of the anhydride of polyaminopolycarboxylic acid include ethylenediaminetetraacetic acid dianhydride, ethylenediaminetetraacetic acid monoanhydride, diethylenetriaminepentaacetic acid dianhydride, diethylenetriaminepentaacetic acid monoanhydride,
4,7,10-tetraazacyclododecane-1,4,4
Two or more amino groups and one or more amino groups in the molecule such as 7,10-tetraacetic acid dianhydride, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoanhydride Those having two or more acid anhydride skeletons are exemplified. Among such anhydrides of polyaminopolycarboxylic acid, monoanhydride of polyaminopolycarboxylic acid is, for example, a dianhydride of the polyaminopolycarboxylic acid obtained by adding water and hydrolyzing one anhydride skeleton. Is also good.

The amount of the anhydride of polyaminopolycarboxylic acid is not particularly limited, and may be appropriately selected depending on the intended amide compound, its use, production cost, and the like. For example, when a compound in which all the amino groups in the compound having an amino group are amidated is intended, the anhydride of the polyaminopolycarboxylic acid is 1 mole times the amino group in the compound having the amino group. It is preferable to use the above.

Examples of the polyaminopolycarboxylic acid include ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, 1,4,7,10-tetraazacyclododecane-
Examples thereof include those having two or more amino groups and two or more carboxyl groups in the molecule thereof, such as 1,4,7,10-tetraacetic acid. In this reaction, the polyaminopolycarboxylic acid used in the reaction is used. A polyaminopolycarboxylic acid corresponding to an anhydride is used. Such a polyaminopolycarboxylic acid may be obtained by hydrolyzing the above-mentioned polyaminopolycarboxylic anhydride by a usual method.

The polyaminopolycarboxylic acid may be used as it is, or may be mixed with an aqueous alkali solution such as an alkali metal hydroxide such as sodium hydroxide or an alkaline earth metal hydroxide such as magnesium hydroxide. It may be used in advance as a metal carboxylate such as an alkali metal salt of polyaminopolycarboxylic acid or an alkaline earth metal salt of polyaminopolycarboxylic acid.

The amount of the polyaminopolycarboxylic acid used is usually 0.1% based on the anhydride of the polyaminopolycarboxylic acid.
Molar times or more. There is no particular upper limit, but if it is too large, it tends to be economically disadvantageous. Therefore, practically, it is 5 mol times or less with respect to the anhydride of polyaminopolycarboxylic acid.

The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction solution.

According to the present invention, a compound having an amino group is reacted with an anhydride of a polyaminopolycarboxylic acid in the presence of the polyaminopolycarboxylic acid. It is carried out by adding an anhydride of polyaminopolycarboxylic acid. The order of adding the compound having an amino group and the anhydride of the polyaminopolycarboxylic acid is not particularly limited, but when water is used as a reaction solvent, the anhydride of the polyaminopolycarboxylic acid, the polyaminopolycarboxylic acid and the amino group are added. It is preferable to add it to a mixture of compounds having the same. Further, the compound having an amino group and the anhydride of the polyaminopolycarboxylic acid may be simultaneously added to the polyaminopolycarboxylic acid in parallel. When the compound having an amino group and the anhydride of the polyaminopolycarboxylic acid are added simultaneously in parallel, the addition of both may be terminated at the same time, or the addition of either one of the two may be more than the addition of the other. May be ended first. When water is used as a reaction solvent and the compound having an amino group and the anhydride of the polyaminopolycarboxylic acid are added simultaneously in parallel, the addition of the compound having an amino group is more effective than the addition of the anhydride of the polyaminopolycarboxylic acid. It is preferable that the process be terminated first. The addition of the compound having an amino group and the anhydride of polyaminopolycarboxylic acid may be continuous or intermittent.

This reaction may be carried out without a solvent, but is usually carried out in the presence of a solvent in view of the physical properties of the reaction solution. Examples of the solvent include a single solvent or a mixed solvent of water and an organic solvent.

Examples of the organic solvent include ethanol, 2
Alcoholic solvents such as -propanol, 1-butanol and diethylene glycol monomethyl ether; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; and diethyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane and the like Ether solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and aromatic hydrocarbon solvents such as toluene and xylene; for example, halogens such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene. And the like. Such organic solvents may be used alone or as a mixture.

The organic solvent may be previously added to the compound having an amino group, polyaminopolycarboxylic anhydride or polyaminopolycarboxylic acid. Water may be added to the compound having an amino group or the polyaminopolycarboxylic acid in advance, but if mixed with a polyaminopolycarboxylic acid anhydride, the hydrolysis reaction of the anhydride may proceed. It is desirable not to add in advance to the anhydride of the carboxylic acid.

The amount of the solvent to be used is not particularly limited. However, if the amount is too large, the volume efficiency becomes poor. Therefore, the amount is practically 100 times or less the weight of the compound having an amino group.

