JPH1171335A - Production of aromatic carboxylic amides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound in high yield and purity by reacting an aromatic carboxylic acid halide with secondary amines having a bulky substituent group in the presence of a carbonate in two phases of water with an organic solvent slightly soluble in water. SOLUTION: (A) An aromatic carboxylic acid halide of formula I [X is a halogen; R is a group substitutable on benzene ring and plural Rs together may form a ring; (b) is an integer of 0-2; (a) is an integer of 3-5] is reacted with (B) secondary amines having bulky substituent group of formula II [R1 and R2 are each independently a secondary or tertiary alkyl and R1 and R2 together may form a ring] in the presence of a carbonate (preferably an alkyl metal carbonate) in two phase system of water and an organic solvent slightly soluble in water (preferably acetic acid esters and/or toluene), preferably at <=40 deg.C to provide the objective aromatic carboxylic amides of formula III. The carbonate is preferably used in an amount of 1-3 equivalent based on the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for synthesizing an aromatic carbonamide having a bulky substituent on a nitrogen atom, and particularly to the presence of a carbonate in an organic solvent-water two-phase system. The present invention relates to a method for synthesizing carboxylic acid amides with high yield and high purity by reacting a carboxylic acid halide with a secondary amine having a bulky substituent.

[0002]

2. Description of the Related Art The above-mentioned aromatic carboxamides having a bulky substituent on a nitrogen atom are useful as photographic additives, raw materials intermediates for pharmaceuticals and agricultural chemicals, and dispersion media. Heretofore, the following methods have been known as methods for producing aromatic carboxamides having a bulky substituent on a nitrogen atom by the production method of the present invention. JP-B-41-20822 A method of obtaining N, N-dicyclohexylbenzamide by removing dicyclohexylamine hydrochloride formed by reacting phosphorus trichloride with dicyclohexylamine in a toluene solvent and then adding benzoic acid chloride to the filtrate. J. Am. Chem. Soc., 86, 5611 (1964) A method in which benzoyl chloride is added to a large excess of a mixture of triethylamine and dicyclohexylamine using dioxane as a solvent to obtain N, N-dicyclohexylbenzamide in a yield of 51%. These methods can be synthesized as long as the acid chloride synthesizes the corresponding N, N-dicyclohexylbenzamide with benzoic acid chloride, but the operation method is complicated and the yield is low. Furthermore, when these methods are applied to the production of the compound represented by the general formula [3] (b ≧ 1), the obtained target product has a low purity and a low yield, as well as by-products and unreacted products. There are many. Generally, when reacting an acid halide with an amine, a method such as adding a base such as triethylamine or the like in excess of the amine as a reaction raw material is used to prevent the raw material amine from forming a salt and inactivating the generated acid by the generated acid. It has been known. For example, US Pat.
No. 111 discloses a method of obtaining a compound represented by the general formula [3] of the present invention by dropping a benzene solution of phthaloyl dichloride into a benzene solution containing twice the amount of dicyclohexylamine. Also, J. Org. Chem., 22, 1015
(1957) describes a similar method for obtaining the corresponding carboxamide from twice the amount of dicyclohexylamine and cinnamoyl chloride. However, in these methods, an equivalent amount of an amine hydrochloride having a bulky substituent is produced, which is very poorly soluble in water and an organic solvent, precipitates as crystals in the reaction solution, and has poor fluidity of the reaction solution and stirring. It becomes difficult. Further, since it is necessary to remove the formed hydrochloride by filtration, the productivity is low and it has been difficult to use it as an industrial production method. Also, a method for producing carboxamides using bulky secondary amines and aliphatic carboxylic acids or derivatives thereof as raw materials is known. For example,
No. 16688 discloses a method in which a mixture of linoleic acid, dicyclohexylamine, p-toluenesulfonic acid and toluene is subjected to a dehydration reaction while heating and stirring, and Japanese Patent Publication No. 46-14657 discloses a method in which methyl linoleate and dicyclohexylamine are used.
Methods for obtaining the corresponding amides by reacting at 0 ° C. for 100 hours are disclosed. However, when these methods are also applied to the synthesis of the compound represented by the general formula [3], they are probably caused by steric hindrance. The desired compound cannot be obtained at all due to a possible decrease in reactivity.

[0003] Accordingly, there has been a demand for a new synthetic method which enables industrial production of an aromatic carbonamide having a bulky substituent on a nitrogen atom.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrial production method capable of obtaining aromatic carboxamides having a bulky substituent on a nitrogen atom in high yield and high purity. It is in.

[0005]

The present inventors have conducted intensive studies to establish an industrial process for producing aromatic carboxamides having a bulky substituent on a nitrogen atom. Aromatic having a bulky substituent on the target nitrogen atom by reacting a secondary amine having a high substituent in the presence of a carbonate, in a two-phase system with water and an organic solvent which is hardly soluble in water They have found that carbonamides can be obtained in high yield and high purity, and have completed the present invention. The object of the present invention has been achieved by the following production method.

An aromatic carboxylic acid halide represented by the following general formula [1] is reacted with a secondary amine having a bulky substituent represented by the general formula [2] to obtain a compound represented by the following general formula [3]. A method for producing aromatic carbonamides, which comprises reacting in the presence of a carbonate in a two-phase system with water and an organic solvent which is hardly soluble in water in the synthesis of the aromatic carbonamides to be produced.

[0007]

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(Wherein, X is a halogen atom, R is a substitutable group on a benzene ring, and when there are a plurality of Rs, a plurality of Rs may be the same or different and may be bonded to each other to form a ring. When a plurality of Rs are bonded to each other to form a ring, the substituent on the benzene ring represented by the general formula [1]
(COX) _b may be present on a ring formed by combining a plurality of Rs with each other. b represents an integer of 0 to 2; a represents an integer of 3 to 5; )

[0009]

Embedded image

(Wherein R₁, R_TwoAre 2nd class independently
Or a tertiary alkyl group. Also R ₁, R_TwoAre each other
They may combine to form a ring. )

[0011]

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(Wherein, R, R ₁ , R ₂ , a and b have the same meanings as those represented by the aforementioned general formulas [1] and [2])

[0013]

Embodiments of the present invention will be described below in detail. The aromatic carboxylic acid halide used in the present invention has the general formula [1] (wherein X is a halogen atom, R is a group substitutable on a benzene ring, and when there are a plurality of Rs, a plurality of Rs are the same or different. When a plurality of Rs are bonded to each other to form a ring, the substituent-(COX) on the benzene ring represented by the general formula [1] may be used. _b ) may be present on a ring formed by a plurality of R's bonded to each other, b represents an integer of 0 to 2 and a represents an integer of 3 to 5). There is no particular limitation, and examples thereof include carboxylic acid halides such as benzoic acid and naphthoic acid derivatives. Examples of the substituent R include a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, a nitro group, a cyano group, and the like, preferably a hydrogen atom, an alkyl group, an aryl group, and more preferably a hydrogen atom. is there. b represents an integer of 0 to 2, preferably 1 or 2, and more preferably 1. As described above, specific examples of the compound represented by the general formula [1] include benzoyl chloride, phthaloyl chloride, isophthaloyl dichloride, terephthaloyl chloride, 1,3,5-tricarbonyl chloride, and 1,4-naphthalene. Dicarboxylic acid dichloride, 2,3-naphthalenedicarboxylic acid dichloride, 2,6-naphthalenedicarboxylic acid dichloride, etc., preferably benzoyl chloride, phthaloyl chloride, isophthaloyl dichloride, terephthaloyl chloride, 1,3,5-trichloride Carbonyl trichloride, more preferably isophthaloyl dichloride and terephthaloyl chloride.

Secondary amine having a bulky substituent on a nitrogen atom
The compounds are not particularly limited as long as they are compounds represented by the general formula [2].
But not R₁, R_TwoBoth of which have 3 to 20 carbon atoms
Or a tertiary alkyl group such as a
Isopropyl, tert-butyl, sec-butyl, sec
-Pentyl group, cyclohexyl group, 6-methylcyclohexyl
Xyl groups and the like. These R₁, R_TwoAre each other
They may be the same or different. Also, R₁, R_TwoAre each other
To form a heterocyclic ring;₁, R _TwoAre each other
Examples of the hetero ring formed by bonding to
20 pyrrolidine rings, piperidine rings and the like. one
Of a secondary amine having a bulky substituent represented by the general formula [2]
Preferred examples are diisopropylamine and di-sec-
Butylamine, N-tert-butylisopropylamine,
Dicyclohexylamine, 2,5-dimethylpyrrolidine
2,6-dimethylpiperidine and the like,
Piperidine, dicyclohexylamine is more preferred
Dicyclohexylamine is particularly preferred.