The present reaction can proceed more smoothly by performing it in the presence of a base.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, for example, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, for example, lithium carbonate, sodium carbonate, and carbonate. Inorganic bases such as alkali metal carbonates such as potassium and alkali metal bicarbonate such as sodium bicarbonate and potassium bicarbonate, and organic bases such as triethylamine and pyridine. The amount of the base to be used is not particularly limited, but if it is too large, it tends to be economically disadvantageous. Therefore, it is practically 50 mole times or less based on the anhydride of the polyaminopolycarboxylic acid. In addition, such a base may be added in advance to a compound having an amino group or a polyaminopolycarboxylic acid.

When water is used as the solvent, the pH of the reaction solution
It is preferable to carry out the reaction while maintaining in a weakly acidic to alkaline region from the viewpoint of improving the yield of the target product. pH
The range is preferably pH 5 to 14, and pH 6
The range of 10 to 10 is more preferable. In this case, for example, the reaction may be performed by adding the above-mentioned inorganic base to the reaction solution and adjusting the pH range of the reaction solution to the above range.

For example, ethylenediaminetetraacetic acid dianhydride,
Compounds having two or more anhydride skeletons in the molecule thereof, such as diethylenetriaminepentaacetic acid dianhydride, wherein one of the anhydride skeletons has an amino group. When the target compound is an amide compound in which the remaining anhydride skeleton is hydrolyzed, the reaction is carried out by using an organic solvent as a reaction solvent and coexisting water required for hydrolysis in the reaction system, The reaction may be carried out using water as a reaction solvent. In particular, it is preferable to use water as the reaction solvent, because the amidation reaction and the ring-opening reaction of the anhydride skeleton can be performed simultaneously. When water is used as the reaction solvent, the pH of the reaction solution at the time of the reaction is preferably in a weakly acidic to alkaline range, and the pH range is preferably pH 5 to 14, more preferably pH 6 to 10.

After the completion of the reaction, the desired amide compound can be taken out by purifying if necessary. When the reaction is performed in the presence of a base,
An amide compound in which a carboxylic acid moiety in the amide compound forms a salt with the base may be obtained.

When the compound having an amino group further has a hydroxyl group in the molecule, the polyaminopolycarboxylic anhydride may react with the hydroxyl group to form an esterified product. When the esterified product is formed, after the completion of the reaction, the reaction solution is weakly alkaline, for example, pH 8-10.
After hydrolyzing the esterified product, it is preferable to take out the desired product.

The amide compound thus obtained includes:
For example, human serum albumin-diethylenetriaminepentaacetic acid conjugate, galactosyl serum albumin-diethylenetriaminepentaacetic acid conjugate, D-Phe-octreoti
de-diethylenetriaminepentaacetic acid conjugate, the following formula (1) An amide compound represented by the following formula (4) An amide compound represented by

The following equation (5) An amide compound represented by the following formula (6) An amide compound represented by

The following equation (7) An amide compound represented by the following formula (8) An amide compound represented by

N- (phenylcarbamoylmethyl) diethylenetriamine-N, N ', N ", N" -tetraacetic acid, N- (4-octylphenylcarbamoylmethyl)
Ethylenediamine-N, N ', N'-triacetic acid, N- (4
-Octylphenylcarbamoylmethyl) diethylenetriamine-N, N ', N ", N" -tetraacetic acid, N-
[(6-dansylaminohexyl) carbamoylmethyl] diethylenetriamine-N, N ′, N ″, N ″
-Tetraacetic acid, N, N "-bis (phenylcarbamoylmethyl) diethylenetriamine-N, N ', N" -triacetic acid and the like.

Such an amide compound can be led to an image diagnostic agent by, for example, coordinating a radioactive or paramagnetic metal element and performing a purification treatment if necessary.

[0035]

According to the present invention, it is possible to produce an amide compound useful as an intermediate for producing an image diagnostic agent or the like by an industrially practicable method.

[0036]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 A 500 mL five-necked separable flask equipped with a reflux device, a stirrer, and a thermometer was charged with 131 g of a 16% by weight aqueous sodium hydroxide solution, and the internal temperature was raised to 80 ° C. After adding 3 g of the hydrochloride of the reduced terminal reduced form of chitosan trisaccharide and 28.6 g of diethylenetriaminepentaacetic acid, 27.5 g of diethylenetriaminepentaacetic dianhydride was continuously added little by little at the same temperature. After stirring and maintaining at the same temperature for 1 hour, 31 g of a 30% by weight aqueous sodium hydroxide solution was added to adjust the pH of the reaction solution to 9. After stirring and maintaining at the same temperature for 1 hour, the mixture was cooled to room temperature. When analyzed by high performance liquid chromatography, the desired formula (1) The yield of the amide compound represented by was 57.6%.