The amount of the secondary amine used in the present invention is preferably 0.8 to 3 mol, more preferably 0.9 to 2 mol, per 1 mol of the acid halide group of the starting aromatic carboxylic acid halide.

The carbonate used in the present invention is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate and potassium carbonate, more preferably sodium carbonate and potassium carbonate. Further, the amount used is preferably 0.5 to 4 mol, more preferably 1 to 2 mol, per 1 mol of the acid halide group of the aromatic carboxylic acid halide as the raw material. When a hydrogen carbonate such as sodium hydrogen carbonate or sodium hydroxide, which is often used in a similar reaction, is used in this reaction, a carboxylic acid is produced in which the raw material amine remains and the carboxylic acid halide is hydrolyzed.

In the present invention, when the reaction temperature is high, the hydrolysis of the aromatic carboxylic acid halide as a raw material occurs competitively, and therefore the reaction temperature is preferably 60 ° C. or lower, more preferably 40 ° C. or lower.

The organic solvent used in the present invention is not particularly limited as long as it is an organic solvent which is hardly soluble in water, but halogen solvents such as methylene chloride and dichloroethane, acetates such as methyl acetate, ethyl acetate and butyl acetate; −
Hydrocarbon solvents such as hexane, toluene and xylene are preferred, ethyl acetate and toluene are more preferred, and toluene is particularly preferred, and these may be used as an appropriate mixture.

The reaction time in the present invention varies depending on the reaction scale and temperature, but is generally less than 8 hours, preferably less than 5 hours, which is industrially advantageous.

[0020]

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

Example 1 Synthesis of N, N, N ', N'-tetracyclohexylisophthalamide. Dicyclohexylamine 1 in a 500 ml three-necked flask
8.1 g (0.1 mol), potassium carbonate 27.6 g
(0.2 mol), and a mixture of 60 ml of toluene was cooled to 20 under water cooling.
Stir at ° C. After slowly adding 60 ml of water, the mixture was stirred for 5 minutes. Isophthaloyl chloride 10.2 g (0.0
(5 mol) is dissolved in 16 ml of toluene and added dropwise over 30 minutes while maintaining the internal temperature at 20 ° C. or lower. After stirring for 30 minutes after dropping, 60 ml of ethyl acetate was added to the reaction solution, and the mixture was separated to obtain an organic layer. The organic layer was added with 30 ml of water, washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained concentrated oil was dissolved in 70 ml of acetonitrile, and the precipitated crystals were filtered. Yield 22.4 g Yield 91% Purity 99.2% (HP
LC) Melting point: 155 to 157 ° C. It is clear from comparison between this example and Comparative Example 1. However, in this example, dicyclohexylamine hydrochloride was not generated at all, and no complicated operations such as reduction in fluidity, filtration, and recrystallization were required. It is.

Example 2 Synthesis of N, N, N ', N'-tetracyclohexylisophthalamide. The reaction and treatment were conducted in exactly the same manner as in Example 1 except that toluene was changed to ethyl acetate. Yield 20.9 g Yield 85
% Purity 99.1% (HPLC)

Example 3 Synthesis of N, N, -dicyclohexylbenzamide. 8. Dicyclohexylamine in a 300 ml three-necked flask
05 g (0.05 mol), potassium carbonate 13.8 g
(0.1 mol), and a mixture of 40 ml of toluene was cooled to 20 under water cooling.
Stir at ° C. After slowly adding 40 ml of water, the mixture was stirred for 5 minutes. Benzoyl chloride (7.0 g, 0.05 mol) was dissolved in toluene (15 ml) and added dropwise over 30 minutes while maintaining the internal temperature at 20 ° C or lower. After stirring for 30 minutes after dropping, 60 ml of ethyl acetate was added to the reaction solution, and the mixture was separated to obtain an organic layer. The organic layer was added with 30 ml of water, washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrated oil obtained is separated into n
After dissolving in 70 ml of a mixture of -hexane / ethyl acetate = 10/1, the mixture was cooled on ice and the precipitated crystals were filtered. Yield 13.6g
Yield 95.0% Purity 98.8% (HPLC) Melting point 94-95 ° C