Example 2 To a 500 mL five-necked separable flask equipped with a reflux unit, a stirrer, and a thermometer, 50 g of a 17% by weight aqueous sodium hydroxide solution and 28.8 g of diethylenetriaminepentaacetic acid were added at room temperature. The temperature rose. At the same temperature, 10 g of a 25% by weight aqueous sodium hydroxide solution was added, and 3 g of the hydrochloride of the reduced terminal reduced form of chitosan trisaccharide was added to 14 g
A solution dissolved in 66 g of an aqueous solution of sodium hydroxide by weight and 27.4 g of diethylenetriaminepentaacetic acid dianhydride were added to
It was added simultaneously in parallel. Here, the solution of the reducing terminal reduced form of chitosan trisaccharide was added continuously over 25 minutes, and the diethylenetriaminepentaacetic acid dianhydride was added continuously over 30 minutes. During this time, the pH of the reaction solution was in the range of 6.9 to 7.5. After the addition is completed, stir and hold at the same temperature for 1 hour,
36 g of a 25% by weight aqueous sodium hydroxide solution was added to adjust the pH of the reaction solution to 9. After stirring and maintaining at the same temperature for 1 hour, the mixture was cooled to room temperature. When analyzed by high performance liquid chromatography, the yield of the target amide compound represented by the above formula (1) was 80.2%.

Example 3 78 g of a 20% by weight aqueous sodium hydroxide solution and 51.7 g of diethylenetriaminepentaacetic acid were added at room temperature to a 500 mL five-neck separable flask equipped with a reflux device, a stirrer, and a thermometer. The temperature rose. At the same temperature, 19 g of a 25% by weight aqueous sodium hydroxide solution was added, and 3 g of a hydrochloride of a reduced terminal reduced form of chitosan trisaccharide was added to 16 g of a salt.
A solution dissolved in 57 g of a weight% aqueous sodium hydroxide solution and 27.5 g of diethylenetriaminepentaacetic acid dianhydride were
It was added simultaneously in parallel. Here, the solution of the reducing terminal reduced form of chitosan trisaccharide was added continuously over 25 minutes, and the diethylenetriaminepentaacetic acid dianhydride was added continuously over 30 minutes. During this time, the pH of the reaction solution was in the range of 7.0 to 7.5. After the addition is completed, stir and hold at the same temperature for 1 hour,
44 g of a 25% by weight aqueous sodium hydroxide solution was added to adjust the pH of the reaction solution to 9. The mixture was stirred and maintained at the same temperature for 1 hour, and cooled to room temperature. When analyzed by high performance liquid chromatography, the yield of the target amide compound represented by the above formula (1) was 82.1%.

COMPARATIVE REFERENCE EXAMPLE 1 To a 500 mL five-neck separable flask equipped with a reflux device, a stirrer, and a thermometer, 3 g of a reducing terminal reduced form of chitosan trisaccharide and 67 g of a 16% by weight aqueous sodium hydroxide solution were added at room temperature. The internal temperature was raised to 80 ° C. At the same temperature, 27.7 g of diethylenetriaminepentaacetic dianhydride was added little by little, and the mixture was stirred and maintained at the same temperature for 15 minutes. When cooled to room temperature and analyzed by high performance liquid chromatography, the yield of the target amide compound represented by the above formula (1) was 45.2%.

Example 4 In a 500 mL five-neck separable flask equipped with a reflux device, a stirrer, and a thermometer, 45 g of a 25% by weight aqueous sodium hydroxide solution, 40 g of 1,4-dioxane, and 28 g of diethylenetriaminepentaacetic acid were added at room temperature. 7 g was added, and the internal temperature was raised to 73 ° C. At the same temperature, a solution prepared by dissolving 3 g of the hydrochloride of the reduced terminal reduced form of chitosan trisaccharide in 57 g of a 16% by weight aqueous sodium hydroxide solution and 27.2 g of diethylenetriaminepentaacetic dianhydride were added simultaneously in parallel. Here, the solution of the reducing end of the chitosan trisaccharide is 2
Over 5 minutes, diethylenetriaminepentaacetic acid dianhydride is
Each was added continuously over 30 minutes. During this time, the pH of the reaction solution was in the range of 7.0 to 7.6. After completion of the addition, the mixture was stirred and maintained at the same temperature for 30 minutes, and 27 g of a 25% by weight aqueous sodium hydroxide solution was added to adjust the pH of the reaction solution to 8. The mixture was stirred and maintained at the same temperature for 30 minutes, and cooled to room temperature. When analyzed by high performance liquid chromatography,
The yield of the target amide compound represented by the above formula (1) was 67.2%.