Example 4 Synthesis of 2,6-dimethylpiperidinoisophthalamide. In a 300 ml three-necked flask, 11.3 g (0.1 mol) of cis-2,6-dimethylpiperidine, potassium carbonate 27.
A mixture of 6 g (0.2 mol) and 60 ml of toluene is stirred at 20 ° C. under water cooling. After slowly adding 60 ml of water, the mixture was stirred for 5 minutes. Isophthaloyl chloride 10.1 g
(0.05 mol) was dissolved in 16 ml of toluene and the internal temperature was adjusted to 20.
The solution was added dropwise over 30 minutes while keeping the temperature at or below. After stirring for 30 minutes after the dropwise addition, 100 ml of ethyl acetate was added to the reaction solution, and the mixture was separated to obtain an organic layer. The organic layer was added with 30 ml of water, washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained concentrated oil was dissolved in 100 ml of a mixed solution of n-hexane / ethyl acetate = 10/1, and cooled with ice, and the precipitated crystals were filtered. Yield 17.6 g Yield 88.1%, purity 98.3%
(HPLC) Melting point 105-107 ° C

Comparative Example 1 Isophthaloyl chloride 1 in a 500 ml three-necked flask
0.2 g (0.05 mol) is dissolved in 180 ml of acetonitrile and stirred at 20 ° C. 36.3 g (0.2 mol) of dicyclohexylamine is slowly dropped therein while maintaining the internal temperature at 20 ° C. After dropping, stirring is continued at 20 ° C. for 30 minutes. With the progress of the reaction, white crystals of dicyclohexylamine hydrochloride were precipitated and the fluidity was lowered. 200 ml of ethyl acetate was added, and the reaction solution was filtered to remove 21.9 g of dicyclohexylamine hydrochloride. The filtrate was washed with 100 ml of water, dried over anhydrous magnesium sulfate and concentrated. The obtained concentrated oil was dissolved in 100 ml of acetonitrile by heating, and after cooling, the precipitated crystals were filtered. 23 g of crude crystals obtained
Was dissolved again in 100 ml of acetonitrile by heating, and the insolubles were filtered off. After cooling, the precipitated crystals were filtered. Yield 18.1 g
Yield 73% Purity 97.2% (HPLC)

Claims (8)

[Claims] An aromatic ketone represented by the following general formula [1]:
Rubonic halide and bulky substitution represented by general formula [2]
By reacting a secondary amine having a group represented by the general formula [3]
Carbon when synthesizing aromatic carbonamides
Two-phase system with water and water-insoluble organic solvents in the presence of acid salts
Aromatic carboxyl characterized by reacting in
Method for producing amides. Embedded image(Where X is a halogen atom and R is a substituent on a benzene ring.
When there are a plurality of functional groups, and R is plural, plural Rs are the same or different.
And they may combine with each other to form a ring.
No. When a plurality of Rs are bonded to each other to form a ring,
Substituent on the benzene ring represented by the formula [1]-(COX)_bIs
A number of R may be present on a ring formed by bonding to each other
No. b represents an integer of 0 to 2; a represents an integer of 3 to 5;
You. )(Where R₁, R_TwoAre independently secondary or tertiary
Shows an alkyl group. Also R ₁, R_TwoAre connected to each other to form a ring
It may be formed. )(Where R, R₁, R_Two, A and b are the aforementioned general formulas
[1], synonymous with general formula [2]) 2. The method for producing an aromatic carboxamide according to claim 1, wherein the carbonate is a carbonate represented by M ₂ CO ₃ (where M represents an alkali metal). 3. The method for producing aromatic carboxamides according to claim 1, wherein the reaction is carried out at a reaction temperature of 40 ° C. or lower. 4. The method for producing an aromatic carboxamide according to claim 1, wherein b in the general formula [1] is 1. 5. The method for producing an aromatic carbonamide according to claim 1, wherein R ₁ and R ₂ in the general formula [2] are cyclohexyl groups. 6. The method for producing aromatic carboxamides according to claim 1, wherein 1 to 3 equivalents of a carbonate is used based on the aromatic carboxylic acid halide. 7. The method for producing an aromatic carbonamide according to claim 1, wherein the organic solvent which is hardly soluble in water is an acetic ester and / or toluene. 8. The compound represented by the general formula [3] is N,
The method for producing aromatic carboxamides according to claim 1, which is N, N ', N'-tetracyclohexylisophthalamide.