Example 5 In a 100 mL four-necked flask equipped with a reflux device, a stirrer, and a thermometer, 1 g of a hydrochloride of a reduced terminal reduced form of chitosan trisaccharide, a 16% by weight aqueous sodium hydroxide solution 3 were placed at room temperature.
4 g and 7.2 g ethylenediaminetetraacetic acid were added.
The internal temperature was raised to 80 ° C., and 6.3 g of ethylenediaminetetraacetic acid dianhydride was continuously added little by little. After stirring and maintaining at the same temperature for 30 minutes, an aqueous solution of 11% by weight sodium hydroxide 1
6 g was added to adjust the pH of the reaction solution to 9. At the same temperature, 30
After stirring and holding for minutes, the mixture was cooled to room temperature. When analyzed by high performance liquid chromatography, the desired formula (5) Was obtained with a corrected area percentage value of 51%. LC / ESI mass spectrometry: m / z = 1326.9
([M + H] ⁺ ), m / z = 1324.9 ([M−
H] ⁺ )

Example 6 80 mL of N, N-dimethylformamide (dehydrated product) and 6.6 g of diethylenetriaminepentaacetic acid were added at room temperature to a 200 mL four-necked flask equipped with a reflux device, a stirrer, and a thermometer. The temperature was raised to 75 ° C. At the same temperature,
6.0 g of diethylenetriaminepentaacetic acid dianhydride was added,
After stirring and maintaining at the same temperature for 30 minutes, 0.3 g of water was added little by little to make the dianhydride a monoanhydride. After stirring and maintaining at the same temperature for 1 hour, 3.5 g of 4-octylaniline was added dropwise over 10 minutes. The mixture was stirred and maintained at the same temperature for 1 hour, and the filtrate obtained by filtering off insolubles was concentrated to obtain 11.8 g of crude crystals. The crude crystals were analyzed by high performance liquid chromatography to find the desired N- (4-octylphenylcarbamoylmethyl) diethylenetriamine-N, N ′,
It was confirmed that N ″, N ″ -tetraacetic acid was obtained (corrected area percentage value: 94.3%).

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Daisaku Nakamura 3-1, Kita-sode, Sodegaura-shi, Chiba F-term in Japan Mediphysics Co., Ltd. 4C090 AA05 BA46 BA48 BD36 CA35 DA22 DA31 4J001 DA01 DB01 DC05 EA23 EA24 EA34 EA37 EA41 EC05 EC08 EC09 EC10 EC44 EC77 EC83 EE44A EE46A FA03 FB01 FC03 JA20

Claims (15)

[Claims] 1. A method for producing an amide compound, comprising reacting a compound having an amino group with an anhydride of a polyaminopolycarboxylic acid in the presence of the polyaminopolycarboxylic acid. 2. The method according to claim 2, wherein the compound having an amino group is a protein,
The method for producing an amide compound according to claim 1, which is a peptide, an amino acid, an amino sugar, or an amine. 3. The method for producing an amide compound according to claim 2, wherein the amino sugar is an amino oligosaccharide or a reduced form of an amino oligosaccharide. 4. The amino oligosaccharide having a molecular weight of 500 to 200.
The method for producing an amide compound according to claim 3, wherein the amide compound is 0. 5. The method for producing an amide compound according to claim 4, wherein the amino oligosaccharide having a molecular weight of 500 to 2,000 is chitosan oligosaccharide or galactosamino oligosaccharide. 6. The method for producing an amide compound according to claim 5, wherein the chitosan oligosaccharide is a chitosan 3 to 10 sugar. 7. The method for producing an amide compound according to claim 5, wherein the galactosaminooligosaccharide is a galactosamine trisaccharide. 8. The polyaminopolycarboxylic acid is ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid or 1,
4,7,10-tetraazacyclododecane-1,4,4
The method for producing an amide compound according to claim 1, which is 7,10-tetraacetic acid. 9. The method for producing an amide compound according to claim 1, wherein the anhydride of the polyaminopolycarboxylic acid is added to a mixture of the compound having an amino group and the polyaminopolycarboxylic acid. 10. The method for producing an amide compound according to claim 1, wherein an anhydride of the compound having an amino group and the polyaminopolycarboxylic acid is added to the polyaminopolycarboxylic acid. 11. The method for producing an amide compound according to claim 10, wherein the compound having an amino group and the anhydride of the polyaminopolycarboxylic acid are simultaneously added to the polyaminopolycarboxylic acid in parallel. 12. The method according to claim 1, wherein the reaction is carried out in the presence of a solvent.
The method for producing an amide compound according to the above. 13. The method for producing an amide compound according to claim 12, wherein the solvent is at least one selected from the group consisting of water and an organic solvent. 14. The method for producing an amide compound according to claim 13, wherein the solvent is water. 15. The method according to claim 1, wherein the reaction is carried out in the presence of a base.
The method for producing an amide compound according to the above.